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To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.

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.

BACKGROUND Intraarterial hepatic (IAH) administration of verapamil should achieve mdr-1-reversing concentrations with reduced cardiac toxicity. The authors have explored the tolerance of its IAH administration and its effects on doxorubicin pharmacodymamics. METHODS Verapamil was given to rabbits by intravenous or IAH administration, and its effects on heart rates were compared. Doxorubicin then was given intravenously either with IAH verapamil or with an IAH control perfusion, and tumor and liver drug concentrations were determined. Hepatic blood flow changes were studied by the administration of 99mTc-albumin macroaggregates (99mTc-MAA) under verapamil IAH perfusions. RESULTS Compared with the intravenous route, IAH administration of verapamil was not toxic, and cardiac effects were reduced significantly. Its effect on doxorubicin distribution was detrimental, because the tumor-liver doxorubicin concentration ratios were lower in the verapamil group (0.23 vs. 3.37; P < 0.05). Tumor doxorubicin concentrations were lower when verapamil was coinfused (43 vs. 573 ng/100 mg tissue; P < 0.05). In normal liver tissue, increased amounts of doxorubicin and metabolites were observed. The verapamil IAH perfusions with 99mTc-MAA confirmed a differential action on tumor and normal vessels; the distribution of radionuclide was diverted away from the tumor bed significantly when verapamil was administered (tumor-to-liver ratio of 25.3 control rabbits vs. 5.99 rabbits who received verapamil; P < 0.05). CONCLUSIONS Reversing the concentrations of verapamil provoked changes in the distribution of the liver blood flow. The hemodynamic effects of verapamil regional perfusions could counteract in vivo its potential mdr-1-reversing properties.

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/m 2 /day 5 days continuous intravenous (i.v.) infusion and cisplatinum 100 mg/m 2 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.

Summary Nonhistone nucleoproteins associated with the nucleolar organizer region (NOR) can be visualized by a silver-staining technique on paraffin-embedded tissues. The number of black dots (Ag NORs) appearing on the nuclei are thought to reflect cell differentiation of certain tumors and can be used as an adjunct in predicting their evolution. We applied this method to determine if Ag NORs counts could be used as a diagnostic aid in borderline tumors of the ovary. Thirty-two cases of adenocarcinomas, 25 cases of borderline tumors, and 14 cases of adenomas were selected from Bouin-fixed archival material after histological examination. Both mean values of Ag NORs counts demonstrated a progressive increase from adenomas to borderline tumors and to carcinomas; the differences were statistically significant. Using discriminant analysis, all cases of benign and malignant tumors except one adenoma and one carcinoma were discriminated as belonging to an individualized group. No difference was found between borderline tumor with peritoneal implants and those without peritoneal implants. The results indicate that the Ag NORs counting procedure may be useful in distinguishing borderline tumors from carcinomas and adenomas. Ag NORs counts cannot, however, predict the clinical behavior of borderline tumors of the ovary.

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%; p0.01). 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 (p0.02). 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.

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 (P0.002). We conclude that neodjuvant chemotherapy is feasible in LAGC, although randomised trials are warranted to demonstrate its efficacy on survival and resection rates.

VX2 is a carcinoma established in rabbits and producing an autocrine growth factor, prostaglandin E2. Pirarubicin is a potent anti-VX2 agent. We investigated whether the oral intake of enprostil--a synthetic prostaglandin E2--or of diclofenac--a potent non-steroidal anti-inflammatory drug--increases the efficacy and decreases the hepatotoxicity of pirarubicin when injected in the portal trunk. Enprostil increased the number of hepatic tumoral nodules and induced hepatic alterations, especially venous dilatation. Paradoxically the combination of enprostil and pirarubicin was at least as effective as pirarubicin or diclofenac on VX2 cells. However, the toxicity was increased, especially with respect to sclerosing cholangitis. Diclofenac proved to be as effective as pirarubicin, and the addition of oral diclofenac to local pirarubicin injection increased its antitumoral effect (P0.02). However, the combination of diclofenac and pirarubicin was more toxic than pirarubicin alone and induced centrolobular necrosis and sclerosing cholangitis.

In a series of 279 hepatectomies performed for cancer between June 1984 and March 1992, 46 were repeat operations, for metastases in 41 patients. The primary tumour was in the colon and rectum (28 patients), APU Doma (five) and miscellaneous (eight). Repeat hepatectomies were performed in 26 per cent of patients who had recurrence after the first liver resection and in 40 per cent of those who had liver recurrence. An unsuspected extrahepatic recurrence was discovered and resected in eight instances and in two other cases a known extrahepatic recurrence was resected during the second hepatectomy. The hospital mortality rate was 2 per cent (one patient); the death was from nosocomial pneumonia. The total morbidity rate including minor complications was 32 per cent, with a higher frequency of haemorrhagic problems after secondary liver resection (12 per cent) than after primary hepatectomy (5 per cent). The rate of postoperative complications after repeat hepatectomy was related significantly to operative blood loss greater than 1500 ml(P = 0·04). The technical problems of repeat hepatectomy were: (1) re-exposure of the liver, considered to be difficult in 67 per cent of second liver resections and 80 per cent of third procedures; (2) the liver parenchyma, which often had histological modifications between first and second resections and was more difficult to ‘work’ as shown by the mean duration of clamping of the hepatic pedicle (54 min for secondary versus 36 min for primary liver resection); and (3) modification of the intraparenchymal vasculobiliary anatomy following liver regeneration after major hepatectomy. Intraoperative ultrasonography was of great benefit. Rates of crude and recurrence-free survival were relatively encouraging at 47 and 33 per cent 3 years after the second liver resection for the whole group. These values were lower for colorectal cancer (37 and 21 per cent 3 years after the second hepatectomy). These figures do not, however, convey the complete picture of the outcome for these patients. During the same follow-up period, 143 recurrences were detected and a mean of 2·9 resections per patient were performed. The indications for repeat hepatectomy are still to be clarified, although the surgical technique is safe.

A case of endometrial carcinoma with argyrophilic cells is described, with a brief review of literature, intending to show that the presence of argyrophilic cells is common. Hum

External beam radiation therapy alone or in combination with curietherapy is the recommended treatment for anal canal carcinoma in some countries. In others, surgery is the sole accepted treatment. The results for 64 patients treated by external radiotherapy alone show excellent survival for stage T1T2 tumors but results are poor for large tumors (stage T4). The overall 5 year crude survival rate is 46%. The 5-year results are better for stage T1T2 (72%) than for stage T3T4 (35%). The presence of inguinal node involvement at first examination is a very poor prognostic sign. Local recurrences and metastases are infrequent for stage T1T2, but are more common for stage T3 and T4. Complications follow radiotherapy more frequently in those with stage T3 and T4 tumors. The analysis of local recurrences, complications and survival shows that radiation therapy may be sufficient treatment for stage T1 and T2 and for some stage T3 tumors. The importance of anal sphincter involvement and the poor quality of life for patients who are cured but develop complications, shows the need for combined treatment with surgery and perhaps with chemotherapy. For small tumors the results obtained by external radiotherapy alone are comparable with those obtained by external radiotherapy and curietherapy in terms of survival and complications.