Expression of the Met/HGF receptor in normal and neoplastic human tissues.

The MET oncogene encodes a transmembrane tyrosine kinase receptor. Recently, hepatocyte growth factor (HGF), a potent growth factor for hepatocytes involved in liver regeneration, has been proposed as a ligand. In this paper, the physiological role of the human Met/HGF receptor is investigated by studying its specific distribution in normal and neoplastic tissues. Northern blot analysis has shown that the MET gene is selectively expressed in several epithelial tissues. High levels of MET mRNA have been found in liver, gastrointestinal tract, thyroid and kidney. Western blot analysis has shown that the levels of the Met protein generally correspond to those of the mRNA. However, in the thyroid, where there is a high level of MET mRNA, the protein was barely detectable, suggesting translational or post-translational regulation. The protein was also detected in the brain. Normal or increased levels of MET mRNA and Met protein were consistently found in fresh samples of carcinomas as well as in epithelial tumor cell lines. In thyroid carcinomas of a specific histiotype the amount of Met protein, almost undetectable in the normal counterpart, was found to be increased more than 100-fold. The tissue distribution of the Met/HGF receptor indicates that this molecule is involved in growth control of epithelial cells other than hepatocytes and suggests that its increased expression may confer a growth advantage to neoplastic cells.

Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer.

The c-met oncogene encodes the receptor for hepatocyte growth factor/scatter factor, a potent mitogen for epithelial cells that also promotes cell motility and invasiveness. We have studied the changes of c-met gene expression that occur during the progression of colorectal tumors. Sixteen adenomas, 123 primitive carcinomas, and 25 liver metastases were examined. In several instances it was possible to compare same-patient samples of normal colon mucosa against primary tumor and primary carcinoma against synchronous metastasis. The expression of the c-met gene was increased from 5- to 50-fold in about 50% of tumors, at any stage of progression, and in 70% of liver metastases. Overexpression was associated with amplification of the c-met gene in only 10% of carcinomas, but in 8 of 9 metastases examined. These data suggest that overexpression of the c-met oncogene contributes a selective growth advantage to neoplastic colorectal cells at any stage of tumor progression. Moreover, amplification appears to give a further selective advantage for the acquisition of metastatic potential.

An open phase I study to assess the biological effects of a continuous intravenous infusion of Interleukin-3 followed by Granulocyte Macrophage-Colony Stimulating Factor.

To assess any synergistic stimulatory effect in vivo of Interleukin 3 (IL-3) and Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) upon white cell and platelet counts, toxicity and antitumour effect, we conducted this phase I study. IL-3 0.25, 0.5 or 5 micrograms/kg/day for 1, 4 or 7 days was given by continuous intravenous (i.v.) infusion to 35 patients with advanced malignancy. 21 of the 35 patients also received sequential or overlapping treatment with continuous i.v. infusion of GM-CSF 1 or 3 micrograms/kg/day for up to 10 days. Monotherapy with IL-3 producted significant dose related increases in platelets and white cell counts. Combinations of IL-3 and GM-CSF also produced increases in white cell counts, but these were no greater than would be expected following GM-CSF treatment alone. There was a trend for platelets to increase more in patients receiving IL-3 and GM-CSF than those receiving IL-3 alone, but this did not reach statistical significance. In general, IL-3 and combinations of IL-3 and GM-CSF were well tolerated and the most common side-effect was fever. A maximum tolerated dose was not reached and antitumour effects were not seen. Future studies using combinations of IL-3 5 micrograms/kg/day and GM-CSF 3 micrograms/kg/day may help to define the optimal therapeutic regimen.

Multicenter Phase II trial of intermediate dose cisplatin and vinorelbine in inoperable non-small cell lung cancer patients.

Vinorelbine (VNB) and cisplatin (CDDP) combination regimen was found active in the treatment of advanced non-small cell lung cancer (NSCLC) patients, but significant toxicity was observed. We evaluated the activity and toxicity of this combination administered at lower doses than previously reported. From March 1992 to March 1994, 99 patients (pts) were enrolled in a multicentric Phase II study and received intravenous CDDP at 80 mg/m2 on day 1, associated with intravenous VNB at 25 mg/m2 on days 1 and 8. Cycles were repeated every 3 weeks. The reduced doses led to a consistently lower myelotoxicity (8% Grade III-IV leukopenia) in comparison to two related Phase III studies, recently published. Conversely, the incidence of neurological toxicity was superimposable. Considering all eligible patients, the overall response rate was 28.3%, and this is similar to the results commonly observed employing the most active CDDP containing regimens. In conclusion, CDDP and VNB combination chemotherapy at the schedule performed in the present study led to a reduction of hematologic toxicity, while an appreciable activity was maintained.

Multimodal management of stages III-IVa malignant thymoma.

PURPOSE: The optimal therapy for locally advanced malignant thymoma is controversial. We review our experience with a multimodal approach in 63 consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and 20 stage IVa disease. Surgery with radical intent was initially performed in 30 cases, while 33 cases not amenable to radical surgery underwent neoadjuvant treatment (radiotherapy in 8 and chemotherapy in 25) before surgical reassessment. All patients, whether or not surgically resected, received radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight stage III and four stage IVa). With the addition of patients radically operated with neoadjuvant treatment, the radical resection rate increased from 46 to 65% in stage III patients, and from 0 to 20% in those with stage IVa disease, respectively. Radical surgery was associated with longer progression free survival and overall survival according to both univariate analysis ( P< 0.001 and P<0.01, respectively) and multivariate analysis after adjustment for age, gender, histology and disease stage ( P<0.001 and <0.02, respectively). Progression free survival (median 56.9 months) was slightly lower in patients undergoing radical surgery after neoadjuvant approaches than in those radically resected ab initio (median not achieved), but overall survival (median not achieved) was similar in both groups. Subtotal surgical resection promoted complete response to subsequent radiation therapy. This condition significantly correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an independent prognostic parameter in locally advanced thymoma treated with a multimodal approach. Preoperative treatment to increase the complete resection rate could improve the overall survival of these patients.

Cea and ca-19.9 as markers of colorectal neoplasms during chemotherapeutic treatment.

Carcinoembryonic antigen and CA 19.9 are markers of colorectal neoplasms, often related to tumor burden. Elevated pre-operative levels parallel disease extent and may foresee adverse prognosis. CEA and CA 19.9 may increase post-operatively, indicating tumor recurrence. Only limited data are available on the influence of chemotherapeutic treatments on these two markers, to detect chemotherapy-induced cytolysis. We measured CEA and CA 19.9 before and after a chemotherapy regimen of five days consisting of folinic acid and 5-fluorouracil in forty patients with colorectal cancer. No consistent fluctuation was detected, the examined tumor markers being related in a given patient only to tumor burden.

Low dose carboplatin (AUC 4.5) combined with vinorelbine in the treatment of advanced non-small cell lung cancer: a single institution phase II study.

Platinum compounds and vinorelbine (VNB) are active in the treatment of non-small cell lung cancer (NSCLC), but moderate toxicity has been reported. The aims of the present study were to assess activity and tolerability of low dose carboplatin (CBDCA): 4.5 AUC according to Calvert formula on day 1, combined with vinorelbine: 25 mg/m2 on days 1 and 8, administered every 4 weeks. Eighty-five advanced NSCLC patients entered the study; all of them were evaluable for toxicity and 83 were evaluable for activity. According to an intent to treat analysis, 26 patients attained a partial response (30.5%; 95% CI 20.5-40.5), 27 (31.7%) obtained a disease stabilization and 30 (35%) progressed. This regimen appeared to be modestly toxic, grade 3-4 leukopenia and thrombocytopenia were observed in less than 5% of cases and grade 2 neuropathy in 10% of cases. Median time to progression and overall survival were 7 and 9 months, respectively. In conclusion, low dose CBDCA (administered following Calvert's formula) and VNB combination is an active and very well tolerated cytotoxic regimen in the treatment of advanced NSCLC. The application of the Calvert formula may have contributed to limit the side effects related to CBDCA.

Non small cell lung cancer treatment with vinorelbine monochemotherapy: a phase II study.

Non small cell lung cancer is one of the leading causes of death in the industrial countries and some 70% of patients have non surgically eradicable disease. Platinum based combined regimens can achieve 35-40% objective responses, but advanced age, low performance status and concurrent diseases can exclude up to 60% of patients from an adequate poliychemotherapy treatment.

Gemcitabine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a phase II study.

BACKGROUND: Lung cancer is the leading cause of cancer death in men worldwide; most cases are not suitable for radical surgery at diagnosis and palliative treatment remains the primary goal of therapy. Cisplatin and gemcitabine are among the most active cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC): they have non-overlapping toxicity and preclinical studies have demonstrated their potential synergistic interaction. PATIENTS AND METHODS: The aims of the present study were to assess the activity and tolerability of cisplatin 80 mg/m2 on day 1, combined with gemcitabine 1000 mg/m2 on days 1 and 8, administered every 3 weeks. A total of 46 consecutive patients with advanced NSCLC entered this study; all of them were evaluable for toxicity and for activity. RESULTS: According to an intent-to-treat analysis, 15 patients attained a partial response (33%), 9 (20%) obtained a disease stabilisation and 22 (47%) progressed. This regimen appeared to be modestly toxic, with grades 3-4 leukopenia and thrombocytopenia observed in 10% and 6% of cases respectively; grade 3 vomiting appeared in 12 patients (26%) and grade 3 mucositis in 1 patient. The median time-to-progression and overall survival were 200 and 400 days, respectively. CONCLUSION: Our study of gemicitabine + cisplatin on stage IV NSCLC patients achieved favourable results in terms of toxicity and overall survival.

Palmar-plantar erythrodysestasia syndrome associated with 5-fluorouracil treatment.

Palmar-Plantar Erythrodysestasia Syndrome (PPES) or Hand-Foot Syndrome (H&F S) is an underestimated adverse reaction to chemotherapeutic agents, mainly related to 5-Fluorouracil. From March 1991 to February 1992, at the San Giovanni Oncologic Hospital of Torino, we observed 12 out of 163 patients (7.3%) displaying PPES while being treated with 5-FU containing regimens. No correlation with type of neoplastic disease, sex, age and total dose of administered 5FU was observed. Dose reductions or drug suspension achieved PPES reversal. The etiopathogenesis remains unclear. Both an idiosyncratic pattern and cutaneous drug accumulation are suggested.

Low dose adriamycin and ifosfamide in the treatment of advanced adult soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are infrequent tumors (up to 1% of all neoplasms) in adult patients. Treatment of advanced disease is largely unsatisfactory. Only a few drugs are active agents and combination regimens offer limited and short-lived activity. High dose chemotherapy may be administered only to limited groups of patients. PATIENTS AND METHODS: We evaluated, in a phase II study, the adriamycin and ifosfamide combination regimen. The drugs were administered at 60 mg/sqm and 6 g/sqm dosage, respectively. The total number of treated patients was 42 of which 40 were evaluable. RESULTS: We observed 6 complete responses (14% response rate) and 6 partial responses (14%). The mean survival was 6 months (median 7.6 months). Toxicity was limited and reversible. CONCLUSION: While high dose chemotherapy may be reserved for selected groups of patients, an adriamycin and ifosfamide combination regimen at conventional doses can be administered to the great majority of patients with suboptimal performance status or with advanced age.

Non small cell lung cancer treatment with carboplatin and vindesine: a phase II study.

A phase II trial aiming to verify the effectiveness of a regimen including carboplatin and vindesine was performed. From November 1989 to September 1990, nineteen patients with advanced small cell lung cancer entered this study. Polychemotherapy treatment included: carboplatin 400 mg/sm, on day 1 and vindesine 3 mg/sm, on days 1 and 15, repeated every 4 weeks, as an outpatient regimen. Observed toxicity was mild; myelodepression, and nausea and vomiting were the main adverse events. No objective response was obtained; 14 no changes in the disease and 4 progressions were detected. The low objective response rate observed in this study is strongly influenced by a set of unfavourable prognostic factors. The median overall survival time [32 weeks] is comparable with the results of other studies.

The monoclonal antibody-defined CAR-3 antigen is a serological marker associated with pancreatic carcinoma.

The monoclonal antibody-defined CAR-3 antigen is a new carcinoma associated marker which is expressed on a mucin-like molecule. Serum concentrations of CAR-3 were assayed in 181 patients with carcinomas of different organs, 20 patients with non-carcinomatous malignancies, 123 patients with inflammatory diseases and 150 healthy controls. Serum levels of CAR-3 were significantly increased in 51% of the patients with pancreatic carcinomas, in 60% of patients with biliary tract carcinomas and in about 15% of the patients with carcinomas of the digestive apparatus. Sera from patients with breast carcinomas were negative, as well as sera from patients with melanomas or sarcomas. CAR-3 values in samples from patients with chronic pancreatitis were constantly negative, as were samples from healthy donors. Significant concentrations of CAR-3 were detected in 20% of the sera from patients with acute pancreatitis and in 15% of the sera from patients with cirrhosis. Because of its high specificity for pancreatic carcinomas compared to chronic pancreatitis, CAR-3 seems a promising marker for distinguishing between neoplastic and chronic inflammatory diseases of the pancreas, whose differential diagnosis is difficult.

Preoperative concurrent radiation therapy and cisplatinum continuous infusion in IIIa (N2) non small cell lung cancer. A pilot study.

From April 1991 to September 1993, 18 patients affected by a presumed operable IIIa (N2) non small cell lung cancer (NSCLC) with histologically confirmed bulky mediastinal metastases, received preoperative concurrent radiation therapy and continuous infusion of cisplatinum (CDDP). The radiotherapy consisted of 2 Gy given 5 days a week for a total dose of 50 Gy; CDDP was administered by means of a central catheter and a portable pump at the daily dose of 6 mg/m2 given on the same days as the radiation therapy (total dose: 150 mg/m2). Two weeks after the end of the treatment, the patients were reevaluated: 5 patients had either local or distant disease progression, the other 13 were submitted to thoracotomy: 12 received a complete resection and 1 patient underwent only a mediastinal lymphadenectomy, because pneumonectomy was impossible due to lack of respiratory function. No histological evidence of cancer cells was observed in the specimens of 6 patients (33%). Radiological response rate was 61% (11/18); resection rate was 66% (12/18) and complete resection rate was 61% (11/18). There was one postoperative death (5%). The 3 year actuarial survival rate is 63.6% for the patients who received a resection with a median survival time of 18 months. All non operated patients died within one year. Combined preoperative treatment was well tolerated. Better results were achieved in patients with squamous cell carcinoma who had a complete resection following a total tumor sterilization with radio-chemotherapy.

Phase II study of the activity and tolerability of a combined regimen of high-dose epirubicin and cisplatin in stage IIIb and IV non-small cell lung cancer.

AIM: To explore the feasibility and activity of a combined regimen of high-dose epirubicin and cisplatin as an alternative to current treatments for non-small cell lung cancer (NSCLC). METHOD: Forty-four patients with stage IIIb or IV NSCLC, median Karnofsky index 90, were enrolled. Epirubicin (60 mg/m2) was administered on days 1 and 2 and cisplatin (100 mg/m2) on day 1. Treatment was repeated every 21 days for a maximum of six cycles. A hematopoietic growth factor (G-CSF) was used only for patients reaching codified nadir count values. RESULTS: A total of 130 cycles were administered with a mean of 2.9 cycles per patient. Of 41 assessable patients one showed a complete response and 15 had partial responses (overall response rate, 39%). Grade 3 or 4 leukopenia and grade 3 hemoglobin toxicity were seen in 40% and 14%, respectively, of the administered cycles. The most common nonhematologic toxic events were nausea and vomiting, mucositis, anorexia, and asthenia. CONCLUSIONS: This epirubicin-cisplatin regimen seemed effective and was generally well tolerated, and therefore suitable for use in an outpatient setting.

Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors.

The Italian Group on Rare Tumors undertook a phase II study of a combination of epirubicin and interleukin-2 in 21 chemotherapy-naive patients with malignant mesothelioma. All patients had bidimensionally measurable disease at CT scan. Treatment included Intravenous administration of epirubicin at a dose of 110 mg/m2 i.v. on day 1, and interleukin-2 at a dose of 9 MU subcutaneously from day 8 to day 12 and from day 15 to day 19. Cycles were repeated every three weeks, up to six times in the absence of progressive disease. Treatment response was evaluated after two cycles of therapy. Only one patient achieved a partial response, resulting in an overall response rate of 5% (1/21) with a median progression-free and overall survival of 5 and 10 months, respectively. Toxicity was relevant and caused treatment discontinuation in many patients. These results do not support the use of such a combination in the management of malignant mesothelioma.

[Metastasis to the penis from carcinoma of the rectum. A clinical case]. / Metastasi al pene da carcinoma del retto. Caso clinico.

Penile metastases are extremely uncommon, with less than 300 reported cases. The primary sites of the responsible carcinoma have been bladder, rectum, prostate, kidney, testis, lung, nasopharynx and melanoma in that order. We report a case confirming the same data: no therapy has been shown to be helpful, the prognosis is very poor, with an average survival of less than one year. On the other hand we pointed out the importance of CT scan as a diagnostic tool for assessing the spread of neoplasm.

[Treatment of N2-3 pulmonary carcinoma. Preoperative radio-chemotherapy]. / Trattamento del carcinoma polmonare N2-3. Radio-chemioterapia preoperatoria.

Preoperative integrated neo-adjuvant radio-chemotherapy was performed in 8 patients suffering from NSCLC bronchial carcinoma at stages IIIA-IIIB (N3 mediastinal). After treatment, 7 patients underwent apparently radical pulmonary exeresis, whereas the patient with adenocarcinoma (T2 N2 M0) was not operated due to the recurrence of disease following supraclavicular lymph node metastasis. Preoperative radio-chemotherapy allows the sub-staging of the disease and the insertion of these patients into the operating programme.

Weekly cisplatin plus capecitabine in metastatic breast cancer patients heavily pretreated with both anthracycline and taxanes.

BACKGROUND: Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer is challenging. This study evaluated the activity and safety of a combination of cisplatin and capecitabine in this setting. PATIENTS AND METHODS: Thirty-nine consecutive patients entered the study. All had experienced failures or relapse after previous treatment with anthracyclines and taxanes plus/minus other chemotherapeutic regimens. The present treatment consisted of intravenous cisplatin 20 mg/m(2) every week for 6 weeks, followed by 1 week of rest, and oral capecitabine 1,000 mg/m(2) twice daily for 14 days, followed by a 7-day rest period. RESULTS: Objective response was obtained in 14 patients (35.9%), with complete remission in 3 (7.7%). Median time to progression was 5.2 months and survival was 10.9 months in the entire population and 8.7 and 16.5 months in the responding patients, respectively. The dose-limiting toxicity for the regimen was leucopenia, while gastrointestinal discomfort was the most frequent cause of capecitabine reduction or delay. CONCLUSIONS: The cisplatin and capecitabine combination regimen is active and manageable. It seems to be non-cross resistant to anthracyclines and taxanes.

Characterization of stable spontaneous metastatic variant lines of RSV-transformed mouse fibroblasts.

The correlation between metastatic potential and a series of biological properties was investigated in two mouse fibrosarcoma lines (SR-BALB and B77-3T3), transformed by different strains of Rous sarcoma virus (RSV). In the absence of selective pressure the metastatic potential was different in the two lines. The SR-BALB sarcoma did produce both spontaneous metastases from s.c. site and i.v. lung colonization with a high incidence (respectively in 60% and 80% of treated animals). Conversely, the metastatic incidence of the B77-3T3 sarcoma was much lower. Differences in lung implantation between the two lines turned out to be even greater when the number of colonies growing in the lung was evaluated. Organ distribution of cells after i.v. injection, tumorigenicity, growth rate in vivo and in vitro, plating efficiency in liquid medium and cloning efficiency in semi-solid agar medium were evaluated in the two lines. A strict correlation was found only between the metastatic potential and the capability of growth in 0.6% ("hard") agar. Such a correlation was supported by the isolation in "hard" agar of highly metastasizing subclones of the low-metastasizing B77-3T3 line.