Effect of estrogen therapy on vascular perlecan and metalloproteinases 2 and 9 in castrated rats.

AIM: To study the effects of estrogen therapy on the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and perlecan in the vascular wall. METHODS: Twenty 180-day-old Wistar rats were castrated and treated 1 week later for a period of 4 weeks with one of the following: (1) placebo; (2) 0.5 µg/day estradiol benzoate (E(2)B); (3) 5 µg/day E(2)B; (4) 50 µg/day E(2)B. A fifth group consisted of rats that had not been castrated. Following treatment, expression of MMP-2 and MMP-9 mRNA (MMP-2([RNA]) and MMP-9([RNA]), respectively) was analyzed by real-time PCR, and expression of MMP-2 (MMP-2([IH])), MMP-9 (MMP-9([IH])) and perlecan was quantified by immunohistochemistry, in carotid walls. RESULTS: There were no differences among castrated groups for MMP-2([RNA]) (p = 0.1969) and for MMP-9([RNA]) (p = 0.1828); however, a correlation was observed between E(2)B dose and MMP-9([RNA]) levels (r = 0.471, p = 0.018). Differences among groups were observed for MMP-2([IH]), MMP-9([IH]) and perlecan (p < 0.0001), wherein higher levels were observed in animals treated with estrogen therapy, correlating with E(2)B doses in the case of MMP-9 (r = 0.441, p = 0.026) and perlecan (r = 0.574, p = 0.005). CONCLUSIONS: Estrogen therapy correlates with higher levels of MMP-2, MMP-9 and perlecan in the extracellular matrix of carotid walls in castrated rats, in a dose-dependent manner. There was a dose-response effect of E(2)B on the expression of MMP-9 mRNA and, possibly, MMP-2 mRNA.

Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens.

BACKGROUND: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients. METHODS: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI). RESULTS: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms. CONCLUSION: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies.

Evaluation of in vitro cytotoxicity of oxaliplatin and 5-fluorouracil in human colon cancer cell lines: combination versus sequential exposure.

Adjuvant therapy has evolved to become the standard care of colon cancer, but the tumor capability of activating effective mechanisms of defence against both chemical and physical cytotoxic agents represents a serious obstacle to the successful therapy. Furthermore, the possibility to have an assay useful to measure the drug sensitivity of tumor cells could be of a great importance. As primary human colon cancer cultures from fresh tumor are technically difficult to obtain, experiments with human cancer cell lines remain essential to explore new adjuvant chemotherapy drugs, to investigate the individual responsiveness to the known agents, and particularly to clarify how these chemotherapeutic agents could be used in maximizing outcomes. In the present study we evaluate the cytotoxic effects of 5-fluorouracil (5-FU) and oxaliplatin (OHP) and of their pharmacological interaction in three human colon cancer cell lines (WiDr, HT-29 and SW620), by using an ATP luminescence assay (ATPlite; Perkin Elmer), displaying high sensitivity, linearity and reproducibility. Cell cycle, apoptosis and CD44 expression were investigated with flow cytometry. Our results show that the drug combinations inhibited the cell growth more than each drug alone in all colorectal cancer cell lines. Interestingly, the sequential exposure of OHP and 5-FU resulted in the most cytotoxic effect in all colon cancer cell lines, when compared to the simultaneous one. Our results focus on the powerful cytotoxic effect of 5-FU-OHP combination, when used in sequential exposure, suggesting interesting implications for a rational use of 5-FU, OHP combination in colon-rectal cancer therapy.

Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells.

BACKGROUND: Increased response rates in studies of patients with colon cancer have indicated that the cytotoxic effects of fluorouracil (5-FU) are potentiated by leucovorin (LV) and by methotrexate (MTX). However, preliminary studies using a sequential combination of MTX, LV, and 5-FU showed no additional potentiation. PURPOSE: We hypothesized that the lack of additional cell kill with this combination could be due to competition of LV with MTX for cellular uptake and reduced folate polyglutamylation. We have tested this possibility by comparing the cytotoxicity of drug combinations containing MTX with that of drug combinations containing trimetrexate (TMTX), an antifolate that does not compete with LV for uptake or polyglutamylation. METHODS: Human lymphocytic leukemia CCRF-CEM cells were exposed to MTX or TMTX for 24 hours and to 5-FU during the last 4 hours of antifolate exposure. LV was administered 30 minutes before 5-FU. RESULTS: After 20 hours of exposure to TMTX or MTX, intracellular levels of phosphoribosyl pyrophosphate were elevated to a similar degree, and these levels did not decrease after a 30-minute exposure to LV. No additional cell kill was observed when LV was added to the MTX/5-FU combination, but cytotoxicity was enhanced when LV was added to the TMTX/5-FU combination. CONCLUSIONS: This study supports the hypothesis that the lack of additional cell kill when high-dose LV is added to the MTX/5-FU combination may be due to competition of MTX with LV for cellular uptake and/or competition of MTX or its polyglutamates with polyglutamylation of reduced folates. Inasmuch as TMTX does not compete with LV and reduced folates for uptake and polyglutamylation, the synergy obtained with the combination of TMTX plus 5-FU and high-dose LV further supports this hypothesis.

Enhancement of trimetrexate cytotoxicity in vitro and in vivo by carboxypeptidase G2.

Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia cell line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. The cytotoxic effect in vitro was detected using a colorimetric assay with a tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Dose-effect relationships of drugs alone and in combination were analyzed by the median effect principle and by the combination indices for quantitation of synergy or antagonism with the aid of a computer program. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure. The concentration of CPG2 required to decrease the cell count to 50% control for these cell lines was 3.5, 2.6, 26.6, and 7.9 x 10(-5) units/ml for CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively. A synergistic cytotoxic effect of trimetrexate after simultaneous continuous exposure with CPG2 was observed with CCRF-CEM cells and with the three resistant cell lines. This drug combination given to BALB/c x DBA/2 F1 mice bearing L1210 cells also produced synergy over a narrow range of drug doses. The activity of this combination in both methotrexate sensitive and methotrexate resistant cell lines indicates that clinical trials of this combination should be undertaken.

Role of folylpolyglutamates in biochemical modulation of fluoropyrimidines by leucovorin.

The growth-inhibitory effect of fluoropyrimidines combined with a short-term exposure to leucovorin and the pattern of polyglutamylation of folates were compared between parental CCRF-CEM cells and a cell line with impaired ability to form polyglutamates (CCRF-CEM/P). The combination of leucovorin with 5-fluorouracil or 5-fluorodeoxyuridine increased the growth inhibition of CCRF-CEM cells compared to the fluoropyrimidine alone in the parent cell line but not in CCRF-CEM/P cells. In addition, leucovorin produced a significant increase in the inhibition of intracellular thymidylate synthase activity caused by 5-fluorouracil or 5-fluorodeoxyuridine as compared to these drugs alone in CCRF-CEM cells, but no increase in inhibition over that produced by the single drugs alone was observed in CCRF-CEM/P cells. Although levels of 5,10-methylene tetrahydrofolate after leucovorin administration were similar in both cell lines, polyglutamylation of this coenzyme was decreased in the CCRF-CEM/P cell line. The inability of CCRF-CEM/P cells to form significant levels of polyglutamates of N5,N10-methylenete-trahydrofolate, may be responsible for the lack of enhanced cell kill observed when a short exposure to leucovorin is used with fluoropyrimidines.

Quality of life evaluation in a randomised trial of chemotherapy versus bio-chemotherapy in advanced melanoma patients.

This study analyses the health related quality of life (HRQOL) of advanced melanoma patients, in a randomised trial comparing bio-chemotherapy (bio-CT) versus chemotherapy (CT). The trial enrolled 178 patients and the median survival was not statistically different between the two arms. HRQOL was assessed at baseline and before each cycle of therapy, using the Rotterdam Symptom Checklist (RSCL) questionnaire completed with 140 patients. At baseline, overall quality of life and psychological distress scores were the most impaired, compared with the normal population. During treatment, the difference between the two arms in the changes from baseline was statistically significant (P=0.03) only in the overall quality of life score, with a decrease of 6.28 points in the bio-CT arm. The mean values decreased significantly in all domains in bio-CT arm, but only in activity level and physical symptom distress scores in the CT arm. Testing HRQOL variables and prognostic clinical factors in a Cox model, only the serum level of lactic dehydrogenase, baseline overall quality of life and the physical symptom distress scores remained significant independent prognostic factors for survival. A score of less than 75 points in the overall quality of life and in the physical symptom distress domains was associated with a Hazard Ratio (HR) of 2.31 (95% Confidence Interval (CI): 1.09-4.90) and 1.92 (95% CI: 1.10-3.36), respectively.

Combination chemotherapy with vinorelbine, ifosfamide, and cisplatin: a phase II study in stage IIIB-IV non-small cell lung cancer.

Forty-five stage IIIB-IV non-small cell lung cancer (NSCLC) patients entered a phase II study designed to evaluate the toxicity and the activity of a combination chemotherapy regimen consisting of vinorelbine (25 mg/m2 days 1 and 8), ifosfamide (3 g/m2 day 1 with uroprotective mesna), and cisplatin (80 mg/m2 day 1). The regimen, VIP, was administered on an outpatient basis every 3 weeks. White blood cell counts were checked weekly, and granulocyte colony-stimulating factor was administered in case of grade 4 neutropenia lasting for more than 48 hours. Leukopenia was the most frequent toxicity, with grades 3 and 4 neutropenia reported in 25% of cycles and 11 episodes of febrile neutropenia recorded in 175 evaluable courses. The combination of vinorelbine and cisplatin did not result in additive neurotoxicity: only five patients experienced grade 2 neurotoxicity after six courses of treatment. Thirty-five patients were evaluable for response. Twenty partial responses (57%) and one complete response (2.8%) were observed, for an overall response rate of 60% (95% confidence interval, 42% to 76%). The median time to progression, measured from the start of treatment, was 7 months (range, 1 to 18+), and median survival for the whole group was 12 months (range, 1 to 18+). VIP is a well-tolerated regimen and shows interesting activity in advanced NSCLC.

Results of a European randomized trial of Etanidazole combined with radiotherapy in head and neck carcinomas.

PURPOSE: The aim of the study was to evaluate the efficacy and toxicity of Etanidazole, a hypoxic cell sensitizer, combined with radiotherapy in the treatment of head and neck squamous cell carcinoma. METHODS AND MATERIALS: A total of 374 patients from 27 European centers were included in this trial between 1987 and 1990. Treatment was either conventional radiotherapy alone (between 66 Gy in 33 fractions and 74 Gy in 37 fractions, 5 fractions per week), or the same radiotherapy dose plus Etanidazole 2 g/m2, three times weekly for 17 doses. A minimization procedure, balancing for center, site, and T stage (T1-T3 vs. T4) was used for randomization. RESULTS: Among the 187 patients in the Etanidazole group, 82% received at least 14 doses of the drug. Compliance to the radiotherapy protocol was 92% in the Etanidazole group and 88% in the control group; the main cause of deviation was acute toxicity, which was observed at an equal rate in the two treatment groups. Fifty-two cases of Grade 1 to 3 peripheral neuropathy were observed in the Etanidazole group vs. 5 cases, all of Grade 1, in the control group (p < 0.001). The 2-year actuarial loco-regional control rates were 53% in the Etanidazole group and 53% in the control group (p = 0.93), and the overall 2-year survival rates were 54% in each group (p = 0.99). CONCLUSION: Adding Etanidazole to conventional radiotherapy did not afford any benefit for patients with head and neck carcinoma. This study failed to confirm the hypothesis of a benefit for patients with N0-N1 disease, which had been suggested by the results of a previous study (10).

Carboxypeptidase G2 enhances trimetrexate cytotoxicity in CCRF-CEM cell lines sensitive and resistant to methotrexate.

Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, degrades folates as well as methotrexate and other folic acid analogs such as aminopterin and dichloromethotrexate, but not the "non-classical" folate antagonist trimetrexate (TMTX). The possibility of enhancing TMTX cytotoxicity of CPG2 induced depletion of intracellular folates was investigated in human leukemic CCRF-CEM cells and in three methotrexate resistant sublines of these cells with different mechanisms of resistance, CCRF-CEM/E, a subline with increased DHFR; CCRF-CEM/P, a subline defective in polyglutamylation and CCRF-CEM/T, a subline with impaired MTX uptake. The cytotoxic effect was detected using a colorimetric assay with MTT. Dose-effect relationships of single drugs alone and in combination were analyzed by the median effect principle and by the combination indices for the quantitation of synergism or antagonism with the aid of a microcomputer. TMTX alone was very effective on the parent and all the resistant cell lines (CCRF-CEM/E, CCRF-CEM/P, CCRF-CEM/T) with ED50 values in the nanomolar range (1.4, 1.6, 1.5 and 0.7 nM, respectively) following 5 days of exposure. The ED50s of CPG2 for these cell lines were 3.5, 2.6, 26.6 and 7.9 X 10(-5) U/ml, respectively. A synergistic cytotoxic effect of TMTX after simultaneous continuous exposure was observed with CPG2 on CCRF-CEM cells and on the three resistant cell lines.

Comparison of in vitro drug sensitivity by inhibition of tritium release from [5-3H]-2'-deoxyuridine and a clonogenic assay.

In a search for a rapid and simple method to determine drug-induced cell lethality, the inhibition of tritium release from [5-3H]-2'-deoxyuridine (ITR) was compared with a standard clonogenic assay. Seven drugs were studied. After a 4 hr incubation period, [5-3H]-2'-deoxyuridine was added to cultures of human colon carcinoma cells (HCT-8) in vitro and four dose-response curves were generated for each drug by sampling the culture medium for tritiated H2O formation 4, 24, 48 and 72 hr later. These curves were compared to those obtained by a standard clonogenic assay. The ED50 values for 5 of the 7 drugs tested, methotrexate, 5-fluorouracil, doxorubicin, vincristine and cisplatin, as measured by inhibition of HCT-8 colony growth, were within 3 times the values observed with the metabolic assay. The ITR highly overestimated the cytotoxicity of 5-fluoro-2'-deoxyuridine: the irreversible inhibition of thymidylate synthase by this nucleoside resulted in an ED50 value 100-fold lower than that observed with the clonogenic assay. Opposite results were obtained with 5-fluorouridine. These data indicate that the ITR can be used to determine drug sensitivity of these cells to a host of compounds although it cannot be used indiscriminately for every antineoplastic agent as a cytotoxicity assay.

Predictive value of some clinical and pathological parameters on upper level axillary lymph node involvement in breast cancer.

The role of radical axillary dissection in breast cancer management is presently under discussion. In this study we have evaluated the relationship between the pattern of metastatic axillary lymph node involvement by level and some of the main prognostic factors (age of the patient, size, grading, estrogen receptor and progesterone receptor status of the primary tumor) in 185 patients with operable breast cancer. The III level appeared to be involved in 31 (16.8%) out the 108 patients with axillary lymph nodes positive for metastases. A discontinuous pattern of axillary involvement (skip metastases) was observed in about 10% of cases. Logistic regression analysis of the data shows that only G3 is significantly correlated with the risk of III level invasion (p less than 0.05). We conclude that, at present, a selection of possible candidates for a less than radical axillary dissection is not as yet feasible. Since the risk for III level invasion cannot be sufficiently defined.

Combination of cisplatin, epirubicin, and cyclophosphamide (PEC regimen) in advanced or recurrent endometrial cancer: a retrospective clinical study.

The combination of cisplatin (50 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) (PEC regimen) was given every 4 weeks to 19 patients with advanced (n.2) or recurrent (n.17) endometrial cancer. The median number of cycles delivered to each patient was 5 (range, 2-8). All patients were evaluable for toxicity and 16 for response. Two (12.5%) patients experienced a complete response and 5 (31.2%) had a partial response, for an overall objective response rate of 43.7%. The median duration of objective response was 10 months (range, 3-28 months). Median survival was 10 months (range, 3-68+ months) in the whole series. According to response to chemotherapy, median survival was 12 months (range, 3-68+ months) for responders and 9 months (range, 6-17 months) for nonresponders. Hematologic toxicity was relatively frequent but it could be easily managed, and significant nonhematologic toxicities were not found except for nausea and vomiting. In conclusion, PEC regimen has a good activity in advanced or recurrent endometrial cancer, but the short duration of responses limits the impact of the treatment on survival time.

Accelerated epirubicin-ifosfamide-dacarbazine regimen in patients with adult soft tissue sarcomas.

BACKGROUND: Neutropenia and infections are the dose-limiting toxicities of the EID regimen and can cause dose reduction and/or delay in chemotherapy administration. The purpose of this study was to verify if EID + G-CSF is feasible with an acceptable toxicity in a day hospital setting and if G-CSF could allow an increase in the dose intensity of the EID regimen by shortening the intervals between the courses. PATIENTS AND METHODS: 20 patients with inoperable primary, metastatic or residual disease after surgery or at high risk of recurrence after complete resection, histologically confirmed adult soft tissue sarcoma, entered the study. The dose and schedule of the chemotherapy agents were epidoxorubicin 30 mg/m2 days 1, 2, 3, dacarbazine 300 mg/m2 days 1, 2, 3, and ifosfamide 2500 mg/m2 with mesna uroprotection days 1, 2, 3. G-CSF, 300 micrograms/day subcutaneously, was administered from day 7 for a maximum of 14 days and discontinued when WBC was greater than 10 x 10(9)/L. Courses were repeated "as soon as possible," but never earlier than 10 days from the previous course and at least 48 hours after the last G-CSF injection. RESULTS: A total of 66 EID + G-CSF courses were administered. A G3 and G4 (WHO) neutropenia occurred in 66% of evaluables courses. Nonhematological toxicity was mild. The median number of G-CSF injections required during any interval between courses was 9 (range: 4-14 injections) and the median interval between courses was 21 days (range: 13-36 days). The median dose intensity at the third course of chemotherapy was 1.15 (range: 0.71-1.62). CONCLUSION: This study shows that G-CSF allows a moderate increase in the delivered dose intensity of chemotherapy with an acceptable toxicity. Further studies are needed to investigate if this increase in DI may translate into an improved response rate.

Chemotherapy and bio-chemotherapy in patients with advanced melanoma: combination therapy with a nitrosourea.

The treatment of advanced melanoma is still disappointing. In a multicenter randomized clinical trial to compare a chemotherapy (CT) with or without low doses of IL-2 and IFN (Bio-CT), the participating centers chose whether or not to add a nitrosourea, carmustine (BCNU) to the therapy. The aim of the present paper is to report the clinical results of the patients (pts) treated in both arms with BCNU. One hundred and seventy-six pts with advanced melanoma were enrolled in the study from 27 centers and a total of 18 pts also received BCNU in 3 centers. No further changes to the protocol criteria were allowed. One patient refused the treatment. No complete responses were observed. Irrespectively of the treatment arm, 9/17 pts showed a partial response to therapy (53%) (5/9 in the CT and 4/8 in the BioCT arm). The most important adverse events observed were hematological: 12 pts presented grade 3 (6 pts) or grade 4 (6 pts) leukocytopenia and 9 pts had grade 4 thrombocytopenia, all of which resolved spontaneously. The addition of a nitrosourea to CT or Bio-CT appears to improve response rates compared to the same regimens without nitrosourea. Patient tolerability is acceptable. Further studies using this combination are warranted.

Increasing dose of continuous infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4'-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients. METHODS: Treatment consisted of epidoxorubicin, 60 mg/m2 days one and two, and ifosfamide, 1.5 g/m2 every 12 hrs as a 72-hr infusion, at the first level. Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program. G-CSF 300 microg/die was administered from days +7 to +14. Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of > or =5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients had to complete at least 2 consecutive cycles, and MTD was defined as the level in which 20% of patients developed a DLT; 10-15 patients were entered in each level. RESULTS: First level: overall, 13 patients entered, 3 were not assessable for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients. Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84 hrs. Eight patients of 29 assessable for response achieved an objective response: 1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%). CONCLUSIONS: If we accept 4-day G4 leukopenia as a reliable cutoff for safety, ifosfamide intensification cannot be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines.

Detection of melanoma cells in peripheral blood and sentinel lymph nodes by RT-PCR analysis: a comparative study with immunohistochemistry.

The presence of lymph node metastases is the best prognostic factor for predicting relapse or survival in melanoma patients. It has been demonstrated that melanoma metastases spread through the first lymph node(s) draining the tumor (sentinel lymph node, SN) to the lymphatic system and that detection of melanoma cells in peripheral blood directly correlates with prognosis in melanoma. To identify lymph node metastases and circulating melanocytes, we developed a single-step reverse transcriptase-polymerase chain reaction assay (RT-PCR) for detection of two melanoma-specific markers: the tyrosinase gene, which encodes an enzyme associated with melanin synthesis, and melanoma antigen-related T-cells, which are present in tumor infiltrating T-lymphocytes. This method detects two tumor cells in a background of 10(7) lymphocytes. Thirty patients with stage I-IV cutaneous melanoma entered the study. Blood samples were taken preoperatively, one month after excision of the primary melanoma lesion and the SN or total lymphadenectomy, and before the start of chemotherapy and every three months thereafter in metastatic patients. SNs were collected from 22 patients, bisected and analyzed by RT-PCR and routine pathological and immunohistochemical tests. The preliminary results indicate that RT-PCR for melanoma markers is a sensitive and valuable method for the detection of micrometastases and for early diagnosis and staging of melanoma.

Adjuvant chemotherapy in early stage uterine sarcomas: an open question.

Uterine sarcomas are aggressive gynecological cancers even at early stage of disease. The most common histological types are represented by leiomyosarcoma, endometrial stromal sarcoma, and carcinosarcoma. The mainstay of treatment of stage I-II disease is total hysterectomy with bilateral salpingo-oophorectomy. Adjuvant radiotherapy may decrease local recurrence rates without any significant impact on survival. Adjuvant chemotherapy is a logical approach, since distant recurrences are more frequent than local failures. The chemotherapy regimens commonly used in advanced uterine sarcomas are similar to the ones for advanced soft tissue sarcomas, with anthracyclines and ifosfamide as the most active drugs. However, carcinosarcomas respond better to cisplatin-based regimens. It is advisable to design international cooperative randomized trials with the aim of defining the role of adjuvant chemotherapy in the treatment of early stage uterine sarcomas.

Regional chemotherapy by a totally infusion pump preceding radiotherapy in advanced cervical carcinoma: a preliminary report.

The authors report the preliminary results of a prospective study on intra-arterial chemotherapy and radiotherapy of advanced cervix carcinoma. The drugs were delivered by a totally implanted Infusaid Model 400 pump and patients received cyclic therapy consisting of Cis-Platinum, Methotrexate and Bleomycin. The catheter tips were positioned during a laparotomy in the hypogastric arteries with sutures and the pump was implanted in a subcutaneous pouch in the abdomen. After chemotherapy all patients had radiotherapy. Five patients entered in the study. Preliminary results suggest that long-term intra-arterial infusion chemotherapy for the treatment of advanced cervix carcinoma is practical for many patients. Two of five patients, after intra-arterial chemotherapy and radiotherapy, had radical hysterectomy.

[Recent pharmacotoxicologic and clinical findings on adriamycin]. / Recenti acquisizioni farmacotossicologiche e cliniche sulla adriamicina.

Anthracycline derivative adriamycin (ADR) is one of the most important anticancer drugs with major clinical application in carcinomas of the brest, endometrium, ovary, testicle, thyroid, lung and in treatment of many sarcomas. It is useful also in haematological cancers including acute leukaemia, multiple myeloma, Hodgkin's disease and the diffuse non-Hodgkin lymphomas. A factor limiting ADR clinical practice is represented by a severe dose-dependent cardiac toxicity, the mechanism of which is still under study, but appears to involve excessive intracellular production of free radicals within myocardium: this is rarely seen at ADR dosage below 500 mg/m2. A series of new anthracycline analogues has recently entered clinical trials: they include 4'-epiadriamycin, 4'-deoxy-adriamycin, aclacynomycin A, carminomycin and N-trifluoroacetyladriamycin-14-valerate. These new agents appear to have different spectrum of action and somewhat less toxicity, however antitumor activity in only now being defined, consequently major clinical interest is still concentrated in the use of ADR. The present article reviews the most relevant data from literature concerning the pharmacology, the toxicology and the clinical use of ADR.