Abstract: INTRODUCTION: Amino-bisphosphonates are potent activators of human gammadelta T cells. The aim of our study was to evaluate the immunomodulating properties of a single-dose of zoledronic acid (ZA) on gammadelta T cells in a select group of disease-free breast cancer patients with osteopenia. MATERIALS AND METHODS: Blood samples were obtained, from 23 patients, before and 7, 28, 56, 90 and 180 days after a single-dose (4 mg) of ZA and analyzed by flow cyometry. RESULTS: A significant decrease of the different gammadelta T cell subsets was observed: Naïve (CD3+/Vdelta2+/CD45RA+/CD27+) after 180 days (P < 0.01); Central Memory (CD3+/Vdelta2+/CD45RA-CD27+) after 28 (P < 0.05), 90 (P < 0.01) and 180 days (P < 0.01); and Effector Memory (CD3+/Vdelta2+/CD45RA-/CD27-) after 56 (P < 0.01) and 90 (P < 0.05) days. Based on the observed gammadelta T cells kinetics patients could be divided in two groups: "responders" that showed a significant decrease in total numbers of gammadelta T cells and "non-responders" that showed no significant change. However, in vitro phosphoantigen stimulation of patients cells did not show significant differences in terms of IFN-gamma response by Vdelta2 T cells. CONCLUSION: We describe for the first time a long-lasting activation of effector subsets of gammadelta T cells in disease-free breast cancer patients after a single-dose of ZA. Our results highlight the need to further investigate the clinical significance of the immunomodulating properties of N-BPs.

Abstract: GOALS OF WORK: Bone metastases are a common cause of morbidity in elderly patients with solid tumors and myeloma. We studied the safety and the effect of a new bisphosphonate, zoledronic acid (ZA), on pain and on quality of life (QoL) in elderly patients with bone metastases. MATERIALS AND METHODS: From January 2004 to December 2005, we have enrolled elderly patients with bone metastasis for receiving ZA administration. Visual analog scale (VAS) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire were used to assess potential benefits of ZA therapy. RESULTS: Eighty-six patients were included; the median age was 75.5 years. Before starting treatment, the mean VAS was 6.8 (+/-0.24), after three infusions 5.4 (+/-0.3), and after six courses 4.5 (+/-0.3) with a significant improvement of bone pain. Moreover, we found a statistically significant improvement of QoL measured by FACT-G questionnaire after six courses (p = 0.010). Median baseline and final value of serum creatinine were 0.73 and 0.72 mg/dl, respectively (p = 0.11); creatinine clearance was also normal for most patients. Osteonecrosis of the jaw was diagnosed in one patient who received a prolonged ZA treatment. CONCLUSIONS: These data confirm the benefits of ZA on pain and QoL also in elderly patients with bone metastasis from solid tumors.

Abstract: Breast cancer growth is regulated by coordinated actions of the estrogen receptor (ER) and various growth factor receptor signalling pathways. This complex interactive signalling potentially explains some of the reasons behind endocrine therapy action and resistance. Recent research into the molecular biology of ER signalling has revealed new molecular targets which, if present in cancer cells, might be additionally targeted using various signal transduction inhibitors to overcome or prevent resistance to endocrine therapy. The dynamic inverse relationship between the expression of ER and growth factor receptors brings more excitement to the potential of restoring ER expression in apparently ER-negative cells by inhibition of growth factor signalling. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signalling pathways. Ongoing clinical trials promise to further improve the present care for breast cancer patients.

Abstract: BACKGROUND: Gemcitabine is an acceptable alternative to best supportive care in the treatment of advanced biliary tract cancers. The human equilibrative nucleoside transporter 1 (hENT1) is a ubiquitous protein and is the major means by which gemcitabine enters human cells. Moreover, recent reports indicate a significant correlation between immunohistochemical variations of hENT1 in tumor samples and survival after gemcitabine therapy in patients with solid tumors. Materials and methods: We used immunohistochemistry to assess the abundance and distribution of hENT1 in tumor samples from radically resected cancer of the ampulla, and sought correlations between immunohistochemical results and clinical parameters including disease outcomes. RESULTS: In the 41 individual tumors studied, 12 (29.3%) had uniformly high hENT1 immunostaining. Statistical analysis showed a significant correlation between hENT1 and Ki-67 (P = 0.04). No statistical significant differences were found between immunohistochemical findings and patient characteristics (sex, age, and tumor-node-metastasis). On univariate analysis, hENT1 and Ki-67 expression were associated with overall survival (OS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.022) and those with high Ki-67 staining showed a shorter survival (P = 0.05). CONCLUSIONS: hENT1 expression is a molecular prognostic marker for patients with resected ampullary cancer and holds promise as a predictive factor to assist in chemotherapy decisions.

Abstract: Cancer patient education can be especially important in topics like side effects of chemotherapy. Information needs of oncology patients are scarcely investigated in Italy. This study aimed to identify the learning needs, the amount of information desired and the preferred methods of information delivery of Italian cancer patients receiving chemotherapy. A total of 111 cancer patients completed a questionnaire developed for this study, which was assessed for validity and reliability. Respondents ranked the following priority information: illness, recovery, treatments, chemotherapy side effects and trajectory of illness. The great majority wanted to receive as much information as possible about all these topics. Most patients showed their wish to be informed along with their relatives, but only a few wanted relatives to be informed before them. The preferred method for receiving information about side effects of chemotherapy was oral conversation, followed by written information. Patients preferred receiving information from the oncologist, followed by the oncology nurse and the general practitioner. Most respondents preferred to be informed before receiving the first cycle of chemotherapy. Results are consistent with the existing literature with regard to information priorities, quantity of information desired and preferred methods of information. In contrast with a non-disclosure dominant culture, Italian cancer patients manifest their wish to be informed a great deal and personally about their condition. In order to meet cancer patients' information needs, health professionals' education and practice should be improved.

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Abstract: OBJECTIVE: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. METHODS: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. RESULTS: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion with respect to the basal time point. For patients with at least a 50% reduction in VEGF levels, the response rate was 45.5% compared with 8.7% in the nonreduced VEGF group (p = 0.014). The median time to progression was 6 months in the reduced VEGF group versus 3.9 months in the other patients (p < 0.0001). In addition, overall survival was longer in patients with VEGF reduction (11.0 months) than in patients without (9.6 months; p = 0.01). CONCLUSION: These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.

Abstract: Primary childhood germ cell tumors (GCTs) represent a rare and heterogeneous group of tumors that varies in histologic differentiation, age of presentation and clinical outcome. In malignant neoplasms, apoptosis is a prognostic marker and a predictive factor of response to therapy. Therefore, the study of the expression and mutation of molecules involved in the regulation of apoptosis could be useful in order to both predict the clinical outcome and design self-tailored therapeutic approaches. We retrospectively analysed tissue samples of 54 childhood GCTs. The expression of p53 and BAX protein was assessed by immunohistochemistry (IHC). Moreover, we investigated the presence of mutations in the BAX and p53 genes SSCP-PCR and direct sequencing. IHC analysis of BAX protein expression showed that 14 out of 54 tumors (26%) had no BAX protein expression, in the remaining 40 patients (74%) the intensity of BAX was low in 20 patients (37%) and high/intermediate in 20 (37%). BAX was mutated in 6 patients. p53 was expressed in 43 patients (79.6%), was not detectable in the remaining 11 (20.4%) and mutated in only 3 patients. p53 mutational status and expression were not correlated to the overall survival (OS). On the other hand, both IHC score and mutations for BAX were correlated to sacrococcygeal primary localization. BAX mutations were inversely correlated with OS (p=0.0419) while BAX IHC intensity was directly correlated with OS (p=0.0376). The stratification for histotype showed a direct correlation between BAX IHC and OS in both immature teratoma (p=0.045) and mixed malignant GCT (p=0.010) while the correlation was lost in mature teratoma (p=0.300). These results indicate that both mutations and BAX protein levels are useful molecular biological markers for prognosis and clinical management of pediatric GCT.

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Abstract: Chemotherapeutic agents cause DNA damage and disrupt DNA replication in proliferating cells. Drug regimens have been designed to kill as many tumor cells as possible with the use of the maximum-tolerated doses of these cytotoxic agents. Damage in proliferating tissues (the bone marrow, gut and skin) and healthy tissues place serious constraints on the use of chemotherapy. To balance toxicity with efficacy, cytotoxic agents are administered in a pulsed manner with breaks between cycles to allow for the recovery of normal tissues. Many chemotherapy regimens are initially efficacious, determining tumor regression or stabilization and prolonged survival. However, responses are generally short-lived, with relapses often marked by aggressive cancers that are resistant to the cytotoxic drug. Cytotoxic chemotherapy remains an important part of optimal therapy for patients in all stages of disease, but its use is limited by toxicity, nonspecificity and the inevitable development of resistance, with serious consequences on the patients quality of life. For these reasons, clinical research is moving to improve our understanding of the altered molecular events in cancer cells and find new targets to be inhibited in order to optimize cytotoxicity and overcome resistance mechanisms. This review aims to explain the rationale behind metronomic and targeted therapies in breast cancer and to examine the main preclinical and clinical (neoadjuvant, adjuvant and advanced settings) studies conducted.

Abstract: PURPOSE: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. EXPERIMENTAL DESIGN: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. RESULTS: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion. CONCLUSIONS: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.

Abstract: AIMS: There is considerable evidence to link cyclooxygenase (COX)-2 to the development of cancer. The aim of this study was to assess COX-2 expression and its subcellular localization in lobular in situ neoplasia (LIN) of the breast and to verify differences in COX-2 expression between different grades of lesions according to the Tavassoli classification. METHODS AND RESULTS: We analysed the expression of COX-2 protein by immunohistochemistry in tissue samples of 51 LIN lesions classified into three grades according to the Tavassoli classification. COX-2 immunostaining was observed in 78.4% of LIN samples and showed a prevalent membranous rather than cytoplasmic pattern. COX-2 was expressed in 16/17 (94.1%) LIN1, 22/25 (88%) LIN2 and 2/9 (22.2%) LIN3. As regards COX-2 expression, a statistically significant difference was found between LIN1 and LIN3 (P = 0.001) and between LIN2 and LIN3 (P =0.001). No difference was found between LIN1 and LIN2. Moreover, a significant negative correlation was found between LIN grade and COX-2 expression (P < 0.0001). CONCLUSIONS: COX-2 is highly expressed in LIN, supporting a role for this protein in the early stage of breast carcinogenesis, representing the rationale for using COX-2 selective inhibitors in the earliest stages of breast cancer.

Abstract: Considerable advances in our understanding of the complex cellular, molecular and genetic mechanisms underlying tumorigenesis over the last decade have contributed to the development of novel and improved targeted therapies in cancer intervention. These novel therapies interfere specifically with signaling pathways essential for tumor cell proliferation, survival and migration, they may be able to inhibit tumor growth and metastasis effectively, with fewer severe adverse events than seen with existing chemotherapeutic interventions, which have a narrow therapeutic index and are associated with severe toxic side effects. Among the most recent advances in anticancer treatments are therapies that target novel cellular entities, such as epidermal growth factor receptor and vascular endothelial growth factor. Monoclonal antibodies and protein tyrosine kinase inhibitors represent two classes among these promising new therapeutic interventions. During the European Society for Medical Oncology Congress 2006 (Istanbul, Turkey, 29 September-3 October) new and emerging biological therapies have represented a central argument of research. These highlights summarize the most interesting studies concerning molecular agents, such as panitumumab, lapatinib, sunitinib, sorafenib, erlotinib, bevacizumab and cetuximab, to provide a comprehensive overview of the important points and news about this area of research discussed during the meeting.

Abstract: BACKGROUND: The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. The aim of the present study was to define the feasibility and efficacy of XELOX administered through a new chronomodulated schedule in untreated advanced colorectal cancer (CRC) patients. METHODS: Chemotherapy-naive patients with advanced CRC were considered eligible for the study accrual. Treatment: oxaliplatin 70 mg/m(2) continuous infusion (c.i.) for 12 h (8:00 a.m. to 8:00 p.m.) days 1, 8 plus chronomodulated oral capecitabine 1,750 mg/m(2)/die (h 8:00 a.m. 25% of total dose; h 6:00 p.m. 25% of total dose; h 11:00 p.m. 50% of total dose), days 1-14 every 21 days. RESULTS: Forty-six patients were evaluated for safety and efficacy (male/female, 20/26). Median age was 64 years (range 28-77 years). Median Eastern Cooperative Oncology Group performance status (PS) was 0 (range 0-1). A total of 324 cycles have been administered: median per patient 6 (range 3-10 courses). Median number of metastatic sites was 1. Metastatic sites distribution was as follows: liver (65.2%), lung (34.8%), and nodes (32.6%). Median follow-up was 14 months (range 6.0-40.3 months). In an intent-to-treat efficacy analysis, objective response and stable disease were recorded in 27 (58.6%) and in 16 patients (34.9%), respectively. The median response duration was 8.0 months (95% CI; 5.03-10.96 months). The median time to progression (TTP) was 9.0 months (95% CI; 6.47-11.52 months). The overall survival (OS) was not reached, with a median value > 24 months (95% CI; 23.66-36.30 months). The grade 3 toxicities were diarrhea (8.7%), liver toxicity (13.1%), fatigue (8.7%), neurotoxicity (2.2%), neutropenia (8.7%), and thrombocytopenia (2.2%). CONCLUSION: This regimen resulted of particular interest for patients with untreated metastatic CRC.

Abstract: Feline soft tissue sarcomas are spontaneous, rapidly growing, and aggressive neoplasms that mimic their human counterpart. The purpose of this study was to evaluate the feasibility and efficacy of electrochemotherapy (ECT) in an adjuvant fashion for the treatment of feline sarcomas, and the possibility of repeated treatments in the case of recurrence. Cats with fibrosarcoma (FSA) were assigned to receive surgery or surgery plus ECT. Feline patients recruited in the ECT study were enrolled in a microscopic arm (39 patients) or a macroscopic arm (19 patients) on the basis of their tumor status (absence or presence of gross disease). Patients received local injection of bleomycin followed by bursts of eight biphasic pulses at a voltage of 1,300 V/cm for postoperative and of 800 V/cm for intraoperative treatments. The median time to recurrence was 4 months for cats treated with surgery alone, 19 months for the postoperative cohort, and 12 months for the intraoperative group. Moreover, ten patients with recurring neoplasms were retreated and experienced responses lasting 6 to 28+ months. Side effects were minimal. Of interest, the metastatic rate (1.7%) in our patients was negligible: only one cat had distant spread. The results suggest that ECT is a well tolerated and potentially useful addition to surgery in controlling high-grade sarcomas. On the basis of these results, additional evaluations are warranted in pets and in humans.

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Abstract: BACKGROUND: Capecitabine and gemcitabine given as fixed dose rate (FDR) has not been demonstrated to be well tolerated in phase I previous studies. The goals of this phase I study were to determine the maximum-tolerated dose of this combination and to describe the dose-limiting toxic effects (DLT) and the safety profile of this way of administration. PATIENTS AND METHODS: Patients with advanced solid tumors were eligible for this study. Capecitabine was administered orally at a dose of 650 mg/m(2) bis in die (b.i.d.) for 14 consecutive days. Gemcitabine was administered at FDR of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8. The cycles were repeated every 21 days. RESULTS: All 20 patients enrolled into the study were assessable for toxicity. Only one out of the first six patients treated at FDR gemcitabine dose of 800 mg/m(2) met protocol-specified DLT criteria (grade 4 neutropenia lasting >or=7 days) during the first two cycles. At these doses the majority of cycles of therapy were, however, delivered without dose reduction or delay. Another similar episode of DLT was observed at the same dose step among the following eight included patients. The dose of FDR gemcitabine 800 mg/m(2) in 80 min on days 1 and 8 plus capecitabine 650 mg/m(2) b.i.d., for 14 consecutive days followed by 1 week of rest is recommended for further study. CONCLUSION: The combination of FDR gemcitabine plus capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.

Abstract: Reelin is a glycoprotein that plays a critical role in the regulation of neuronal migration during brain development and, since reelin has a role in the control of cell migration, it might represents an important factor in cancer pathology. In this study, 66 surgical specimens of prostate cancer were analyzed for reelin expression by immunohistochemical method. The reelin expression was correlated with Gleason score and individual Gleason patterns. Reelin expression was found in 39% prostate cancers. Stromal tissues, normal epithelial cells and prostate intraepithelial neoplasia (PIN) of any grade around and distant from cancer were always negative for reelin. Reelin was found in malignant prostatic epithelial glands of 50% cases Gleason score 10, 52% Gleason score 9, 56% Gleason score 8, 18% Gleason score 7, while no sample of prostate cancers with Gleason score 6 showed reelin expression (P=0,005). As reelin staining is frequently found in high Gleason score prostate cancers, we explored whether reelin expression is influenced by single Gleason patterns. While Gleason 3 pattern did not show reelin immunoreactivity, reelin expression was found in 35% Gleason 4 patterns and 45% Gleason 5 patterns (P<0.001). Our results demonstrated for the first time that reelin is expressed in prostate cancer and not in benign prostate tissue and its expression occurs in higher Gleason score and correlates significantly with increasing of single Gleason patterns. This suggests reelin may behave as a specific histological marker and may represent a useful biomarker to predict aggressive phenotypic behavior of prostatic cancer cells.

Abstract: BACKGROUND: Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study. METHODS: Fifty-nine patients were enrolled and received 30 Gy WBRT with concomitant TMZ (75 mg/m2/day) for ten days, and subsequently TMZ (150 mg/m2/day) for up to six cycles. The primary end points were clinical symptoms and radiologic response. RESULTS: Five patients had a complete response, 21 patients had a partial response, while 18 patients had stable disease. The overall response rate (45%) exceeded the target activity per study design. The median time to progression was 9 months. Median overall survival was 13 months. The most frequent toxicities included grade 3 neutropenia (15%) and anemia (13%), and only one patient developed a grade 4 thrombocytopenia. Age, Karnofsky performance status, presence of extracranial metastases and the recursive partitioning analysis (RPA) were found to be predictive factors for response in patients. Overall survival (OS) and progression-free survival (PFS) were dependent on age and on the RPA class. CONCLUSION: We conclude that this treatment is well tolerated, with an encouraging objective response rate, and a significant improvement in quality of life (p < 0.0001) demonstrated by FACT-G analysis. All patients answered the questionnaires and described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QoL, this provides useful information to share with patients in discussions regarding chemotherapy treatment of these lesions.

Abstract: AIMS: The histological modification produced by neoadjuvant chemoradiation on primary rectal cancer has been investigated by many authors, and a prognostic value of tumor regression grade (TRG) has been identified. Tumor regression grade on metastatic mesorectal lymphnodes has been never evaluated. The purpose of this study is to analyse the TRG on mesorectal lymphnodes (lymphnode regression grade, LRG) after preoperative chemoradiation in rectal cancer patients and to determine the correlation with TRG of primary tumor. METHODS: Surgical specimens from 35 patients who underwent chemoradiation were included. LRG on mesorectal lymphnodes was assessed by immunohistochemistry. Response to treatment was evaluated by a 5-point LRG based on the ratio of residual tumor to fibrosis. RESULTS: Complete pathologic response (LRG 1) was observed in 18 patients (51%). In 4 patients (11%) no regression was observed (LRG 5). In 4 cases only reactive lymphnodes were found. LRG on lymphnodes significantly correlated with TRG on primary tumor (p<0.05). CONCLUSIONS: Neoadjuvant chemoradiation determines a tumor regression on mesorectal lymphnodes as on primary tumor; further studies are needed to evaluate the prognostic value of LRG.

Abstract: Vgamma9Vdelta2 T cells have the ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumours and to display strong cytolytic as well as bactericidal activities. This suggests a direct involvement of Vgamma9Vdelta2 T lymphocytes in immune control of cancer and infections. These observations have recently aided development of novel immunotherapeutic approaches aimed at Vgamma9Vdelta2 T cell activation. Nitrogen-containing bisphosphonates (N-BPs) play a crucial role in Vgamma9Vdelta2 T lymphocyte activation and in the acquisition of effector functions. The preliminary results of these innovative strategies are encouraging. Moreover, compelling evidence in the literature supports the hypothesis that the antitumour effect of bisphosphonates is exerted through direct as well as indirect mechanisms. An additional and not yet well explored mechanism by which N-BPs may display antineoplastic effect is related to their immunomodulatory properties. It is fascinating that N-BPs influence the immune system in various but interrelated ways, being able to enhance the innate and to promote the adaptive immune responses. For all these reasons, Vgamma9Vdelta2 T lymphocytes represent a particularly interesting target for immunotherapeutic protocols based on N-BP administration. All these unexpected effects of N-BPs on the immune system have opened new and intriguing possibilities of therapeutic use for these drugs.

Abstract: Electrochemotherapy (ECT) is a new therapeutical technique that combines the administration of trains of biphasic pulses with the local application of poorly permeant anticancer molecules, thus obtaining increased chemotherapy uptake. The purpose of this study was to prospectively assess the adjuvant potentialities of ECT for the treatment of different incompletely excised canine sarcomas. Twenty-two privately owned dogs with incomplete surgical excision of high grade sarcomas were treated with bleomycin injected within the tumor bed (1.5 IU/mg) followed by the sequential application of trains of biphasic pulses (8 pulses, 1300 V/cm, 50+50 micros duration, 1 Hz frequency). The overall response rate was 95% (21 out of 22 patients) with a mean time to recurrence of 730 days. At the time of writing 11 dogs were still in remission, three dogs had died of unrelated causes, one had local recurrence and the owner declined further treatment, one had limb amputation following recurrence, four had both local recurrence and distant metastases that led to euthanasia, and two were retreated following tumor recurrence and are disease free at 850 and 1947 days. The only observed toxicity was wound dehiscence in three patients. Electrochemotherapy is well tolerated and has effectiveness against incompletely excised sarcomas in companion animals. Further investigations are warranted to improve the currently available protocols.

Abstract: Docetaxel is a complex diterpene obtained from Taxus Brevifolia, and it is one of the most widely used anticancer agents. The main mechanism of citotoxic action depends on stabilization of microtubules leading to cell mitotic arrest. Independently from the schedule, the primary dose limiting toxicity of docetaxel using is neutropenia. The most common acute side effects related with docetaxel are hypersensivity reactions and dermatitis. There are also other toxicities that may be cumulative in both onset and severity; an important dose limiting side effect in patients who receive multiple cycles of the drug is fluid retention. In previous clinical trials docetaxel resulted often associated with fluid retention, even if phisiopatology of this effect is still unknown. In the majority of cases its manifestations are edema or pleural effusion. We report two cases of patients who developed repeated episodes of pericardial effusion after docetaxel infusion.

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Abstract: Pancreatic cancer is the fourth most common cause of cancer death in Western society and is a leading cause of cancer death worldwide. Its incidence and mortality rates are almost identical. Surgery is the only treatment theoretically curative, but < 20% of all patients admitted with ductal adenocarcinoma of the pancreas undergo resection and at best, 25% of those survive for 5 years. The identification of prognostic factors that are able to stratify patient populations recognizing those that could able to benefit by a radical surgical treatment and/or a chemotherapeutic treatment. This paper is a not only a detailed review of existing studies evaluating pancreatic cancer biomarkers, but also a critical evaluation of the real clinical use of these kinds of prognostic factors with the purpose to help discriminate between a variety of factors which, so far, can be considered really useful in everyday clinical practice. Although no single marker has been shown to be perfect in predicting patient outcome, a profile based on the best of these markers may prove useful in directing patient therapy. The markers with the strongest evidence as independent predictors of patient outcome include, p16, MMP7 and vascular endothelial growth factor.

Abstract: The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.

Abstract: OBJECTIVE: Recent evidence suggests an association between obesity and Attention Deficit/Hyperactivity Disorder (ADHD) or ADHD traits. The characteristics of obese subjects with a higher probability of ADHD symptoms are still unclear. We explore the hypothesis that obese adolescents with sleep/alertness problems represent a subgroup at high risk for ADHD traits, independently from associated symptoms of anxiety/depression. The aim of this study was to assess the relationship between parent reports of sleep/alertness problems and ADHD traits in a clinical sample of obese adolescents, controlling for symptoms of anxiety/depression. METHODS: Seventy obese subjects (age range, 10-16 years) were included. The parents filled out the Sleep Disturbance Scale for Children (SDSC), the Conners Parents Rating Scale-Revised (Short Version) (CPRS-R:S), and the Child Behavior Checklist (CBCL). The ADHD Rating Scale (ADHD-RS) was completed by a child psychiatrist. RESULTS: Using multiple regression models controlling for symptoms of anxiety/depression, scores of excessive daytime sleepiness on the SDSC were significantly associated with ADHD traits on the CPRS-R:S as well as on the ADHD-RS. CONCLUSIONS: Obese adolescents described as excessively sleepy by their parents may be at higher risk of ADHD symptoms, independently from symptoms of anxiety/depression. Although the clinician may overlook a potential diagnosis of ADHD in obese adolescents described as sleepy, the results of this study suggest to systematically look for symptoms of ADHD in this subgroup of obese patients. Further studies using objective methods to assess sleep/alertness disturbances are needed to gain insight into the relationship between sleep/alertness disturbances and ADHD in obese individuals.

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Abstract: PURPOSE: It is well known that bone metastases from breast cancer usually show osteolytic changes. We retrospectively analysed the computed tomography (CT) appearance of bone metastases to quantify the distribution of lytic, mixed and sclerotic changes in a series of patients presenting with neoplastic bone involvement from breast cancer. MATERIALS AND METHODS: Between 1996 and 2005, 468 women with a diagnosis of breast cancer were referred to our department for staging or follow-up CT examinations. Staging CT examinations detected systemic metastases in 142/468 patients, 60 of which had bone involvement. Patients with a second primary tumour or bone metabolic disorders were excluded from this retrospective analysis. RESULTS: In patients with bone metastases, CT identified 18 with osteolytic lesions (30%), 32 with osteosclerotic lesions (53.3%) and ten with mixed lesions (16.7%). Analysis of the cases observed for the first time during the 1996-2000 period showed osteolytic lesions in 53.6% (15/28), osteosclerotic lesions in 32.1% (9/28) and mixed lesions in 14.3% (4/28). Results were 9.4% (3/32), 71.9% (23/32) and 18.7% (6/32), respectively, for the same groups in the 2001-2005 period. Histological analysis of all cases included 81.9% of infiltrative ductal carcinoma, 11.2% of infiltrative lobular carcinoma, 3.7% of ductal lobular mixed carcinoma and 3% of medullar carcinoma. We found no statistically significant correlation between histological type of breast cancer and radiological appearance of bone metastasis. A significant difference between patients treated with or without zoledronic acid was observed, with a higher prevalence of osteosclerotic lesions in the former group of patients (p<0.05). CONCLUSIONS: We observed an increasing prevalence of osteosclerotic bone metastasis when comparing the 1996-2000 period with the 2001-2005 period. The significance of these distribution changes is not clear. However, we found a significant correlation of osteosclerotic lesions with zoledronic acid treatment. The advent of third generation bisphosphonates may have changed the CT appearance of bone metastasis from breast cancer.

Abstract: BACKGROUND: Bisphosphonate (BP) therapy has become a standard of therapy for patients with malignant bone disease. In vivo preclinical and preliminary clinical data indicate that BPs may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. DESIGN: This review will describe the preclinical evidences of action of BPs on osteoclasts and tumor cells. In addition, the effects of principal BPs on skeletal disease progression in patients with breast cancer, prostate cancer, non-small-cell lung cancer and other cancers will be reported. The preliminary clinical data from retrospective trials on the effect of zoledronic acid (ZA) on survival will be described and the ongoing adjuvant phase III trial will be analyzed. CONCLUSIONS: This review will describe the preliminary clinical evidences from prospective studies on the effect of ZA treatment on the prevention of bone metastasis.

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Abstract: PURPOSE: No standard chemotherapy has been so far definitely settled for elderly patients with metastatic breast cancer (MBC). In order to identify a regimen with acceptable efficacy and low burden of non-overlapping toxic effects, a combination consisting of liposomal pegilated doxorubicin (PLD) with alternating oral and intravenous vinorelbine (NVB) has been investigated in a phase II study. METHODS: Thirty-four consecutive patients (median age 71 years; range 65-82) with MBC have been enrolled. Based on 4-weekly cycles, PLD 40 mg/m(2) plus NVB 25 mg/m(2) i.v., have been administered intravenously on day 1 and oral NVB 60 mg/m(2) on day 15. RESULTS: All patients were assessable for safety and efficacy. In all, 17 responses were documented with three complete responses (CR) and 14 partial responses, with an overall response rate of 50% (95% CI 36-66). Median overall survival time was 13 months and the median time to progression 8 months. Interestingly, all the patients with CR are still alive with a disease-free survival of more than 1 year. The main toxicity was neutropenia: grade 3 in 15% and grade 4 in 11% of patients, respectively. Febrile neutropenia was recorded in three patients not requiring dose reduction. Other frequently reported adverse events included: anemia, nausea, vomiting, stomatitis, all rarely severe. The evaluation of quality of life (QoL) did not show any significant change during the study. CONCLUSIONS: Our data suggest that this combination is active and well tolerated in elderly patients with MBC and could represent another efficacious chance for the management of this population.

Abstract: Squamous cell carcinomas (SCC) of the skin are commonly described in cats. Reported treatments include surgery, radiation therapy and photodynamic therapy. This preliminary study reports on the management of these lesions combining the local administration of bleomycin (plus hyaluronidase for a more uniform distribution) with permeabilizing biphasic electric pulses. Nine cats with SCC graded T(2)-T(4) were treated over a 5 year period, and each cat received two sessions of electrochemotherapy (ECT) 1 week apart. The side effects of this treatment were minimal and limited to mild erythema of the nose. Seven of the cats (77.7%) had a complete response lasting up to 3 years. ECT seems to be a safe and effective option for the treatment of feline sun-induced squamous cell carcinomas and warrants further investigation.

Abstract: OBJECTIVE: The objective was to prospectively determine CT density changes in bone metastases, before and after intravenous zoledronic acid for a maximum period of 12 months. PATIENTS AND METHODS: Twenty-three consecutive patients presented with bone metastases and underwent therapy with zoledronic acid from December 2004. All patients underwent CT of the chest, abdomen, and pelvis. Bone density, measured in Hounsfield units (HU), was determined by segmenting lesions in the same anatomical area of the metastasis sites on the axial images of the sequential series of CT examinations. The effects of zoledronic acid were evaluated by calculating absolute and relative increases in bone density. RESULTS: The patients presented with multiple metastases in 65% of the cases. When compared with the baseline, all groups demonstrated a significant increase in bone density, which significantly (p < 0.01) correlated with the number of zoledronic acid administrations. There was increased bone density of at least 100% in 57%, and an increase of at least 50% in 87% of the patients. This increase was significant in both lytic and sclerotic metastases after 3 months of therapy. No significant bone density difference was found in normal-appearing bone. CONCLUSION: Bone density measured by CT increases at metastatic sites after zoledronic acid treatment, regardless of the type of metastasis, in contrast to apparently normal bone.

Abstract: Electrochemotherapy (ECT) is a novel anticancer therapy that is currently being evaluated in human and pet cancer patients. ECT associates the administration of an anti-tumor agent to the delivery of trains of appropriate waveforms. The increased uptake of chemotherapy leads to apoptotic death of the neoplasm thus resulting in prolonged local control and extended survival. In this paper we describe the histological features of a broad array of spontaneous tumors of companion animals receiving pulse-mediated chemotherapy. Multivariate statistical analysis of the percentage of necrosis and apoptosis in the tumors before and after ECT treatment, shows that only a high percentage of necrosis and apoptosis after the ECT treatment were significantly correlated with longer survivals of the patients (p < 0.0001 and p = 0.004, respectively). Further studies on this topic are warranted in companion animals with spontaneous tumors to identify new molecular targets for electrochemotherapy and to the develop new therapeutical protocols to be translated to humans.

Abstract: In the present study, the prognostic impact of factors involved in the apoptosis pathway were tested on 67 consecutive patients treated with surgical resection. Included in the study were all patients resected for pancreatic adenocarcinoma from 1988 to 2003. Expression analysis for p53, Bax, and Bcl-2 were performed by immunohistochemical staining. Apoptotic cells were identified by the TUNEL method. These data were correlated with survival. Sixty-seven tumor specimens were included in the study. A strong positive correlation was recorded between p53 overexpression and Bax expression levels (P < 0.001). By univariate analysis, overall survival seemed to be improved with Bcl-2 and Bax expression (respectively, P = 0.0379 and 0.0311). The median survival time in patients with low apoptotic index was better versus those with a high index (P = 0.0127). Lymph node involvement was the only clinico-pathologic parameter that significantly correlated with overall survival (P = 0.0202). By a multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was the apoptotic index (P = 0.040). Tumor's overexpression of both Bax and Bcl-2 resulted the strongest independent prognostic factor (P = 0.013). This is the first study to report a statistically significant association of apoptosis to overall survival for pancreatic cancer patients treated with surgical resection. The contemporary overexpression of Bax and Bcl-2 represents the strongest prognostic factor.

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Abstract: Zoledronic acid (Zometa, ZOL) is increasingly used to treat tumour-induced bone disease, and is also reported to have antiangiogenic properties in vivo. In this study, we have investigated the correlations between changes in the proangiogenic cytokine, vascular endothelial growth factor (VEGF), and markers of bone resorption in a cohort of patients with metastatic bone disease, following a single infusion of ZOL. Twenty-four consecutive selected cancer patients with scintigraphic and radiographic evidence of bone metastases were treated for the first time with a single infusion of 4 mg ZOL. Patients were considered ineligible if they had received any steroid therapy, radiotherapy, chemotherapy, immunotherapy or haemopoietic growth factors in the 4 weeks before or during the study period. Circulating levels of VEGF and beta crosslinked type I collagen C-telopeptide (betaCTX) were measured at base-line and at 1, 2, 7 and 21 days following ZOL infusion. The majority of our patients (23/24) developed a significant reduction in circulating levels of betaCTX at just 1 day after the single zoledronic acid infusion, median percentage decrease 67.05% (95% CI, 52.39%; 76.27%). This reduction persisted at all following time points in almost all subjects in our patient population (day 2, 95.8%; day 7, 100%; day 21, 91.7%). The median decrease at day 2 was 85.67% (95% CI, 78.23%; 90.16%); at day 7, 67.38% (95% CI, 67.38%; 86.98); and at day 21, 76.89% (95% CI, 35.00%; 83.16%). Moreover, a linear regression model with variance analysis demonstrated a statistically significant correlation between median VEGF and betaCTX circulating levels at each of the time points (1, 2, 7 and 21 days after ZOL infusion). The present work demonstrates that a single infusion of ZOL was able to induce a rapid and long lasting decrease of betaCTX plasma levels in the majority (23/24) of the included cancer patients. Furthermore, we found that there is a correlation between the levels of VEGF and betaCTX following ZOL treatment. Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome.

Abstract: Bone metastases are common in patients with many types of cancer, especially breast and prostate cancer--in which the incidence is approximately 70% among patients with advanced metastatic disease. Aminobisphosphonates (NBPs) have entered clinical practice in the treatment of bone metastases from several neoplasms, including breast and prostate adenocarcinoma, as a result of their anti-resorption properties. However, evidence has accumulated on the direct anti-tumour effects of NBPs. This review describes the metabolic pathways that are putative molecular targets of NBPs and that are involved in the prenylation processes of several intracellular small GTP-binding proteins (ras family related proteins). The latter regulate the intracellular survival and proliferative pathways of tumour cells and could be the intracellular molecular targets of the NBPs responsible for the direct anti-cancer effects, even if definitive conclusions cannot be drawn at present. Different mechanisms have been reported to account for the anti-neoplastic action of NBPs, including: the induction of apoptosis; cell cycle perturbations; and anti-invasive, anti-migration and anti-angiogenic effects. Moreover, this review describes the most important clinical studies that demonstrate the activity of NBPs in preventing skeletal-related events induced by bone metastases. The main pharmacokinetic pitfalls of NBPs are described, and methods of overcoming these pitfalls through the use of liposome vehicles are proposed. Finally, the principal pre-clinical studies on the interaction between NBPs and other biological agents are also described; these studies may enable reductions in the in vivo NBP concentrations required to achieve anti-tumour activity. To date, however, the real molecular targets of NBPs are not completely known and new technological platforms are required in order to detect them and to develop new anti-cancer strategies based on the use of NBPs.

Abstract: PURPOSE: To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC). PATIENTS AND METHODS: Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival. RESULTS: The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis. CONCLUSION: Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.

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Abstract: CASE REPORT: The case of a breast cancer patient with a progressive increase of CA 19.9 that indicated gastrointestinal metastasis is reported. After the observation of an increased CA 19.9 serum value (104.00; n.v. 0.0-37.00) a colonoscopy was performed. This examination showed the presence of an erythematous and granular zone near the ileocecal valve. Histological examination of biopsies taken during the colonoscopy revealed atypical monomorphic cells between the organoid pattern of the colon-type ducts. Immunohistochemical staining was positive for cytokeratin 7 and for estrogen receptors, consistent with metastatic epithelial malignancy. After eleven months, the patient presented with signs of intestinal obstruction, requiring an ileocolic bypass. At definitive histological examination, the tumor exhibited features of mammary metastases. CONCLUSION: This is the first report in the literature of an ileocecal valve metastasis from breast cancer diagnosed by an increase of CA 19.9, which is a marker of primary colorectal carcinoma.

Abstract: Mucosal melanomas account for 1% of all malignant melanomas in humans. Treatment options include surgery, chemotherapy, immunotherapy and radiation therapy; however, local recurrence and distant dissemination are still frequent. We treated locally aggressive spontaneous canine oral melanomas that, because of their advanced stage, were not treatable with conventional strategies. A cohort of 10 dogs with oral melanoma was enrolled over a 4-year period. The dogs received two sessions of local bleomycin, followed by the application of trains of biphasic pulses. The treatment was well tolerated and resulted in an overall response rate of 80% with 50% long-term control. Of interest, only one of the dogs died of metastatic disease, and four of the long-term survivors showed a vitiligo-like discoloration at the site of treatment, potentially suggesting a recruitment of the immune system by the therapy. Further studies are needed to characterize this approach and to determine its suitability for head and neck mucosal melanoma.

Abstract: BACKGROUND: Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. METHODS: Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. RESULTS: A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%-56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 - 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 - 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 - 11.82). CONCLUSION: OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

Abstract: It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. The recent progress of scientific research has notably increased knowledge about biological events involved in lung cancer pathogenesis and progression, thanks to the use of molecular biology and immunohistochemistry techniques. Lots of the genetic alteration found in small cells lung cancer (SCLC) and in not small cells lung cancer (NSCLC) concern the expression of cell cycle genes, actually recognized as onco-suppressor genes and the lack of equilibrium between oncogenes and oncosuppressor genes. The present review of literature widely describes the cell cycle control, the lung cancer molecular pathogenesis, the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors, on the basis of the various hystological types too. Such data suggest the potential use of this knowledges in clinical practice both as prognostic factors and innovative therapeutic possibilities and they impose the necessity of new studies about cell cycle control and lung carcinogenesis.

Abstract: BACKGROUND: There is evidence that the anti-neoplastic effect of non-steroidal anti-inflammatory drugs is attributable to cyclooxygenase-2 (COX-2) inhibition, but the exact mechanisms whereby COX-2 can promote tumour cell growth remain unclear. One hypothesis is the stimulation of tumour angiogenesis by the products of COX-2 activity. To data, there have been few clinicopathological studies on COX-2 expression in human ampullary carcinoma and no data have been reported about its relation with tumour angiogenesis. Objective: To investigate by immunohistochemistry the expression of COX-2 and the angiogenesis process in a series of primary untreated ampullary carcinomas. METHODS: Tissue samples from 40 archival ampullary carcinomas were analysed for COX-2, vascular endothelial growth factor (VEGF), and an endothelial cell marker von Willebrand factor (vWF) by immunohistochemistry, using specific antibodies. RESULTS: COX-2 expression was detected in 39 tissue samples (97.5%), of which two (5%) were graded as weak, 26 (65%) as moderate, and 11 (27.5%) as strong. Only one lesion (2.5%) was negative for COX-2 expression. VEGF expression was detected in 36 tissue samples (90%). A significant positive correlation was found between COX-2 and VEGF expression. No statistic correlation was found between COX-2 expression and microvessel density. CONCLUSIONS: COX-2 is highly expressed in ampullary carcinomas. This suggests an involvement of the COX-2 pathway in ampullary tumour associated angiogenesis, providing a rationale for targeting COX-2 in the treatment of ampullary cancer.

Abstract: INTRODUCTION: Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We designed this trial to investigate the modification of the vascular endothelial growth factor (VEGF) and interferon-gamma (IFN-gamma) in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. MATERIALS AND METHODS: Forty-five metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF and IFN-gamma during the treatment with cetuximab (initial dose of 400 mg/m(2), followed by weekly infusions of 250 mg/m(2)) plus weekly irinotecan (90 mg/m(2)). The circulating levels of the cytokines were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. RESULTS: Basal serum VEGF median levels were significantly decreased just at the first day (after the first treatment infusion (P = 0.016). The VEGF persisted at the following time points reaching the highest statistical significance 92 days after the first infusion (P < 0.0001). On the contrary, IFN-gamma values showed a statistical significant increase one day after the first infusion (P < 0.0001). This effect persisted 21 days after the treatment start (P = 0.001), but was no more evident at the following time points. Moreover, a linear regression model with variance analysis showed a significant negative correlation between VEGF and IFN-gamma values 1, 21 and 50 days after the treatment beginning (P = 0.002, 0.001 and 0.047, respectively). CONCLUSIONS: This study suggests that a cetuximab may induce a modulation of VEGF circulating levels. The reduction of VEGF serum levels is a sudden and long lasting phenomenon. Moreover, in our study we identified a IFN-gamma increase, even if the specific role of this behavior remains to be investigated.

Abstract: BACKGROUND: The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. FDR gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. The goals of this phase I study were to determine the maximum-tolerated dose (MTD) of chronomodulated capecitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT), the safety profile of this way of administration. METHODS: Patients with advanced solid tumours who had failed to response to standard therapy or for whom no standard therapy was available were eligible for this study. Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days, followed by a 7-day rest period. RESULTS: All 27 patients enrolled onto the study were assessable for toxicity. The most common toxicities during the first two cycles of chemotherapy were fatigue, diarrhoea and hand foot syndrome (HFS). Only one out of the nine patients treated at capecitabine dose of 2,750 mg/m2 met protocol-specified DLT criteria (fatigue grade 4). However, at these doses the majority of cycles of therapy were delivered without dose reduction or delay. No other episodes of DLT were observed at the same dose steps and at the lower dose steps of capecitabine (1,500/1,750/2,000/2,250/2,500 mg/m2). The dose of 2,750 mg/m2 is recommended for further study. Tumor responses were observed in patients with metastatic breast and colorectal cancer. CONCLUSION: High doses of chronomodulated capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.

Abstract: The epidermal growth factor receptor (EGFR), which participates in signalling pathways that are deregulated in cancer cells, is frequently mutated in colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We evaluated the efficacy of cetuximab in weekly combination with irinotecan in metastatic colorectal cancer patients refractory to previous treatments based on oxaliplatin or irinotecan. We included 55 heavily pretreated patients (colon/rectum: 34/11, M/F: 16/29, median age 63 years, range: 27-79) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy and a irinotecan-based second-line regimen. Patients were followed for tumour response and were also evaluated for the time to tumour progression, and safety of treatment. Cetuximab was given at an initial dose of 400 mg m(-2), followed by weekly infusions of 250 mg m(-2). Irinotecan was administered weekly at the dose of 90 mg m(-2). All patients were assessable for treatment efficacy and safety response rate was 25.4% (95% CI: 21.7-39.6%); 38.2% (95 CI: 18.6-39.8%) of patients showed a disease stability as the best response. As a consequence, the overall tumour control rate was 63.6% (95% CI: 46.4-70.6%). The median time to progression was 4.7 months (95% CI: 2.5-7.1 months) and the median survival time was 9.8 months (95% CI: 3.9-10.1 months). The most common G3-4 noncutaneous side toxicities were: diarrhoea (16.4%), fatigue (12.7%) and stomatitis (7.3%). 89.1% of patients developed skin toxicity and 32.6% of cases was of grade 3-4. No allergic reactions were identified at any courses in any patients. Fever was documented in 27.3% of patients and was most commonly recorded after the first administration. Cetuximab has clinically significant activity even in heavily pretreated colorectal cancer patients progressed after both oxaliplatin and irinotecan-based chemotherapy regimens.

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Abstract: A 76-year-old woman with a history of dyspnoea, weight loss and abdominal pain, was admitted to our Hospital. Sonographic and tomographic examinations showed the presence of a large adrenal gland tumor and the promptly performed adrenalectomy and splenectomy proved that the lesion was an adrenal gland carcinoma infiltrating the spleen. One month after surgical treatment, the patient's general condition dramatically worsened due to development of perirenal abscess and renal infarction; finally, the patient died. In accordance with literature, we decided to only perform adrenalectomy and splenectomy that are the treatment of choice in these cases. In fact, complications are unforeseeable and avoiding the resection of the kidney surely offered the patient a better life quality.

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Abstract: CASE REPORT: Primary low-grade fibromyxoid sarcoma (LGFMS) is an extremely rare tumour of the salivary glands and arises from undifferentiated pluripotential mesenchymal cells. We report a case of a huge (17 x ll x 10 cm) primary LGFMS of the parotid gland of a 57-year-old woman. Clinically, a 12x8 cm firm, non-tender, left parotid mass was observed, facial nerve function was not impaired and no enlarged lymph nodules were palpated on the neck. A contrast axial CT scan showed intense enhancement of the enlarged left parotid gland. The fine needle aspiration biopsy (FNAB) was compatible with sarcomatous tissue. The tumour was removed en bloc and the facial nerve was sacrificed; surgical margins were free from disease. Microscopically, the tumour consisted of fibrous and myxoid tissue with varying grades of cellularity and gradual transitions between the two. Post-operative radiotherapy was carried out on the left neck region and parotid tumour bed. Thirty-six months after surgery the patient presents good general conditions without any evidence of local or regional disease. CONCLUSION: The largest primary LGFMS of the parotid gland described in the literature is reported and a review of the literature on such neoplasms is also provided.

Abstract: Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. Moreover, in vivo preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. This comprehensive review critically reports the several preclinical evidences of action of bisphosphonates on osteoclasts, lymphocytes and tumour cells. In addition, all the clinical trials evaluating the effects of principal bisphosphonates on skeletal disease progression in patients with breast cancer, prostate cancer, non-small cell lung cancer and other cancers have been reported. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is actually approved for the treatment of bone metastases from any solid tumour in many countries. Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. This issue and the other topics relating to the safety of bisphosphonates are discussed in this review.

Abstract: Bisphosphonate (BPs) therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that BPs exert their direct or indirect antitumoral effects on cancer growth factor release, on cancer cell adhesion, invasion and viability, on cancer angiogenesis and on cancer cell apoptosis. Here, after a brief analysis on clinical indications, on the last generation amino-bisphosphonates (N-BP) and on biochemical pathways as molecular targets of BPs, we will discuss the molecular mechanisms of these antitumor effects. Recent evidence suggests that part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect. For this reason, we will analyse all the in vitro and in vivo preclinical reports and the first clinical evidence of anti-angiogenic activity exerted by this class of drugs. Several patents have been reported in the review, considering the recents activities observed for these drugs. Taking together all the major results obtained in the described studies, it is possible to affirm that BPs, particularly zoledronic acid and pamidronate, could potentially represent a very powerful tool for angiogenesis inhibition leading to a better control of cancer growth and progression. The translation into the clinical setting of the preclinical evidence of an antiangiogenic power of these drugs is becoming an imperative need and should represent the objective of future clinical trials.

Abstract: HtrA1 is a serine protease homologue to the bacterial serine-protease HtrA, also known as DegP, a heat shock-induced envelope-associated serine protease. It has been shown that over-expression of HtrA1 in human cancer cells inhibits cell growth and proliferation in vitro and in vivo, thus, suggesting a possible role as a tumor suppressor. The expression of HtrA1 was investigated in depth by means of immunohistochemistry in a large group of human lung cancer specimens and corresponding lymph node metastases. Univariate analysis showed, that the only statistically significant correlation was found between the HtrA1 expression level detected in the primary tumors and in the lymph node metastases. This result was also confirmed when the analysis was restricted only to the cases where both the primary tumor and the autologous lymph node metastasis were available. Our data suggest that HtrA1 may be involved in lung cancer progression by targeting several molecular pathways.

Abstract: BACKGROUND: Electrochemotherapy (ECT) is a novel anticancer therapy that combines the delivery of trains of appropriate waveforms with the local administration of chemotherapy agents. The purpose of this investigation was to assess the adjuvant potentials of ECT for the treatment of incompletely excised mast cell tumors (MCT). MATERIALS AND METHODS: Twenty-eight privately-owned dogs with incompletely removed MCT were treated with intralesional bleomycin (1.5 IU/cm2) followed by the application of trains of biphasic pulses (8 pulses, 1300 V/cm, 50 + 50 micros duration, 1 Hz frequency). RESULTS: The overall response rate was 85% with a mean estimated time to recurrence of 52.76 +/- 6.5 months (range: 39.99 to 65.54 months, 95% CI). At the time of writing this report, the median survival time was not reached. Three dogs died of metastatic disease that they developed at the same time of local recurrence, one developed multiple cutaneous nodules at different locations and one with recurrence was re-treated and is currently disease-free after 22 months. No major local or systemic toxicities were noted for the duration of the study. CONCLUSION: ECT is a safe and effective therapy for incompletely excised MCTs in companion animals. Its ease of administration, lack of toxicities and low cost make it an attractive alternative to standard treatments and warrants further investigation.

Abstract: Colorectal cancer (CRC) represents a major health problem in the Western world. Approximately 60% of patients with CRC require systemic therapy for metastatic disease, either at diagnosis or at disease recurrence. Until recently, classic chemotherapeutic agents have been combined in the treatment of advanced CRC. The recent considerable development of novel monoclonal antibodies that target key components of biological pathways has expanded the options to treat advanced CRC patients. These newer agents more specifically target unique features of the cancer cell and its surroundings and so attempt to exploit the progress that has been made in the understanding of basic cell biology. Two targets in particular--the process of new blood vessel development, or angiogenesis, and the EGF receptor and its signalling pathway--are exploited by the newest monoclonal antibodies available for use in this setting. This clinical review focuses on the defining role of the two most clinically advanced novel agents, bevacizumab and cetuximab in metastatic colorectal cancer.

Abstract: Paraneoplastic syndromes are a group of clinical disorders associated with malignant diseases that are not directly related to the physical effects of primary or metastatic tumor. Those that are associated with the secretion of circulating peptides may be used as a useful tool in monitoring patients after the start of chemotherapy. Most of the paraneoplastic syndromes represent an interesting tool of internal medicine. Moreover, they also represent a starting point for a work up in patients with an occult neoplasia, even though the clinical presentation may be very multifaceted. As consequence of all these considerations, the present editorial represents a useful tool for a rational approach to paraneoplastic syndromes.

Abstract: Epidemiological studies suggest that regular intake of nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced incidence of gastrointestinal cancer. Several lines of evidence indicate that the antineoplastic effect of NSAIDs is attributable to COX-2 inhibition. The aim of our study was to assess COX-2 expression in a series of primary untreated ampullary carcinomas and its possible correlation with clinicopathological parameters. In the present study, 45 surgical specimens of invasive ampullary carcinomas were histologically classified into pancreaticobiliary, intestinal, and unusual types. COX-2 expression by immunohistochemical method was analyzed. High COX-2 expression was detected in 35 (77.8%) ampullary carcinomas. Among these, 20/21 (95.2%) were classified as intestinal, 9/18 (50%) pancreaticobiliary, and 6/6 (100%) unusual type. A significant statistical difference in terms of COX-2 expression was found between pancreaticobiliary vs intestinal type (P=0.002). Furthermore, a negative significant statistical correlation was found between T factor and COX-2 expression (P=0.047). The different COX-2 expression among histopathological types supports the concept of histogenetical difference of ampullary carcinomas. Furthermore, the high rate of COX-2 expression in the intestinal subtype of ampullary carcinoma may represent the rational for a histotype-tailored therapy targeting COX-2.

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Abstract: PURPOSE: The aim of the present study was to evaluate the effects of piroxicam, a widely used nonsteroidal anti-inflammatory drug, alone and in combination with cisplatin (CDDP), on cell growth of mesothelioma cells. EXPERIMENTAL DESIGN: Cell proliferation, cell cycle analysis, and microarray technology were done on MSTO-211H and NCI-H2452 cells treated with piroxicam. Moreover, the effects of piroxicam and CDDP on tumor growth and survival of mouse xenograft models of mesothelioma were determined. RESULTS: Piroxicam treatment of MSTO-211H and NCI-H2452 cells resulted in a significant inhibition of proliferation. Cell cycle analysis revealed that there was an increase in the rate of apoptosis in MSTO-211H cells and an increase in the cells accumulating in G2-M in NCI-H2452. Moreover, a marked tumor growth inhibition and an extended survival of mice treated with a combination of piroxicam and CDDP in MSTO-211H cell-induced peritoneal mesotheliomas was observed. Last, GeneChip array analysis of MSTO-211H mesothelioma cell line revealed that piroxicam treatment caused up-regulation of metabolic pathway-associated genes and down-regulation of genes related to RNA processing apparatus. Of note, epidermal growth factor receptor, one of the new biological targets of chemotherapy for mesothelioma, was down-regulated and HtrA1, a serine protease recently shown to be an endogenous mediator of CDDP cytotoxicity, was up-regulated following piroxicam treatment both in vitro and in vivo. CONCLUSION: These data suggest that piroxicam sensitizes mesothelioma cells to CDDP-induced cytotoxicity by modulating the expression of several target genes. Therefore, piroxicam in combination with CDDP might potentially be useful in the treatment of patients with mesothelioma.

Abstract: For patients with malignant bone disease, bisphosphonate therapy is the standard treatment. Preclinical and preliminary clinical data suggest that bisphosphonates have direct or indirect antitumor effects: they affect growth-factor release, cancer-cell adhesion, invasion and viability, angiogenesis, and apoptosis of cancer cells. These effects might be enhanced through co-administration with chemotherapy agents, biological agents, or both. We survey the biochemical pathways and molecular targets of bisphosphonates, and discuss the molecular mechanisms of these antitumor effects, as well as the documented antineoplastic preclinical effects of bisphosphonates used in combination with cytotoxic and biological drugs. Moreover, the positive interactions between bisphosphonates and farnesyltransferase inhibitors, KIT receptor tyrosine kinase inhibitors (e.g. imatinib mesylate) and cyclo-oxygenase-2 inhibitors are discussed in relation to their potential synergistic and additive effects. We briefly discuss identification of new molecular targets of bisphosphonates from genomic and proteomic analysis, and highlight the cellular consequences of drug-related enzyme inhibition.

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Abstract: PURPOSE: To identify potential prognostic molecular factors in ampullary adenocarcinoma that could be of significant importance. To this end, we examined the possible prognostic significance of cyclooxygenase-2 (Cox-2) and Survivin expression and the apoptotic index in a cohort of uniformly treated patients with ampullary cancer treated with radical surgical excision. EXPERIMENTAL DESIGN: The entry criteria were that the patients have a pathologic diagnosis of ampullary cancer which had been resected. Expression analysis for Cox-2 and Survivin was done by immunohistochemical staining. Apoptotic cells were identified by the terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. RESULTS: Thirty-nine tumor specimens from resected ampullary adenocarcinoma patients were included. By univariate analysis, overall survival was affected by Cox-2 expression and TUNEL staining (respectively, P = 0.0003 and 0.03). Survivin expression did not influence the overall survival in our patient population (P = 0.123). Patients' clinicopathologic features (gender, age, and T and N factors) did not influence outcome. In multivariate Cox regression analysis, Cox-2 expression (relative risk, 4.330; P = 0.005) was the only variable that significantly affected overall survival. CONCLUSIONS: The results of the present article provide, for the first time, evidence that Cox-2 expression, but not Survivin expression, may represent a significant prognostic factor after surgical resection in patients affected by cancer of the ampulla of Vater. Further studies are required to determine whether Cox-2 inhibitors may be useful for the therapy or prevention of ampullary carcinoma.

Abstract: AIMS: There is considerable evidence that links COX-2 to the development of cancer. The aim of our study was to assess, by immunohistochemistry, COX-2 expression in ductal carcinoma in situ (DCIS) and its possible correlation with HER-2/neu, vascular endothelial growth factor (VEGF) expression and other common immunohistochemical parameters (p53, ER, PGR, Ki67). METHODS AND RESULTS: Tissue samples of 49 archival cases of DCIS without any invasive component were analysed for COX-2, HER-2/neu, VEGF, oestrogen and progesterone receptors, Ki67 and p53 by immunohistochemistry using specific antibodies. COX-2 expression was detected in 43 (87.8%) tissue samples, of which 12 (24.5%) were graded as weak, 22 (44.9%) as moderate and nine (8.4%) as high expression. Only six (12.2%) lesions were negative for COX-2 expression. VEGF expression was detected in 93.8% of samples; 66.7% of lesions were found to be positive for HER-2/neu expression. Furthermore, COX-2 expression was significantly correlated with VEGF expression (P = 0.003). A significant positive correlation was also observed between COX-2 and HER-2/neu expression (P < 0.0001). CONCLUSIONS: Our results suggest that COX-2 is highly expressed in DCIS and takes part in the molecular pathway implicated in progression of breast cancer and may provide a rationale for targeting COX-2 in preinvasive breast cancer therapy.

Abstract: BACKGROUND: Chronic anemia is a well-recognized complication of both cancer and cytotoxic treatments and is associated with symptoms (e.g., fatigue, dyspnea) that may induce or exacerbate functional deterioration. The use of recombinant human erythropoetin (rHuEPO epoetin alfa) clearly increased haemoglobin (Hb) levels, decreased transfusion needs and allowed recovery of quality of life in anemic cancer patients (pts) undergoing chemotherapy (CT). The purpose of this open-label, non randomized, pilot study was to assess the safety and efficacy of an intensive 19-day epoetin alfa treatment in anemic patients with solid tumors receiving chemotherapy. PATIENTS AND METHODS: Treatment: patients received a single induction s.c. dose of epoetin alfa 40,000 IU day 1 and twice a dose of 10,000 IU s.c. (8.00 a.m.- 8:00 p.m.) on days 3, 5, 8, 10, 12, 15, 17 and 19. The total dose of epoetin alfa per patient was 200, 000 IU. Iron supplementation: 125 mg i.v. days and 8. Soluble transferrin receptor (sTfR) levels were performed on days 1,8 and 15. This epoetin induction regimen was not followed by an epoetin maintenance therapy. PATIENTS: Twenty-nine anemic (Hb< or =11.5 g/dL) pts with non myeloid malignancies undergoing CT were included in the study. RESULTS: At baseline the mean Hb level was 9.41 g/dl. On day 8, the mean Hb level increased to 10.07 g/dl (p<0.0001), reaching 10.68 g/dl on day 15 (p<0.0001). On days 22 and 29, the mean Hb levels increased to 10.93 and 11.05 g/dl, (p=0.002 and 0.033, respectively). No patient received blood transfusions. The global mean increase of Hb level was 1.64 g/dl (basal to d 29). It was defined as a major response: an increase of Hb levels > 1.5 g/dl. A rate of 62% (18/29 patients) of major responses was observed on day 21. Moreover, 25/29 patients (86.2%) presented an increase of Hb levels > 1 g/dl after 21 days. On days 8 and 15, the mean sTfR levels had increased significantly ( p=0.021 and 0.001, respectively). The increase of mean sTfR level after 15 days correlated significantly with the increase of mean Hb level in the first two weeks of epoetin therapy (p=0.05). Epoetin alfa has been well tolerated so far in the study. CONCLUSION: The results of the present study suggest that an induction dose of 40,000 IU of epoetin alfa, followed by 8 maintenance doses of 20,000 IU each, may improve the standard response in terms of both time to response and Hb increase. Moreover, the Hb levels seemed to increase after epoetin therapy discontinuation (d22-29).

Abstract: BACKGROUND: There is a lack of data in the literature concerning the identification of potential prognostic factors in ampullary adenocarcinoma. AIMS: To examine the prognostic significance of Bax, Bcl-2, and p53 protein expression and the apoptotic index in a large cohort of uniformly treated patients with radically resected ampullary cancer. METHODS: All patients with a pathological diagnosis of ampullary cancer and radical resection were evaluated. Expression analysis for p53, Bax, and Bcl-2 was performed by immunohistochemistry. Apoptotic cells were identified by terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Thirty nine tumour specimens from patients with radically resected ampullary adenocarcinoma were studied. A positive significant correlation between Bax and p53 expression was found by rank correlation matrix (p < 0.001). A trend towards a positive correlation was found between the apoptotic index and p53 expression (p = 0.059). By univariate analysis, overall survival was influenced by Bax expression, p53 expression, and TUNEL staining (p = 0.001, p = 0.01, and p = 0.03, respectively). Bcl-2 expression did not influence overall survival in these patients (p = 0.55). By multivariate Cox regression analysis, the only immunohistochemical parameter that influenced overall survival was Bax expression (p = 0.020). CONCLUSIONS: These results provide evidence that apoptosis may be an important prognostic factor in patients with radically resected ampullary cancer. This study is the first to assess the clinical usefulness of Bax expression in radically resected ampullary cancer.

Abstract: Pancreatic cancer is one of the most aggressive gastrointestinal cancer with less than 10% long-term survivors. The apoptotic pathway deregulation is a postulated mechanism of carcinogenesis of this tumour. The present study investigated the prognostic role of apoptosis and apoptosis-involved proteins in a series of surgically resected pancreatic cancer patients. All patients affected by pancreatic adenocarcinoma and treated with surgical resection from 1988 to 2003 were considered for the study. Patients' clinical data and pathological tumour features were recorded. Survivin and Cox-2 expression were evaluated by immunohistochemical staining. Apoptotic cells were identified using the TUNEL method. Tumour specimen of 67 resected patients was included in the study. By univariate analysis, survival was influenced by Survivin overexpression. The nuclear Survivin overexpression was associated with better prognosis (P = 0.0009), while its cytoplasmic overexpression resulted a negative prognostic factor (P = 0.0127). Also, the apoptotic index was a statistically significant prognostic factor in a univariate model (P = 0.0142). By a multivariate Cox regression analysis, both the nuclear (P = 0.002) and cytoplasmic (P = 0.040) Survivin overexpression maintained the prognostic statistical value. This is the first study reporting a statistical significant prognostic relevance of nuclear and cytoplasmic Survivin overexpression in pancreatic cancer. In particular, patients with high nuclear Survivin staining showed a longer survival, whereas patients with high cytoplasmic Survivin staining had a shorter overall survival.

Abstract: The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

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Abstract: OBJECTIVES: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. METHODS: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. TREATMENT: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1-14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. RESULTS: Most frequent related G3-4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3-4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0-15.7 months), the median response duration 2.8 months (95% confidence interval 1.2-5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7-6.3 months). The 1-year survival rate was 53.8%. CONCLUSIONS: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC.

Abstract: We report the case of a 47-year-old HIV-negative male affected by a perianal ulcer which occurred after chemoradiation delivered for anal cancer. In spite of a negative biopsy the lesion was highly suspected to be a disease recurrence. Uncontrollable pain and anal stenosis were also present; abdominoperineal resection with a large excision of perianal tissues and reconstruction with bilateral musculocutaneous gracilis flaps was therefore performed. Histology did not confirm tumor recurrence. Thirteen months after surgery, the patient is still alive and free of disease. The introduction of radiotherapy and concomitant chemotherapy has revolutionized the treatment of anal cancer, avoiding demolitive surgery in a large subset of patients. Radionecrosis is an uncommon but potentially devastating event occurring in up to 10% of patients undergoing radiotherapy for anal cancer. It causes clinical (pain, anal stenosis, mucositis and diarrhea) and diagnostic problems (recurrence vs. benign post-attinic lesion). In the present article we review this uncommon complication, discuss the technical surgical aspects associated with a very large perianal tissue removal, and data of the most recent literature in this field.

Abstract: Significant progress has been made in the development of effective, convenient and well-tolerated means to prevent chemotherapy-induced nausea and vomiting (CINV). Nevertheless, a substantial minority of patients continue to have suboptimal antiemetic control, and additional treatment approaches are needed. One avenue of investigation being pursued involves the evaluation of a new 5-hydroxytryptamine (5-HT(3)) receptor antagonist (palonosetron) that differs from available serotonin antagonists in its markedly longer half-life (40 h) and greater binding affinity for the type-3 serotonin receptor. Analysis of available clinical data demonstrates that palonosetron is an active and well-tolerated new 5-HT(3) antagonist. Moreover, single-dose palonosetron, prior to chemotherapy, has demonstrated improved control of CINV through the full period of emetic risk with a single dose. Palonosetron is recommended as the preferred treatment of acute and delayed emesis prevention with moderate emetic risk chemotherapy in the most recently published evidence-based antiemesis consensus guidelines. Further studies incorporating dexamethasone to 5-HT(3) antagonists will be necessary to determine the relative efficacy of palonosetron compared with available agents. These trials could open a new era in the treatment of CINV.

Abstract: The expression of the extracellular matrix-related genes, such as fibronectin, laminin and tenascin C, and apoptosis-related genes, such as bax, bcl2 and survivin, was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and by immunohistochemistry in normal breast tissue and benign and malignant breast tumors and then correlated to several clinical parameters: estrogen and progesterone receptors, Ki67, ErbB2, tumor size, lymph node status and grading. Seventy-three breast tissue samples were examined. After RNA extraction, an RT-PCR was performed to detect fibronectin, laminin, tenascin C, bax, bcl2 and survivin gene expression. Thirty-two samples were evaluated also by immunohistochemistry at the protein level to detect fibronectin, laminin, tenascin C, bax and survivin. We found a significant correlation (P=0.025) between fibronectin gene expression and lymph node status, and a significant negative correlation (P=0.049) between laminin gene expression and Ki67. In addition, we found a statistically significant increase in survivin transcription in malign tumors compared to fibroadenomas (P=0.024). The negative correlation between laminin transcription and Ki67 could suggest that laminin impacts negatively on tumor proliferation, and the positive correlation between fibronectin and lymph node status may lead to consider fibronectin as predictive of long distance metastasis.

Abstract: BACKGROUND: Induction chemotherapy followed by surgical resection or definitive radiotherapy for patients affected by stage IIIA N2 bulky non-small cell lung cancer (NSCLC) has been investigated in several trials. PATIENTS AND METHODS: In this present study, 52 patients with stage IIIA N2 bulky NSCLC with cytologically or histologically confirmed mediastinal lymph node involvement received paclitaxel 175 mg/mq on day 1, carboplatin AUC 5 on day 1 and gemcitabine 1,000 mg/mq on day 1 and 8 every 3 weeks for three cycles as induction chemotherapy. RESULTS: Objective response (4 complete remission and 36 partial remission) was achieved in 40/52 patients. No early or toxic deaths were observed. Twenty-two patients were surgically explored. Fifteen were excluded for resection for biopsy-proven residual tumour in mediastinal nodes. Complete surgical resection was performed in 15 patients with confirmed pathological downstaging. Pathological complete response was achieved in 4 patients. No surgery-related mortality or significant morbidity was reported. Adjuvant radiotherapy was delivered in 15 patients, and 30 patients received definitive radiotherapy. CONCLUSION: In the present study, the combination of paclitaxel, carboplatin and gemcitabine has been a safe and active regimen in poor-prognosis stage IIIA N2 bulky NSCLC.

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Abstract: BACKGROUND: Experimental evidence suggests that lung cancer development and progression can be linked to an increased proliferation rate. AIMS/METHODS: To evaluate the immunohistochemical expression of seven components of the cell cycle machinery in a series of well characterised non-small cell lung cancer (NSCLC) specimens (n = 105). RESULTS: Multivariate analysis revealed that simultaneous loss of expression of three of these factors--cyclin D1, the cyclin dependent kinase inhibitor p16, and the tumour suppressor retinoblastoma protein Rb2/p130--correlated with survival, confirming the hypothesis that the cyclin D1-p16-retinoblastoma tumour suppressor pathway is inactivated in most lung cancer samples. CONCLUSIONS: These results suggest that loss of control of cell cycle checkpoints is a common occurrence in lung cancer and support the idea that functional cooperation between different cell cycle regulatory proteins constitutes another level of regulation in cell growth control and tumour suppression.

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Abstract: BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.

Abstract: BACKGROUND: To report the efficacy of induction treatment (IT) protocol with concurrent radiochemotherapy in locally advanced non-small-cell lung cancer (NSCLC), and to analyze downstaging as a surrogate end point. PATIENTS AND METHODS: Patients with histo- or cytologically confirmed stage IIIA or IIIB NSCLC were treated according to an IT protocol followed by surgery. Downstaging was assessed for all resected patients. RESULTS: In the period between February 1992 and July 2000, 92 patients were enrolled in the study (57 IIIA, 35 IIIB). Response was observed in 63 patients; 56 patients underwent radical resection. Patients downstaged to stage 0-I (DS 0-I) showed a statistically significant improved disease-free survival (26.2 months pStage 0-I versus 11.2 months pStage II-III; P=0.0116) and overall survival (median 32.5 months pStage 0-I versus 18.3 months pStage II-III; P=0.025). Patients with DS 0-I had a significantly lower probability (P=0.0353) of developing distant metastases estimated in 0.2963 odds ratio. CONCLUSION: Neoadjuvant radiochemotherapy is feasible with good pathological DS results. Pathological downstaging was confirmed to have high predictive value. Its use is suggested in the short-term evaluation of induction protocols efficacy in locally advanced NSCLC.

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Abstract: BACKGROUND/AIMS: Abnormalities of the proteins involved in cell cycle checkpoints are extremely common among almost all neoplasms. This study aimed to investigate the expression of four components of the cell cycle machinery-p21, p16, p53, and proliferating cell nuclear antigen (PCNA)-in non-small cell lung cancer (NSCLC). METHODS: The expression of p21, p16, p53, and PCNA was examined in 68 well characterised NSCLC specimens using immunohistochemistry. The coregulation of these proteins and their influence on survival were analysed using both univariate and multivariate analyses. RESULTS: By univariate analysis, the expression of all the proteins examined, except for PCNA, was significantly correlated with survival. In multivariate analysis, the only immunohistochemical parameter able to influence overall survival was p16, confirming the hypothesis that the RB-p16 tumour suppressor pathway is inactivated in most lung cancer samples. Finally, the group of patients with NSCLC who were negative for both p21 and p16 had a significantly shorter overall survival. CONCLUSIONS: These results suggest that loss of control of cell cycle checkpoints is a common occurrence in lung cancers, and support the idea that functional cooperation between different cell cycle inhibitor proteins constitutes another level of regulation in cell growth control and tumour suppression.

Abstract: OBJECTIVE: Radical surgical treatment improves the prognosis of patients affected by Inferior Vena Cava (IVC) thrombosis concomitant to renal carcinoma. However, thrombus extension above the infrahepatic IVC represents a major technical topic for surgeons because of the possible occurrence of uncontrollable haemorrhages and tumor fragmentation. We report the results of an innovative surgical approach to caval thrombosis including the isolation of the IVC from the liver as routinely performed during liver harvesting. In the presence of retro-hepatic IVC thrombosis, this technique improves vascular control and allows to perform a large cavotomy with an en-bloc removal of the thrombus and the tumor. METHODS: From January 1995 through June 2003, 15 patients with renal cancer and caval thrombosis were treated at our Institution. Four, ten and one patients were respectively affected by an infrahepatic (Level I), retro-hepatic (Level II) and atrial (Level III) IVC thrombosis. RESULTS: All patients underwent radical surgical treatment. In presence of Level II caval thrombosis, the patients underwent the above reported surgical technique. Perioperative mortality was absent; major morbidity occurred in one patient (6.7%). The thrombus was radically removed in all cases. After a mean follow-up of 53.9 months (5-100 months) all patients but one are still alive. One patient died 9 months after surgery with multiple bilateral pulmonary metastases. CONCLUSIONS: Isolation of the retro-hepatic IVC is a safe and effective manoeuvre to significantly reduce perioperative mortality and morbidity in patients affected by Level II caval thrombosis concomitant to renal carcinoma.

Abstract: BACKGROUND: A study was undertaken to analyse the potential prognostic value of the immunohistochemical expression of cyclooxygenase-2 (COX-2) and p27 in 29 malignant mesotheliomas already screened for the expression of p21 and p53. METHODS: Immunohistochemistry was used to determine the expression of COX-2 and p27. The correlation with survival of these factors and of p21 and p53 expression was assessed by univariate and multivariate analyses. RESULTS: A positive statistically significant correlation was found between p27 and p21 expression (p<0.0001), but there was a negative correlation between COX-2 expression and both p27 (p = 0.001) and p21 (p<0.0001). No statistically significant correlation was recorded between p53 and all the other immunohistochemical parameters. Univariate analysis showed that overall survival was strongly influenced by p21, p27, and COX-2 expression, but multivariate Cox regression analysis showed that the only immunohistochemical parameter to influence overall survival of patients with mesothelioma was COX-2. CONCLUSIONS: These findings suggest that COX-2 expression may be a useful prognostic parameter for mesothelioma.

Abstract: AIM: The primary aims of this study were activity and toxicity evaluation of a new raltitrexed and oxaliplatin-based regimen, as a first-line chemotherapy, in patients with metastatic colorectal cancer (MCC). Survival evaluation was considered a secondary endpoint. PATIENTS AND METHODS: Forty-four patients were enrolled into this phase II trial. Treatment consisted of raltitrexed 3 mg/m2 iv on d 1 and oxaliplatin 70 mg/m2 iv on d 1 and d 8 every 3 wk. RESULTS: Twenty patients (45.5%) achieved a response [95% confidence interval (CI): 30.1% to 54.1%], 18 (40.9%) had stable disease, and only 6 (13.6%) developed progressive disease. After a median follow-up time of 14.7 mo (range 6.3-18.6 mo), the median time to disease progression was 6 mo (range 2.0-16.7) (95% CI: 4.4-7.6) and the overall survival was 14.8 mo (range 3-23) (95% CI: 11.2-18.4). Neutropenia was the most common hematological side effect, while transient AST/ALT increase, neurotoxicity, asthenia, and diarrhea were the most common nonhematological side effects. CONCLUSIONS: Our data confirmed that oxaliplatin administered weekly plus raltitrexed is an active combination in newly diagnosed patients with advanced colorectal carcinoma that merits further investigation versus the classic schedule in a randomized, phase III trial.

Abstract: OBJECTIVES: We retrospectively evaluated the relevance of thymidylate synthase (TS) expression in normal colonic mucosa as a predictive factor of toxicity in colorectal cancer patients receiving adjuvant fluorouracil (5-FU)-based chemotherapy. METHODS: TS expression was immunohistochemically assessed on normal colonic mucosa from 50 patients with colorectal cancer Dukes' stages B (15 patients) and C (35 patients) treated with 5-FU-based adjuvant chemotherapy. RESULTS: The incidence of grade 2-3 diarrhea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (p < 0.0001). Moreover, patients with low TS expression in normal colonic mucosa developed weight loss and worsening of the performance status (according to ECOG score) more commonly than patients with high TS expression (p = 0.005 and p = 0.02, respectively). Furthermore, low TS expression in normal colonic mucosa significantly correlated with a higher rate of a delay of chemotherapy courses, dose reduction and treatment discontinuation. CONCLUSIONS: Immunohistochemical TS expression in normal colonic mucosa may represent an important predictive parameter for identifying a subset of patients with a high risk of developing severe 5-FU-related toxicities.

Abstract: This study was designed to elucidate the possible relationship between tumour related genes and angiogenesis in colon cancer. The protein expression of p53, bcl-2, Von Willebrand factor and vascular endothelial growth factor (VEGF) were analysed by immunohistochemistry in 57 paraffin-embedded colon cancer. The results showed that microvessel density (MVD) was lower in VEGF negative tumours than in VEGF positive ones (P<0.0001). MVD and VEGF in p53 negative tumours were significantly lower than in p53 positive tumours (respectively, P=0.003 and P<0.0001). Moreover, positive correlations were recorded between VEGF expression and MVD, and bcl-2 expression (respectively, P<0.0001 and P=0.009). Our data confirm the central role of VEGF in angiogenesis and suggest direct correlations among p53, bcl-2 and VEGF expression in colon cancer.

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Abstract: Colorectal cancer represents a major health problem in the western world. A lot of drugs have been employed in treatment of this disease, but only few data are available about predictive factors for response to anticancer treatments in colorectal cancer. Aim of this paper is to review the main data about this investigation field. Using a Medline database search (1966-2003) we reviewed all the relevant papers that investigate clinical and molecular predictors for response to the main drugs used in the treatment of colorectal cancer patients, both in adjuvant and in advanced setting. Moreover we comprehensively reviewed all the data published in abstract form during the most significant international meetings. Our review put in evidence the most important predictive factors for response in colorectal cancer patients treated with anticancer chemotherapy both in adjuvant and in advanced setting. The predictive factors are clustered on the basis of the different anticancer drugs. The results of this review provide the rationale basis for personalizing anticancer treatment in colorectal cancer patients by molecular and clinical features, aiming to improve response rate and reduce toxicities.

Abstract: AIMS: To evaluate the prognostic impact of tumour angiogenesis assessed by vascular endothelial growth factor (VEGF), microvessel density (MVD), and tumour vessel invasion in patients who had undergone radical resection for stage IB-IIA non-small cell lung cancer (NSCLC). METHODS: Fifty one patients (42 men, nine women; mean age, 62.3 years; SD, 6.9) undergoing complete surgical resection (35 lobectomy, 16 pneumonectomy) of pathological stage IB (n = 43) and IIA (n = 8) NSCLC were evaluated retrospectively. No patient underwent postoperative chemotherapy or neoadjuvant treatment. Tumour specimens were stained for VEGF and specific MVD markers: CD31, CD34, and CD105. RESULTS: VEGF expression significantly correlated with high CD105 expression (p < 0.0001) and tumour vessel invasion (p = 0.04). Univariate analysis showed that those patients with VEGF overexpression (p = 0.0029), high MVD by CD34 (p = 0.0081), high MVD by CD105 (p = 0.0261), and tumour vessel invasion (p = 0.0245) have a shorter overall survival. Furthermore, multivariate Cox regression analysis showed that MVD by CD34 (p = 0.007), tumour vessel invasion (p = 0.024), and VEGF expression (p = 0.042) were significant predictive factors for overall survival. Finally, the presence of both risk factors, tumour vessel invasion and MVD by CD34, was highly predictive of poor outcome (odds ratio, 3.4; 95% confidence interval, 1.7 to 6.5; p = 0.0002). CONCLUSIONS: High MVD by CD34 and tumour vessel invasion are more closely related to poor survival than the other neoangiogenetic factors in stage IB-IIA NSCLC. This may be because these factors are more closely related to the metastatic process.

Abstract: Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-alpha and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.

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Abstract: PURPOSE: To provide specialists and general practitioners with a review of the more recent data about anthracycline-induced cardiotoxicity and diagnostic methods utilized to reveal it. DESIGN: Reviewers identified studies concerning anthracycline cardiotoxicity, with special emphasis to those dealing with its pathogenesis and tools utilized for diagnosing it, by searching MEDLINE and reviewing references for retrieved articles. RESULTS: Three different clinical patterns of cardiotoxicity were described: acute, chronic and late. Highly sensitive tests are necessary for evaluating, during the time, the cardiotoxic effects associated with anthracycline-based therapy and to predict the development of cardiac dysfunction. For this reason, endomyocardic biopsy and radionuclide-based angiocardiography are considered the "gold standard". However, the bidimensional echocardiography is the most commonly performed because of its high specificity and sensitivity combined with low costs. CONCLUSIONS: The peer review of the most recent scientific literature clearly demonstrate that cardiotoxicity is an important complication of anthracycline-based therapy and that the cumulative dose greater than 550 mg/m2 is the main independent risk factor. For the evaluation of anthracycline-related cardiotoxicity, bidimensional echocardiography remains still the easier and faster method.

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Abstract: Both statins and bisphosphonates may inhibit cancer proliferation by two main different mechanisms: inducing apoptosis along cholesterol synthesis pathway and by antiangiogenic properties. Moreover, also an immunomediated mechanism could be involved in anticancer properties of these molecules. The association of these two drugs could represent an interesting pharmacological approach in anticancer treatment. The available data offer the rationale for future in vitro studies aimed at evaluating proapoptotic and antiangiogenic action of this association. If the results of vitro studies should confirm the hypothesis that statins potentiate the action of bisphosphonates, further clinical investigations could be mandatory to evaluate the efficacy of this new pharmacological approach in anticancer therapy.

Abstract: The regimen with paclitaxel and platinum compound (carboplatin or cisplatin) is the standard chemotherapy for patients with advanced ovarian cancer. Ototoxity for carboplatin and paclitaxel alone or combined is rarely observed. We report the case of a 35-year old female with advanced ovarian cancer who developed sudden bilateral sensorineural hearing loss related to paclitaxel and carboplatin based chemotherapy. This uncommon adverse effect of carboplatin and paclitaxel alone or combined is discussed and the literature reviewed. Hearing monitoring should be mandatory to evaluate the real incidence of clinical and sub-clinical hearing modification induced by carboplatin and paclitaxel based chemotherapy.

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Abstract: PURPOSE: The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. Experimental Design: Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. RESULTS: Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

Abstract: In this minireview the authors examine and discuss the radioprotective compounds and the new combination therapies for the prophylaxis of radiation-induced emesis. Radiation-induced emesis is an important secondary effect of this anticancer treatment and it represents one of the causes of therapy interruption and decay of life quality before the introduction of optimal control of radiation-induced emesis with new antiemetic drugs which ensure the continuance of radiotherapy and avoid time breaks, that could negatively influence the efficacy of anticancer treatment. The incidence, the severity or the latency of radiotherapy-induced nausea and vomiting are correlated both with the treatment features (fractions, total dose, irradiation site) and with the main clinical characteristics of the patients. In contrast to the very extensive literature on the prevention of chemotherapy-induced emesis, relatively few studies about the prevention of nausea and vomiting in patients submitted to radiotherapy have been published. Among antiemetic drugs for the prevention of emesis, benzamides and in particular metoclopramide, are widely used in clinical practice. The introduction of selective 5-HT3 antagonists in clinical practice produced an important improvement in control of chemotherapy induced emesis, but few published studies were aimed at evaluating the efficacy of these drugs in the prophylaxis of nausea and vomiting due to radiation exposure. We herewith present a brief summary of Clinical practice guidelines for the use of antiemetics in anticancer therapy recently published by ASCO (American Society of Clinical Oncology).

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Abstract: BACKGROUND: Although bone marrow is a common site of micrometastases for non-small cell lung cancer (NSCLC), thrombocytopathia and hemorrhagic diathesis are rare causes of death. CASE REPORT: A 57-year-old patient was admitted to the emergency room because of massive nosebleeding and hemoptysis. Routine blood analysis showed thrombocytopenia and prolonged bleeding time; results of functional platelet tests suggested concomitant thrombocytopathia. Routine chest X-ray revealed an 18 mm large spot in the right superior lobe. During the first hour of recovery the patient had another episode of nosebleeding. A bone marrow biopsy showed a wide infiltration with neoplastic cells. Histology was compatible with NSCLC. The clinical conditions and hematological parameters progressively deteriorated, and on the third day the patient died because of hypovolemic shock. CONCLUSION: This is a very rare clinical presentation of NSCLC characterized by massive bleeding due to thrombocytopenia and thrombocytopathia secondary to wide bone marrow infiltration.

Abstract: Defects in the apoptotic pathway represent a critical element in the progression of neoplastic disease and may also concur to determine treatment efficacy at the cellular level. Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling. In this study we analyzed, by immunohistochemistry, the expression of Fas protein in a group of 68 NSCLC (non-small cell lung cancer) specimens. Statistical analyses did not show any significant relationship between Fas immunohistochemical expression and clinical parameters of lung cancer patients, except for nodal status. Our data do not support the use of Fas as a molecular prognostic role in NSCLC. On the other hand, considering the role of the Fas-pathway in chemotherapy-induced apoptosis, further studies are required to analyze the potential value of Fas expression in predicting the response of NSCLC patients to chemotherapy.

Abstract: BACKGROUND: Liver toxicity can be observed during treatment with most chemotherapic agents, and represents one of the principal causes of dose reduction or chemotherapy delays. S-Adenosylmethionine (AdoMet) plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. Our study was aimed at assessing the protective effect of AdoMet supplementation in cancer chemotherapy-induced liver toxicity. PATIENTS AND METHODS: Fifty cancer patients who developed, for the first time, anticancer chemotherapy-induced liver toxicity were studied. Enrolled patients received oral AdoMet supplementation. RESULTS: AST, ALT and LDH levels recorded at the moment of the recognition of liver toxicity were significantly reduced after one week of AdoMet therapy (respectively p: 0.009, 0.0005 and 0.012). AST, ALT and LDH decrease was confirmed after two weeks of treatment. Furthermore, the effect on these enzyme levels persisted in the following chemotherapy courses, permitting our patients to perform the scheduled chemotherapy courses with a minimal number of dose reductions or administration delays. The efficacy of AdoMet supplementation was not influenced by the presence of liver metastases, and no appreciable side-effects were recognized. CONCLUSION: The results of our study clearly demonstrate a protective effect of AdoMet in cancer chemotherapy-induced liver toxicity. Further large phase III studies are required to assess the real clinical benefit associated with AdoMet supplementation.

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Abstract: The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-alpha, interferon-gamma (IFN-gamma), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-alpha circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p < 0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to the median basal values 2 days after zoledronic acid administration. Moreover, in patients who experienced fever, the TNF-alpha and IL-6 increases were higher than in patients without fever. No statistically significant differences in IFN-gamma were identified at different time points in patients with and without fever. Our results show that zoledronic acid induces transient TNF-alpha and IL-6 increases and that these increases are higher in patients who have developed fever, suggesting that these cytokines could be responsible for fever pathogenesis. The sharp reduction in serum calcium levels observed in patients with fever may be related to zoledronic acid pharmacokinetic modifications.

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Abstract: Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion, invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.

Abstract: Raltitrexed (Tomudex; TOM) hepatotoxicity is usually characterized by a transient and self-limiting increase in transaminase levels. How this may condition daily clinical practice is still unclear. The aim of this study was to investigate predictive factors of TOM hepatotoxicity. In total, 130 patients were treated at two medical oncology institutions with TOM (3 mg/m2) (52 patients) or TOM plus oxaliplatin (TOMOX) (100 mg/m2 day 1 or 70 mg/m2 day 1, 8) (78 patients). A multinomial logistic regression (adjusted for multilevel data) was performed (on all administered chemotherapy courses) to assess the dependence of hepatic toxicity on a set of clinical factors correlated with patient, disease and treatment characteristics. Creatinine clearance was calculated by the Cockcroft formula before each chemotherapy course. Most of the patients presented colorectal cancer (95%) and metastatic disease (93%). Out of the 130 patients, 41 were aged 70 or more, while 119 (91.5%) had a good performance status (PS) (ECOG 0 or 1). Before chemotherapy, liver metastases were present in 78 (60%) patients and elevated transaminase in 25 (19%). A total of 584 courses were administered (252 TOM and 332 TOMOX). National Cancer Institute Common Toxicity Criteria grade 1/2 and 3/4 transaminase toxicity was observed in 62 and 20% of patients, respectively. To control transaminase increase, glutathione (GSH) or ademethionine (SAMe) was administered in 96 and 129 cycles, respectively. Hepatotoxicity conditioned delays (a week or more) in 60 (10%) chemotherapy cycles and was the reason for the discontinuation of chemotherapy in eight (6%) patients. Among the factors evaluated with multivariate analysis, sex, age, PS, creatinine clearance, previous chemotherapy treatment, presence of liver metastases and oncology centre were not significantly associated with TOM hepatotoxicity. Elevated baseline transaminase levels (p=0.001), number of chemotherapy cycles (p<0.001), TOM cumulative dose (p=0.018), unprolonged intervals between courses (p<0.001) and TOMOX regimen (p<0.001) emerged as factors predictive of hepatotoxicity. In the same analysis, GSH (p<0.001) and SAMe (p<0.001) were hepatoprotective agents. This study confirmed TOM-based hepatotoxicity as a clinical relevant side-effect and a major factor for treatment delays or discontinuation. Predictive and protective factors listed above could assist the management of this toxicity that has probably been underestimated until now.

Abstract: INTRODUCTION: Oxaliplatin, a third-generation platinum analogue, is a novel compound with proven anti-tumor activity in colorectal cancer. Moreover, oxaliplatin appears to be relatively well tolerated and easy to handle, even on an outpatient basis. PATIENTS AND METHODS: Five advanced colorectal cancer patients treated with oxaliplatin-based chemotherapy developed, after the end of oxaliplatin infusion, similar idiosyncratic reactions characterized by chills, high fever, hypotension, abdominal pain, nausea and often diarrhoea. Venous blood for IL-6 and TNF-alpha assessment was drawn just after the beginning of the reaction and 15 and 30 minutes later. After drawing the third venous sample, intravenous dexamethasone (8 mg) was administered and the drawing of other two venous samples was performed (180 and 360 minutes after the beginning of the reaction). RESULTS: TNF-alpha and IL-6 serum concentrations significantly decreased after steroid therapy administration. The decrease of TNF-alpha and IL-6 levels went along with the clinical complete regression of symptoms and signs in all the 5 patients. No statistically significant correlation was found between other laboratory parameters and basal cytokine levels or cytokine decrease after steroid therapy. DISCUSSION: Our results clearly show that that idiosyncratic reaction observed in colorectal cancer patients after oxaliplatin infusion may be due to a massive release of cytokines such as TNF-alpha and IL-6. Symptom regression following steroid therapy administration went along with significant decrease of cytokines levels, confirming that TNF-alpha and IL-6 play a role in the pathogenesis of this reaction.

Abstract: More than 550,000 American people died for cancer only in 1998 and more than third of them were over 65 years of age. According to recent data in next decade more than 70% of all the deaths for tumour will be verified in the population over 65 years. The cancers mostly frequently associated with the deaths in the elderly population are the tumour of the lung, colon, prostate and breast. Therefore the geriatrics oncology is progressively assuming a central and essential role within the medical oncology. One of the aspects of great interest in the treatment of the cancers of the elderly patient (> 65 years) is the study about some pharmacokinetic modifications of the antitumour medicines in such band of age, and the study about some pattern of toxicity characteristics in the elderly patients. In this ambit there are a few studies in literature devoted specifically to such aspect. This study represents an attempt of revision of the literature finalized to analyse the toxicological and pharmacokinetic characteristics of the principal chemotherapeutic agents used in the therapy of elderly patients affected with cancer. In the last part of the review we have tried to synthesize the state of the art of the achieved results about the medicines that have shown a better therapeutic index and a better impact on the clinical benefit in such population of patients.

Abstract: PURPOSE: Recently, new experimental data suggested that, besides inhibiting osteoclasts, bisphosphonate may also have an antitumor effect. Antiangionetetic activity is one of the possible mechanisms of anticancer activity attributed to bisphosphonates. The purpose of this study was to evaluate the modifications in angiogenic cytokines levels after pamidronate infusion. EXPERIMENTAl DESIGN: Twenty-five consecutive cancer patients with bone metastases treated monthly with disodium pamidronate infusion were evaluated prospectively for circulating levels of vascular endothelial growth factor (VEGF), gamma-IFN, interleukin (IL)-6, and IL-8 at different time points: just before and after 1, 2, and 7 days after pamidronate infusion. RESULTS: Basal VEGF levels decreased significantly 1, 2, and 7 days after pamidronate infusion. gamma-IFN and IL-6 levels increased 1 day after the infusion but rapidly decreased after 2 days. Moreover, our data showed a statistically significant negative correlation between VEGF and gamma-IFN levels (P < 0.0001) and a positive correlation between VEGF and IL-8 (P = 0.04). CONCLUSIONS: This study confirms that pamidronate could have antiangiogenic properties through a significant and lasting decrease of VEGF serum levels.

Abstract: BACKGROUND: Mesothelioma is the most commonly occurring primary pleural neoplasm. Several studies have documented an increase in the incidence of this malignancy during the last decades. Although the association between asbestos exposure and development of mesothelioma is generally accepted, the exact mechanism of carcinogenesis is unknown. Recently, Simian virus 40 large T antigen (SV40 Tag) expression has been detected in pleural mesothelioma. The ability of SV40 oncoproteins to inactivate p53 and retinoblastoma tumour suppressor proteins has been proposed as an important step in the pathogenesis of human mesothelioma. METHODS: To obtain a better understanding of the molecular mechanisms of the pathogenesis of mesothelioma, the expression of the cell cycle inhibitor p21(WAF1/CIP1) (p21), a downstream target of p53, was evaluated immunohistochemically in a group of 29 mesothelioma specimens already characterised for the presence of SV40 Tag sequences. RESULTS: Statistical analysis did not reveal any correlation between p21 expression and histopathological type of mesothelioma using the kappa(2) test (p=0.577). A significant positive relationship was found between p21 expression level and the patients' overall survival according to the Kaplan-Meier survival curves and using a log rank test (median difference in survival 7 months, 95% CI 4.8 to 9.9; p<0.001). CONCLUSIONS: Determination of p21 expression bears a prognostic significance in patients affected with mesothelioma, further underlining the role of SV40 in the pathogenesis of malignant pleural mesothelioma.

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Abstract: A rare case of papillary pneumocytoma of the lung is reported. The immunohistochemical positivities for EMA, cytokeratin and TTF-l strongly support the hypothesis that the neoplastic cells are originated from type 2 pneumocytes. The tumour also presented areas displaying stroma of non-specific mixoid appearance, simulating a benign tumour of the salivary gland type. We propose that these mixoid areas constitute structures of metaplastic origin.

Abstract: Interleukin-2 (IL-2) therapy is associated with serious toxic effects on the cardiopulmonary system. Less frequent toxicity is described in liver and the gastrointestinal system. A case of severe liver toxicity is described in a patient who underwent long-term immunotherapy with IL-2 (4.5 MU/m(2) s.c. daily, 5 days per week for 6 weeks, with 4 weeks of interval) plus interferon-alpha (IFN-alpha) (3 MU s.c. t.i.w., also covering the intervals between IL-2 cycles) for a metastatic renal carcinoma. A review of the literature is provided. The patient tolerated well the immunotherapy scheduled with apparently only a World Health Organization (WHO) G3 anemia and a G2 asthenia and is still alive, with a disease-free survival of 28 months. Notwithstanding a complete absence of liver function test abnormality during all scheduled clinical controls, the patient developed portal hypertension due to liver cirrhosis, which was histologically demonstrated. All common etiologic viral and toxic agents were ruled out. Long-term IL-2 therapy can induce liver cirrhosis. The appearance of liver and spleen enlargement during IL-2 therapy can be considered an indicator of liver damage. Thus, in this setting, closer monitoring is warranted despite normal liver function tests.

Abstract: PURPOSE: Colorectal cancer (CRC) is one of the major health problems of the Western world and the proportion of elderly patients with CRC is growing. Raltitrexed ('Tomudex'), a specific thymidylate synthase inhibitor, has shown efficacy and manageable toxicity in elderly CRC patients. In this retrospective study, the tolerability of raltitrexed in patients with CRC was examined in relation to age. PATIENTS AND METHODS: Toxicity parameters, graded according to World Health Organization criteria, were assessed in two patient groups: < 70 and > or = 70 years old. In total, 56% (50 out of 90) of patients treated with raltitrexed (3 mg/m2 as a 15-minute intravenous infusion every 3 weeks) were aged > 70 years (M:F 28:22; Eastern Cooperative Oncology Group performance status 0-1:2 38:12). RESULTS: Overall, 437 cycles of chemotherapy were administered and grade 3-4 toxicity was reported in < 10% of patients. There were no clinically significant differences between the two age groups, apart from grade 3-4 asthenia, which was reported by 6% and 0% of patients aged > or = 70 and < 70 years, respectively. This was in spite of a significantly lower calculated mean creatinine clearance in patients aged > or = 70 years compared with those patients < 70 years of age. CONCLUSION: The raltitrexed toxicity profile does not appear to be significantly influenced by age; however caution is recommended in the management of elderly patients, particularly in the presence of impaired renal function.

Abstract: INTRODUCTION: In the past the unfavourable profile of toxicity of antineoplastic drugs employed (i.e. cisplatinum) weakened the role of chemotherapy in aged patients with non-small cell lung cancer (NSCLC). Recently, new active drugs with lesser toxicity have became widely used in this setting. In this prospective study we evaluated the efficacy and tolerability of gemcitabine in elderly patients with stages III-IV NSCLC. MATERIALS AND METHODS: From December 1996 to April 1999, we enrolled 52 previously untreated elderly patients with advanced/metastatic NSCLC. Gemcitabine was administered at 1000 mg/mq i.v. over 30 minutes weekly for three consecutive weeks every 28 days. The planned number of cycles was three while responding or stable patients received chemotherapy until disease progression or the ninth cycle. A total of 291 cycles were delivered with a median number of 6 cycles (range: 3-9). An evaluation of the quality of life was performed every three courses of gemcitabine. RESULTS: After three cycles of treatment, a complete response was seen in four patients (7.7%), partial response in 16 patients (30.8%) with an overall response rate of 38.5%. Nineteen patients (36.5%) showed stable disease, while thirteen patients (25%) progressed. Median progression-free survival was 22 weeks, median duration of response 26 weeks, median overall survival 34 weeks and 1-year overall survival 46.1%. A statistically significant improvement in the quality of life was registered only after the first three cycles of gemcitabine (p = 0.045). Toxicity was extremely mild. CONCLUSION: In elderly patients with stages III-IV NSCLC gemcitabine showed good activity with a mild toxicity and could be considered a valid therapeutic option in this setting.

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Abstract: A case of a 32-years old man with a long lasting history of inflammatory bowel disease (IBD) is described. He was treated in the past with adequate medical therapy with considerable improvement of the symptoms. However, after the resolution of the last episode of abdominal pain and diarrhoea, because of multiple protruding masses and sub-stenotic regions found during a colonoscopy, the patient underwent a right enlarged hemicolectomy with jejunal resection. During the surgical procedure 16 enlarged lymphnodes were removed. The histological examination of the surgical specimen showed the presence of numerous Reed-Sternberg cells, compatible with a diagnosis of Hodgkin's disease (HD). None of the removed lymphnodes showed the presence of tumor cells, and in addition the systemic staging procedure was negative. After staging, the ABVD regimen was started, achieving a complete clinical and pathological response. This is a rare case of primary extranodal HD localized to the colon, in a patient with a long standing history of IBD, who showed an optimal response to chemotherapy. The case and the differential diagnosis with other pathological entities of the bowel is discussed.

Abstract: The rates of delayed nausea and vomiting by moderately emetogenic chemotherapy in patients with previous experience of acute emesis are usually quite high. This is a pilot study aiming to evaluate the safety of a new antiemetic schedule to prevent delayed emesis in this subset of patients. During 5 consecutive cycles of moderately emetogenic chemotherapy, we evaluated 50 patients (15 males) who experienced acute emesis in the first cycle of treatment. The regimen for prevention of delayed emesis consisted of daily tropisetron (5 mg orally from d 2 to d 6 of each chemotherapeutic cycle) associated to ACTH-Depot (1 mg intramuscularly 24 and 68 h after the initiation of chemotherapy). In 77% of chemotherapy cycles, there was a total elimination of nausea and vomiting, whereas in the remaining 23% of cycles, there was a major response defined as < or = 2 vomiting episodes per cycle or nausea grade 1 according to the WHO. The efficacy of the antiemetic regimen persisted during the entire treatment program without the appearance of toxic effects. The proposed antiemetic regimen is highly active in preventing delayed nausea and vomiting episodes in patients receiving moderately emetogenic chemotherapy. Moreover, no toxic effects were observed. These promising results require confirmation by a randomized trial.

Abstract: BACKGROUND: Gemcitabine is an antimetabolic drug for solid tumors. Although its pharmacokinetics as well as its side-effects are well known, paroxysmal atrial fibrillation associated to the administration of this drug has not yet been described. PATIENTS AND METHODS: We describe the case of a 78-year-old man with pancreatic adenocarcinoma who presented repeated paroxysmal atrial fibrillation episodes 18-24 hours after every gemcitabine infusion which resolved with antiarrhythmic drugs. This clinical history was positive for a remote brief episode of atrial fibrillation, which resolved spontaneously, and the patient had no predisposing factors for supraventricular arrhythmias (systemic hypertension, diabetes or coronary artery disease). RESULTS: Cardiac work-up revealed only a mild mitral-valve prolapse and complete right bundle branch block. During the arrhythmia episodes no other precipitating factors were reported. The close temporal relationship of the arrhythmia to drug administration and the recurrence of arrhythmia upon rechallenge allowed to hypothesize an intrinsic pro-arrhythmic effect of gemcitabine or its metabolite 2',2'-difluorodeoxyuridine. CONCLUSIONS: The occurrence of atrial fibrillation during the administration of gemcitabine may be considered as a cardiac arrhythmia drug-related toxicity. This side-effect of gemcitabine infusion is a previously unreported sign of drug toxicity; therefore, a high level of awareness to this problem is warranted when this drug is administered.

Abstract: Prostate carcinoma occurs infrequently in patient less than 50 years old with an incidence of 0.8% to 1.1%. In literature are described less than 20 cases occurred in younger men (< 40 years old). A 36 year-old man with a two-months history of lower back pain, anorexia and loss of weight, showed at clinical examination a mild enlargement of inguinal lymph nodes and right inferior leg and scrotus edema. CT scan demonstrated marked enlargement and fusion of pelvic, inguinal, sacral and periaortic nodes with a pelvic mass that caused local ureterohydronephrosis and obstruction of the urinary flow. X-rays showed osteoblastic metastases. At total body scintigram were observed fixation areas corresponding to lumbar metamers, pelvis, thigh bones, left humeral head, left acromioclavicular articulation and multiple ribs. Tumor markers resulted negative except prostate specific antigen (PSA: 500 mgr/ml) and prostatic acid phosphatase (PAP: 208 U/l); prostate biopsy showed an undifferentiated carcinoma. The patient was submitted to right percutaneous nephrostomy, chemotherapy (PEB, cisplatinum, etoposide and bleomycin for 6 cycles) and ormonotherapy (LHRH analogues) reporting a clinical partial response. After 6 months the disease progressed and was started a second line chemotherapy. After 18 months from diagnosis patient is still alive with progressing disease. Our patient represents, with respect to many features, an original clinical case of prostate carcinoma occurring in young age, for the atypical association of an undifferentiated carcinoma with high levels of PSA and PAP and with osteoblastic-pattern of bone metastases. Further studies would be useful to identify new risk factors for development of prostate cancer in young men in order to achieve early diagnosis.

Abstract: Peripherally Inserted Central Catheters (PICC) represent an alternative for critical patient care, and are safer to implant in home patients. The authors report on their experience with the first 200 4 Fr Groshong PICC implanted during the last 18 months. The procedure can be easily applied at home (98% successful implant rate), without the need for fluoroscopic or ultrasound guidance. Moreover, the authors believe that the X-ray control after implant is not strictly necessary. After 11,570 days/catheters, only 5 devices were explanted because of complications: 4 because of sepsis and peripheral phlebitis, and the last was explanted by another medical staff for unclear reasons. The complications needing no explanation were a total of 32: for 12 of them the external portion of tube was damaged during use, while for the other 20 the internal clots were resolved with forced flushing. The authors conclude that Groshong PICC can be considered the gold standard for home care management of critical patients, taking into account the quality of pure silicon, the presence of a valve and the specially-made closed-tip.

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