Caroline Bognel

Prognostic factors in primary gastrointestinal non-Hodgkin's lymphoma. A multivariate analysis, report of 106 cases, and review of the literature.

The authors have reviewed 106 cases of primary gastrointestinal non‐Hodgkins lymphoma (GI‐NHL) treated at the Institut Gustave‐Roussy (IGR), France, between 1975 and 1986. The occurrence was 55 in the stomach, 26 in the small intestine, ten ileocecal, seven in the large intestine, and eight patients had multiple involvement. Patients were clinically staged according to the Ann Arbor staging system using the modification of Musshoff for Stage IIE. All histologic material of the 106 patients were reviewed and graded according to the Working Formulation (WF) and the Kiel classifications. Most patients received combination chemotherapy as part or all of their primary treatment program (95 patients, 90%). Seventy five patients (71%) had a multimodality treatment. The overall 5‐year survival rate was 60%. Sixteen variables were tested by univariate analyses for prognostic influence on survival. Of these, only clinical stage (P < 0.001), the achievement of initial complete remission (CR) (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.01), mesenteric involvement (P = 0.03), and serosal infiltration (P = 0.05) were significant prognostic factors. Important variables were tested by a multivariate analysis using the Cox model taking into account different treatment modalities. Only three variables entered the regression analysis at a significant level: clinical stage (P = 0.02), surgical resection (P = 0.03), and histologic grade (Kiel) (P = 0.04). When the achievement of initial CR was introduced into the model, it was the most significant variable (P < 0.001) whereas all other variables became nonsignificant except for the histologic grade (Kiel) (P = 0.004). Based on results of the multivariate analyses we propose two prognostic classifications of patients: one at the initial evaluation depending on clinical stage, surgical resectability, and histologic grade (Kiel); the other at the end of primary treatment depending on the achievement or not of CR and the histologic grade.

Electrochemotherapy on liver tumours in rabbits.

Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLMs cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EP-dependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects. When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies.

Efficacy of combined 5-fluorouracil and cisplatinum in advanced gastric carcinomas. A phase II trial with prognostic factor analysis

Combined chemotherapy has demonstrated a degree of efficacy in gastric carcinoma. As 5-fluorouracil (5FU) and cisplatinum are two of the most active drugs, we have tested the efficacy of combined 5FU and cisplatinum in a prospective phase II trial. Cycles were administered every 4 weeks and consisted of 5FU 1000 mg/m2/day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m2 on day 2. Cycles were repeated according to tolerance and efficacy. 87 patients entered the study, 57 with metastatic or recurrent tumour (M) and 30 with locally advanced gastric cancer (LAGC). The response rate for the 83 evaluable patients was 43% [95% confidence interval (CI) 30-56%]. There were four complete responses (5%), 32 partial responses (39%), 34 cases of stable disease and 13 cases of progressive disease. Responses were more frequent in patients with a good performance status (P = 0.02), with their primary located in the cardia (P = 0.003), with a non-linitis plastica tumour form (P = 0.003) or a tumour containing less than 50% of independent cells (P = 0.016). Median survival was 9 months for the total population. It was better in patients with a good performance status (P = 0.01), and those who did not have linitis plastica (P = 0.005). Toxicity was acceptable, although grade 3-4 neutropenia was reported in 22% of the cycles, mucositis in 14% and 3 patients died of septic complications. The combination of 5FU and cisplatinum is effective in terms of tumour response in advanced gastric cancer and warrants testing with the other active regimens.

Neoadjuvant chemotherapy in locally advanced gastric carcinoma-A phase II trial with combined continuous intravenous 5-fluorouracil and bolus cisplatinum.

Locally advanced gastric adenocarcinomas (LAGC) have a poor prognosis, particularly when tumours are bulky, located in the cardia or in the event of locoregional lymph node involvement. Patients bearing these tumours were entered in a phase II trial of neoadjuvant chemotherapy, combining continuous intravenous 5-fluorouracil (5FU) (1000 mg/m2 for 5 days) and cisplatinum (CDDP) (100 mg/m2 on day 2) repeated every 4 weeks, for one to six cycles according to response and tolerance. 30 patients have been entered, 26 after clinical evaluation (CAT scan and upper gastrointestinal endoscopy) and 4 with unresectable tumours at prior laparotomy. Median age was 60 years, 15/30 patients had a tumour of the cardia, 15/30 had enlarged lymph nodes and 7/30 had linitis plastica (diffuse type). A mean number of three cycles was administered (range 1-6). 27 of the 30 patients were evaluable for response. One patient achieved a complete response (CR) and 14 a partial response (56%; 95% confidence interval 38-74%). No patient had tumour progression, and only 1/6 with linitis plastica responded. 28 patients underwent surgery, and 23 had a macroscopically complete resection (77% of the 30 entered patients); RO resections were performed in 60% of the cases, mainly after an objective response (13/15 versus 4/12 in nonresponders). No pathological CR were seen. Grade 4 neutropenia was observed in eight cycles (5 patients), with five septic complications and one death due to toxicity. Four postoperative complications were observed: 2 cases of severe pneumonia and 2 subphrenic abscesses. One postoperative death, due to intravascular disseminated coagulation, was observed at day 30. Median survival was 16 months and the 1-, 2- and 3-year survival was 67, 42 and 38%, respectively. Patients with linitis plastica had a significantly shorter survival (P < 0.002). We conclude that neodjuvant chemotherapy is feasible in LAGC, although randomised trials are warranted to demonstrate its efficacy on survival and resection rates.

Borderline and malignant serous tumor arising in pelvic lymph nodes: evidence of origin in benign glandular inclusions.

This report describes two cases of malignant serous cancers with areas of borderline malignancy, which appear to have arisen within benign glandular inclusions of coelomic origin in pelvic or para-aortic lymph nodes. The patients were 44 and 62 years of age. In both cases the nodes contained benign glandular inclusions lined by a single layer of epithelium which resembled that of tubal epithelium. The location of the glandular epithelium varied from within the fat near the node to intracapsular, subcapsular, or interfollicular positions. The number of glands ranged from few to extensive. In both cases the glandular inclusions disclosed epithelial proliferations, ranging from minor degrees of stratification with formation of small papillae of atypical cells (borderline serous tumor) to almost solid tumor typical of serous cancer. In both cases, the borderline and cancerous tumors exhibited areas of transition which appeared to arise from benign glands. Although benign glandular inclusions of coelomic origin are well documented to occur in pelvic or para-aortic lymph nodes of 5-20% of women and have been considered to be of significance only because of the possibility of the misdiagnosis of cancer, it should now be recognized that the glandular inclusion cysts themselves can become neoplastic.

Malignant melanoma of the skin. Prognostic factors derived from a multifactorial analysis of 239 cases

Two hundred thirty-nine cases of primary cutaneous malignant melanoma were submitted to a multifactorial analysis of histological criteria. Three of those criteria, namely, Breslows thicknesses, ulceration, and mitotic activity, were found to be significant for prognosis.

Pharmacokinetics and antitumor effects of mitoxantrone after intratumoral or intraarterial hepatic administration in rabbits

Abstract The intratumoral (i.t.) delivery of anticancer drugs aims at controlling tumor growth and thereby provides palliative treatment for liver neoplasms. Mitoxantrone is a good candidate for local or regional administration because (1) its metabolism is mainly hepatic, (2) it has a steep dose-response curve for multiple solid tumors, and (3) its fixation in tissues is sustained without vesicant effects after extravasation. We compared the tolerance, pharmacokinetics, and antitumor effects of mitoxantrone on hepatic VX2 tumors in rabbits treated with i.t. intraarterial hepatic (i.a.h.) or i.v. mitoxantrone, i.t. ethanol; or i.t. 0.9% NaCl and in control animals. Tumor growth rates (TGRs) were evaluated at 9 days after treatment. Myelosuppression was the limiting toxicity of i.v. mitoxantrone at 1.5 mg/kg (maximal tolerated dose, MTD), but neither i.t. nor i.a.h. administration led to hematologic toxicity at the same dose. The mitoxantrone retained in tumors after i.t. administration was seen as blue-stained areas of complete necrosis according to histologic analysis. Pharmacokinetic parameters showed a significantly decreased systemic exposure to the drug after both regional treatments, although the i.a.h. route appeared to have an edge over the i.t. route. TGRs were significantly reduced after i.t. mitoxantrone (81±62%), i.a.h. mitoxantrone (337±110%), and i.t. ethanol treatments (287±117%) as compared with control values (886±223%; p<0.01). Treatment with i.v. mitoxantrone (816±132%) had no antitumor effect, nor did NaCl injections (868±116%). Mitoxantrone given i.t. induced the highest antitumor effects, resulting in a 3.5-fold reduction in TGRs as compared with i.a.h. mitoxantrone and i.t. ethanol treatments (p<0.02). Treatment with i.t. mitoxantrone provided efficient antitumor therapy without producing major side effects. This method should be considered as palliative treatment for nonresectable liver tumors and other localized malignancies.

Gastric carcinoma with argyrophilic cells: Light microscopic, electron microscopic, and immunochemical study

An immunochemical study of a gastric adenocarcinoma with argyrophilic cells showed two areas of tumor that react differently with the usual histochemical reagents as well as with immune sera against gastrin and mucoprotein associated with antigens. Ninety per cent of the tumor cells were PAS positive and contained M2 antigen, and some also contained M1 antigen. About 30 per cent of the M2-positive cells stained strongly with an antigastrin serum as well as with the argyrophilic reagents. The remaining 10 per cent of tumor cells were signet-ring cells located in several clumps in the tumor. These cells were positive for both PAS and alcian blue and contained intestinal M3 antigen. Forty-five per cent of them also contained M1 gastric antigens. Carcinoembryonic antigen (CEA) was found in the cytoplasm of each tumor cell. The presence of CEA and M1 antigen together indicates a fetal pattern, suggesting that the cells originate from very immature gastrointestinal stem cells.

Carcinomas of the colon with multidirectional differentiation. Report of two cases and review of the literature

SummaryTwo cases of colonic carcinomas with multidirectional differentiation are presented. Both tumors showed light microscopic and immunohistochemical evidence of areas of adenocarcinomatous, squamous cell carcinomatous, and neuroendocrine differentiation. Only six similar cases have been previously reported. These highly malignant tumors support the recent concept of a multipotential stem cell within the mucosa of the gastrointestinal tract capable of differentiation in several directions.

Phase I and pharmacological study of intra-arterial hepatic administration of pirarubicin in patients with advanced hepatic metastases

Intra-arterial hepatic (i.a.h.) administration of the doxorubicin analogue pirarubicin was evaluated in a phase I trial, based on preclinical studies that showed an advantage of pirarubicin over doxorubicin after locoregional hepatic administration. Pirarubicin was given to 9 patients with metastatic liver disease with intrapatient dose escalation. Of the 58 cycles evaluable for tolerance, no hepatobiliary or vascular toxicity was observed. The dose-limiting toxicity was granulocytopenia: the maximum administered doses ranged from 50 to 120 mg/m2, suggesting variable rates of pirarubicin hepatic extraction between patients. Pharmacokinetic data obtained in 7 patients, in which a direct comparison of intravenous (i.v.) and i.a.h. administration was possible, indicated a median i.v./i.a.h. ratio of 7.4 for the maximal plasma concentration, and a median ratio of 4 for the area under the plasma concentrations versus time curves, suggesting a high pirarubicin hepatic extraction. An unexpectedly high response rate was observed: two complete (colorectal carcinoma) and two partial responses. These data demonstrate that i.a.h. pirarubicin not only produced high locoregional concentrations and reduced systemic exposure, but can also achieve responses in metastatic liver disease of colorectal origin.