Piero Sismondi

Abstract: ABSTRACT: INTRODUCTION: Livial Intervention Following Breast Cancer; Efficacy, Recurrence and Tolerability Endpoints (LIBERATE - ClinicalTrials.gov number NCT00408863), a randomized, placebo controlled, double-blind trial which demonstrated that tibolone (Livial), a tissue selective hormone replacement therapy (HRT) increased breast cancer (BC) recurrence HR 1.40 (95% CI 1.14-1.70; p=0.001) entered a subgroup of women into a study of Bone Mineral Density (BMD). METHODS: Women with surgically excised primary BC (T1-3, N0-2, M0) within the last 5 years complaining of vasomotor symptoms, were assigned to tibolone 2.5mg daily or placebo treatment for a maximum of 5 years. The BMD sub-study enrolled 763 patients utilizing dual-energy X-ray absorptiometry (DXA) scanning at baseline and at 2 years. RESULTS: In the bone sub-study 699 out of 763 women were eligible (345 allocated to tibolone and 354 to placebo) after undergoing DXA scans, 300 (43%) women had normal BMD, 317 (45%) osteopenia and 82 (11.7%) osteoporosis. Low body mass index (<0.001), Asian race (p<0.001) and late age at menarche (p<0.04) predicted for low bone mass at baseline. Tibolone increased BMD by 3.2% at the lumbar spine and 2.9% at the hip compared to placebo (both p<0.001). The majority of fractures (55%) occurred in osteopaenic patients. Women with normal BMD had increased recurrence on tibolone 15.6% (22/141) compared to placebo 6.9% (11/159) p=0.016, whereas no increased BC recurrence was seen in women with low BMD; 7.4% (15/204) on tibolone versus (6.7% (13/195) on placebo. CONCLUSIONS: Tibolone is contraindicated after BC treatment as it increases BMD and BC recurrence. Risk of BC recurrence was elevated in BC women with normal BMD (compared to low) who took tibolone.

Abstract: Due to the low occurrence of cancer during pregnancy, limited data are available about outcome of infants exposed to chemotherapy in utero. We report the case of a newborn who developed transient ventricular hypocinesia and late-onset infection after in utero exposure to four epirubicin cycles for pregnancy-associated breast cancer. Moreover, we provide an overview of literature on neonatal outcome after anthracyclines-based chemotherapy regimen during pregnancy. Existing data support use of anthracyclines, as few cases of fetal cardiac toxicity were reported and most of short-term complications were transient. Need for prospective collection of data and longer follow-up is highly recognized.

Abstract: Climacteric symptoms such as hot flushes and vaginal dryness are very common in breast cancer patients, resulting either from age or adjuvant therapy. Tibolone, a synthetic steroid, is effective in reducing these symptoms in healthy post-menopausal women, but this has never been studied in a large breast cancer population.

Abstract: BIGLIA N., BOUNOUS V.E., MALABAILA A., PALMISANO D., TORTA D.M.E., D'ALONZO M., SISMONDI P. & TORTA R. (2012) European Journal of Cancer Care Objective and self-reported cognitive dysfunction in breast cancer women treated with chemotherapy: a prospective study The objective of this study is to investigate if changes in cognitive functions can be recognised in patients undergoing chemotherapy for breast cancer. Forty women with breast cancer and without depression underwent cognitive evaluation before and after 6 months of chemotherapy; emotional evaluation was performed before and after 1, 3 and 6 months of chemotherapy. Self-reported cognitive deficit evaluation was included. Global cognitive functioning before starting chemotherapy was good. After 6 months of treatment there was a significant decline in some cognitive functions, particularly involving the attention subdomain. Objective cognitive deficit resulted independent from the emotional status. On the contrary, self-perceived mental dysfunction was unrelated to the objective cognitive decline, but it was associated with depression and anxiety. Breast cancer chemotherapy can induce domain-specific cognitive dysfunction. Patients' self-perception of mental decline is unrelated to objective cognitive deficit. Breast cancer patients negatively judge their cognitive performances if they have a negative emotional functioning.

Abstract: The role of magnetic resonance imaging (MRI) in the local staging of breast cancer is currently uncertain. The purpose of this prospective study is to evaluate the accuracy of preoperative MRI compared to conventional imaging in detecting breast cancer and the effect of preoperative MRI on the surgical treatment in a subgroup of women with dense breasts, young age, invasive lobular cancer (ILC) or multiple lesions.

Abstract: INTRODUCTION: Breast cancer and its treatment negatively affect the important aspects of a woman's life such as sexual health, cognitive functions, body image, and weight. Abrupt estrogen deficiency following chemotherapy and/or hormonal therapy plays an important role in worsening of sexuality. AIM: To evaluate the impact of breast cancer treatment on sexual functioning, cognitive function, and body weight in premenopausal women. METHODS: Thirty-five women with a premenopausal diagnosis of breast cancer who are candidate to adjuvant treatment completed validated questionnaires on menopausal symptoms, sexuality, partner relationship, depression, body image, and cognitive functions after surgery (T0), then after chemotherapy or at least 6 months of endocrine therapy (T1), and after 1 year (T2). In addition, gynecological and dietological examinations were performed. MAIN OUTCOME MEASURE: The following validated questionnaires were used: Greene Climacteric Scale, Beck Depression Inventory, Body Attitude Test, McCoy revised Italian version McCoy Female Sexuality Questionnaire, Cues for Sexual Desire Scale, Dyadic Adjustment Scale, Numeric Matrix Test and Rey auditory-verbal learning test, to measure cognitive functions, a recall 24 H questionnaire to evaluate food intake, Minnesota Leisure Time Physical Activity questionnaire and Eating Attitude Test-40, while anthropometric and plicometry data were assessed by a dietitian. RESULTS: Low levels of sexual functioning were registered at baseline; a further decrease in sexual activity, quality of the partnered relationship, desire, and arousability was demonstrated at T1 and T2. We found a significant increase in hot flushes and anxiety. Nonsignificant deterioration of body image was demonstrated. Although women reported losing memory and concentration, "chemobrain" effect was not demonstrated as cognitive tests improved after 6 months, probably because of "learning effect." Women who had undergone chemotherapy gained weight and fat disposition was typically android. CONCLUSIONS: Young women undergoing adjuvant breast cancer therapy experience a heavy impairment in important quality of life domains as sexuality and targeted support interventions are needed.

Abstract: The study aim is to evaluate the efficacy and safety of two low-dose vaginal estrogen treatments (ETs) and of a non-hormonal vaginal moisturizer in postmenopausal breast cancer survivors with urogenital atrophy. Eighteen patients receiving estriol cream 0.25 mg (n = 10) or estradiol tablets 12.5 microg (n = 8) twice/week for 12 weeks were evaluated and compared with eight patients treated with polycarbophil-based moisturizer 2.5 g twice/week. Severity of vaginal atrophy was assessed using subjective [Vaginal Symptoms Score (VSS), Profile of Female Sexual Function (PFSF)] and objective [Vaginal Health Index (VHI), Karyopycnotic Index (KI)] evaluations, while safety by measuring endometrial thickness and serum sex hormones levels. After 4 weeks, VSS and VHI were significantly improved by both vaginal ETs, with further improvement after 12 weeks. PFSF improved significantly only in estriol group (p = 0.02). Safety measurements did not significantly change. Vaginal moisturizer improved VSS at week 4 (p = 0.01), but score returned to pre-treatment values at week 12; no significant modification of VHI, KI, PFSF was recorded. Both low-dose vaginal ET are effective for relieving urogenital atrophy, while non-hormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal.

Abstract: BRCA1 and BRCA2 mutation carriers have a 54-85% and 45% lifetime risk of developing breast cancer, respectively, and a 18-60% and 11-27% lifetime risk of developing ovarian cancer, respectively. Oral contraceptives (OCs) significantly reduce the risk of ovarian cancer also in BRCA1/BRCA2 mutation carriers. The association between OC use and breast cancer risk in these women is controversial. Some studies showed a modestly increased risk especially among BRCA1 mutation carriers. The risk appears to be greater for women who took OCs for at least 5 years and who took OCs before the age of 30 years. Other studies reported that duration of use before first full-term pregnancy has a positive association with breast cancer risk. Salpingo-oophorectomy reduces the risk of coelomic epithelial cancer of 80-95% and the risk of breast cancer of approximately 50%. BRCA1 and BRCA2 mutation carriers should be encouraged to undergo prophylactic bilateral salpingo-oophorectomy at the age of 35-40 years or when childbearing is complete. Short-term use of hormone replacement therapy may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction obtained with salpingo-oophorectomy.

Abstract: OBJECTIVE: Breast cancer patients with >3 involved nodes (N+) have a poor outcome. Chemotherapy (CT), alone or combined with endocrine therapy (ET) in hormone receptor (HOR)-positive patients, is the standard for these women. However, there are still questions surrounding the optimal adjuvant CT regimen. METHODS: 244 patients with >3 N+ were randomized to receive either four 3-weekly courses of epirubicin (E: 100 mg/m(2), day 1) followed by four 4-weekly cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF: 600, 40, 600 mg/m(2), days 1, 8: n = 122) or four 3-weekly courses of paclitaxel (T: 175 mg/m(2), day 1) followed by four 3-weekly cycles of epirubicin and vinorelbine (E: 75 mg/m(2), day 1; V: 25 mg/m(2), days 1, 8: n = 122). After CT, tamoxifen (plus an LH-RH analog in menstruating women) was given to all HOR-positive patients over a period of 5 years. Overall survival (OS) was the primary end point. Relapse-free survival (RFS) and toxicity were secondary end points. RESULTS: At a median follow-up time of 102 months (range 3-146), OS and RFS did not differ significantly between groups (E-CMF vs. T-EV: OS, HR 0.94, 95% CI 0.59-1.48, p = 0.8; RFS, HR 0.86, 95% CI 0.57-1.29, p = 0.45). The lack of any difference between assigned treatments was confirmed by multivariate analysis (E-CMF vs. T-EV: RFS, HR 0.98, 95% CI 0.64-1.48, p = 0.9). The 2 regimens showed different toxicity profiles. In fact, significantly more women assigned to E-CMF were affected by stomatitis (p = 0.001) while significantly more women in the T-EV group developed peripheral neuropathy (p < 0.0001) and musculoskeletal disorders (p < 0.0001). However, side effects were moderate and manageable and no toxic death occurred in either arm of the study. CONCLUSIONS: T-EV was safe and moderately toxic but was not superior to E-CMF.

Abstract: OBJECTIVE: Fertility-sparing surgery has been proposed for the treatment of borderline ovarian tumors. The aim of this study was to evaluate the outcome of patients submitted to cystectomy (CYS) compared with patients treated by unilateral salpingo-oophorectomy (USO) or bilateral salpingo-oophorectomy with/without total hysterectomy (radical surgery, RS). METHODS: We reviewed retrospectively the data of patients treated in 3 institutions for borderline ovarian tumors. One hundred and sixty-eight patients underwent laparoscopic or laparotomic surgical treatment from 1985 to 2006. Tumor recurrence rate, disease-free survival and site of recurrences were evaluated. Specific prognostic factors, such as stage, histology, micropapillary subtype, exophytic tumor growth, intraoperative spillage, endosalpingiosis, staging procedures, and route of surgery were analysed. RESULTS: Thirty-five patients underwent cystectomy, 50 unilateral salpingo-oopohorectomy, and 83 radical surgery. Twelve patients in the CYS group (34.3%), 10 in the USO group (20.0%), and 5 (6.0%) in RS group relapsed. Five-year progression-free survival (PFS) was 59.6%, 78.4%, and 93.5% in CYS, USO and RS groups, respectively. None of the relapsed patients died of disease. CONCLUSIONS: Cystectomy is an effective surgical strategy for patients with borderline ovarian tumor. The higher risk of local relapses is not associated with a reduction in the overall survival. The procedure should be offered to young patients with bilateral tumors and to very young ones, considering the higher risk of local relapse.

Abstract: OBJECTIVES: To assess the efficacy and the tolerability of gabapentin 900 mg/day compared to vitamin E for the control of vasomotor symptoms in 115 women with breast cancer. The secondary objective was to evaluate the effect of the treatments on the quality of sleep and other aspects of the quality of life. METHODS: A hot flush diary was completed daily; sleep quality and other menopausal symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS) and the SF-36 Health Survey. RESULTS: The prescribed treatment with gabapentin was never started by 28.3% of the patients and was interrupted by 28% for side-effects (dizziness and somnolence). Among the women allocated to vitamin E, 16.36% never started therapy and 34.78% dropped out because of inefficacy. Hot flush frequency and score decreased by 57.05% and 66.87%, respectively (p < 0.05) in the gabapentin group. The effect of vitamin E was fairly small: hot flush frequency and score were reduced by 10.02% and 7.28%, respectively (p > 0.05). Gabapentin was also particularly effective in improving the quality of sleep (PSQI score reduction: 21.33%, p < 0.05). CONCLUSION: Gabapentin appears to be effective for the treatment of hot flushes with a favorable effect on quality of sleep. Vitamin E has only marginal effect on vasomotor symptoms.

Abstract: BACKGROUND: Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2alpha is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models. RESULTS: We down-modulated AP-2alpha expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl) gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2alpha via the binding to one or more functional AP-2alpha binding sites present in its regulatory region. Analysis of migration in AP-2alpha null mouse embryo fibroblasts also reveals an essential role for AP-2alpha in cell movement via the activation of a distinct genetic programme. CONCLUSION: We show that AP-2alpha plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2alpha regulated gene Axl is an essential player in GN-11 neuron migration.

Abstract: PURPOSE: The aim of axillary reverse mapping (ARM) is to preserve arm lymphatics in patients with breast cancer who underwent surgical axillary staging. PATIENTS AND METHODS: From June 2007 to December 2008, 49 patients who required axillary dissection (AD) underwent ARM. One milliliter of patent blue dye was injected in the ipsilateral arm, and all blue nodes identified during AD were sent separately for pathologic examination. Main variables associated with the detection rates of blue lymphatics, the pathologic status of blue and nonblue nodes, and the complications of the procedure were analyzed. Results Identification rates of blue lymphatics and blue nodes were 73.5% and 55.1%, respectively. Blue node identification was influenced by the time elapsed between injection of blue dye and surgery (P = .002) but not by the learning curve of the procedure. Although the blue node was clear of metastases in 24 of 27 patients, three patients with extensive nodal metastatic involvement (ie, pN2a and pN3a) showed breast cancer metastatic cells in the blue nodes as well. The only adverse effect of the procedure was skin tattooing at the injection site, which disappeared within 4 months in almost 80% of the procedures. CONCLUSION: In patients with clinically negative axillary nodes, additional study is warranted to assess whether ARM may be used to spare the lymphatics from the arm. In the presence of extensive nodal disease, this technique may identify metastatic blue nodes, which demonstrates that there is not reliable separation of arm and breast lymphatic pathways.

Abstract: Breast conserving therapy (BCT) including postoperative irradiation of the remaining breast tissue is generally accepted as the best treatment for the majority of patients with early-stage breast cancer. The question is whether there is a necessity for irradiating all patients. Between 2001 and 2005, 749 women aged 55-75 years with infiltrating breast carcinoma were randomly assigned to breast conservative surgery, with or without radiotherapy (RT), to evaluate the incidence of in-breast recurrence (IBR). After 5 years of median follow-up, the cumulative incidence of IBR was 2.5% in the surgery-only arm and 0.7% in the surgery plus RT arm. There are no differences in terms of overall survival and distant disease-free survival. The preliminary evaluation suggests that breast irradiation after conservative surgery can be avoided without exposing these patients to an increased risk of distant-disease recurrence. Prolonged follow-up will further clarify the possible risks and late sequelae potentially induced by breast RT.

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Abstract: BACKGROUND: Vasomotor symptoms and bone loss are complications frequently induced by adjuvant treatment for breast cancer. Tibolone prevents both side-effects, but its effect on cancer recurrence is unknown. The aim of this study was to show non-inferiority of tibolone to placebo regarding risk of recurrence in breast-cancer patients with climacteric complaints. METHODS: Between July 11, 2002, and Dec 20, 2004, women surgically treated for a histologically confirmed breast cancer (T(1-3)N(0-2)M(0)) with vasomotor symptoms were randomly assigned to either tibolone 2.5 mg daily or placebo at 245 centres in 31 countries. Randomisation was done by use of a centralised interactive voice response system, stratified by centre, with a block size of four. The primary endpoint was breast-cancer recurrence, including contralateral breast cancer, and was analysed in the intention-to-treat (ITT) and per-protocol populations; the margin for non-inferiority was set as a hazard ratio of 1.278. This study is registered with ClinicalTrials.gov, number NCT00408863. FINDINGS: Of the 3148 women randomised, 3098 were included in the ITT analysis (1556 in the tibolone group and 1542 in the placebo group). Mean age at randomisation was 52.7 years (SD 7.3) and mean time since surgery was 2.1 years (SD 1.3). 1792 of 3098 (58%) women were node positive and 2185 of 3098 (71%) were oestrogen-receptor positive. At study entry, 2068 of 3098 (67%) women used tamoxifen and 202 of 3098 (6.5%) women used aromatase inhibitors. The mean daily number of hot flushes was 6.4 (SD 5.1). After a median follow-up of 3.1 years (range 0.01-4.99), 237 of 1556 (15.2%) women on tibolone had a cancer recurrence, compared with 165 of 1542 (10.7%) on placebo (HR 1.40 [95% CI 1.14-1.70]; p=0.001). Results in the per-protocol population were similar (209 of 1254 [16.7%] women in the tibolone group had a recurrence vs 138 of 1213 [11.4%] women in the placebo group; HR 1.44 [95% CI 1.16-1.79]; p=0.0009). Tibolone was not different from placebo with regard to other safety outcomes, such as mortality (72 patients vs 63 patients, respectively), cardiovascular events (14 vs 10, respectively), or gynaecological cancers (10 vs 10, respectively). Vasomotor symptoms and bone-mineral density improved significantly with tibolone, compared with placebo. INTERPRETATION: Tibolone increases the risk of recurrence in breast cancer patients, while relieving vasomotor symptoms and preventing bone loss. FUNDING: Schering-Plough (formerly NV Organon, Oss, Netherlands).

Abstract: The relevance of the progestagen component in combined hormone replacement therapy (HRT) for breast cancer risk has been long debated. In vitro studies have shown that progestins exert both genomic transcriptional and non-genomic effects that can enhance the proliferation, invasiveness and spread of breast cancer cells. According to a novel hypothesis, progestins can still activate cancer stem cells in patients with pre-existing, clinically undetected breast cancer. However, some experimental and clinical data suggest that different progestins may have a different impact on the pathophysiology of malignant breast cells. In vitro studies on estrogen receptor (ER)+ breast cancer cells have shown that the addition of medroxyprogesterone acetate (MPA) to estradiol (E(2)) produces a significantly higher increase of the mRNA levels and activities of estrogen-activating enzymes aromatase, 17beta hydroxysteroid dehydrogenase type-1 and sulfatase when compared with progesterone plus E(2). In randomised trial performed on ovariectomised adult female monkeys, oral E(2) plus MPA have resulted in a significantly greater proliferation of breast lobular and ductal epithelium when compared with placebo, whereas E(2) plus micronised progesterone have not. In the same experimental model, oral E(2) plus MPA have been found to induce the expression of genes encoding epidermal growth factor receptor (EGFR) ligands and downstream targets, whereas E(2) alone or E(2) plus micronised progesterone had no or modest effects on EGFR-related genes. In last years, some clinical studies on HRT users have shown that androgenic progestin- or MPA-based formulations are associated with an increased breast cancer incidence, whereas micronised progesterone- or dydrogesterone-based formulations are not. Further basic and clinical investigations on this topic are strongly warranted to elucidate whether the choice of the progestagen component in combined HRT could be of clinical relevance as for breast cancer risk.

Abstract: BACKGROUND: Estrogen is an established enhancer of breast cancer development, but less is known on its effect on local progression or metastasis. We studied the effect of estrogen receptor recruitment on actin cytoskeleton remodeling and breast cancer cell movement and invasion. Moreover, we characterized the signaling steps through which these actions are enacted. METHODOLOGY/PRINCIPAL FINDINGS: In estrogen receptor (ER) positive T47-D breast cancer cells ER activation with 17beta-estradiol induces rapid and dynamic actin cytoskeleton remodeling with the formation of specialized cell membrane structures like ruffles and pseudopodia. These effects depend on the rapid recruitment of the actin-binding protein moesin. Moesin activation by estradiol depends on the interaction of ER alpha with the G protein G alpha(13), which results in the recruitment of the small GTPase RhoA and in the subsequent activation of its downstream effector Rho-associated kinase-2 (ROCK-2). ROCK-2 is responsible for moesin phosphorylation. The G alpha(13)/RhoA/ROCK/moesin cascade is necessary for the cytoskeletal remodeling and for the enhancement of breast cancer cell horizontal migration and invasion of three-dimensional matrices induced by estrogen. In addition, human samples of normal breast tissue, fibroadenomas and invasive ductal carcinomas show that the expression of wild-type moesin as well as of its active form is deranged in cancers, with increased protein amounts and a loss of association with the cell membrane. CONCLUSIONS/SIGNIFICANCE: These results provide an original mechanism through which estrogen can facilitate breast cancer local and distant progression, identifying the extra-nuclear G alpha(13)/RhoA/ROCK/moesin signaling cascade as a target of ER alpha in breast cancer cells. This information helps to understand the effects of estrogen on breast cancer metastasis and may provide new targets for therapeutic interventions.

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Abstract: The events occurring during tumor formation and progression display similarities to some of the steps in embryonic morphogenesis. The family of AP-2 proteins consists of five different transcription factors (alpha, beta, gamma, delta, and epsilon) that play relevant roles in embryonic development, as demonstrated by the phenotypes of the corresponding knockout mice. Here, we show that AP-2alpha and AP-2gamma proteins play an essential role in tumorigenesis. Down-modulation of AP-2 expression in tumor cells by RNA interference (RNAi) led to enhanced tumor growth and reduced chemotherapy-induced cell death, as well as migration and invasion. Most of these biological modulations were rescued by AP-2 overexpression. We observed that increased xenotransplant growth was mostly due to highly enhanced proliferation of the tumor cells together with reduced innate immune cell recruitment. Moreover, we showed that migration impairment was mediated, at least in part, by secreted factors. To identify the genetic programs involved in tumorigenesis, we performed whole genome microarray analysis of AP-2alpha knockdown cells and observed that AP-2alpha regulates specific genes involved in cell cycle, cell death, adhesion, and migration. In particular, we showed that ESDN, EREG, and CXCL2 play a major role in AP-2 controlled migration, as ablation of any of these genes severely altered migration.

Abstract: Aromatase inhibitors (AIs) have become the first-choice endocrine drugs for postmenopausal breast cancer patients since they are associated with superior activity and better general tolerability when compared with tamoxifen both in the adjuvant and metastatic settings. As a consequence, the question is no more if a postmenopausal patient should have AIs as part of her adjuvant treatment, but when should it be started or which one should be preferentially used. Newer compounds, generally defined as third-generation AIs, are biochemically more selective and potent when compared with older ones, and they also show superior clinical activity. As yet, no large randomised study has been published comparing the three third-generation AIs on the market. Nevertheless, both laboratory and clinical data suggest that the steroidal (exemestane) and non-steroidal (anastrozole, letrozole) AIs may have slightly different toxicity profiles, probably due to the low androgenic action of the formers. While waiting for randomised data on clinical efficacy of third-generation AIs, such differences may help select the best drug in elderly patients with a low cumulative risk of relapse and a significant amount of co-morbidities, such as cardiovascular disease or osteoporosis.

Abstract: Gene expression profiles were studied by microarray analysis in 2 sets of archival breast cancer tissues from patients with distinct clinical outcome. Seventy-seven differentially expressed genes were identified when comparing 30 cases with relapse and 30 cases without relapse within 72 months from surgery. These genes had a specific ontological distribution and some of them have been linked to breast cancer in previous studies: AIB1, the two keratin genes KRT5 and KRT15, RAF1, WIF1 and MSH6. Seven out of 77 differentially expressed genes were selected and analyzed by qRT-PCR in 127 cases of breast cancer. The expression levels of 6 upregulated genes (CKMT1B, DDX21, PRKDC, PTPN1, SLPI, YWHAE) showed a significant association to both disease-free and overall survival. Multivariate analysis using the significant factors (i.e., estrogen receptor and lymph node status) as covariates confirmed the association with survival. There was no correlation between the expression level of these genes and other clinical parameters. In contrast, SERPINA3, the only downregulated gene examined, was not associated with survival, but correlated with steroid receptor status. An indirect validation of our genes was provided by calculating their association with survival in 3 publicly available microarray datasets. CKMT1B expression was an independent prognostic marker in all 3 datasets, whereas other genes confirmed their association with disease-free survival in at least 1 dataset. This work provides a novel set of genes that could be used as independent prognostic markers and potential drug targets for breast cancer.

Abstract: BACKGROUND: The superiority of new generation aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast carcinoma has emerged from several randomized trials. However, until now not all previous studies have shown a mortality benefit. METHODS: A pooled analysis of 2 prospective multicentric trials, sharing the same study design and nearly identical inclusion criteria, was performed. In both trials, women treated previously with tamoxifen for 2 or 3 years were randomly assigned to either continuing tamoxifen for an additional 2 or 3 years or to having their treatment switched to aminoglutethimide or anastrozole for a comparable time period. Mortality was analyzed according to allocated treatment and other patient and tumor variables. RESULTS: In all, 828 postmenopausal women, mostly with estrogen receptor (ER)-positive and node-positive tumors who had been monitored for a median time of 78 months (range, 6-141 months) were analyzed. Of these women, 415 were randomly selected to continue tamoxifen and 413 switched to aminoglutethimide or anastrozole. All-cause mortality and breast cancer-specific mortality were significantly improved by the switch: all-cause mortality: hazard ratio (HR) = 0.61 (0.42-0.88) P = .007; breast cancer-specific mortality: HR = 0.61 (0.39-0.94) P = .025. No increase was recorded in breast cancer-unrelated mortality in women after switching. Multivariate analysis showed that patient age, tumor size, allocated treatment, and nodal status, in that order, were independent mortality predictors. CONCLUSIONS: Switching to an aromatase inhibitor after 2 or 3 years of tamoxifen therapy significantly improves survival compared with continuing 2 or 3 years of additional tamoxifen treatment.

Abstract: The purposes of the study are to evaluate the efficacy and safety of mirtazapine 30 mg/daily for 12 weeks to reduce hot flushes (HF) in women with previous breast cancer and to assess the influence of the same treatment on sleep quality and other menopausal symptoms. A prospective pilot trial was conducted in 40 breast cancer patients with at least seven HF per day. A HF diary was completed daily; sleep quality and other menopausal symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS) and the SF-36 Health Survey. Treatment was never started by 13 out of 40 patients (32.5%) and was interrupted by 7 out of 27 patients (25%) due to of the occurrence of side effects (mostly somnolence). In the remaining 20 patients who completed the three months treatment period, there was a 55.6% (p < 0.05) reduction in HF frequency and 61.9% (p < 0.05) reduction in HF score as compared to baseline. A significant reduction in the MRS score (32.8%; p < 0.05) was observed. Mirtazapine appears to be effective in reducing HF in breast cancer survivors. The more frequent side effect was somnolence. A sizeable compiliance problem has been observed due to the reluctance to take antidepressant drugs and to side effects.

Abstract: A growing body of evidence support the association between the use of hormone replacement therapy (HRT) and a higher risk of both invasive lobular carcinoma (ILC) and invasive ductal-lobular mixed carcinoma (IDLC). Overall biological and clinical features of ILC entail a more cautious diagnostic and therapeutic approach as compared with invasive ductal carcinoma (IDC). ILCs are more frequently multifocal, multicentric and/or bilateral. Mammography and ultrasound show, therefore, significant limitations, while the higher sensitivity of magnetic resonance imaging in the detection of multifocal and/or multicentric lesions seems to improve the accuracy of preoperative staging of ILCs. Early diagnosis is even more challenging because the difficult in the localization and the sparse cellularity of lobular tumours may determine a false negative core biopsy. ILC is characterized by low proliferative activity, C-ErbB-2 negativity, bcl-2 positivity, p53 and VEGF negativity, oestrogen and progesterone positive receptors, low grade and low likelihood of lymphatic-vascular invasion. However, this more favourable biological behaviour does not reflect into a better disease-free and overall survival as compared with IDC. Since lobular histology is associated with a higher risk of positive margins, mastectomy is often preferred to breast conservative surgery. Moreover, only few patients with ILC achieve a pathologic response to preoperative chemotherapy and, therefore, in most patients mastectomy can be regarded as the safer surgical treatment. The preoperative staging and the follow-up of patients with ILC are also complicated by the particular metastatic pattern of such histotype. In fact, metastases are more frequently distributed to the gastrointestinal tract, peritoneum/retroperitoneum and gynaecological organs than in IDC.

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Abstract: Many patients with a history of breast cancer (BC) will suffer from vasomotor symptoms, which can be induced or exacerbated by treatment with tamoxifen or aromatase inhibitors. The LIBERATE trial was designed as a randomized, double-blind, multicenter trial to demonstrate that tibolone 2.5mg/day (Livial) is non-inferior to placebo regarding BC recurrence in women with vasomotor symptoms surgically treated for primary BC within the last 5 years. Secondary objectives are effects on vasomotor symptoms as well as overall survival, bone mineral density and health-related quality of life. Mean age at randomization was 52.6 years, and the mean time since surgery was 2.1 years. The mean daily number of hot flushes and sweating episodes was 7.3 and 6.1, respectively. For the primary tumor, Stage IIA or higher was reported for >70% of the patients. In subjects whose receptor status was known, 78.2% of the tumors were estrogen receptors positive. At randomization, tamoxifen was given to 66.2% of all patients and aromatase inhibitors to 7%. Chemotherapy was reported by 5% at randomization. The adjuvant tamoxifen use in LIBERATE allows a comparison with the Stockholm trial (showing no risk of BC recurrence associated with hormone therapy), which was stopped prematurely subsequent to HABITS. The LIBERATE trial is the largest, ongoing, well-controlled study for treatment of vasomotor symptoms in BC patients.

Abstract: AP-2 proteins are a family of developmentally-regulated transcription factors. They are encoded by five different genes (alpha, beta, gamma, delta, and epsilon) but they share a common structure. AP-2 plays relevant roles in growth, differentiation, and adhesion by controlling the transcription of specific genes. Evidence shows that the AP-2 genes are involved in tumorigenesis and for instance, they act as tumor suppressors in melanomas and mammary carcinomas. Here we investigated the function of the AP-2alpha protein in cancer formation and progression focusing on apoptosis and migration. We introduced AP-2alpha-specific siRNA (as oligos or in retroviruses) in HeLa or MCF-7 human tumor cells and obtained a pronounced down-modulation of AP-2a mRNA and protein levels. In these cells, we observed a significant reduction of chemotherapy-induced apoptosis, migration, and motility and an increase in adhesion suggesting a major role of AP-2a during cancer treatment and progression (migration and invasion). We have data suggesting that migration is, at least in part, regulated by secreted factors. By performing a whole genome microarray analysis of the tumor cells expressing AP-2alpha siRNA, we identified several AP-2alpha-regulated genes involved in apoptosis and migration such as FAST kinase, osteopontin, caspase 9, members of the TNF family, laminin alpha 1, collagen type XII, alpha 1, and adam.

Abstract: OBJECTIVE: To develop a method for adapting the best available cancer practice guidelines (CPGs) to the regional oncology network in Piedmont (NW of Italy, with about 4.3 million residents). METHODS: Four CPG were developed by multidisciplinary working groups, involving local opinion leaders, coordinated by the same team (including epidemiologists and health economists). The major features of these guidelines were: (a) to cover all the phases ofthe disease (from diagnosis to palliative care); (b) to satisfy common standards for evidence based guidelines; (c) to be coherent with the local health organization and resource availability. In the first three CPGs, regarding common cancers (colon-rectum, breast, lung), recommendations were graded according to the underlying level of evidence, from A to C, and treatment was organized by specialty. In the last guideline, regarding a rare condition (soft tissue sarcomas, STS), a grading system reflecting also the clinical importance of the decision was adopted and treatment recommendations were organized by clinical scenarios. In each guideline, some implementation tools, including a set of process and outcome indicators for audit monitoring, were provided. RESULTS: The four CPGs have been published between 2001 and 2004. The number ofrecommendations ranged between 38 (STS) and 103 (colon-rectum), with some differences in the distribution by specialty and grading. The CPGs have been disseminated through the oncology network and local health coordinators have been involved in the implementation. The impact of the CPGs is being evaluated by different approaches (analyses of administrative data, sample surveys and user's interviews). CONCLUSIONS: To adapt evidence based guidelines to a specific regional health organization is feasible and may be usefil for diseases requiring a multidisciplinary approach and continuity of care.

Abstract: Estrogen exerts a primary regulatory role on a wide variety of physiological processes in different tissues and organs. Agonistic ad antagonistic compounds are widely used in human health and, therefore, a deep understanding of their mechanisms of action at the molecular level is mandatory. The effect of 17beta-estradiol and three antiestrogenic drugs, comprising two selective estrogen receptor modulator (SERM, 4-OH-tamoxifen, Raloxifene) and the pure antiestrogen ICI 182,780, on genome-wide gene expression levels was evaluated in breast carcinoma cell lines by DNA microarray analysis. Different clusters of genes, showing specific coregulation patterns, were found. First, several groups of genes displaying temporal-specific up- or down-regulation were characterized. Second, clusters of genes responding to different antiestrogenic drugs in either antagonstic or agonistic fashion, were found. Genes responding specifically to antiestrogens, but not to estrogen, were also identified. In addition, each individual compound exhibited a very specific gene regulation. Bioinformatic analysis was applied to the regulatory sequences of different groups of genes and confirmed that specific pathways and secondary responses are activated at each temporal point and in response to different compounds. Our results underline the complexity of genomic responses to estrogen in breast cancer cells and strongly suggest that the molecular characterization of estrogen agonists and antagonists used in human therapy should be carefully studied.

Abstract: In order to assess the correlation of pathological and radiological features of ductal carcinoma in situ (DCIS) of the breast and their association with surgical outcome, a consecutive series of 150 patients was retrospectively examined. Pathological slides from all patients were divided into three categories according to the pathological EPWG (European Pathologist Working Group) and DIN (Ductal Intraepithelial Neoplasia) classifications, which showed very good inter-correlation (r=0.99) (whole series). Mammographic images from 46 of these cases were blindly classified into five categories according to the level of radiological suspicion (R), morphology of calcifications (Ca) and preoperative results of needle biopsy (C/B) (limited series). No significant differences in the distribution of clinical and pathological variables were detected among whole and limited series. The lesions were grouped into two (low versus high) pathological (PRG), radiological (RRG and CaRG) and needle biopsy (C/BRG) risk groups. PRG was associated with both RRG (p=0.002) and CaRG (p=0000), but not with C/BRG. Correlations with surgical outcome were also explored, with lesions of high PRG being more likely to undergo re-excision for inadequate first wide local excision [odds ratio (OR)=2.1], mastectomy (OR=2.6) and nodal staging procedures (OR=3.8) in the whole series. Conversely, no significant correlation was found between PRG, RRG, CaRG and C/BRG with surgical outcome in the limited series. We suggest that pathological features of DCIS are associated with surgical outcome and may be predicted by mammography.

Abstract: BACKGROUND: It is debated whether all patients with a positive sentinel node dissection (SLND) should be submitted to axillary lymph node dissection (ALND). Models have been developed to estimate the likelihood of nonsentinel node (non-SLN) metastases. METHODS: The accuracy of the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram and MD Anderson scoring system for the prediction of non-SLN status was tested in a consecutive series of 186 SLN-positive breast cancer patients. A multivariate analysis was performed to assess which parameters independently predicted the presence of non-SLN metastases. RESULTS: The predictive accuracy of the MSKCC nomogram measured by the receiver operating characteristic curve was 0.71, and it was best in patients with <10% risk of non-SLN metastases (sensitivity 100% and specificity 96%). The MD Anderson score predicted non-SLN involvement with low accuracy because it classified 85% of the patients in the intermediate-risk groups. Only SLN macrometastases and tumor multifocality independently predicted non-SLNs involvement. CONCLUSIONS: The MSKCC nomogram can help individualize the surgical treatment of SLN-positive breast cancer when the likelihood of further axillary involvement is low or surgical risks are higher.

Abstract: We studied whether dynamic contrast-enhanced MRI (DCE-MRI) could identify histopathological characteristics of breast cancer. Seventy-five patients with breast cancer underwent DCE-MRI followed by core biopsy. DCE-MRI findings were evaluated following the scoring system published by Fischer in 1999. In this scoring system, five DCE-MRI features, three morphological (shape, margins, enhancement kinetic) and two functional (initial peak of signal intensity (SI) increase and behavior of signal intensity curve), are defined by 14 parameters. Each parameter is assigned points ranging from 0 to 1 or 0 to 2, with higher points for those that are more likely to be associated with malignancy. The sum of all the points defines the degree of suspicion of malignancy, with a score 0 representing the lowest and 8 the highest degree of suspicion. Associations between DCE-MRI features and tumor histopathological characteristics assessed on core biopsies (histological type, grading, estrogen and progesterone receptor status, Ki67 and HER2 status) were studied by contingency tables and logistic regression analysis. We found a significant inverse association between the Fischer's score and HER2-overexpression (odds ratio-OR 0.608, p = 0.02). Based on our results, we suggest that lesions with intermediate-low suspicious DCE-MRI parameters may represent a subset of tumor with poor histopathological characteristics.

Abstract: OBJECTIVE: To describe the prevalence of hormone replacement therapy (HT) use by postmenopausal women doctors and doctors' wives in Italy and to explore the relationship between their personal characteristics and HT use. DESIGN: A total of 500 women doctors and 500 men doctors answering on behalf of their female partners were interviewed by a specialised company in the first months of 2003. Questions were meant to explore medical, behavioural and professional characteristics, personal use of HT, reasons for or against HT use and side effects of HT. The distribution of doctors' specialisation (general practitioners (GPs), gynaecologists, medical oncologists) in the sample interviewed was the same as that of the Italian medical community. RESULTS: Overall, 37% of women doctors and 39% of doctors' wives had ever used HT after menopause, of which 64 and 58%, respectively, were current users. The median duration of HT in the past users was 2.7 years for women doctors and 3.7 for doctors' wives. There were wide differences of HT use according to the type of specialisation: gynaecologists were more willing to use HT (56-59%) than GPs (30-31%) or medical oncologists (16-30%).Vasomotor symptoms (68-69%), followed by the prevention of osteoporosis (28-39%), were the main reasons for commencing HT. The main reasons not to take or to stop HT were the absence or resolution of menopausal symptoms. Only 8% of women doctors and 4% doctors' wives stopped HT after the publication of the WHI data. CONCLUSIONS: In Italy, women doctors/doctors' wives personally use HT much more than postmenopausal general population.

Abstract:

Abstract: OBJECTIVE: The aim of this study was to compare laparoscopic and abdominal approach in the treatment of endometrial cancer in our department. STUDY DESIGN: From January 1999 to November 2002, 77 patients underwent surgery for stages I-III endometrial cancer. The first group of 36 patients had abdominal hysterectomy as well as salpingo-oophorectomy, with or without lymphadenectomy. The remaining 41 patients received laparoscopic assisted vaginal hysterectomy as well as salpingo-oophorectomy, with or without lymphadenectomy. In this retrospective study, we have compared the surgical results, the short- and long-term morbidity and the outcome of the two patient groups. RESULTS: Body mass index (BMI) was significantly higher in the laparoscopic group (27.3 versus 24.6; p=0.009). The average time for surgery was significantly longer for the laparoscopic group (143.6 min versus 109.7 min; p=0.0001), but lymphadenectomy was performed in more patients (63.4% versus 25%; p=0.001). Postoperative hospital stay was significantly longer in patients undergoing the abdominal approach (4.59 days versus 3.18 days; p<0.0001). No blood transfusions were performed and the rates of complications were similar in the two groups. No differences were found in recurrence and survival rate. CONCLUSIONS: In our experience, laparoscopic and abdominal surgery can achieve similar results in the treatment of endometrial cancer. In our series, even with the BMI and the number of lymphadenectomies being higher in the laparoscopic group, the rates of complications were similar in the two groups.

Abstract: Antiestrogens used for breast cancer (BC) treatment differ among each other for the ability to affect estrogen receptor (ER) activity and thereby inhibit hormone-responsive cell functions and viability. We used high-density cDNA microarrays for a comprehensive definition of the gene pathways affected by 17beta-estradiol (E2), ICI 182,780 (ICI), 4OH-tamoxifen (Tamoxifen), and raloxifene (RAL) in ER-positive ZR-75.1 cells, a suitable model to investigate estrogen and antiestrogen actions in hormone-responsive BC. The expression of 601 genes was significantly affected by E2 in these cells; in silico analysis reveals that 86 among them include one or more potential ER binding site within or near the promoter and that the binding site signatures for E2F-1, NF-Y, and NRF-1 transcription factors are significantly enriched in the promoters of genes induced by estrogen treatment, while those for CAC-binding protein and LF-A1 in those repressed by the hormone, pointing to novel transcriptional effectors of secondary responses to estrogen in BC cells. Interestingly, expression of 176 E2-regulated mRNAs was unaffected by any of the antiestrogens tested, despite the fact that under the same conditions the transcriptional and cell cycle stimulatory activities of ER were inhibited. On the other hand, of 373 antiestrogen-responsive genes identified here, 52 were unresponsive to estrogen and 25% responded specifically to only one of the compounds tested, revealing non-overlapping and clearly distinguishable effects of the different antiestrogens in BC cells. As some of these differences reflect specificities of the mechanism of action of the antiestrogens tested, we propose to exploit this gene set for characterization of novel hormonal antagonists and selective estrogen receptor modulators (SERMs) and as a tool for testing new associations of antiestrogens, more effective against BC.

Abstract: We evaluated whether concurrent radiotherapy (RT) affected delivery and toxicity of adjuvant intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in women with operable breast cancer. The medical charts of 321 consecutive breast cancer patients who received CMF either alone for 6 cycles, or for 4 cycles following of an anthracycline (A-CMF) were reviewed. One hundred forty-four women underwent radiotherapy concurrently with CMF. Optimal CMF delivery (success as opposite to failure) was defined as the combined achievement of an average relative dose intensity (aRDI) > or = 85% and an average percent of the total dose (aPTD) > or = 90% for the three drugs in the CMF regimen. Multivariate logistic regression analysis showed that concurrent-RT did not affect CMF delivery (OR for success 1.391 p=0.230). The sequential A-CMF regimen (OR for success 0.208, 95% C.I. 0.120-0.360, p<0.001) and age > or = 56 (OR for success 0.351, 95% C.I. 0.200-0.161, p<0.001) were independently associated with suboptimal CMF delivery. Moreover, concurrent RT was independently associated with increased leukopenia, thrombocytopenia, upper abdominal pain, mucositis and fatigue. Our retrospective analysis suggests that concurrent-RT has no impact on optimal CMF delivery, but it increases the burden of CMF-related toxicity.

Abstract: BACKGROUND: Tamoxifen, for many years the 'gold standard' in the adjuvant setting for the management of endocrine sensitive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy due to the development of resistance. This provided the rationale for a switching trial with anastrozole, the updated results of which are reported here. PATIENTS AND METHODS: This trial investigated the efficacy of switching to anastrozole for women already receiving tamoxifen. After 2-3 years of tamoxifen treatment, postmenopausal, node-positive, ER-positive patients were randomized to receive either anastrozole 1 mg/day or to continue tamoxifen, 20 mg/day, giving a total duration of 5-years treatment. The primary end point was disease-free survival and secondary endpoints were event-free survival, overall survival and safety. RESULTS: A total of 448 patients were enrolled. At a median follow-up time of 64 months (range 12-93), 63 events had been reported in the tamoxifen group compared with 39 in the anastrozole group [HR 0.57 (95% CI 0.38-0.85) P = 0.005]. Relapse-free and overall survival were also longer in the anastrozole group [HR 0.56 (95% CI 0.35-0.89) P = 0.01 and 0.56 (95% CI 0.28-1.15) P = 0.1]. However, the latter difference was not statistically significant. Overall more patients in the anastrozole group experienced at least one adverse event (209 versus 151: P = 0.000). However, numbers of patients experiencing serious adverse events were comparable (37 versus 40, respectively: P = 0.7). CONCLUSIONS: Switching to anastrozole after the first 2-3 years of treatment was confirmed to improve event-free and relapse-free survival of postmenopausal, node-positive, ER-positive early breast cancer patients already receiving adjuvant tamoxifen.

Abstract: Breast cancer has the highest incidence of all types of cancer in women. Age and family history are the strongest risk factors, but sex hormones also play an important role, as demonstrated by epidemiological studies reporting a consistent association by reproductive personal history and breast cancer risk. The acceptability of preventive strategies by healthy women is closely related to their lifetime risk of developing breast cancer. Although surgical prevention may be considered in carriers of BRCA1/2 mutation, this option cannot be advocated for the majority of women whose risk is only moderately increased. In these women, chemoprevention with tamoxifen may reduce the incidence of estrogen receptor (ER)-positive breast carcinoma by 30-50%. Other drugs such as raloxifen and aromatase inhibitors (AIs) are currently being tested in this setting. Tamoxifen has been the most successful hormonal treatment over the last 30 years and, until recently, the most active drug in endocrine-sensitive breast cancer. In premenopausal breast cancer, tamoxifen still represents the therapy of choice, alone or in association with ovarian suppression. Conversely, in postmenopausal women it has been overtaken by third-generation AIs as first-choice drugs both in the adjuvant and metastatic settings. Many other issues, such as the optimal sequence between tamoxifen and AIs, the duration of AIs treatment, and the association of ovarian suppression and AIs in premenopausal patients still await the completion of randomized clinical trials. Furthermore, it is likely that treatment tailoring will be increased by the definition of patient subgroups that could derive larger benefits from AIs (progesterone receptor-negative, HER-2-overexpressing) or other new drugs.

Abstract: Thousands of women are treated each year for gynaecological cancers; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, chemotherapy and/or radiotherapy to the pelvic region. The aim of this paper is to review the biological and clinical evidence in favour and against hormone replacement therapy (HRT) use after gynaecological cancers. With the exception of breast and endometrial cancer, there is no biological evidence that HRT may increase the recurrence risk. In women with previous endometrial cancer, HRT use is not supported by univocal and conclusive data to formulate specific recommendations, whereas most authors suggest that oestrogens may be used after adequate information about risks and benefits. The use of HRT in breast cancer patients is, at present, considered contra-indicated, even if results of clinical trials are not concordant. Therapeutic non-hormonal alternatives may be proposed to these patients.

Abstract: Patients with estrogen receptor (ER)+/progesterone receptor (PR)- and/or HER-2 overexpressing breast carcinomas may derive lower benefit from endocrine treatment. We examined retrospectively data from 972 breast cancer patients who received tamoxifen (725), tamoxifen + Gn-RH analogs (127) and aromatase inhibitors (120) as adjuvant treatments. ER+/PR- versus ER+/PR+ tumours were characterised by larger size (P = 0.001), higher tumour grade (P = 0.001), higher Ki-67 expression (P = 0.001) and lower mean ER (P = 0.000) and HER-2 expression (P = 0.000). At univariate analysis, tumour grading [hazard ratio (HR) = 4.0; 95% confidence interval (CI) = 1.4-11.1; P = 0.007], nodal status (HR = 3.4; 95% CI 1.2-5.7; P = 0.000), tumour diameter (HR = 2.9; 95% CI 1.7-4.7; P = 0.000) lack of PR expression (HR = 2.1; 95% CI 1.3-3.4; P = 0.002) and HER-2 overexpression (HR = 1.9; 95% CI 1.0-3.5; P = 0.03), as well as Ki 67 expression (HR = 1.7; 95% CI 1.0-2.7; P = 0.04) were associated with shorter disease-free survival (DFS). At the multivariate analysis, nodal status (HR = 3.6; 95% CI 1.9-6.8; P = 0.0001), lack of PR expression (HR = 2.3; 95% CI 1.3-4.0; P = 0.003) and tumour diameter (HR = 2.1; 95% CI 1.1-3.8; P = 0.018) retained their prognostic significance, whereas HER-2 overexpression was associated with a trend towards shorter DFS that was of borderline statistical significance (HR = 2.0; 95 % CI 1.0-3.9; P = 0.05). Our data suggest that lack of PR expression and HER-2 overexpression are both associated with aggressive tumour features, but the prognostic information of PR status on the risk of recurrence in endocrine-treated breast cancer patients is stronger.

Abstract: The increasing number of breast cancer patients who suffer from menopausal symptoms is mainly due to the extensive use of adjuvant treatments in the younger women. Both short and long-term side effects of oestrogen deficiency may severely impact on the quality of life of these women and should not be underestimated. Hormonal treatments are contraindicated in breast cancer survivors mainly due to the concern that dormant micrometastases may be stimulated to grow. Alternative non-hormonal remedies are now available to alleviate symptoms and to prevent chronic diseases associated with oestrogen deficiency. Urogenital atrophy is an important consequence of oestrogen deprivation that can be effectively treated by vaginal estrogens, although systemic absorption occurs with conventional doses. Preliminary data suggest that much lower doses of vaginal estrogens can alleviate urogenital atrophy without influencing serum estrogenic levels. Further research is warranted to confirm whether vaginal estrogens are safe in symptomatic breast cancer patients who are non-responsive to alternative treatments.

Abstract: OBJECTIVE: To evaluate the efficacy and tolerability of long-term treatment with venlafaxine at low dose for the reduction of vasomotor symptoms in breast cancer survivors. DESIGN: Forty consecutive breast cancer patients suffering troublesome hot flushes have been treated for 8 weeks with venlafaxine XR 37.5 mg/day in an open-label study. Vasomotor symptoms have been evaluated before starting treatment and every 4 weeks with a hot flushes diary pointing out the number and the severity of vasomotor symptoms. A Beck Depression Inventory (BDI) was completed at baseline and at the end of the treatment. RESULTS: Thirty patients had completed the first 4 weeks of treatment, reporting a reduction of hot flushes frequency of 39% as compared to baseline (p<0.001). After 8 weeks of treatment, a further significant reduction was observed both for the hot flushes frequency (-53%; p<0.001) and for the hot flushes score (-59%; p<0.001), a measure which reflects both the number and the severity of hot flushes. Very few side effects were reported, mostly nausea in the first 2 weeks of assumption and mouth dryness. Only 23 women had completed BDI at week 8; a reduction of 23% was observed (p=0.000). CONCLUSION: Venlafaxine is an effective treatment for the relief of vasomotor symptoms in patients previously treated for breast cancer. A favourable effect is maintained also in those patients using tamoxifen as adjuvant therapy. The use of the low dose (37.5 mg/day) is associated with minimal side effects and produces a good improvement in hot flushes if pursued over 8 weeks.

Abstract: AIM OF THE STUDY: To assess whether the pathological characteristics of breast carcinomas arising in post-menopausal women who ever used hormonal replacement therapy (HRT) differ from those of post-menopausal patients who never used HRT. MATERIALS AND METHODS: Six hundred and forty three consecutive breast cancer patients were entered in a case control-study. Cases were represented by 111 breast cancer patients who had used or were using HRT at the time of diagnosis, while the remaining 532 patients who never used HRT were chosen as controls. RESULTS: Tumour diameter was smaller in HRT users (17.6 vs 22.1 mm; p=0.002) and tumours of lobular histology were almost twice more frequent among HRT users as in 'never users' (21 vs 12%; p=0.01). No differences were found in grading, hormonal receptor status and axillary nodal status. The expression of c-erb B-2, p53, Ki67 and PS2 measured by immunohistochemistry was similar in the two groups. CONCLUSIONS: Our findings suggest that HRT use may modify the pathological presentation of breast cancer. Further studies are indicated, while other clinical-pathological characteristics did not differ according to HRT use.

Abstract: We compared dynamic contrast-enhanced MRI (DCE-MRI) and sonography (US) for monitoring tumour size in 21 patients with breast cancer undergoing primary chemotherapy (PCT) followed by surgery. The correlation between DCE-MRI and US measurements of tumour size, defined as the product of the two major diameters, was 0.555 (P=0.009), 0.782 (P<0.001), and 0.793 (P<0.001) at baseline, and after two and four cycles of PCT, respectively. The median tumour size was significantly larger when measured by DCE-MRI than by US at baseline (1472 vs 900 mm(2), P<0.001) and after two cycles of PCT (600 vs 400 mm(2), P=0.009). After PCT, the median tumour size measured by the two techniques was similar (256 vs 289 mm(2) for DCE-MRI and US, respectively, P=0.859). The correlation with the histopathological major tumour diameter was 0.824 (P<0.001) and 0.705 (P<0.001) for post-treatment DCE-MRI and US, respectively. Measurements of the final major tumour diameter by DCE-MRI tended to be more precise, including cases achieving a pathological complete response. Randomized trials are warranted to establish the clinical impact of the initial discrepancy in tumour size estimates between DCE-MRI and US, and the trend towards a better definition of the final tumour size provided by DCE-MRI in this clinical setting.

Abstract: The San Antonio Breast Cancer Symposium is now considered the most important international breast cancer meeting worldwide. On 8-11th December 2004, approximately 6700 participants attended the meeting and shared the latest findings from breast cancer research. All the main fields of breast cancer research and treatment were covered. This report will focus on the most relevant advancements in the pharmacotherapy of breast cancer. The selected presentations have been grouped together in separate sections, including the fields of prevention, early disease and advanced disease. The most promising data from translational research have also been included, with particular regard to those who will most likely influence the management of breast cancer patients in the future.

Abstract: Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.

Abstract: There is strong epidemiological, experimental and clinical evidence that the etiology of breast cancer is closely related to long-term exposure of breast epithelium to sex steroid hormones. Estrogens can enhance the development of breast cancer by stimulating cell proliferation rate and thereby increasing the number of errors occurring during DNA replication, as well as by causing DNA damage via their genotoxic metabolites produced during oxidation reactions. Anti-estrogenic drugs, including tamoxifen, raloxifene and anastrozole, have been tested with promising results in the chemoprevention of breast cancer in high-risk women. As for the use of exogenous sex-steroids in the gynecological practice, data about breast cancer risk associated with oral contraception are reassuring, and available data on oral hormone replacement therapy (HRT) use for not more than 5 years have failed to detect a significant increase in the risk of developing a breast cancer. Long-term HRT administration increases the incidence of this tumor slightly, with a relative risk ranging from 1 to 2 depending on hormone preparation. Estrogens alone, even if taken for long periods of time, seem to be safer than estrogen/progestin combinations. New administration routes and novel hormone regimens are currently under evaluation, and these new HRT modalities could have different impact on breast cancer risk because of their metabolic and pharmacodynamic effects.

Abstract: PURPOSE: Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor-positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required. PATIENTS AND METHODS: We conducted a prospective randomized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole. After 2 to 3 years of tamoxifen treatment, patients were randomly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d, for a total duration of treatment of 5 years. Disease-free survival was the primary end point. Event-free survival, overall survival, and safety were secondary end points. RESULTS: Four hundred forty-eight patients were enrolled. All women had node-positive, estrogen receptor-positive tumors. At a median follow-up time of 36 months, 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group (P = .0002). Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group (hazard ratio [HR] = 0.35; 95% CI, 0.18 to 0.68; P = .001 and HR = 0.15; 95% CI, 0.03 to 0.65; P = .003, respectively). Overall, more adverse events were recorded in the anastrozole group compared with the tamoxifen group (203 v 150, respectively; P = .04). However, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group (33 of 150 events v 28 of 203 events, P = .04). CONCLUSION: Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.

Abstract: BACKGROUND: The need to dissect axillary nodes in patients with early breast cancer and clinically negative axilla remains controversial. The aim of the study was to assess the role of axillary radiotherapy (RT) in reducing axillary metastases in patients with early breast cancer who did not receive axillary dissection. PATIENTS AND METHODS: From 1995 to 1998, 435 patients over 45 years old with breast cancer up to 1.2 cm and no palpable axillary nodes were randomized 214 to breast conservation without axillary treatment and 221 to breast conservation plus axillary RT. RESULTS: After a median follow-up of 63 months, overt axillary metastases were fewer than expected: three cases in the no axillary treatment group (1.5%) and one in the RT group (0.5%). Expected cases were 43 in the no axillary treatment group and 10 in the RT group. Rates of distant metastases and local failures were low, and 5-year disease free survival was 96.0% (95% confidence interval, 94.1%-97.9%) without significant differences between the two arms. CONCLUSIONS: This study suggests that occult axillary metastases might never become clinically overt and axillary dissection might be avoided in patients with small carcinomas and a clinically negative axilla. Axillary RT seems to protect the patients from axillary recurrence almost completely.

Abstract: This study aimed to describe the prevalence of hormone replacement therapy (HRT) use by women doctors and doctors' wives in northern Italy, to explore the relationship between their personal characteristics and HRT use, and to gather information about the use of alternative remedies. A questionnaire was mailed to all physicians born between 1935 and 1955 included in the database of the Medical Register of Turin County (Northern Italy). The questions were meant to explore medical, behavioral, and professional characteristics; personal use of HRT; reasons for and against HRT use; side effects and use of other therapies. 56.5% of postmenopausal women who completed the questionnaire had used HRTand 68.3% of them were current users. The median duration of HRT use was 3.7 years. Only 18.5% of the women had used HRT for 5 years or more; in this case, HRT was started significantly earlier than in the other groups. More than 50% had taken oral HRT, while 39% had used patches; estrogens only had been taken by 21.9%. HRT users had a significantly lower basal body mass index and more vasomotor and dystrophic symptoms at menopause onset compared with non-HRT users. More women on HRT were in good physical health and had an active sex life. Previous breast cancer and family history of cardiovascular diseases were inversely associated with HRT use. The main reason for not taking HRT or stopping it was fear of breast cancer (43.7% and 34.8%, respectively); irregular bleeding and weight gain were also frequently reported as a reason for HRT (30% and 22%). Overall, 22% of women had used alternative drugs to alleviate menopausal symptoms or prevent menopause-related diseases, mainly tibolone (21% among never HRT users and 2% among HRT users; p = 0.015) and phytoestrogens. The prevalence and duration of use of HRT by Italian physicians is consistent with the available data from other Western countries, and is much higher than in the general population. This is in contrast with the very low prevalence of use in the general population and may lead, in the near future, to a larger use of HRT in Italy.

Abstract: BACKGROUND: Nerve sparing is suggested for cancer surgery, but no experience is available for deep endometriosis. The aim of this study was to laparoscopically identify the pelvic nerves in the posterior pelvis. METHODS: A total of 24 patients operated for deep endometriosis were considered. During surgery and on videotapes of the procedures, we evaluated single- or double-sided resection of the uterosacral ligaments and other structure's visualization of the inferior hypogastric and the splanchnic nerves. The most important objective criteria for resection of the nerves was urinary retention after surgery, which was compared to surgical resection on the videotapes. RESULTS: Visualization of the inferior hypogastric nerves was possible in 20 of 22 patients (90.1%). Eight of the 24 patients had at least one inferior hypogastric nerve resected (33.3%). In seven patients (29.2%) resection of the uterosacral ligaments was bilateral, and in three of these the nerves were resected. Postoperatively, the median residual urine volume after the first spontaneous voiding was 40 ml (range, 20-400). Seven of eight patients (29.2%) with resection of the nerves had urinary retention and self-catheterization at discharge. The difference in urinary residuum after first voiding between patients undergoing self-catheterization and patients released without the catheter was significant ( p < 0.01). The median time to resume the voiding function in patients with self-catheterization was 18 days (range, 9-45). CONCLUSIONS: Nerve visualization is possible by means of laparoscopic surgery for deep endometriosis in a high rate of patients. Careful technique is necessary, but the laparoscopic approach may help. Even single-sided radical dissection can induce important urinary retention.

Abstract: Breast carcinoma is the most frequent tumor in the female population. Many factors can influence the risk of breast cancer; some of them, such as old age and breast cancer 1/2 (BRCA1/BRCA2) gene mutations, are associated with a fourfold increase in risk. A previous diagnosis of atypical ductal or lobular hyperplasia or having a first-degree relative with a carcinoma are factors associated with a two- to fourfold increase in risk. A relative risk between 1 and 2 is associated with longer exposure to endogenous hormones as a result of early menarche, late menopause and obesity, or with recent and prolonged use of hormone replacement therapy (HRT) or with behavioural factors such as high alcohol and fat intake. Is it possible to modify breast cancer risk in postmenopausal women? Risk factors related to lifestyle can be changed, even if it is not clear whether modifying these behavioural factors during the postmenopausal period will influence the overall breast cancer risk. For instance, the influence of exogenous hormones throughout life (both oral contraceptives and HRT) should be evaluated according to the individual risk-benefit ratio. The problem is even more complex for women who carry genetic mutations and for those who have close relatives with breast cancer, who may be candidates for risk reduction strategies. Prophylactic bilateral mastectomy is still controversial, but is frequently offered to or requested by this group of women and may be indicated in BRCA1/BRCA2 carriers. Chemoprevention with tamoxifen and with the new selective estrogen receptor modulators, namely raloxifene, is very promising and deserves a thorough discussion for all high-risk women.

Abstract: PURPOSE. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows analysis of both tumor volume and contrast enhancement pattern using a single tool. We sought to investigate whether DCE-MRI could be used to predict histological response in patients undergoing primary chemotherapy (PCT) for breast cancer. PATIENTS AND METHODS. Thirty patients with breast cancer, clinical diameter > 3 cm or stage III A/B, received anthracycline and taxane based PCT. DCE-MRI was performed at the baseline, after two cycles and after four cycles of PCT, before surgery. Histological response was assessed using a five-point scheme. Grade 4 (small cluster of dispersed residual cancer cells) and grade 5 (no residual viable cancer cell) were defined as a major histopathological response (MHR). RESULTS. Univariate analysis showed that a > 65% reduction in the tumor volume and a reduction in the early enhancement ratio (ECU) after two cycles of PCT were associated with a MHR. Multivariate analysis revealed that tumor volume reduction after two cycles of PCT was independently associated with a MHR (odds ratio [OR] 39.968, 95% confidence interval [CI] 3.438-464.962, p < 0.01). ECU reduction was still associated with a MHR (OR 2.50, 95% CI 0.263-23.775), but it did not retain statistical significance (p = 0.42). Combining tumor volume and ECU reduction after two cycles of PCT yielded a 93% diagnostic accuracy in identifying tumors achieving a pathological complete response (pCR) (histopathological grade 5). CONCLUSIONS. DCE-MRI allows prediction of the effect of neoadjuvant chemotherapy in breast cancer. Although in our study tumor volume reduction after two cycles had the strongest predictive value, DCE-MRI has the potential to provide functional parameters that could be integrated to optimize neoadjuvant chemotherapy strategies.

Abstract: The activator protein 2 (AP-2) transcription factors are essential proteins for oestrogenic repression of the ERBB2 proto-oncogene in breast cancer cells. In the present study, we have examined the possible oestrogenic regulation of AP-2 genes themselves in breast-tumour-derived lines. As early as 1 h after oestrogen treatment, AP-2gamma mRNA was markedly increased, whereas AP-2alpha was down-regulated, but with slower kinetics, and AP-2beta was not affected at all. Addition of anti-oestrogens ablated these effects. Modulation of the protein levels corresponded to changes in the transcript levels, thus suggesting that in oestrogen-treated cells, an inversion of the balance between AP-2alpha and AP-2gamma isoforms occurs. The 5'-untranslated region (5'-UTR) of the human AP-2gamma gene contains one consensus and one degenerate oestrogen-responsive element (ERE). Reporter constructs carrying the AP-2gamma promoter and the 5'-UTR were up-regulated by oestrogens in transient transfection assays. Deletion of the most conserved (but not of the degenerate) ERE from reporter constructs abrogated the oestrogenic response, although both ERE-containing segments were footprinted in DNaseI protection assays. In vitro binding assays demonstrated the ability of oestrogen receptor alpha (ERalpha) to bind to this site, and chromatin immunoprecipitation analysis of the endogenous gene showed that ERalpha occupies this region in response to oestrogens. We conclude that AP-2gamma is a primary oestrogen-responsive gene and suggest that AP-2 proteins may mediate some oestrogenic responses.

Abstract: Estrogen controls key cellular functions of responsive cells including the ability to survive, replicate, communicate and adapt to the extracellular milieu. Changes in the expression of 8400 genes were monitored here by cDNA microarray analysis during the first 32 h of human breast cancer (BC) ZR-75.1 cell stimulation with a mitogenic dose of 17beta-estradiol, a timing which corresponds to completion of a full mitotic cycle in hormone-stimulated cells. Hierarchical clustering of 344 genes whose expression either increases or decreases significantly in response to estrogen reveals that the gene expression program activated by the hormone in these cells shows 8 main patterns of gene activation/inhibition. This newly identified estrogen-responsive transcriptome represents more than a simple cell cycle response, as only a few affected genes belong to the transcriptional program of the cell division cycle of eukaryotes, or showed a similar expression profile in other mitogen-stimulated human cells. Indeed, based on the functions assigned to the products of the genes they control, estrogen appears to affect several key features of BC cells, including their metabolic status, proliferation, survival, differentiation and resistance to stress and chemotherapy, as well as RNA and protein synthesis, maturation and turn-over rates. Interestingly, the estrogen-responsive transcriptome does not appear randomly interspersed in the genome. In chromosome 17, for example, a site particularly rich in genes activated by the hormone, physical association of co-regulated genes in clusters is evident in several instances, suggesting the likely existence of estrogen-responsive domains in the human genome.

Abstract:

Abstract: OBJECTIVE: The primary aim of this study was to evaluate the prognostic and predictive value of pretreatment serum hemoglobin level (Hb) in advanced ovarian cancer; second aim was to perform a preliminary investigation of intratumoral microvessel density (IMD). METHODS: The influence on survival and response to treatment of several clinico-pathological features, including Hb, was analyzed in 72 patients with advanced ovarian cancer. IMD was assessed in tumor specimens of 25 of the 72 patients to compare three different endothelial markers: anti-FactorVIII, anti-CD31 and anti-CD34. In this subgroup of patients, a preliminary analysis of the prognostic and predictive value of IMD, and its relationship with Hb and other clinico-pathological features, was performed. RESULTS: Hb >or= 12 g/dl was significantly associated with a better overall survival in univariate analysis (P = 0.0181) and was the only independent prognostic variable in multivariate analysis (P = 0.0160). Hb was directly related to progression-free survival (P = 0.0240) and complete response to treatment (P = 0.016). In the preliminary investigation of IMD, mean microvessel count did not show any significant difference among the three endothelial markers used, but anti-CD34 revealed a more consistent staining reaction. The relationship between IMD and complete response to treatment was found near to statistical significance (P = 0.05); Hb and IMD were inversely related (r = -0.47; P = 0.045). CONCLUSIONS: Hb has a prognostic and predictive value in advanced ovarian cancer. In our preliminary study, which was performed on a limited number of patients, we found anti-CD34 to be an optimal marker for IMD determination, IMD to be a possible predictive factor of complete response to treatment, and IMD and Hb to be inversely related.

Abstract: OBJECTIVE: Thousands of women are treated each year for cancer; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, or chemotherapy, or the need for radiotherapy to the pelvic region. In most cases the oncologist and the gynaecologist would advise these women against the use of HRT. The purpose of this paper is to review biological and clinical evidences in favour and against HRT use in the different tumours and to propose an algorithm that can help choosing the treatment for the single woman. METHODS: We performed a systematic literature review through April 2002 concerning: (1) biological basis of hormonal modulation of tumour growth; (2) epidemiological data on the impact of HRT on different cancers risk in healthy women; (3) safety of HRT use in cancer survivors; (4) alternatives to HRT. RESULTS: With the exception of meningioma, breast and endometrial cancer, there is no biological evidence that HRT may increase recurrence risk. In women with previous breast and endometrial cancer HRT is potentially hazardous on a biological basis, even if published data do not show any worsening of prognosis. CONCLUSIONS: Even if a cautious approach to hormonal-dependent neoplasias is fully comprehensible and the available alternative treatment should be taken into greater consideration, the reticence to prescribe HRT in women previously treated for other non hormone-related tumours has neither a biological nor a clinical basis. An algorithm based on present knowledge is proposed.

Abstract: Estrogens exert a key biological role in mammary gland epithelial cells and promote breast carcinogenesis and tumor progression. We recently identified a new large set of estrogen responsive genes from breast cancer (BC) cells by DNA microarray analysis of the gene expression profiles induced by 17beta-estradiol in ZR-75.1 and MCF-7 cells. The purpose of the present study was to test whether the expression pattern of hormone regulated genes from this set identifies estrogen receptor (ERalpha) positive, hormone responsive BC cells. To this aim, we carried out in silico metanalysis of ERalpha positive and ERalpha negative human BC cell line transcriptomes, focusing on two sets of 171 and 218 estrogen responsive genes, respectively. Results show that estrogen dependent gene activity in hormone responsive BC cells is significantly different from that of non-responsive cells and, alone, allows to discriminate these two cellular phenotypes. Indeed, we have identified 61 genes whose expression profile specifically marks ERalpha positive BC cells, suggesting that this gene set may be exploited for phenotypic characterization of breast tumors. This possibility was tested with data obtained by gene expression profiling of BC surgical samples, where the ERalpha positive phenotypes were highlighted by the expression profile of a subset of 27 such hormone responsive genes and four additional BC marker genes, not including ERs. These results provide direct evidence that the expression pattern of a limited number of estrogen responsive genes can be exploited to assess the estrogen signaling status of BC cells both in vitro and ex-vivo.

Abstract: Previous studies had shown that there is little concern about endometrial cancer risk with hormone replacement therapy (HRT), whereas the risk of ovarian cancer is still debated. A new paper based on the women's health initiative (WHI) study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion that also for endometrial and ovarian cancer risk, as the first WHI publication did for breast cancer risk, the previous large studies have been confirmed. About follow-up the authors conclude that, "The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen." These conclusions deserve a thorough analysis and must be read in the light of the burden of available epidemiological and clinical data and of recommended clinical practice. In the WHI trial the use of continuous combined HRT has resulted in a considerable increase of both imaging and invasive exams, to investigate women with bleeding or spotting, but the findings of these exams have been invariably negative. As far as, all published studies agree on the fact that continuous combined HRT either has no effect or significantly reduces the risk of both endometrial hyperplasia and cancer, there should be no reason to close-watching endometrium of women using this regimen with a different strategy from that employed on any healthy woman.

Abstract: AIMS: Negative sentinel node may predict tumour-free axillary nodes in breast cancer. We report the performance of sentinel node dissection at our Institution.METHODS: We analysed data from 212 consecutive women with primary invasive breast tumours less than 3 cm in diameter and no axillary lymphadenopathy who underwent radioguided sentinel node dissection by means of 99mTc-colloidal albumin between 1999 and 2002. Completion axillary node dissection was performed if sentinel nodes contained metastases or if no sentinel nodes were identified.RESULTS: Sentinel nodes were identified in 207/212 of the patients. Fifty-seven patients had tumour-positive sentinel nodes. Only tumour diameter showed significant association with sentinel node status (p<0.000). Per-operative histologic evaluation had a sensitivity of 67.3% and a negative predictive value of 90.4%. No subset of sentinel node positive patients was identified for whom axillary node dissection could be safely avoided. No recurrences were detected at a median follow-up of 15 months.CONCLUSION: Radioguided sentinel node dissection offers a reliable way to assess nodal status in most breast cancer patients. In our experience, both preoperative lymphoscintigraphy and intraoperative histologic evaluation add useful information to the procedure.

Abstract: During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. OBJECTIVE: The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. METHODS: 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. RESULTS: In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. CONCLUSIONS: The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.

Abstract: BACKGROUND: Biological markers capable of predicting the risk of recurrence and the response to treatment in breast cancer are eagerly awaited. Estrogen and progesterone receptors (ER, PgR) in tumor cells mark cancers that are more likely to respond to endocrine treatment, but up to 40% of such patients do not respond. Here, the expression of a group of estrogen-regulated genes, previously identified by microarray analysis of in vitro models, was measured in breast tumors and possible associations with other clinicopathological variables were investigated. METHODS: The expression of CD24, CD44, HAT-1, BAK-1, G1P3, TIEG, NRP-1 and RXRalpha was measured by quantitative real-time RT-PCR on RNA from eighteen primary breast tumors. Statistical analyses were used to identify correlations among the eight genes and the available clinicopathological data. RESULTS: Variable expression levels of all the genes were observed in all the samples examined. Significant associations of CD24 with tumor size, CD44 with lymph node invasion, and HAT-1 and BAK-1 with ER positivity were found. The possible combinatorial value of these genes was assessed. Unsupervised hierarchical clustering analysis demonstrated that the expression profile of these genes was able to predict ER status with an acceptable approximation. CONCLUSIONS: Eight novel potential markers for breast cancer have been preliminarily characterized. As expected from in vitro data, their expression is able to discriminate ER- versus ER+ tumors.

Abstract: Breast surgery evolves towards always more precise, but less invasive techniques. The halstedian concept of radical surgery has been abandoned and the majority of patients are now allowed to preserve their breasts provided they receive radiation therapy after surgery. In many institutions standard axillary lymph-node dissection is being replaced by the less invasive and probably also more accurate staging technique known as sentinel-node dissection. Nevertheless, the procedure requires interdisciplinary collaboration and rigorous quality control monitoring to provide optimal results. Many issues, some of which will be discussed in the light of our personal experience, still need to be tested in clinical controlled trials.

Abstract: Angiogenic factors produced by tumor cells are essential for tumor growth and metastasis. In our study, the expression of Angiopoietin-1 (ANG1) and Angiopoietin-2 (ANG2) mRNA in archival human breast cancer tumor samples and in 6 breast cancer cell lines was investigated. Total RNA from biopsies of 38 breast cancer patients was extracted and ANG1 and ANG2 mRNA expression was measured by means of quantitative real-time RT-PCR (Taqman). Matching data with available clinicopathologic and biochemical data revealed a significant association between ANG2 expression and axillary lymph node invasion. Univariate and multivariate survival analysis, by means of Kaplan-Meier method and Cox's proportional hazards model, showed significant and independent association between ANG2 mRNA level and both disease-free (p < 0.0001) and overall survival (p < 0.0003). An important fact is that, notwithstanding the small number of cases examined, this association was confirmed also in the group of lymph node-negative patients (DFS, p < 0.003; OS, p < 0.020). Immunohistochemical analysis demonstrated that Ang2 is expressed by both tumor cells and endothelial elements. Expression in tumor cells was confirmed by studying a panel of human breast carcinoma cell lines in culture by RT-PCR. In ZR75.1 and T47D cells, expression of ANG2 mRNA was increased up to 10-fold by treatment with estrogen within 24 hr. Although preliminary, these data suggest a possible role of ANG2 as a prognostic factor for primary breast cancer.

Abstract: BACKGROUND: Many members of the human kallikrein gene family were found to be differentially expressed in various malignancies and some of them are useful diagnostic/prognostic markers. KLK9 is a newly discovered human kallikrein gene that is expressed in several tissues including thymus, spinal cord, testis, prostate, breast, and ovary. Like other kallikreins, the KLK9 gene was found to be regulated by steroid hormones, mainly estrogens and progestins, in cancer cell lines. EXPERIMENTAL DESIGN: We studied the expression of KLK9 by quantitative RT-PCR in 169 breast cancer patients of different stages, grades and histological types. We also compared the relation between KLK9 expression and other clinicopathological variables and patient survival. RESULTS: KLK9 expression is significantly higher in patients with early stage cancers (p = 0.039) and in patients with small tumor size (< 2 cm) (p = 0.028). Kaplan-Meier survival curves demonstrated that KLK9-positive patients have longer disease-free and overall survival (p = 0.015 and 0.036, respectively). Univariate and multivariate analysis also indicates that KLK9 expression is associated with increased disease-free and overall survival. When the Cox proportional hazard regression analysis was applied to subgroups of patients, KLK9 expression was found to be a significant predictor of disease-free survival in the estrogen receptor (ER) and progesterone receptor (PR) negative subgroups of patients (Hazard Ratio 'HR' = 0.28, and 0.38, respectively, and p = 0.011 and 0.028, respectively). After adjusting for other known prognostic variables, KLK9 retained its independent prognostic value in these subgroups of patients. Similar results were obtained for overall survival. CONCLUSIONS: KLK9 is a new potential independent marker of favorable prognosis in breast cancer.

Abstract: Due to the younger age and the ever wider use of adjuvant chemotherapy and antiestrogens, menopausal symptoms are a frequent cause of concern for breast cancer patients. OBJECTIVES: To determine the prevalence of menopausal symptoms, and to explore the attitudes toward Hormone Replacement Therapy (HRT) or other treatments and the willingness to take oestrogen in breast cancer patients. METHODS: A questionnaire-based survey on 250 breast cancer patients treated and followed-up at our department. Of them 144 (Group A) were in postmenopause and 106 (Group B) were in premenopause at time of diagnosis. RESULTS: Adjuvant therapy with tamoxifen or tamoxifen plus chemotherapy is associated with a significant worsening of menopause-related symptoms of women belonging to Group A. These women are more concerned about risk of breast cancer recurrence than about risk of osteoporosis (P=0.05) and heart disease (P=0.006). Seventy-eight percent are against the use of HRT; only 22% would consider taking HRT mainly for vasomotor symptoms relief and osteoporosis prevention. The incidence of vasomotor and dystrophic symptoms is significantly higher in women belonging to Group B treated with chemotherapy and/or hormonotherapy as compared with postmenopausal women (P<0.000 and P=0.02, respectively). Premenopausal women are more concerned about risk of breast cancer recurrence than older women (P=0.09) and at the same time are significantly more worried about the impairment of the quality of life due to adjuvant therapy (P=0.005). Younger women are more prone to consider HRT than postmenopausal women (P=0.05). Sixty-six percent are against HRT use, and 34% would consider taking HRT to alleviate vasomotor and dystrophic symptoms and to prevent osteoporosis. CONCLUSIONS: Breast cancer survivors are interested to treatments that may improve their quality of life, but fear of HRT persists among these women and their doctors, despite new evidence suggesting the low probability of detrimental effects.

Abstract: BACKGROUND: Struma ovarii is a rare disease. Malignant transformation is even rarer. Data about its management are lacking. We describe the first reported case of a malignant struma ovarii treated and staged by laparoscopy. CASE: A 49-year-old patient was operated by laparoscopy for a right ovarian teratoma. The patient did not show symptoms of hyperthyroidism. The ovarian teratoma was removed in a plastic bag and definitive histology showed foci of papillary adenocarcinoma in a struma ovarii. The patient was then staged by laparoscopic surgery undergoing left adnexectomy, multiple peritoneal and omental biopsies, and common iliac and paracaval lymph node sampling. Hysterectomy was not performed. The postoperative course was uneventful and the patient was released on the second day. Thyroglobulin level was monitored and the patient is free of disease after more than 1 year. CONCLUSION: The preoperative diagnosis of malignant struma ovarii is difficult. Even with cautious evaluation of the patient, some risk of wrong diagnosis is possible. This is why a meticulous technique of laparoscopic surgery in removing the ovary is important. Laparoscopic staging may also intervene in very limited cases; the expertise to perform open staging of the patient is necessary but the postoperative course is fast.

Abstract: KLK14 (formerly known as KLK-L6) is a recently identified member of the human kallikrein gene family. This family harbours several genes aberrantly expressed in various cancers as well as established (PSA/hK3, hK2) and potential (hK6, hK10) cancer markers. Similar to other kallikrein genes, KLK14 was found to be regulated by steroid hormones, particularly androgens and progestins, in breast and ovarian cancer cell lines. Preliminary studies indicated that KLK14 is differentially expressed in breast, ovarian, prostatic and testicular tumours. Given the above, we determined the prognostic significance of KLK14 expression in breast cancer. We studied KLK14 expression in 178 histologically confirmed epithelial breast carcinomas by quantitative reverse transcription-polymerase chain reaction and correlated with clinicopathological variables (tumour stage, grade, histotype etc.) and with outcome (disease-free survival and overall survival), monitored over a median of 76 months. KLK14 mRNA levels ranged from 0 to 1,219 arbitrary units in breast cancer tissues, with a mean+/-s.e. of 136+/-22. An optimal cutoff value of 40.5 arbitrary units was selected, to categorise tumours as KLK14-positive or negative. Higher concentrations of KLK14 mRNA were more frequently found in patients with advanced stage (III) disease (P=0.032). No statistically significant association was found between KLK14 and the other clinicopathological variables. KLK14 overexpression was found to be a significant predictor of decreased disease-free survival (hazard ratio of 2.31, P=0.001) and overall survival (hazard ratio of 2.21, P=0.005). Cox multivariate analysis indicated that KLK14 was an independent prognostic indicator of disease-free survival and overall survival. KLK14 also has independent prognostic value in subgroups of patients with a tumour size </=2 cm and positive nodal, oestrogen receptor and progestin receptor status. We conclude that KLK14 expression, as assessed by quantitative reverse transcription-polymerase chain reaction, is an independent marker of unfavourable prognosis for breast cancer.

Abstract: Many kallikrein genes were found to be differentially expressed in various malignancies, and prostate specific antigen (encoded by the KLK3 gene) is the best tumour marker for prostate cancer. Prostate specific antigen has recently been shown to be an independent favourable prognostic marker for breast cancer. KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13.4. KLK15 has 41% similarity to KLK3 and the encoded protein, hK15, can activate pro-prostate specific antigen. We studied the expression of KLK15 by real-time quantitative reverse transcriptase-polymerase chain reaction in 202 tissues from patients with breast carcinoma of various stages, grades and histological types. KLK15 expression was found to be a significant predictor of progression-free survival (hazard ratio of 0.41 and P=0.011) and overall survival (hazard ratio of 0.34 and P=0.009). When all other known confounders were controlled in the multivariate analysis, KLK15 retained its prognostic significance. Higher concentrations of KLK15 mRNA were found more frequently in node negative patients (P=0.042). No association was found between KLK15 expression and any other clinicopathological variable. Further, KLK15 is an independent prognostic factor of progression-free survival and overall survival in the subgroup of patients with lower grade and those with oestrogen receptor and progesterone receptor negative tumours in both univariate and multivariate analysis. KLK15 levels of expression were slightly higher (although not statistically significant) in the oestrogen receptor negative and progesterone receptor negative subgroups of patients. KLK15 is up-regulated by androgens in breast cancer cell lines. Time-course and blocking experiments suggest that this regulation is mediated through the androgen receptor.

Abstract: BACKGROUND: KLK5 is a newly discovered human kallikrein gene. Many kallikrein genes have been found to be differentially expressed in various malignancies, and prostate-specific antigen (PSA; encoded by the KLK3 gene) is the best tumor marker for prostate cancer. Like the genes that encode PSA and other kallikreins, the KLK5 gene was found to be regulated by steroid hormones in the BT-474 breast cancer cell line. METHODS: We studied KLK5 expression in 179 patients with different stages and grades of epithelial breast carcinoma by quantitative reverse transcription-PCR (RT-PCR), using LightCycler((R)) technology. An optimal cutoff point equal to the detection limit (65th percentile) was used. KLK5 values were then compared with other established prognostic factors in terms of disease-free (DFS) and overall survival (OS). RESULTS: High KLK5 expression was found more frequently in pre-/perimenopausal (P = 0.026), node-positive (P = 0.029), and estrogen receptor-negative (P = 0.038) patients. In univariate analysis, KLK5 overexpression was a significant predictor of reduced DFS (P <0.001) and OS (P <0.001). Cox multivariate analysis indicated that KLK5 was an independent prognostic factor for DFS and OS. KLK5 remained an independent prognostic variable in the subgroups of patients with large tumors (>2 cm) and positive nodes. Hazard ratios derived from Cox analysis and related to DFS and OS were 2.48 (P = 0.005) and 2.37 (P = 0.009), respectively, for the node-positive group and 3.03 (P = 0.002) and 2.94 (P = 0.002), respectively, for patients with tumor sizes >2 cm. KLK5 expression was also associated with statistically significantly shorter DFS (P = 0.006) and OS (P = 0.004) in the subgroup of patients with grade I and II tumors. CONCLUSIONS: KLK5 expression as assessed by quantitative RT-PCR is an independent and unfavorable prognostic marker for breast carcinoma.

Abstract: Kallikreins are a group of serine proteases with diverse physiological functions. KLK13 (previously known as KLK-L4) is a novel kallikrein gene located on chromosome 19q13.4 and shares a high degree of homology with other kallikrein family members. Many kallikrein genes were found to be differentially expressed in various malignancies, and their regulation is controlled by steroid hormones in prostate and breast cancer cell lines. We studied the expression of KLK13 by quantitative reverse transcriptase-polymerase chain reaction in 173 patients with epithelial breast carcinoma. An optimal cutoff point equal to the 40th percentile was defined, based on the ability of KLK13 to predict disease-free survival. KLK13 values were then associated with other established prognostic factors and with disease-free survival and overall survival. Higher positivity for KLK13 expression was found in older, oestrogen receptor positive patients. In univariate analysis, KLK13 expression is a significant predictor of improved disease-free survival and overall survival (P<0.001 and P=0.009, respectively). Cox multivariate analysis indicated that KLK13 was an independent prognostic variable in the subgroups of patients with Grade I-II tumours and in patients who were oestrogen receptor and progesterone receptor positive, and node positive. Hazard ratios derived from Cox analysis, related to disease-free survival and overall survival were 0.22 (P=0.001) and 0.24 (P=0.008), respectively, for the Grade I-II group; 0.36 (P=0.008) and 0.44 (P=0.038), respectively, for the node positive group and 0.36 (P=0.008) and 0.18 (P=0.008), respectively, for the oestrogen receptor positive group. The adjusted hazard ratio for progesterone receptor positive patients for disease-free survival was 0.25 (P=0.012). For patients in the node positive and oestrogen receptor positive subgroup (n=51) the adjusted hazard ratio was 0.25 (P=0.006) and for the node positive and progesterone receptor positive subgroup (n=46) the hazard ratio was 0.24 (P=0.008). Taken together, these data suggest that higher KLK13 expression in these subgroups of breast cancer patients is associated with an approximately 55 to 80% reduction in the risk of relapse or death. We conclude that KLK13 expression, as assessed by quantitative reverse transcriptase-polymerase chain reaction, is an independent favourable prognostic marker for breast carcinoma.

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Abstract: PURPOSE OF INVESTIGATION: Surgery and radiotherapy achieved equivalent results for FIGO stages Ib-IIa invasive cervical carcinoma. The integration of radiotherapy and surgery provided the same results for a selected series of patients without increasing the rate of complications. The aim of the study was to verify if, applying a radio-surgical protocol, the reduction of the surgery extension on the parametrium in one of two consecutive series might achieve the same results in terms of survival and recurrence rates with fewer complications. MATERIAL AND METHODS: We analysed actuarial survival (with >10-year follow-up), local control rates and morbidity of 390 patients who had different the kinds of surgery applied in the radio-surgical treatment protocol: Protocol A: brachytherapy plus type III radical hysterectomy vs Protocol B: brachytherapy plus type II radical hysterectomy. Patients were all included in an analysis of complications according to the French-Italian glossary. RESULTS: Analyses showed no differences in terms of survival, patterns of recurrences and onset time within the two protocols. Urinary complications were more frequent and severe in protocol A vs protocol B (G2: 26.5% vs. 6.1%; G3: 5.3% vs. 3.6%). CONCLUSION: Our study pointed out that the reduction of the surgery extension allowed the same overall survival and relapses with fewer complications particularly in terms of grade of severity.

Abstract: BACKGROUND: Hot flashes are frequent in postmenopausal breast cancer patients, especially when treated with tamoxifen. Estrogen replacement therapy is the most effective treatment for hot flashes, but its use is controversial in breast cancer survivors. Progestins may offer a good alternative for the control of hot flashes in this setting; in particular, oral megestrol acetate has been proven effective in a randomized, placebo-controlled clinical trial. With the aim of further improving these results, we have designed a randomized study comparing oral megestrol acetate with depot intramuscular (i.m.) medroxyprogesterone acetate (MPA) for the control of hot flashes in postmenopausal patients with a history of breast cancer. PATIENTS AND METHODS: Seventy-one postmenopausal patients were randomized to receive an i.m. injection of depot MPA 500 mg on days 1, 14 and 28, or oral megestrol acetate 40 mg daily for 6 weeks. Patients recorded daily the number and severity of their hot flashes; response was defined as a > or =50% decrease in the number and severity of hot flashes. RESULTS: At week 6, hot flashes were reduced by 86% on average in the whole group of patients, without significant differences between the two progestins. Response was obtained by 75 and 67% of patients receiving MPA or megestrol, respectively (P = 0.5). Responders were followed to assess maintenance of response (without further treatment), which was significantly better with i.m. MPA: in this group, 89% of responders still showed a benefit at week 24, compared with 45% in the megestrol group (P = 0.03). CONCLUSIONS: Our study shows that a short cycle of i.m. depot MPA injections provides significant and long-lasting relief from postmenopausal hot flashes in patients with a history of breast cancer, offering an alternative to estrogen replacement therapy or prolonged administration of oral megestrol.

Abstract: OBJECTIVES: The purpose of this study was to evaluate the clinical efficacy and tolerability of high-dose (HD) chemotherapy with growth factor support in primary breast cancer with extensive nodal involvement. PATIENTS AND METHODS: Fifty-three patients with ten or more involved nodes were recruited and were given three cycles of standard-dose fluorouracil, epidoxorubicin and cyclophosphamide followed by one single course of high-dose CEP (cyclophosphamide, etoposide and cisplatin). No autologous progenitor support was used. RESULTS: Five-year actuarial disease-free and overall survival were 40 and 60%, respectively. High-dose CEP required a median of 22 days of hospitalization and was associated with grade G3--4 nausea and vomiting in two thirds of the cases. Hematological toxicity was comparable to that of high-dose therapies delivered with autologous progenitor support. No therapy-related mortality was observed. CONCLUSIONS The efficacy of treatment was comparable to the best results of conventional therapy, with only a trend for improved survival. High-dose CEP was feasible with acceptable toxicity. Although this regimen does not require stem cell harvesting and storage, it requires clinical support comparable to autotransplantation procedures and side effects are not so manageable to recommend its use outside specialized units.

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Abstract: Nuclear receptors regulate target gene expression in response to steroid and thyroid hormones, retinoids, vitamin D and other ligands. These ligand-dependent transcription factors function by contacting various nuclear cooperating proteins, called coactivators and corepressors, which mediate local chromatin remodeling as well as communication with the basal transcriptional apparatus. Nuclear receptors and their coregulatory proteins play a role in cancer and other diseases, one leading example being the estrogen receptor pathway in breast cancer. Coregulators are often present in limiting amounts in cell nuclei and modifications of their level of expression and/or structure lead to alterations in nuclear receptor functioning, which may be as pronounced as a complete inversion of signaling, i.e. from stimulating to repressing certain genes in response to an identical stimulus. In addition, hemizygous knock-out of certain coactivator genes has been demonstrated to produce cancer-prone phenotypes in mice. Thus, assessment of coactivator and corepressor expression and structure in tumors may turn out to be essential to determine the role of nuclear receptors in cancer and to predict prognosis and response to therapy.

Abstract: PURPOSE: To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor-positive patients with early breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m(2) orally days 1 to 14, methotrexate 40 mg/m(2) intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points. RESULTS: Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable. CONCLUSION: The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.

Abstract: Raloxifene is a selective oestrogen receptor modulator (SERM) that has anti-oestrogenic effects on breast and endometrial tissue and oestrogenic actions on bone, lipid metabolism and blood clotting. In postmenopausal women raloxifene decreases bone turnover and increases bone mineral density, reducing the incidence of vertebral fractures. Unlike tamoxifen, raloxifene does not cause endometrial hyperplasia or cancer, as demonstrated by endometrial monitoring with ultrasonography and biopsy during treatment. Evidence suggests that raloxifene lowers total low-density lipoprotein cholesterol levels behaving like oestrogens, but does not increase high-density lipoprotein cholesterol levels. In randomised clinical trials on postmenopausal women with osteoporosis, raloxifene reduced the risk of newly diagnosed ER-positive invasive breast cancer by 76% during a median of 40 months of treatment. However, raloxifene does not alleviate early menopausal symptoms, such as hot flushes and urogenital atrophy, and may even exacerbate some of them. In conclusion, raloxifene may be an alternative for the prevention of long-term effects of oestrogen deficiency (osteoporosis and heart diseases) in women with previous breast cancer not having hot flushes. For symptomatic patients, the association of raloxifene with different drugs which have demonstrated efficacy in the control of vasomotor symptoms is now under evaluation.

Abstract: A national collaborative group has conducted a multicenter prospective study on the use of a specific glossary for the complications associated with the treatment of cervical cancer, which were analytically described in 1989. This report analyzes the urologic complications with particular reference to radical surgery in stage IB-IIA cancer cases. In the prospective multicenter clinical study 2024 patients with frankly invasive cervical cancer were enrolled (IB = 1041; IIA = 308; IIB = 384; IIIA-B = 237; IV = 54). This report considers 1349 patients with stage IB-IIA disease. Treatment modalities in this group of patients were: type III radical surgery in 21.9%; type III radical surgery followed by radiotherapy in 20.8%; type III radical surgery preceded by radiotherapy in 7.3%; type II radical surgery in 3.1%; type II radical surgery followed by radiotherapy in 8.4%; type II radical surgery preceded by radiotherapy in 18.8%; surgery plus chemotherapy plus radiotherapy in 3.5%; radiotherapy alone in 16%. In this case series 873 complications were registered, and among these 341 (39.1%) were described in the urinary tract. Among 277 bladder complications 47.3% were grade 1; 47.3% grade 2, and 5.4% grade 3. Among 64 ureter complications 59.4% were grade 1; 17.2% grade 2, and 23.4% grade 3. Distribution of severe urinary complications was different according to site (bladder or ureter) and treatment modalities (radical surgery alone: bladder 1.3%, ureter 1.3%; radical surgery followed by radiotherapy: 1.4% bladder, 2.8% ureter; radical surgery preceded by radiotherapy: 3% bladder, 0% ureter). Different distributions of severe urinary complication were also observed in respect to stage (IB vs IIA); treatment: elective vs nonelective. In 673 patients treated with radical surgery plus or minus radiotherapy 123 relapses were registered (18.2%). Incidence of relapse was not different in patients suffering from mild/severe complications vs patients without complications. Disease-free survival, death from tumor, and death from other causes were not different in the group with complications in comparison to the group without complications.

Abstract: Prostate-specific antigen (PSA) is a serine protease expressed at high levels in prostate epithelium, and elevated PSA in serum is a well-established marker of prostate cancer. Recently, the relative proportions of free PSA and PSA complexed to the serine protease inhibitor alpha 1-antichymotrypsin have become important variables in distinguishing between prostate cancer and benign prostatic hyperplasia. Numerous studies have demonstrated the production of PSA in female tissues such as the breast, and low levels of PSA are present in female sera. The objective of this study was to measure and compare the relative proportions of free PSA and PSA complexed to the serine protease inhibitor alpha 1-antichymotrypsin in the serum of women with breast cancer or benign breast disease or women with no known malignancies. PSA was measured with an established immunoassay for total PSA and a novel immunoassay for free PSA, both of which had a detection limit of 0.001 microgram/liter (1 ng/liter). The percentage of breast cancer patients with free PSA as the predominant molecular form (> 50% of total PSA) in serum was five times higher than that of healthy women or women with benign breast disease, and PSA decreased in the serum of breast cancer patients after surgery. The diagnostic use of free PSA for breast cancer is limited at this point, due to the low diagnostic sensitivity (approximately 20%); however, free PSA as the predominant molecular form shows a high diagnostic specificity (approximately 96%) in comparison to women free of breast cancer or with benign breast disease. These results suggest that the clinical applicability of free PSA for breast cancer diagnosis and the biological mechanism behind its increase should be further investigated.

Abstract: DNA chips are small, solid supports such as microscope slides onto which thousands of cDNAs or oligonucleotides are arrayed, representing known genes or simply EST clones, or covering the entire sequence of a gene with all its possible mutations. Fluorescently labeled DNA or RNA extracted from tissues is hybridized to the array. Laser scanning of the chip permits quantitative evaluation of each individual complementary sequence present in the sample. DNA chip technology is currently being proposed for qualitative and quantitative applications, firstly for the detection of point mutations, small deletions and insertions in genes involved in human diseases or affected during cancer progression; secondly, to determine on a genome-wide basis the pattern of gene expression in tumors, as well as in a number of experimental situations. The extraordinary power of DNA chips will have a strong impact on medicine in the near future, both in the molecular characterization of tumors and genetic diseases and in drug discovery and evaluation. Quantitative applications will soon spread through all fields of biology.

Abstract: AIM OF THE STUDY: Validation of the sentinel node (SN) technique in breast cancer by means of lymphoscintigraphy. MATERIALS AND METHODS: From December 1996 to January 1999 102 T1-T2 breast carcinoma cases were recruited in Turin. 99mTc-human serum albumin colloids were injected subdermally the day before surgery (mean activity, 5.2 +/- 2.5 MBq). Scintigraphic imaging was performed after injection. After identification of the SN during surgery by a hand-held gamma probe, the SN was excised and sent for histologic examination. SN histology was compared with that of other axillary nodes. RESULTS: The SN detection rate was 86.3%; among 88 cases with an identified SN, 37 (42%) had axillary metastases; the SN was metastatic in 35 cases (sensitivity, 94.6%); in 51.3% of pN+ cases (19/37) the SN was the only metastatic site. In two of the 53 negative SNs, SN histology did not match with that of the remaining axilla (negative predictive value, 96.2%; staging accuracy, 97.7%). CONCLUSIONS: Our results agree with those reported in the literature; however, except in clinical trials and experienced structures axillary lymph node dissection should not be abandoned when mandatory for prognostic purposes, considering that at present SN biopsy alone is not completely accurate for axillary staging, especially in the absence of an adequate learning period.

Abstract: Sex Hormone-Binding Globulin (SHBG), the plasma carrier for androgens and estradiol, inhibits the estradiol-induced proliferation of breast cancer cells through its membrane receptor, cAMP, and PKA. In addition, the SHBG membrane receptor is preferentially expressed in estrogen-dependent (ER+/PR+) breast cancers which are also characterized by a lower proliferative rate than tumors negative for the SHBG receptor. A variant SHBG with a point mutation in exon 8, causing an aminoacid substitution (Asp 327-->Asn) and thus, the introduction of an additional N-glycosylation site, has been reported. In this work, the distribution of the SHBG variant was studied in 255 breast cancer patients, 32 benign mammary disease patients, and 120 healthy women. The presence of the SHBG mutation was evaluated with PCR amplification of SHBG exon 8 and Hinf I restriction fragment length polymorphism (RFLP) procedure. This technique allowed us to identify 54 SHBG variants (53 W/v and 1 v/v) in breast cancer patients (21.2%), 5 variants (4 W/v and 1 v/v) in benign mammary disease patients (15.6%), and 14 variants (W/v) in the control group (11.6%). The results of PCR and RFLP were confirmed both by nucleotide sequence of SHBG exon 8 and western blot of the plasma SHBG. No differences in the mean plasma level of the protein were observed in the three populations. The frequency of the SHBG variant was significantly higher in ER+/PR+ tumors and in tumors diagnosed in patients over 50 years of age than in the control group. This observation suggests the existence of a close link between the estrogen-dependence of breast cancer and the additionally glycosylated SHBG, further supporting a critical role of the protein in the neoplasm.

Abstract: The demand for hormone replacement therapy (HRT) by women who enter the menopause is rapidly increasing in all developed countries. The concern that HRT may enhance morbidity and mortality from malignant diseases still limits the widespread adoption of hormonal treatments. Overall, epidemiological data on cancer incidence and HRT are reassuring, although long-term or inappropriate therapies may slightly increase the risk of developing malignant diseases. Many commercial hormonal compounds are currently available and the safest HRT regimen with regard to cancer risk must be identified. It is equally important that the best strategies for breast and endometrial surveillance in women commencing HRT be outlined, bearing in mind that the diffusion of hormonal therapies may be halted by unnecessary medical interventions.

Abstract: The aim of this study was to determine the concentration and to evaluate the prognostic value of pepsinogen C (PepC) in breast cancer patients. PepC is an aspartic proteinase that is involved in the digestion of proteins in the stomach and is also synthesized by a subset of human breast tumors. PepC concentrations were measured with a highly sensitive immunofluorometric assay, which uses two monoclonal antibodies that are specific for PepC and has a detection limit of 0.1 ng/ml. Breast tumor cytosols from 151 patients (median follow-up, 67 months), stratified according to nodal status, were evaluated. An optimal cutoff value, equal to 1.75 ng/mg of extracted protein, was first defined by statistical analysis. PepC status was then compared with other established prognostic factors, in terms of disease-free survival (DFS) and overall survival (OS). High PepC concentrations were found in small (P = 0.003) and well-differentiated tumors (P = 0.042) as well as in stage I (P = 0.003) and node-negative patients (P = 0.040). Statistically significant associations of PepC concentration with patient age and estrogen receptor and progesterone receptor status were not observed. In univariate Cox regression analysis of the entire cohort of patients, negative PepC proved to be a significant predictor of reduced DFS (P = 0.0086) and OS (P = 0.025). Multivariate analysis in subgroups of patients defined by nodal status indicated that PepC status was a strong predictor of DFS (P = 0.0039) and the strongest factor for predicting OS (P = 0.0046) in node-positive but not in node-negative patients. Our results suggest that PepC may be used as an independent favorable prognostic factor in node-positive breast cancer patients because there were no significant associations between PepC and the other prognostic factors evaluated in this group of patients.

Abstract: Epidemiological and biological data on HRT and breast cancer risk are reviewed. Some aspects deserve consideration. (1) The majority of epidemiological data have been gathered from populations where high estrogen doses (> or = 1.25 mg daily of conjugated estrogens) were used as first line therapy. (2) HRT does not increase the risk in overweight women, even in the series in which a risk increase (in longterm users) is found. This could be as a result of the fact that oral estrogens, through their metabolic and hepatocellular effects, reverse some biological features of obesity (e.g. increased insulin-like growth factor I activity and decreased sex hormone binding globulin level) which potentially increase breast cancer risk, so balancing the estrogen stimulation. (3) The progestin addition seems to increase the risk when the 19 nor-testosterone derivatives are used. These androgenic compounds contrast the metabolic and hepatocellular effects of oral estrogens. To sum up, the possibility does exist that even the longterm use of oral estrogens at the right ('low') dose, with the addition of a non-androgenic progestin, will be shown to be associated with a very limited breast cancer risk increase.

Abstract: Available epidemiologic data suggest the possibility that the use of oral conjugated equine estrogens (CEE) 0.625 mg/day as a first-choice dose could be associated with a very limited (if any) breast cancer risk increase. Some biological peculiarities of oral CEE back the possibility of a limited detrimental effect on breast tissue, due to either direct or indirect actions. Direct actions. Some experimental findings suggest that the 17 alpha-dihydroderivatives of equilenin and equilin (15% of the CEE components) have a non-estrogenic or even an anti-estrogenic effect on breast tissue. This could partially counterbalance the stimulatory action of the other CEE components. Indirect actions. Oral estrogens, through their metabolic and hepatocellular effects (emphasized by the first liver passage) cause a sharp increase in sex hormone binding globulin (SHBG) level which is followed by a lower quantity of both estrogen and androgen in the free, bioavailable, form. More importantly, they cause a decrease in circulating insulin-like growth factor I (IGF-I) activity, due to both a reduction in IGF-I synthesis by the liver and an increase in IGF-binding protein-1 level. A strong relationship between breast cancer risk and the concentration of circulating IGF-I in premenopausal women has been recently found. Actually, estrogens and IGF-I have a synergistic effect on cell proliferation, and IGF-I is necessary for maximum estrogen-receptor activation in breast cancer cell lines. The possibility does exist that the SHBG level increase and the IGF-I bioavailability decrease, caused by oral CEE, balance the increased estrogen stimulation on breast tissue.

Abstract: OBJECTIVE: To ascertain whether the frequency of pelvic pain recurrence is reduced and time to symptoms recurrence is prolonged in women with symptomatic endometriosis undergoing conservative surgery and post-operative hormonal therapy compared with women treated with surgery only. Pregnancy rates and time to conception in women wanting children were also evaluated. DESIGN: A multicentre, prospective, randomised controlled study. SETTING: Nineteen Italian academic departments and teaching hospitals specialising in reparative and reconstructive surgery. POPULATION: A total of 269 women undergoing conservative surgery for mild to severe symptomatic endometriosis. METHODS: After surgery the women were assigned to treatment with subcutaneous goserelin depot injections for six months or to expectant management. Dysmenorrhoea, deep dyspareunia, nonmenstrual pain and general discomfort were graded according to a verbal rating scale from 0 (absent) to 3 (severe) and the scores summed to give a total symptoms score. Only patients with at least one preoperative moderate or severe symptom were enrolled. The women were evaluated regularly for two years. MAIN OUTCOME MEASURES: Post-operative pain recurrences (total symptoms scores > or = 5), time to recurrence, pregnancy rates and time to conception in the two study groups. RESULTS: At one- and two-year follow up visits, 14/107 (13.1%) and 19/81 (23.5%) patients had moderate or severe symptoms recurrence in the goserelin group compared with, respectively, 22/103 (21.4%) and 27/74 (36.5%) in the expectant management group (P = 0.143 at 1 year and 0.082 at 2 years). Time to symptoms recurrence was significantly longer in the goserelin group according to survival analysis (Wilcoxon test, P = 0.041). Among women wanting children, few conceptions occurred in both the goserelin (8/69, 11.6%) and the expectant management group (14/76, 18.4%). There was no significant difference at survival analysis (Wilcoxon test, P = 0.427). CONCLUSION: Post-operative treatment with goserelin significantly prolonged the pain-free interval after conservative surgery for symptomatic endometriosis and did not influence reproductive prognosis.

Abstract: The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast cancer patients. This study also included an arm combining tamoxifen with chemotherapy. Fifteen-year results showed no difference between tamoxifen and tamoxifen plus chemotherapy, while both treatments were significantly superior to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244 pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2 years of goserelin) to six CMF cycles. No difference has emerged so far between the tamoxifen and CMF arms at a median follow-up time of 62 months. Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment and then to be randomly allocated to further 2 years of tamoxifen or to 2 years of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been entered, 375 of whom have been randomized to tamoxifen (n = 188) or aminoglutethimide (n = 187). Preliminary results (median follow-up time 32 months) show no major difference in patients' outcome. A new trial (ITA trial) with a similar design but employing anastrozole in place of aminoglutethimide has been activated in 1998. The GROCTA 03 study investigated the potential superiority of alternating adjuvant chemotherapy over standard CMF. This study, which included 107 node-positive ER-negative pre-menopausal women, was prematurely closed because more patients allocated to the triple alternated chemotherapy appeared to have relapsed and died at the first interim analysis. The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial which included 53 patients with ten or more involved nodes and a maximum age of 55 years. These patients were scheduled to receive three standard CEF cycles followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2; cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program proved to be feasible but was not superior to CMF-based chemotherapy we had previously employed in a comparable group of patients in previous GROCTA trials. These findings prompted us to explore new HDC programmes with the use of peripheral stem cell support and in addition the possible value of new drugs such as Taxol and vinorelbine. New-generation trials will also explore the value of new prognostic indicators such as tumor proliferative activity, which are prospectively used to allocate patients to different treatment options.

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Abstract: Constitutive activation of the RON gene, known to code for the tyrosine-kinase receptor for Macrophage Stimulating Protein (also known as Scatter Factor 2), has been shown to induce invasive-metastatic phenotype in vitro. As yet, nothing is known about the expression of this novel member of the MET-oncogene family in spontaneously occurring human cancers. Here we report that Ron is expressed at abnormally high levels in about 50% primary breast carcinomas (35/74 patients). Among these, the expression is increased more than 20-fold in 12 cases and the overexpressed protein is constitutively phosphorylated on tyrosine residues. Notably, Ron is only barely detectable in epithelial cells of the mammary gland, and its expression remains unchanged in benign breast lesions (including adenomas and papillomas). Overexpression was observed in different histotypic variants of carcinomas; it is associated with the disease at any stage and correlates with the post-menopausal status. In breast carcinoma cells grown in vitro, activation of the Ron receptor resulted in proliferation, migration and invasion through reconstituted basement membranes. Altogether, these data suggest a role for the RON gene in progression of human breast carcinomas to the invasive-metastatic phenotype.

Abstract: The objective of this study was to determine the influence of transdermal estradiol administration on insulin-like growth factor I (IGF-I) serum level in a series larger than those published to date. Thirty-nine postmenopausal women with vasomotor symptoms were studied; blood samples (after overnight fast) were obtained just before and at the 6th month of treatment with transdermal estradiol 0.05 mg/day, and serum levels of IGF-I, growth hormone and sex hormone binding globulin (SHBG) were evaluated. Sixteen of the 39 women did not show variations of IGF-I values (group A), while 11 showed an increase (group B) and 12 showed a decrease (group C) by at least 20% with transdermal estradiol treatment. IGF-I basal levels were higher in group C as compared to group A (p < 0.05) and to group B (p < 0.01), intermediate in group A, and lower in group B. Group C showed a significant increase of SHBG values with transdermal estradiol treatment. Transdermal estradiol seems to induce a bimodal effect on IGF-I serum levels, depending on IGF-I basal values. This could be caused by a different responsivity to estrogen action on the liver (the major site of circulating IGF-I production) and also, possibly, by a different degree in insulin sensitivity changes caused by estrogen.

Abstract: The prognostic value of p53 protein accumulation in breast cancer, especially as detected by methods other than immunohistochemistry, has not been established unequivocally. A sensitive immunofluorometric assay of p53 protein employing DO-1 and CM-1 antibodies was used in this study to assay extracts of 171 breast carcinomas from northern Italy. p53 over-expression, demonstrated in 36 (21%) tumours, was associated with lack of oestrogen receptor (ER) expression but was not related to patient age, stage, lymph node status, tumour size, histologic type, grade or progesterone receptor (PR) expression status in contingency tables. An increased risk for cancer relapse of p53-positive patients compared to p53-negative patients was determined using multivariate Cox regression analysis, which also showed that p53 protein over-expression was an independent predictor of reduced disease-free survival in node-positive and ER+ patients but not in node-negative or ER- individuals. The equivalent analysis for assessing the impact of p53 status on overall survival was not statistically significant, possibly reflecting the short patient follow-up. Our results suggest that an immunoassay of p53 protein, applicable to cytosolic extracts prepared for steroid hormone receptor analyses, may provide information for breast cancer prognosis.

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Abstract: There is still no clear account on the role that progestins play in human breast cancer, and the issue continues to be debated. The effects of progestins on breast cell proliferation have been investigated in a number of different experimental systems with conflicting results. Progesterone has been reported to both stimulate and inhibit the growth of experimental mammary tumors, depending upon the dose and the experimental models. Epidemiological studies on the effect of combined hormone replacement therapy (HRT) on breast cancer risk in menopausal women are limited because the use of a progestin in addition to estrogens was not widely adopted until 10 years ago. Taking meta-analysis into account estrogen-progestin use did conclude that there is not an excess risk in combined HRT users. Epidemiological studies have provided conflicting results, ranging from a protective effect to a deleterious effect of progestin addition on breast cancer risk. Progestins include a large family of molecules characterised by different binding capacities to androgen receptors. This implies that they should be considered as distinct yet related, therapeutic agents. The use of different progestins may account for the controversial results obtained in studies conducted in different geographic areas.

Abstract: The efficacy and tolerability of granisetron in the management of acute and delayed emesis was compared with that of a multiple antiemetic drug combination regimen, including metoclopramide, dexamethasone, lorazepam and orphenadrine. The trial was a randomized, cross-over study involving 111 patients with gynecological cancers undergoing chemotherapy with cisplatin. Granisetron was significantly more effective than the combination regimen during the first 24 h after chemotherapy; complete response, rates were 67 and 48%, respectively (p = 0.002). There was a significant reduction in the effectiveness of the combination during the second treatment cycle, compared with the first. In contrast, the efficacy of granisetron did not differ between the two cycles. The response rate during the 6 days after chemotherapy was 40.8% in both groups. At the end of the study, 55% of patients preferred granisetron and 23% preferred the combination (p < 0.001). Granisetron was well tolerated. The principal adverse event was headache, which was reported in 7% of patients. The results of this study confirm that granisetron is effective in the treatment of cisplatin-induced nausea and vomiting during the 24 h after chemotherapy.

Abstract: A multicentric randomized trial was performed in premenopausal women with node-positive, estrogen-receptor-negative breast tumors to assess the potential superiority of alternating adjuvant chemotherapy over 'standard' CMF chemotherapy. Between January 1989 and June 1992, 107 patients were entered into the study and randomly allocated to receive either cyclophosphamide 100 mg/m2 per as on days 1-14, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously (i.v.) on days 1, 8 (CMF), every 4 weeks for a total of 6 cycles, or the following regimens: CMF as previously; epidoxorubicin 75 mg/m2 i.v. on day 1 and vincristine 0.75 mg/m2 i.v. on days 1, 8 (EV); mitomycin-C 10 mg/m2 i.v. on day 1 and vindesine 2 mg/m2 i.v. on days 1, 8 (MVs). The three regimens were given every 4 weeks for a total of 6 cycles according to the following schedule: CMF, EV, MVs, CMF, EV, MVs. At a median follow up of 48 months (range 30-72), 40 patients have relapsed and 17 have died overall. More patients in the triple-combination arm have relapsed and more have died, the latter difference tending toward statistical significance (p = 0.06). There was no statistical difference in the site of relapse between the two groups. Total duration of adjuvant therapy was similar in the two arms (312 chemotherapy cycles in the triple arm and 308 in the CMF arm). Treatment toxicity was also comparable, although more patients in the triple-combination arm were still regularly menstruating 6 months after the completion of chemotherapy. This study failed to show any advantage ensuing from the use of alternating chemotherapy in patients with early breast cancer.

Abstract: The aim of this work was to evaluate transvaginal sonography (TVS) in the study of tubal patency as part of the investigation of female infertility. Fifteen women underwent tubal patency by ultrasonography while air and saline solution were instilled into the uterus to provide positive contrast. In three cases of TVS detection of tubal obstruction the findings were compared with hysterosalpingography, which confirmed the presence of the occlusion. In one case the exam was suspended for the excessive pelvic pain of the patient. In one patient TVS tubal control was impossible for the presence of large multiple uterine myomas. Transvaginal sonography with the use of a simultaneous intrauterine saline infusion offers certain advantages over hysterosalpingography, such as the elimination of iodinated contrast and ionizing radiation. TVS provides complete examination of the entire pelvis, thus delineating uterine and ovarian abnormalities, and it is more convenient and less expensive. It should be performed by an experience sonographist with standard sonographic equipment. In conclusion, tubal patency can be performed as an outpatient procedure in the routine infertility clinic.

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Abstract: BACKGROUND: Tissue Polypeptide-specific Antigen (TPS) and CA 15.3 are two of the most widely studied tumor markers in the serum of breast cancer patients. TPS is a tumor associated proliferative marker which belongs to the cytoskeleton. CA 15.3 is a high molecular weight glycoprotein of clinical relevance in the monitoring of treatment and the detection of recurrence in breast cancer patients. PATIENTS AND METHODS: Serum values of TPS and CA 15.3 were measured in a prospective series of patients with primary breast cancer (n=267) and benign breast disease (n=46). The cut-off levels (95% specificity) determined for each test were 80 U/I for TPS and 30 k/U/l for CA 15.3. RESULTS: The diagnostic sensitivity was 0.31 for TPS and 0.32 for CA 15.3 for the detection of breast cancer. Serum TPS levels in breast cancer patients showed a relatively low positivity rate (33%), which was comparable with that of CA 15.3. Higher concentrations of TPS were found in cases with locally more advanced disease as well as in G3 tumors. By contrast, CA 15.3 basal levels were solely related to tumor size and nodal involvement. TPS and CA 15.3 levels were not related to estrogen and progesterone receptor status, peritumoral vessel invasion, multifocality and the in situ component of the tumor. After primary treatment, 20 patients developed distant metastases. In metastatic breast cancer patients TPS was more frequently and more markedly elevated than CA 15.3. In progressive disease, elevated values of TPS and CA 15.3 were found in 85% and 50%, respectively. The mean lead time was 10 months for TPS and 14 months for CA 15.3. Increasing values of TPS were independent of the site of metastasis, whereas elevated levels of CA 15.3 were mainly related to visceral metastasis. Local recurrences were usually associated with low levels of TPS and CA 15.3. By contrast, elevated values of TPS in locally recurred cases indicated rapidly progressive disease. CONCLUSIONS: Our study indicates that TPS and CA 15.3 are not helpful in distinguishing patients with breast cancer from patients with benign breast lesions. Nevertheless, at the time of diagnosis increased serum levels of the markers may facilitate the selection of high risk patients for whom additional treatment and careful follow up studies should be undertaken. Furthermore, TPS seems to be a reliable tumor marker for the early diagnosis of metastatic breast carcinoma independent of the site of metastasis, while increasing values of CA 15.3 are mainly related to visceral involvement.

Abstract: Creatinine kinase BB (CK-BB) is elevated in many tumours including those of the breast. We have recently described a new, highly sensitive and specific method for measuring CK-BB, based on monoclonal antibodies and time-resolved fluorometry. Using this method, we quantitated CK-BB in 172 breast tumour cytosols and examined the associations between CK-BB and other clinicopathological variables and patient survival. High CK-BB levels were seen more frequently in tumours from patients who were younger (age < 50 years), patients who qualified for chemotherapy and patients with oestrogen receptor-positive tumours. No association was seen between CK-BB and tumour stage, grade, size, histological type or the progesterone receptor. In univariate analysis, the risk of relapse or death was higher in the group with tumours containing high CK-BB levels but the difference did not reach statistical significance. In multivariate analysis, the risk of death was statistically significantly higher in the high-CK-BB group. Analysis of subsets of patients revealed that patients with oestrogen receptor-negative cancer have higher risk of death if their tumours contain high levels of CK-BB. Our data suggest that, in general, CK-BB is associated with more aggressive tumours but its value as a prognostic indicator is limited. CK-BB content of breast tumours may be more useful as an aid in selecting therapy directed at inhibiting this enzyme activity and thus depriving tumour cells of their energy source.

Abstract: Tubal patency testing by transvaginal sonography has been implemented in our infertility clinic since 1991. We report our experience with this technique during the last year of routine outpatient activity. A total of 154 infertile patients, including three patients on two occasions, underwent tubal patency testing by transvaginal sonography; 36 also underwent laparoscopy or hysterosalpingography, with a further three undergoing both. A detailed account of the method used to visualize the passage of air and saline through the salpinx is described. The 'gold standard' for tubal patency was laparoscopy. In any cases that were doubtful or if there was tubal occlusion, laparoscopy was advised. The diagnoses by transvaginal sonography in the 154 patients consisted of: 106 with bilateral tubal patency (68.8%), 34 with unilateral tubal occlusions (22.1%), and 13 with bilateral occlusion (8.4%); one case was undiagnosed. Tubal disease was present in 25 out of the 36 (69.4%) patients undergoing laparoscopy or hysterosalpingography (69.4%). The sensitivity, specificity, accuracy, positive and negative predictive values were respectively 80, 85, 82.7, 85 and 80% for the 29 patients undergoing transvaginal sonography and laparoscopy. When the number of tubes examined was considered, these values were respectively 85, 91.6, 89.3, 85 and 91.6%. No discordance was observed in the ten patients undergoing hysterosalpingography. Demonstration of the tubal course relies on a positive contrast medium filling the tubal lumen. Air and saline were successful for this purpose. In our study, the results of tubal patency testing by transvaginal sonography were very similar to those of hysterosalpingography, but differed in about 10% of the cases from those of laparoscopy. The most difficult problem to rule out was distal tubal occlusion without hydrosalpinx. Tubal patency testing by transvaginal sonography can be used safely as a first-step examination of tubal patency. Easy tubal passage can allow medical treatment, while a doubtful or frankly occluded salpinx should be investigated by laparoscopy.

Abstract: The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

Abstract: Prostate specific antigen (PSA) is a tumor marker used widely for the diagnosis and monitoring of prostatic adenocarcinoma. Recently, we provided evidence that PSA may also be produced by breast tumors. In this report we examined quantitatively the PSA levels in 199 breast tumors, 48 tissues with benign breast disease (BBD, 34 fibroadenomas), and 36 normal breast tissues. Significant amounts of PSA (> or = 0.030 ng of PSA per mg of total protein) were found in 28% of breast tumors, 65% of BBD tissues, and 33% of normal breast tissues. PSA positivity in breast tumors was highest in stage I disease (34%) and decreased with disease stage (24% in stage II and 18% in stage III-IV). Using polymerase chain reaction amplification we have shown PSA mRNA presence in patients with PSA protein-positive tissues (benign and malignant) but not in patients with PSA protein-negative tissues. Our data suggest that PSA is expressed frequently by normal breast tissue, by tissue of benign breast diseases, and by breast cancer tissue. Highest expression is seen in benign breast disease and lowest expression in advanced stage cancerous tissue. As PSA production is mediated by steroid hormones and their receptors, we propose that PSA may be a new marker of steroid hormone action in the normal or diseased female breast. The role of this enzyme in the development of breast diseases including breast cancer is currently unknown.

Abstract: Prostate-specific antigen (PSA) is thought to be produced exclusively by prostatic epithelial cells and is currently used as a tumor marker of prostatic adenocarcinoma. We recently found that 30% of breast cancers contain PSA immunoreactivity (IR-PSA). To examine the prognostic value of PSA in female breast cancer, we measured IR-PSA in tumor cytosols of 174 breast cancer patients and classified the breast cancers as either PSA positive or PSA negative based on an IR-PSA cutoff level of 0.03 ng/mg. IR-PSA was present in 27% of the patients. IR-PSA presence was associated with early disease stage, small tumors, and estrogen receptor-positive tumors. We used the Cox proportional hazards regression model to analyze survival of patients in association with PSA status and found that patients with IR-PSA-positive tumors had a reduced risk for relapse and death in univariate analysis (P = 0.02 and 0.06, respectively) and a reduced risk for relapse in multivariate analysis (P = 0.03). Further analysis indicated that the effect of IR-PSA on relapse-free survival was evident in node-positive or estrogen receptor-negative patients. Our study suggests that IR-PSA is an independent favorable prognostic marker for breast cancer and may be used to identify a subgroup of estrogen receptor-negative and/or node-positive patients who have good prognoses.

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Abstract: Epithelial ovarian cancer probably occurs due to activation of several different combinations of genes, which produce cancers that vary biologically and clinically. We tested this hypothesis in 100 consecutive ovarian carcinomas by molecular biology techniques at the DNA and protein levels in three genes (erbB-2, myc, ras), which are frequently altered in this tumor system. Abnormally high expression of erbB-2 gene encoded p185 protein was observed in 31% of the samples, while erbB-2 gene amplification was detected by Southern analysis in 8%. ErbB-2 abnormal gene expression did not significantly affect the clinical outcome of patients, conferring a marginal worsening of survival. In 25 out of 96 (26%) tumor samples there was myc amplification. Higher levels of the ras-encoded p21 protein than in normal ovaries and benign ovarian tumors were found in 45% of the samples. Simultaneous overexpression of p185 and p21 was associated with shorter disease free (p = 0.02) and overall survival (p = 0.04) at significance levels notably higher than those observed for these oncoproteins singly. In addition, survival of patients with myc amplification and high p185/p21 coexpression was significantly worse (p < 0.05) than that of patients with normal levels. Our data suggest that concurrent abnormal gene expression may act synergistically to endow ovarian tumor cells with a highly aggressive phenotype. Evaluation of these genes may be helpful in the biological characterization of ovarian cancer and in defining individual patient prognosis.

Abstract: BACKGROUND. It has been shown that the p53 gene is mutated in 30-80% of ovarian carcinomas and that the genetic alterations most often manifest as an accumulation of mutant p53 protein in tumor tissue. The prognostic significance of these findings for patients with ovarian cancer, however, must be established clearly. METHODS. Mutant p53 protein in 90 consecutive epithelial ovarian carcinomas was quantitatively analyzed using a time-resolved immunofluorometric procedure. In contrast to immunohistochemical techniques, this method uses two anti-p53 antibodies. The Cox model was used to evaluate the strength of the associations between the prognostic markers and disease relapse or death at univariate and multivariate levels. Kaplan-Meier survival curves were calculated for patients who were p53-positive or negative and for subgroups with a different clinical stage, histologic grade, or residual postsurgical tumor. RESULTS. The positivity rates for p53 included 1/21 (5%) with Stage I disease, 1/6 (17%) with Stage II, 29/51 (57%) with Stage III, and 8/12 (67%) with Stage IV (total = 39/90, 43%). Patients with p53-negative tumors had a significantly longer disease free survival than did patients with p53-positive tumors (P = 0.03); these results were similar for overall survival (P = 0.06). Multivariate analysis revealed that the presence of postsurgical residual tumor was the only predictor significantly associated with poor patient outcome. However, when patients were divided into groups based on histologic grade, patients with well (G1) and moderately (G2) differentiated tumors had a significantly higher risk of cancer relapse and death if mutant p53 protein was present in their tumors compared with patients who were negative for mutant p53 protein (< 0.01). CONCLUSIONS: The immunofluorometric measurement of mutant p53 protein accumulation in epithelial ovarian carcinomas of a low histologic grade was associated significantly with an increased risk for cancer relapse and death. A similar trend also was suggested for early stage disease and in the absence of residual tumor after surgery. These increased risks, however, were not found for patients with high grade or advanced stage cancer or for those with residual tumor. To the authors' knowledge, this is the first report suggesting that p53 tumor protein accumulation is a marker of poor prognosis in a subset of patients with ovarian cancer.

Abstract: Unlike parenteral estrogens, oral estrogen administration in menopause causes, through its hepatocellular action, a significant decrease of circulating insulin-like growth factor I (IGF-I) levels; this effect is opposed by the addition of an androgenic progestogen. In vitro studies show that IGF-I is a potent mitogen for 'estrogen responsive' breast cancer cells. Moreover, some findings in breast cancer patients and in women treated with tamoxifen suggest that reduction of circulating IGF-I could be protective to the breast. However, by also considering (1) the potential action on breast cancer cells of IGF-II, (2) the possible consequences of the growth hormone (GH) increase caused by the IGF-I reduction and (3) the fact that in vitro results are not simply transferable to the in vivo condition, other 'scenarios' can be envisaged, besides the favorable one. In support of the latter, there are epidemiologic data which suggest that oral estrogen use could have some favorable peculiarities with regards to breast cancer risk. The associated decrease in circulating IGF-I level could well be one of these peculiarities.

Abstract: Endometriosis is a common cause of pelvic pain and infertility in young women. Transvaginal sonography is major means for diagnosing ovarian In our study, we scanned 60 patients with endometriomata who underwent laparotomy or laparoscopy. We compared preoperative ultrasonographic diagnosis with histological reports. The sonographic criteria for the diagnosis of endometriomata were (1) cystic structure with low, homogeneous echogenicity and (2) thick cystic wall with regular margins. In 50 patients, sonography suggested an endometrioma. In 47 cases, the diagnosis was correct. The false-positive cases were all caused by cystic teratomas with a homogeneous sonographic pattern. Ten false-negative cases were diagnosed by ultra-sonography as functional ovarian cysts (5), teratomas (3), and benign ovarian cystoma (1). Only 1 case of a 5-mm endometrioma was demonstrated by laparoscopy but not by TVS. The sensitivity of TVS for diagnosing endometriomata was 82.4% and specificity 97.7%; the positive and negative predictive values were 94% and 92.8%, respectively. The diagnostic accuracy of TVS was 93%. In our experience, TVS is a very specific means for diagnosing endometriomata when the typical pattern is detected; however, the sensitivity of the technique needs to be improved.

Abstract: The MET oncogene encodes the receptor for Hepatocyte Growth Factor/Scatter Factor, a unique growth factor that induces not only proliferation of epithelial cells, but also cell motility and invasiveness. DNA level and expression of the Met/HGF receptor gene were examined with Southern- and Western-blot analyses, respectively, in human ovary, benign ovarian tumors and epithelial ovarian carcinomas. The Met/HGF receptor was detectable in the surface epithelium of normal ovary. The level of expression was unchanged in benign ovarian tumors of various origins. Fourteen out of 67 malignant carcinomas (20%) showed a 3- to 10-fold increase in expression. In 5 additional cases the Met/HGF protein was overexpressed over 50-fold. This represents a total of 28% of cases. Overexpression was not associated with MET gene amplification. Overexpressing tumors belonged to different histotypic variants, but showed a well-differentiated phenotype. Clinically, overexpression was associated with disease at any pathologic stage, but was significantly correlated with premenopausal status of patients. These data suggest that expression of the Met/HGF receptor may add a selective growth advantage to a narrow subset of differentiated ovarian cancers in premenopausal patients.

Abstract: 444 endometrial carcinomas were retrospectively reviewed. Disease-free survival (DFS) was 83.6% at five years and 80.5% at ten years. 349 T1 cancers were treated by TAH-BSO and post-operative irradiation; 22.6% of them were over-staged. DFS ranged from 100% to 91% in 270 low-risk T1 patients, dropping to 84% in intermediate risk patients and to 44% in high-risk patients. DFS was 93% and 66% in the patients overstaged as pT2 and pT3, respectively; it was 82% for ovarian spread and 45% for pelvic peritoneum/parametrium invasion. T2-T3 patients were treated with preoperative irradiation and bilateral hysterectomy. DFS was 90.5% vs. 72.2% and 2/2 vs. 3/7 when the lesion was understaged. The results of irradiation were similar to literature data, but 53% of patients (all in poor general conditions and/or very old) died from associated diseases. Relapses were observed in 13.6% of cases (62/444 patients); 29 (6%) were local recurrences and 33 (7.6%) were distant metastases, which correlated well with recurrences and 33 (7.6%) were distant metastases, which correlated well with risk factors. Severe complication (G3) were observed in 6.3% of cases.

Abstract: Tamoxifen is actually considered the drug of choice for the hormonal treatment of early and metastatic breast cancer due to its efficacy and low toxicity. In addition, clinical trials of adjuvant therapy have demonstrated a 35% decrease in controlateral breast cancer in women receiving tamoxifen compared with controls, suggesting a potential role for this drug in chemoprevention of breast cancer in healthy women at increased risk of disease. Although tamoxifen is usually classified as an estrogen antagonist it also has partial estrogenic effects in some tissues such as liver, bone and uterus. The estrogenic action of tamoxifen on lipid metabolism and bone mineral density suggests additional benefits in protection against cardiovascular diseases and osteoporosis in postmenopausal women. Of particular interest could be the use of tamoxifen as an alternative to traditional estrogen replacement therapy in postmenopausal women previously treated for breast cancer or at increased risk of disease due to family history or histology on breast biopsy. The potential adverse effects of tamoxifen are partially similar to those of ERT and includes an increased risk of endometrial cancer, hepatic diseases, thromboembolic alterations and ocular toxicity. The mechanism of action of tamoxifen is briefly examined and the potential toxic effects and benefits of tamoxifen treatment are discussed.

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Abstract: OBJECTIVE. Since 1990 we have undertaken a trial to evaluate if TVS, even without contrast media, could diagnose tubal patency. MATERIALS AND METHODS. A detailed description of the technique is given. Two hundred and seventy-three patients underwent sonosalpingography in our department in the period 1990-1993. The sonographic findings were matched in 43 cases to hysterosalpingography and in 55 cases to laparoscopy. RESULTS. Tubal patency was demonstrated in 218 patients (80.5%), monolateral patency in 41 (15.1%) patients and bilateral tubal occlusion in 12 (4.4%) patients. In the 43 patients undergoing hysterosalpingography, discordance between the two examinations was observed in five cases (11.6%). However, only six out of 86 salpinxes had different results (6.9%). In only one case was total discordance observed. In three out of four other cases the difference was due to patency diagnosed at SSG and occlusion at HSG. Of the 55 patients undergoing laparoscopy 12 cases (21.8%) had discordant results. Complete discordance was observed in two cases while in ten cases one salpinx had a different patency report. The discordance goes to 12.7% when we take into account all the salpinxes evaluated. CONCLUSION. Sonosalpingography gives very similar results to hysterosalpingography and may be used on clinical basis for tubal patency evaluation.

Abstract: Oral oestrogen treatment in postmenopausal women causes a decrease of insulin-like growth factor I (IGF-I) serum level, probably through a hepatocellular effect. To explore the possibility that the androgenic progestogens oppose this effect, serum IGF-I and sex hormone binding globulin (SHBG) were evaluated in two groups of patients treated respectively with oral conjugated oestrogens (oCE) or transdermal oestradiol (tdE2), in a first phase with the addition of dydrogesterone (DYDR), a non-androgenic progestogen, and subsequently with the addition of norethisterone acetate (NETA). With respect to basal values, treatment with oCE+DYDR caused an increase of SHBG (P < 0.002) and a decrease of IGF-I serum levels (P < 0.05); the shift to NETA addition opposed both effects: SHBG levels decreased partially but significantly (P < 0.01 vs. oCE + DYDR) and IGF-I returned to basal values with a significant increase with respect to the oCE + DYDR phase (P < 0.02). No changes were observed in the tdE2 + DYDR treated women; in this group the shift to NETA addition caused a significant decrease of SHBG values (P < 0.001 vs. before treatment and vs. tdE2 + DYDR phase) and a slight increase of IGF-I values. These differential effects on IGF-I and SHBG serum levels might be relevant as far as breast cancer risk is concerned.

Abstract: The protein product of c-erbB-2 and ras oncogene has been examined for its prognostic potential in both node positive and node negative breast cancer. Using a western blot analysis, levels of these proteins were determined in 159 primary human breast tumor specimens. We examined relationships between gene expression and coexpression with other established markers of prognosis, as well as clinical outcome. Multivariate analysis showed that nodal involvement was the most powerful prognostic factor for predicting overall survival (< 0.000) and disease-free survival (p = 0.001), whereas c-erbB-2 expression was second only to nodal status for predicting overall survival in the whole series (p = 0.05). A separated stepwise analysis was conducted for node negative patients who did not receive any kind of adjuvant treatment and for node positive ones who underwent adjuvant chemo or hormonotherapy. c-erbB-2 expression independently predicted poor survival among node negative tumors (p = 0.001) and was associated with ras expression among node positive cases (p = 0.04). If adjuvant treatment is included in the model, coexpressing tumors are less responsive to Tamoxifen and CMF regimens than those with low levels of protein expression (p = 0.04). These results are potentially of clinical value in separating a subset of node positive breast cancer patients for more intense postsurgical treatment. Among node negative patients, the sole expression of c-erbB-2 enhanced levels, is more likely to retain a predictive value in relation to the response after conventional adjuvant treatment.

Abstract: GNRH analogs (GNRHAs) are currently used in the treatment of prostatic and breast cancer and in several benign gynecological conditions. Because of their ability to suppress sex hormone secretion and the supposed role of these hormones in the physiopathology of fibrocystic mastopathy, GNRHAs have been proposed for the management of severe breast pain and nodularity. In preliminary studies the treatment with GNRHAs for 3-6 months improves clinical and radiologic manifestations of mastopathy, also when breast pain has been recurrent or refractory to other hormonal drugs. Further studies are required to determine the optimal length of treatment and the adverse effects induced by estrogen deficiency in premenopausal women. There is evidence that an early menopause reduces woman's lifetime risk of breast cancer. According to this data, a high-dose GNRHAs regimen associated with estrogen replacement therapy (ERT) has been proposed as chemopreventive agent for premenopausal women at high risk of breast cancer. The definition of the long term effects of GNRHAs on bone and lipid metabolism is essential before a large trial of chemoprevention can be carried out.

Abstract: Monoclonal antibody SP-2 to the tumour-associated antigen 90K was generated by immunisation with conditioned medium of human breast cancer cells. We investigated whether circulating levels of 90K can influence the prognosis of patients with breast cancer. Serum samples were obtained from 425 patients with histologically proven breast cancer with no clinical evidence of disease after surgery (NED) and in 310 patients with metastatic disease. Serum 90K was determined by a new immunoradiometric assay (IRMA). Antigen levels in NED patients were elevated in 18.5% of cases, mean levels being higher than in healthy controls (P = 0.001). Among 375 evaluable patients, the 75-month overall survival for 90K-negative (< or = 11 U ml-1) and 90K-positive (> 11 U ml-1) patients was 78% and 53% respectively (P = 0.004). The prognostic value of 90K appeared to be limited to patients with node-positive disease. Number of metastatic axillary lymph nodes and level of 90K antigen were the only independent variables for predicting overall survival. Patients with metastatic breast cancer had elevated 90K in 51.3% of cases. High 90K levels were significantly associated with the presence of metastases to liver, shorter disease-free interval and younger age. We conclude that an elevated 90K antigen level in serum is a predictor of poor prognosis in breast cancer.

Abstract: The aim of this study was to evaluate the efficiency of transvaginal sonography and sonography plus needle biopsy in detecting pelvic malignant recurrence.We scanned 24 patients already treated for gynecological malignancy, 21 of whom underwent needle biopsy under sonographic guidance. Thirteen patients were affected by cervical cancer, ten by ovarian cancer, and one by endometrial-ovarian carcinoma.Sonography detected 16 solid or cystic-solid masses (median size 52 mm, range 15-85 mm), one case of ascites, and one liquid mass (hematoma). All the patients in whom a suspicious mass was detected had recurrence. In the six patients in whom no mass was visible, two had recurrence. Needle biopsy was able to demonstrate recurrence in 17 patients (also in two false-negative scans). In one, even though sonography detected a mass, the histological sample was negative, but recurrence was later diagnosed by laparotomy.Accuracy, sensitivity and specificity of transvaginal sonography were respectively 91.6%, 89.4% and 100%. The positive predictive value was 100% and the negative predictive value was 71.4%. Transvaginal sonography was shown to be a useful means of detecting pelvic recurrence.

Abstract: BACKGROUND: Oophorectomy is one of the treatments of choice for premenopausal women with advanced breast cancer. However, in recent years LH-RH analogs have replaced surgical castration (or ovarian irradiation) on the basis of the comparable therapeutic activity shown by these drugs in phase II studies. Moreover, the combination of tamoxifen and LH-RH analogs has gained popularity among clinicians attempting to obtain a 'total estrogen blockade' according to the same rationale previously proposed for advanced prostatic cancer. However, it has thus far not been proven that medical castration is as effective as oophorectomy or ovarian irradiation, nor is there enough evidence that tamoxifen could improve the efficacy of ovarian ablation. PATIENTS AND METHODS: Eighty-five perimenopausal patients with estrogen receptor or unknown positive metastatic breast cancer were randomly allocated to receive one of the following treatments: surgical castration (or ovarian irradiation); goserelin; surgical castration (or ovarian irradiation) plus tamoxifen; goserelin plus tamoxifen. The study was performed according to a 2 x 2 factorial randomised design. RESULTS: While overall there was no significant difference in the response rates observed after two by two grouping, a trend did favour oophorectomy (or ovarian ablation) with respect to treatment activity. In fact, the best response rate was observed in patients allocated to this treatment (46.6% OR -95% CL: 21.2-72.9) while the lowest rate was observed in patients treated with oophorectomy plus tamoxifen (11.1% OR: CL: -3.4-25.6). Response to goserelin and goserelin plus tamoxifen was 27.2% (+/- 18.6) and 45% (+/- 21.8), respectively. Logistical regression analysis suggested that there might be a different interaction between tamoxifen and goserelin or oophorectomy (ovarian irradiation), respectively. Nevertheless, patient survivals were comparable, irrespective of allocated treatment. This indicates that two by two grouping has some value with respect to treatment efficacy and shows that oophorectomy (or ovarian irradiation) and goserelin have comparable efficacies. Tamoxifen did not improve the efficacy of gonadal ablation, although it did enhance the activity of goserelin treatment. CONCLUSIONS: The results of the present study confirm prospectively that the efficacy of chemical castration is comparable to that of oophorectomy (or ovarian irradiation). The concurrent use of tamoxifen can probably enhance the activity of goserelin, but it also induces more side effects. However, it doesn't appear that 'total estrogen blockade' is more effective than gonadal ablation alone. Indeed, the question of whether chemical and surgical castration have the same effect in breast cancer is still open as is the one concerning the interaction between tamoxifen and gonadal ablation. Both questions should be addressed by prospective studies.

Abstract: We have recently reported that about 30% of breast tumors produce prostate specific antigen (PSA). We examined here, 99 primary ovarian cancer tumors and found relatively low levels of PSA in only three tumors. One patient with metastatic ovarian cancer from a primary breast tumor, produced relatively high levels of PSA and responded well to antiestrogen treatment although she was steroid receptor-negative. Another patient with metastatic ovarian cancer from a primary breast tumor did not produce PSA and did not respond to treatment although she was steroid hormone receptor-positive. This data describe for the first time, ectopic PSA production by a breast tumor at the ovarian metastatic site and further support the view that PSA is a favourable prognostic indicator in breast cancer.

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Abstract: We analysed the complications of 215 patients with uterine cervix cancer, treated by radiotherapy (RT) alone. It was done according to the rules of the Franco-Italian glossary, presented at the 7th ESTRO meeting, held in The Hague on September 1988. They were ranked by organ sites and by degrees of gravity. The analysis was done on the total number of complications and they were scored at the highest reached grade of gravity. Seventy one complications were found in 55 patients; they were studied by patient, degree of severity, time of onset, organ system and grade, time of onset and grade, time of onset and organ sites, stage and RT doses and brachytherapy volumes. The importance of the study of complications is stressed, particularly when treatment combines external RT and brachytherapy; some guidelines are given to avoid severe complications.

Abstract: Several chromosomal regions are found to be consistently amplified in human breast cancers. For two of these regions, 8p12 and 10q26, we previously reported the amplification of genes encoding FGF receptors, FGFRI/FLG and FGFR2/BEK, in about 12% of breast tumors. The PLAT gene, encoding the tissue-type plasminogen activator, is also located close to or within the 8p12 region. In the present study, we show that both FGFRI and PLAT can be amplified in breast as well as ovarian carcinomas. FGFRI amplification was detected in 14.5% of breast and 7.8% of ovarian tumors, whereas PLAT was found to be amplified in 15.6% and 19.4% of the tumors, respectively. Each gene could be amplified independently of the other. These data raised the question of which gene is selected for amplification at 8p12. In most cases, the levels of expression of FGFRI and PLAT in breast tumors were comparable to their level of expression in normal mammary tissue. However, FGFRI was expressed above the normal level in a certain number of cases. This gene could be a good candidate as "driver" of the 8p12 amplification, but it cannot account for all complex molecular events taking place in this region.

Abstract: Reporting and scoring treatment complications in gynecological cancers is difficult because of the variety of normal tissues, anatomical structures and treatment disciplines involved, making it impossible to compare series of patients treated in different institutions even with the same strategy. An international group of experts (gynecologists, radiotherapists and surgeons) developed a multidisciplinary database to identify, score and report early and late normal tissue damage regardless of treatment strategy. The principles involve: (1) The identification of relevant organs and tissues; (2) An accurate definition of the type and score of each complication; (3) Reporting combinations of complications of various degrees; (4) A computerized format for data acquisition, update and retrieval. In the present version, the "Glossary" describes five degrees of increasing severity (0 to 4) in 14 organs and/or normal tissues. The rationale of the glossary leaves it open for as yet undescribed types of complications. This paper contains the definition and scoring for each type of complication, general guidelines for their use.

Abstract: In postmenopausal women oral ethinylestradiol causes a reduction in circulating insulin-like growth factor 1 (IGF-1) and an increase in serum growth hormone levels. There are no data on the effect of conjugated estrogens, the preparation most often used in estrogen replacement treatment (ERT), on these parameters. We evaluated serum IGF-1 and growth hormone levels, together with the levels of sex hormone binding globulin (SHBG), an indicator of estrogen hepatocellular action, before and after 6 months of ERT in two comparable groups of postmenopausal women. Sixteen women were treated with oral conjugated estrogens, 0.625 mg/day, and 14 with transdermal estradiol, 0.05 mg/day. In the women treated with oral conjugated estrogens, an increase in SHBG (p < 0.001), a decrease in IGF-1 (p < 0.001) and an increase in growth hormone (p < 0.05) serum levels were observed. No such effects were seen with the use of transdermal estradiol, devoid of hepatocellular effects. Undoubtedly, oral conjugated estrogens, 0.625 mg/day, through a hepatocellular effect, cause marked modifications in the IGF-1/growth hormone axis, which may have clinical relevance. For instance, the decreased IGF-1 level, together with the increased level of SHBG, might provide some explanation of the favorable epidemiological data on breast cancer risk in women receiving oral conjugated estrogens.

Abstract: In this study, 30 patients with metastatic breast cancer were treated with 5-Fluorouracil (5-FU) and high-dose Folinic acid, using a new sequential dosing schedule. Our treatment consisted of one day i.v. infusion of 500 mg/m2 of Folinic acid over two hours. One hour after the beginning of Folinic acid infusion, 5-FU (500 mg/m2) was given by i.v. bolus injection. The complete and partial response rates achieved (CR+PR) were 21% in a population of patients pretreated with chemotherapy including 5-FU. Cutaneous and bone metastasis responded best to our treatment. There were no treatment related deaths or withdrawals from the study. The drug related toxicities observed in this study were usually mild to moderate and easily controllable. Thus preliminary results of our study suggest that response rate, quality of life and time to disease progression for the responders improved by this sequential treatment.

Abstract: 504 evaluable node positive oestrogen receptor (ER) positive breast cancer patients were randomly allocated to receive either 5 years tamoxifen treatment or chemotherapy [six courses of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 4 courses of epirubicin] or a combination of both treatments. At a median follow-up of 5 years tamoxifen appeared to be more effective than chemotherapy, the difference being highly significant in postmenopausal women. The addition of chemotherapy to tamoxifen was not able to significantly improve the results achieved by tamoxifen alone, irrespective of menopausal status. Trends were similar even after stratification for the number of involved nodes. The protective effect of tamoxifen in terms of reduction of the odds of death increased with time and no rebound phenomena on recurrence or death has occurred so far after the completion of tamoxifen treatment. Overall, the prognostic value of number of involved nodes and of progesterone receptor (PgR) status was confirmed by multivariate analysis. However, the predictive value of PgR was lost in patients receiving tamoxifen alone. Similarly, the degree of ER positivity was not predictive of the response to tamoxifen. Tamoxifen treatment should still be regarded as the gold standard for postmenopausal ER positive patients. In younger women the antioestrogen proved to be safe and at least as effective as chemotherapy. However, the analysis of the annual risks suggests that the concurrent or the sequential use of chemotherapy and tamoxifen might represent a more appropriate treatment for this patient subset, particularly for those with four or more involved nodes. Different cut-offs of ER and PgR assays from those we have arbitrarily employed in the present analysis should probably be used to select more properly the patients who can benefit from endocrine therapy.

Abstract: Almost all of the epidemiological studies on the consequences of estrogen replacement treatment (ERT) refer to subjects treated with oral conjugated equine estrogens (CEE). These studies suggest that breast cancer (BC) risk is limited and can only be seen after long-term and/or high dosage use. Orally administered estrogens present a number of metabolic and endocrine peculiarities, some of which could be important in reducing the risk to the breast. Actually, these peculiarities are opposite to those observed in post-menopausal women with abdominal obesity (AO), a group which has recently been identified to be at high risk. AO (as other situations in which an increase in BC risk does exist) shows a sex-hormone-binding-globulin (SHBG) level reduction, which causes an increase of both estrogenic and androgenic activity. Further features of AO, possibly involved in BC risk, could be: i) increased free fatty acid (FFA) levels; ii) hyperinsulinemia; iii) increase of circulating insulin-like growth-factor-I (IGF-I) activity. On the contrary oral estrogens, through their hepatocellular effects, cause: i) a clearcut SHBG increase; ii) a trend to reduced circulating IGF-I activity. As a consequence, the possibility that oral estrogens are characterized by a favourable balance between estrogenic activity and biological modifications protective to the breast, is worth consideration. Even non-oral estradiol have a possible protective action through FFA level reduction; however, due to the absence of hepatocellular effect, it does not influence SHBG levels and IGF-I activity. It seems difficult to extend data on the relationship between BC and oral CEE to other types of types of ERT. For the latter, further study will be necessary.

Abstract: Neoadjuvant chemotherapy in operable breast carcinoma (Ia-IIb) may influence the disease development reducing recurrence rate. A survey was conducted from 1975 to 1989 in an attempt to evaluate if pre- and peri-operative chemotherapy is able to improve the survival rate. However, available literature shows that only some Authors observed an increased disease free-survival rate among N- patients.

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Abstract: Postoperative infectious complications are a frequent cause of morbidity and mortality in the surgical patient. The septic events usually involve the urinary or respiratory tracts or occur at the operative site. The incidence depends on the surgeon's experience, the surgical procedure applied and the clinical status of the patient. Radical hysterectomy with pelvic lymphadenectomy is associated with a high risk of postoperative infections. Factors that influence the risk are prolonged preoperative hospitalization, duration of operation, younger age, obesity, estimated blood loss and lack of antibiotic prophylaxis. Appropriate administration of prophylactic antibiotics requires awareness of the following considerations: the choice of antibiotic agent, the dosage and the timing of administration for maximum benefit without adverse effects. In this review we evaluate the results of studies that use different regimens of antibiotic prophylaxis for prevention of infectious morbidity after radical hysterectomy.

Abstract: Transvaginal sonography was used in 78 patients to evaluate tubal patency as a control in infertility workup. The cervix was fitted with a Semm cervix-adapter (Wisap); air and saline were injected through it. Careful scanning of the uterine angles and of the tubes permitted to demonstrate bilateral passage of the contrast medium in 52 of the 55 patients and monolateral passage in 3. 21 patients had also other conventional evaluations of tubal patency. Two patients were excluded from protocol. Total agreement with hysterosalpingography (HSG) was found in 69.2% of the cases, partial agreement in 23%. Total agreement with laparoscopy (LPS) was found in 83.3% of the cases. In conclusion transvaginal sonosalpingography (TSSG) can be used as a first ambulatorial evaluation of tubal patency in infertility work-up.

Abstract: Radical hysterectomy is associated with a high risk of postoperative infectious morbidity. A series of 73 patients who underwent abdominal radical hysterectomy with pelvic lymphadenectomy is presented. Hospital charts were reviewed to determine the influence of surgical characteristics and of different antibiotic prophylaxis regimens on postoperative septic complications. The overall incidence of postoperative infections was 31.5%; in 13 patients had urinary tract infections (17.7%), 3 surgical site-related infections (4.1%) and 6 febrile morbidity (8.2%). There were also 3 cases of phlebitis and 3 infectious events at distant sites. No interaction was observed between the examined risk factors and the overall infectious morbidity. Time of surgical procedure and average blood transfusion show a trend toward increased values in patients with complications compared to patients with regular postoperative course. The most important current controversy about the use of prophylaxis in radical hysterectomy concerns the duration of postoperative treatment. In this series the major part of the subjects received a long-term antibiotic prophylaxis regimen (greater than 72 hours), and only 18% received a perioperative prophylaxis. Women without postoperative complications were more frequently treated with a long-term antibiotic prophylaxis (82%) compared to women with infectious morbidity (65%). Moreover, in patients with complications, the proportion of cases who needed an additional antibiotic therapy was lower in the group receiving long-term prophylaxis (20%) compared to the short-term group (83%).

Abstract: Operative transvaginal sonography (OTVS) is widely used in clinical Obstetrics and Gynecology, however it has no definite role in Gynecologic Oncology. Between January 1990 and February 1991, we performed 18 ultrasonically-guided biopsies on suspected pelvic malignancies. The aim of our work was to assess to efficiency of OTVS in imaging, evaluating and biopsying pelvic masses. Fifteen patients had already been treated for gynecological malignancy, 3 were at their first evaluation. We used a Bruel & Kjaer mechanical transducer (7.5 MHz, type 8538). Biopsy needles were Menghini type (Surecut) 23 cm long, 16 or 18 G. The paper describes the results of the 18 biopsies. One false negative histological evaluation and one inadequate sample were obtained. No complications were observed. From our preliminary data, ultrasound-guided transvaginal scans may be usefully used in imaging and biopsying pelvic masses. It is a safe technique, easy to perform and well accepted by the patients.

Abstract: It has been demonstrated that AG inhibits the peripheric conversion of androstenedione into estrogens and produces an adrenal suppression, equivalent to surgical adrenalectomy. As breast cancer is responsive to hormonal therapy, AG has been used in the treatment of metastatic breast cancer. Since 1984, at I Clinica Ostetrica e Ginecologica of University of Torino, 48 patients with advanced breast cancer, previously treated with chemotherapy and hormonotherapy, have been given AG 1 g/day and hydrocortisone 40 mg/day. Six patients (12%) obtained CR, nine (19%) a PR, eleven (23%) a SD, twenty two (46%) a PD. The efficacy of AG has been evaluated as related to the following prognostic factors: menopausal status, hormone receptors, disease free interval, age, prior tamoxifen exposure. This study shows that bone involvement is the most responsive localization to AG. In conclusion AG is still an effective therapeutic choice in metastatic breast cancer treatment.

Abstract: Mammography is an effective method for finding lesions of the breast which are occult at clinical examination. For occult lesions biopsy, including as little surrounding tissue as possible, it is necessary that they be located before surgery in order to improve the pathological process and the cosmetic outcome for the patients. Among the clinically occult lesions shown only by mammography, the frequency of breast cancers ranges from 10% to 47%. There are several different techniques for locating hidden lesions of the breast. We have employed the insertion of a single rigid needle into the breast, with X-ray confirmation of correct positioning. Forty-nine patients underwent this technique in our Institution and in all cases we were able to achieve a correct insertion of the needle at the X-ray check (the tip of the needle was less than 1 cm from the lesion). The target lesion was removed (as confirmed by X-ray of the surgical specimen) in all cases at the first attempt. In our study we found 11 invasive and 7 in situ tumours (36%). No complications delaying the surgical biopsy or the recovery of the patients were observed.

Abstract: From May 1987 to May 1989 sixty one pre- and perimenopausal women with advanced or recurrent breast cancer entered in an open non comparative study. They were treated, as a first-line therapy, with goserelin (Zoladex ICI-118630) a long acting gonadotropin-releasing hormone (LH-RH)-analogue in a depot formulation. Fifty three patients were evaluable for response; median age at entry was 41 years (range 28-56). Serum concentrations of 17 beta estradiol, LH and FSH were significantly suppressed within the first four weeks of therapy and remained suppressed for the whole duration of treatment. Subjective responses were observed, such as pain reduction and/or performance status improvement in 58% of patients. Overall objective response (CR + PR) occurred in 16 (30.2%) patients in all major sites of disease with a median time to response of 12 weeks (range 8 to 48 weeks) and a lifetable median duration of response of 36 weeks (range 16 to 76 weeks). The lifetable median time to progression was 17 weeks (range 5 to 76 weeks). Goserelin depot was well tolerated with no withdrawal due to possible adverse reactions. The observed subjective and objective response rates are comparable to those induced by surgical oophorectomy. Goserelin provides a well tolerated medical alternative to ovarian ablation, without the morbidity associated to surgery. In conclusion the present paper suggests that this innovative chemical estrogen deprivation, in premenopausal breast cancer patients, might be favorably investigated as an adjuvant therapy in future clinical trials.

Abstract: Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer: such resistance may occur in primary therapy or be acquired during treatment. The most commonly used antineoplastic agents in the treatment of disseminated breast cancer are adriamycin, methotrexate and cyclophosphamide. Cell lines selected for resistance to adriamycin often develop cross-resistance to structurally dissimilar antineoplastic drugs with different mechanisms of cytotoxic action; this phenomenon has been called pleiotropic or multidrug resistance (MDR). In vitro models of MDR have shown that this type of resistance is accompanied by a decrease in cellular drug accumulation, mediated by the over-expression of a 170 kD plasma membrane glycoprotein referred to as P170. Glycoprotein P170 is an energy-dependent multidrug efflux pump, whose activity can be inhibited in vitro by a variety of agents including verapamil, quinidine and reserpine. P170 is over-expressed also in some human malignancies, and evidence exists about its role in examples of clinical resistance in vitro. Clinical trials using verapamil, a calcium channel blocker which selectively enhances drug cytotoxicity in MDR cell lines, have been prompted for leukemia and ovarian cancer. In addition other approaches are the subject of current preclinical investigations. Several observations as well the phenomenon of "atypical" MDR in cell lines which do not overexpress P170, suggest that also other factors are involved in multidrug resistance. Qualitative or quantitative changes in the activity of topoisomerases, protein kinase-related systems and glutathione S-transferase, may confer pleiotropic resistance. As the role of these genes and their regulation is clarified, they may also serve as useful targets for pharmacologic intervention in the treatment of drug-resistant human tumors. The mechanisms involved in resistance to methotrexate and cyclophosphamide are less studied, particularly in vivo samples. Methotrexate resistance is probably a complex multifactorial phenomenon; in some cases it is due to an increase in the expression of the drug target dihydrofolate reductase, often as a result of gene amplification, but in other cases a transport defect of the methotrexate or alterations of the activity of different enzymes have been reported. Cyclophosphamide (CP) resistance has been attributed to an increased activity of two different enzymes, glutathione S-transferase, also involved in MDR phenotype, and aldehyde dehydrogenase, which catalyzes inactivation of CP in non cytotoxic metabolites. This paper reviews the current state of our knowledge of chemo-resistance and the utility of available markers to identify potentially resistant tumors in vivo; the strategies that might be used to overcome this phenomenon are also described.

Abstract: c-erbB-2 and ras expression was measured on tumor extracts from 132 human primary breast carcinomas, by immunoblotting analysis. Expression of the c-erbB-2-encoded p185 protein was observed in 39% of the samples and found to correlate with c-erbB-2 gene amplification, detected by Southern analysis in 19 of the 77 available tumor DNAs. p185 expression was linked to the absence of progesterone receptors, but it was not related to lymph-node status or to other clinico-pathological parameters. Levels of the ras-encoded p21 proteins higher than in normal breast tissues were found in 71% of the samples. No significant correlation was seen between p21 level and the available clinical parameters. Conversely, there was a strong positive correlation between p21 and p185 levels. Analysis of follow-up data revealed that p185 expression was associated with a shorter time to relapse and death. Most notably, the contemporaneous expression of p185 and of high p21 levels was more effective than p185 expression alone in identifying cases with poor prognosis. The prognostic value of p185/p21 co-expression was particularly significant in progesterone-receptor-positive tumors. Our data suggest that c-erbB-2 and ras may act synergistically to endow breast-tumor cells with a highly aggressive phenotype.

Abstract: The paper reviews the studies published between 1982 and 1989 on the subject of the use of LHRH analogs in gynecological oncology. Following the analysis of hormonal changes induced by analogue therapy in premenopausal women with advanced stage breast cancer, the clinical results obtained through the clinical treatment of this neoplasia are reported. Results to date are encouraging and analogue therapy still represents an alternative to surgical sterilisation. The clinical findings in postmenopausal women are less encouraging. In both pre- and postmenopause groups, findings were correlated to the receptorial status and site of metastases. The possibility of associating analogues to other hormone replacement therapies, or to chemotherapy is then discussed. Lastly, preliminary data concerning the use of analogue therapy in advanced-stage ovary cancer are analysed. The current indications for therapy and problems still to be resolved concerning the use of LHRH analogue therapy in the context of gynecological oncology are summarised by way of conclusion.

Abstract: The preoperative localisation of occult mammary lesions can be performed using fine needle biopsies, thus limiting esthetic damage in those patients in whom histological tests prove the lesion to be benign. Various methods have been proposed over the past 20 years. The purpose of this paper is to evaluate published data in order to determine which is the most appropriate method in terms of simplicity and efficacy.

Abstract: The use of LHRH analogues in gynecological oncology is related to the capacity of these compounds to determine pharmacological sterilisation which represents an alternative to surgical ovariectomy in the treatment of hormone-sensitive carcinoma. The modes of administration, metabolism and mechanisms of action of these drugs are illustrated. A section of the action of these drugs are illustrated. A section of the work is dedicated to the side-effects; they are divided into adverse effects, in the accepted meaning of the term, and the consequences of secondary hypoestrogenism. The paper concludes with the presentation of experimental data, both in animal studies and in vitro, which are the basis for the use of analogue therapy in the treatment of advanced stage breast cancer.

Abstract: Between November 1, 1983 and June 30, 1987, 510 node-positive, estrogen receptor (ER)-positive breast cancer patients have been randomly allocated to receive either chemotherapy (six intravenous [IV] cyclophosphamide, methotrexate, and fluorouracil [CMF] courses followed by four IV epirubicin courses) or 5 years of tamoxifen treatment or a combination of both therapies. After a median follow-up of 40 months, patients receiving the combined treatment achieved the best results, and those treated with chemotherapy alone achieved the worst, the difference being particularly evident in postmenopausal women. However, while the concurrent use of chemotherapy and tamoxifen did improve the results achieved by chemotherapy alone, particularly in postmenopausal women and in those with four or more involved nodes, it did not significantly improve the results achieved by tamoxifen alone, particularly in patients with higher ER tumor concentrations. Side effects were more numerous and more severe in patients receiving chemotherapy (with or without tamoxifen). Our findings, although still preliminary, confirm that tamoxifen should be the treatment of choice for postmenopausal breast cancer patients with node-positive, ER-positive tumors. In addition, the findings suggest that tamoxifen may represent a safe alternative to chemotherapy (at least to the cytotoxic regimen we used) for younger women, provided they have ER-positive tumors. In patients with ER-positive tumors, the addition of chemotherapy to tamoxifen does not seem to improve significantly the effectiveness of tamoxifen alone.

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