Abstract: Capecitabine is an oral fluoropyrimidine which is transformed to 5-Fluorouracil inside tumor cells, where it achieves high drug concentrations. Capecitabine is an active drug diffusely utilized in the treatment of various types of tumors, such as breast, colorectal, gastric, head and neck carcinoma. In our experience, capecitabine-induced hypertriglyceridemia does not seem to be a rare adverse effect as it is observed in 10% of treated patients. It is necessary to monitor the lipidic profile of patients treated with capecitabine also in consideration of the frequent presence of comorbidities in cancer populations, the concomitant toxicity related to other drugs used in combination regimens, and cardiovascular effects characteristic of biological target therapy.
Abstract: A group of 62 patients with different advanced cancers and with an anaemic condition were treated with a short course of darbepoetin administered on two different schedules as supportive therapy. The response rates (i.e. a haemoglobin increase of at least 1 g in 1 month) were 45.7% overall, 52.3% with weekly administration and 39% with 3-weekly administration. Darbepoetin activity was higher in men than in women, in younger patients than in older patients and in moderately anaemic patients than in severely anaemic patients, but these differences were not significant. Darbepoetin administration appears to be useful in rapidly reversing anaemia related to advanced cancer. However, the results reported in the literature for alpha-erythropoietin remain more appealing.
Abstract: BACKGROUND: Aim of this study was to evaluate the activity of a combination regimen of chemotherapy containing mitomycin C (MMC) and etoposide (ETO) in advanced colorectal carcinoma. METHODS: Fourteen pretreated patients received MMC 2 mg/m2 and ETO 60 mg/m2, days 1-5 every 28 days. The clinical study was interrupted since no clinical response was observed in 14 patients following four courses of chemotherapy. An in vitro study was then performed on HTC-8 cell line. The cytotoxic activity of the MMC/ETO combination was tested by sulforhodamine B assay and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry. RESULTS: While MMC and ETO were singularly active, the simultaneous exposure of cells to both drugs and the sequence MMC-->ETO ensued in antagonistic interaction at all levels of killed cell fraction. Conversely, the sequence ETO-->MMC produced a synergistic interaction. CONCLUSIONS: These results suggest that the activity of the MMC/ETO combination is highly schedule-dependent and that the experimental drug associations should be based on a preclinical rationale before clinical trials are designed.
Abstract: Among a large series of cancer patients treated with a combination of chemotherapy and sessions of hyperthermia, particular attention was given to a specific group of patients with advanced cancer who refused standard, aggressive, treatment. In these cases, hyperthermia was associated to low-dose (metronomic) chemotherapy. No toxicity was reported in any of our patients, while a marginal benefit in terms of tumour progression was observed. During therapy, we could detect a coagulative perturbation that deserves careful discussion. In our opinion, this experience should be matter of debate to conclude if current response criteria (WHO/UICC and RECIST) in treating cancer patients are really suitable tools to evaluate new, and non-aggressive anticancer strategies.
Abstract: This study focuses on a case of a 67-year-old woman with occult breast cancer involving the axillary lymph nodes. The instrumental examinations employed, positron emission tomography included, were not useful in diagnosing the disease. When the patient was surgically treated micro-invasive breast cancer was diagnosed. This peculiar malignant pathology is a matter of discussion especially because it is hardly diagnosable. Because of such diagnostic difficulties it may happen that micro-invasive carcinoma progression can easily mislead routine diagnostic screenings performed on women over 50.
Abstract: Different pathological and predictive factors are used to stratify patients submitted to radical surgery for colorectal carcinoma. In addition to stage and histotype, the surgeon's technique and decisions also appeared to affect the prognosis. The aim of the present study was to evaluate if the extent of lymphadenectomy was associated with a different long-term outcome in a pool of 117 patients. In particular, in patients classified as Dukes' B, some evidences seem to suggest that the staging procedure depends on a correct surgical lymphadenectomy with a higher risk of understaging colorectal carcinomas when the number of removed nodes is limited. Moreover, the promptness in forwarding patients to the chemotherapist seems to influence the disease-free survival.
Abstract: BACKGROUND: Age-related physiological changes may lead to an increased toxicity of chemotherapy in the elderly, thus making tumor treatment difficult in this increasing subset of patients. OBJECTIVE: Since many trials claimed a favorable therapeutic index with raltitrexed, the aim of our preliminary study was to evaluate the anticancer activity and the toxic profile of this drug in the elderly. METHODS: Thirteen elderly patients with colorectal cancer, aged 75-90 years, were enrolled in a monochemotherapy treatment with raltitrexed. Due to their advanced age, the drug was administered with a 33% reduction of the dose. RESULTS: One partial response, four disease stabilizations, and two disease progressions were observed in 7 patients with advanced colorectal cancer. The patients with response or disease stabilisation had a satisfactory time to progression. Four out of 6 patients treated in the adjuvant setting for Dukes' C colorectal cancer remain disease free at observation periods of 15+ to 29+ months. Toxicity was virtually absent in all patients. CONCLUSIONS: The activity of monochemotherapy with raltitrexed appears to be appealing, above all because it is observed in the absence of toxicity. Though recent reports suggest some concern about severe complications of treatment with raltitrexed, administration of reduced doses of this drug seems to be a putative therapy for those patients who, because of their age, are highly susceptible to the adverse effects of chemotherapy.
Abstract: A nitroxylated analog of daunorubicin, ruboxyl (RBX), showed low toxicity but significant lympholytic effect in preclinical evaluations. A series of studies in vitro and in animals demonstrate that RBX is a putative agent in the treatment of many neoplasms. We report the results of a study in mice in which RBX showed selective B-lymphocyte immunosuppression. On the basis of this experience, RBX was administered to 3 patients with multiple myeloma and two patients with Waldenström's disease. The results of this pilot clinical study show that this compound has good activity and low myelotoxicity and cardiotoxicity, but seems to be characterized by a threatening immunosuppressive effect.
Abstract: The activity of epirubicin, cisplatin and 5-fluorouracil (5-FU), as single agents or in combination (ECF), was investigated in three human colon cancer cell lines by two different assays (cell-counting assay and sulforhodamine B assay) in vitro. 5-FU was tested with both short and continuous exposure. Particular interest was focused on the results obtained in the HCT8-FU cell line, a subline with experimentally induced resistance to 5-FU. The positive modulation of both cisplatin and epirubicin cytotoxicity by 5-FU makes the ECF regimen an attractive protocol for combination therapy in colorectal cancer.
Abstract: Thirty-one patients with advanced colorectal cancer were treated with a regimen of epirubicin, cisplatin and continuous-infusion (c.i.) 5-fluorouracil (5-FU) (ECF regimen). Twenty-seven patients were evaluable for response rate (RR), progression-free survival (PFS) and overall survival (OS). In this study, the ECF chemotherapy yielded a 51% RR with a PFS of more than 8 months, an OS of more than 11 months and tolerable toxicity. In spite of the perplexity concerning the use of anthracyclines in colorectal cancer, the ECF regimen seems to be a possible treatment even for this malignancy. Controlled studies with ECF versus standard treatments and versus 5-FU alone in c.i. are necessary.
Abstract: Inhibition by ruboxyl, a nitroxyl derivative of daunorubicin, source preparation and 5-fluorouracil was compared in metastases of experimental colorectal carcinoma to murine liver. The indices of metastasis inhibition were 84.43 and 70%, respectively. In rats receiving the drugs by continuous intravenous infusion for 7 days, the number of metastases was reduced (ruboxyl--1.0 +/- 1.4; 5-fluorouracil 3.2 +/- 1.3.
Abstract: We evaluated the activity of ruboxyl (Rbx), a nitroxyl analogue of daunorubicin (Dauno), in experimental models of hepatic metastases from colorectal carcinoma (CRC) and compared it with its parent compound and with 5-fluorouracil (5FU). In mice treated by intraperitoneal injections Rbx and 5FU proved more effective than Dauno: the Index of Inhibition of Metastases in comparison with controls was 43% for Dauno, 70% for 5FU and 84% for Rbx. In BDIX rats implanted with the syngeneic cell line DHD K12/TRb, both Rbx and 5FU, administered as a continuous intravenous infusion for 7 days, reduced the development of liver metastases from a median of 23.8 +/- 2.16 for controls to 3.2 +/- 1.3 for 5FU and 1.0 +/- 1.4 for Rbx (p < 0.0001 versus controls for both treatments): the comparison of Rbx and 5FU showed a trend in favour of this new anthracycline. Median survival was prolonged from 40.6 +/- 3.4 days in controls to 56.0 +/- 5.8 days with Rbx and 58.0 +/- 4.69 days with 5FU. Considering that in a phase I study Rbx showed only minor and manageable toxic side effect, its activity in the clinical treatment of CRC metastases may deserve further attention.
Abstract: Among the different investigated biomarkers, cell proliferation has provided valuable information on the clinical outcome of patients with malignant tumors. In the present study, we analyzed the potential relevance of fractional incorporation (FI) of a nucleotide precursor (3H-thymidine, 3H-dT) into DNA of tumor cells, determined on the primary tumor, on long-term clinical outcome of a series of patients with colorectal cancer. Determination of 3H-dT FI was carried out on fresh tumor material obtained at surgery as part of the clinical management of the primary tumor in 28 patients with colorectal cancer. Analysis of the relation between the FI and clinico-pathological characteristics of the tumor showed a trend of an inverse relation between the biomarker and Dukes' stage and no relation with tumor site. At 6 year follow-up, alive patients had a statistically significant higher median FI value (2.4%; range: 1.1-6.5%) than dead patients (1%; range: 0.3-4.5%) (p=0.02). Owing to the simplicity of this inexpensive methodology, the preliminary results of our study would indicate the potential of FI, a metabolic-kinetic parameter, to give prognostic information in colorectal cancer patients.
Abstract: The authors observed a long-lasting response to uninterrupted vinorelbine treatment in a 72-year-old patient with a stage IIIB unresectable non-small cell carcinoma. The progressive tumor mass reduction was assessed by computed tomographic scans over a 2-year period. In the literature, data of randomized trials confirm that the appeal of single-agent vinorelbine therapy in elderly patients is also good for the patient's quality of life during treatment.
Abstract: AIMS AND BACKGROUND: There is much interest in nitroxyl derivatives of cytotoxic agents. We evaluated the potential activity of magnizil, a derivative of 5-fluorouracil, on human gastrointestinal tumors in 3 different in vitro and in vivo experimental models. METHODS: The activities of magnizil and 5-fluorouracil were comparatively determined in vitro on the HT29 cell line by a clonogenic assay and on tumor clinical specimens by an antimetabolic assay. The activity of both the drugs against human tumors was also assessed in mice with the subrenal capsule assay. RESULTS: A similar cytotoxic activity was found for magnizil and 5-fluorouracil on the HT29 cell line. As regards human tumors, a lower activity was observed for the nitroxyl derivative than for 5-fluorouracil, with response rates of 25% and 50%, respectively, at comparable concentrations. Moreover, among the tumors transplanted in the subrenal capsule of mice, two were sensitive to magnizil and 3 to 5-fluorouracil. CONCLUSIONS: Even though experimental results on human tumors indicate a somewhat lower activity for magnizil than the parent compound, its low toxicity and the possibility to clinically use high doses suggest the opportunity to further investigate the potential of this new anticancer agent on larger series of colorectal cancers in experimental systems.
Abstract: 10 patients with advanced colorectal cancer were treated with elevated doses of carmustine and mitomycin C. The regimen was potentiated by lonidamine and supported by autologous bone marrow transplantation. The results of this pilot study were encouraging, with a response rate of 50% and a significantly better survival for responders versus non-responders. No appreciable toxicity of the therapy was observed. This aspect, together with the simplicity of the procedure, calls for further investigations to confirm the good therapeutic index of the treatment.
Abstract: A paradigmatic case in which anticancer chemotherapy could paradoxically lead to immune restoration is reported. A patient with hairy cell leukemia was unsuccessfully treated with alpha-interferon. Treatment had to be withdrawn because of unusual toxicity and therapy with cytotoxic drugs had to be administered. Not only did the anticancer agents produce a complete remission of the disease, but the immunological profile of the patient improved. This case report raises the problem of the interference of chemotherapy with the immune system in cancer patients.
Abstract: The effects of isocaloric carbohydrate-based vs. fat-based total parenteral nutrition (TPN) regimens on cancer cell proliferation and host nutritional status were evaluated in 27 patients with tumours of the gastro intestinal tract consecutively assigned to receive for 14 days: a glucose-based (A) or a lipid-based (B) TPN formula, or an oral diet (C) isocaloric and isonitrogenous to A and B. Cancer cell replication rate was evaluated by thymidine labelling index (LI) on tumour samples before and at the end of each nutritional regimen. The number of replicating cells increased by 32.2% in patients receiving regimen A. LI decreased by 24.3% in patients given regimen B. LI values were slightly increased (+15%) in patients maintained on regimen C. Nutritional status remained within normal limits. None of the LI changes observed between and within the three arms of the trial were found to be statistically significant. Thus we failed to prove that glucose consistently stimulates or lipids inhibit tumour proliferation despite a trend in this sense.
Abstract: Eighty-seven colorectal adenocarcinomas from untreated patients were investigated by short term tumor cultures to test in vitro sensitivity to 5-fluorouracil and mitomycin C. This study reports the preliminary results of a multistep program aimed at the prospective clinical application of the assay. At present this in vitro experience was performed in parallel with a clinical trial carried out with the same drugs. The in vitro activity of the two anticancer agents is in agreement with the response rate reported in monochemotherapy; our data would suggest an increase of responses using the combination of fluorouracil and mitomycin in comparison to single drug therapy. A low cosensitivity rate and a high number of cases sensitive to one drug but resistant to the other, account for the use of this test as screening of active drugs in the individual patient.
Abstract: A case of cancer-related hemolytic-uremic syndrome is reported. The patient presented a spontaneous recovery, which is unusual in this clinical picture. Mitomycin C is regarded as responsible for this toxic event in most cases. The case history reported here is discussed in relation to dose and scheduling of mitomycin C, and a safe maximum dosage is suggested.
Abstract: Working with the antimetabolic chemopredictivity assay on short term cultures we evidenced a correlation between in vitro chemosensitivity of colorectal cancer and fractional incorporation of radionucleotides. Four different drugs (5-FU, mitomycin C, 4'-iododeoxydoxorubicin and ruboxyl, a nitroxyl derivative of daunorubicin) were tested on 102 tumor cultures. The extent of 3H-TdR and 3H-UdR incorporation into DNA and RNA in the related control cultures was in relationship with the chemosensitivity of the tumor. Along with the labeling index this simple metabolic-kinetic trait may gain a role for the screening of tumor phenotypes sensitive to chemotherapy.
Abstract: Forty-four cases of different untreated gastrointestinal tumors were studied with regard to cell kinetic activity. As a pilot experiment, we also determined the 3H-TdR Labeling Index (LI) in 28 patients in basal conditions and after 15 days of nutritional manipulation with prevalently lipid-based or glucose-based feeding to ascertain whether selective nutritional regimens could affect tumor proliferation. Preliminary results from this study indicate that a kinetic perturbation is induced in tumor cells by nutritional manipulation. Lipid-based feeding seems to produce effects similar to those of chemical or physical anticancer agents, thus suggesting a possible supporting role of nutritional manipulation in cancer treatment strategy.
Abstract: Four cases of multiple myeloma (MM) are reported in which the coexistence and/or the alternance of different plasma cell clones were observed. Genetic instability is typical of all tumors but in MM it is particularly striking due to the M component marker. In this respect, malignancies reveal the presence of an unremitting competition of different cell populations for the phenotype prevalence. When this phenomenon is related to the clinical picture it is possible, as in our cases, to ascertain that the appearance of new clones often corresponds to significant changes in the disease evolution.
Abstract: Five patients with oligoarticular rheumatoid arthritis were treated with intra-articular injections of methotrexate and orgotein in the knee joints. The employed dose of the antimetabolite was very low and orgotein was simultaneously administered to prevent local tissues from cytolysis-related damage. Clinical results were fairly good and support the hypothesis that methotrexate may be used intra-articularly as an immunosuppressor rather than at the heavily toxic doses required for a cytostatic effect.
Abstract: A short-term antimetabolic assay, which considers the interference with [3H]thymidine incorporation as an indicator of drug effect, has been used to comparatively assess the chemosensitivity of different tumor lesions from the same patient. The analysis was performed on primary tumors and their synchronous metastases from 67 patients with breast, ovarian, gastrointestinal and germ cell testicular tumors. A remarkable difference in sensitivity to cytostatic drugs was observed between the two lesions. In contrast, a strong association in chemosensitivity (81.7% agreement rate; p less than 0.01) was observed between two synchronous metastases from 17 patients with breast, ovarian, germ cell testicular tumors or malignant melanoma. In addition, the predictive relevance of the antimetabolic assay on clinical response to chemotherapy was analyzed in relation to the type of tumor lesion tested in vitro in a retrospective correlative study on 57 patients with advanced ovarian and germ cell testicular tumors. The objective clinical response was significantly correlated to the in vitro sensitivity of metastases (83.7% agreement rate; p less than 0.01), but not to that of the primary tumor.
Abstract: A case of prolymphocytic leukemia (PL) is reported, which showed a good response to a new antiblastic schedule (4-epidoxorubicin-asparaginase-dexamethasone) in spite of the resistance to other chemotherapy regimens. However during the course of the disease it was possible to observe the terminal appearance of a small aneuploid cell population in the peripheral blood of the patient and, in the same time, the clinical condition deteriorated considerably. The significance of this neoplastic progression and the pros and cons of aggressive chemotherapy regimens remain to be carefully evaluated in PL and related disorders.
Abstract: The chemosensitivity of 26 non-pretreated colorectal carcinomas (primary tumors and/or colorectal metastases) was studied by an in vitro antimetabolic assay, which evaluates the interference of drugs on the incorporation of 3H-thymidine and 3H-uridine in short-term cultures of human tumors. Our results correlate with the response rate obtained in clinical studies with monochemotherapy and justify the possibility of a future prospective study using individually tailored chemotherapy regimens. Doxorubicin-analogues, with an overall in vitro efficacy in 16.0% and 14.3% for 4-epidoxorubicin (epi-DX) and 4-deoxydoxorubicin (deo-DX), respectively, seem to deserve a modest role in the treatment of colorectal cancer, provided that a careful selection of patients is performed. Variability in anthracycline activity is indeed evident, also in our study, in relation to the different neoplastic picture of the various patients.
Abstract: Six patients with high-risk multiple myeloma and one patient with primary amyloidosis were treated with a melphalan-peptichemio-prednisone association (PMP). The response trend seems promising, also in view of the low regimen bone marrow toxicity, but further studies could better evaluate the optimal PMP scheduling and peptichemio side effects.
Abstract: A brief survey of the problems related to leukemic cell differentiation is proposed. The role of cytosine-arabinoside among the differentiation inducers and its potential clinical utility is discussed on the basis of the present literature. The authors report a case of myelomonocytic leukemia which displayed a differentiative response to cytarabine treatment.
Abstract: A case of non-producer multiple myeloma (MM) is described and compared with the previous reports. Some recurrent clinical traits seem to characterize this disease. It is interesting that reported cases seem to show a low aggressivity. Some biological problems connected with this form of disease are discussed.
Abstract: The 4th case of plasma cell neoplasm associated with a hypereosinophilic syndrome is described and compared with the previous reports. Hypereosinophilia in the present patient displayed some borderline traits with eosinophilic leukemia. Myeloproliferative disorders of the eosinophilic line often present as a precancerous state, but sometimes they seem to acquire malignant independence. In our patient the occurrence of a plasmocytoma with a dramatic course leads to suspect an underlying complex genetic aberration.
Abstract: A case of chronic neutrophilic leukemia associated with multiple myeloma is described. The patient appears to be the longest surviving case reported in the literature. Since myeloma developed several years after leukemia, the possible precancerous role of myeloproliferative syndromes is proposed.
Abstract: Data on lymphocyte biology indicate that the humoral system of B-cells is specifically active with precise analogies at all mucosal levels. Might there be a corresponding function for T-lymphocytes at the cutaneous structure level? Certain physiological findings appear to suggest that the two main lymphocyte populations share the role of "first defence barrier".
