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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.

Background: Major hepatectomy after prolonged intra-arterial hepatic chemotherapy (IAHC) is extremely rare, because IAHC usually fails to reduce the tumor volume sufficiently or obtain a long duration of response, or both, and because it impairs hepatic function. The present report was done to study the frequency, feasibility, and results of hepatectomy following IAHC., Study Design: This retrospective study consisted of 14 patients treated with at least six courses of IAHC (mean of 17.6, median of 13, range of six to 48 courses) for hepatic tumors: colorectal metastases (n = 9), apudoma metastases (n = 4), and hepatoblastoma (n = 1). Systemic chemotherapy was associated in eight cases during (n = 5) or after (n = 3) IAHC. Initially, multiple hepatic tumors were unresectable in ten cases. They eventually became resectable, but were associated with extensive extrahepatic sites of involvement in four cases. All patients underwent curative major hepatectomy after a careful and specific morphologic and functional hepatic assessment. Right portal vein embolization was performed preoperatively upon three patients, resulting in 38, 44, and 77 percent hypertrophy of the left lobe before hepatectomy. Hepatectomy was also performed upon three patients with hepatic arterial thrombosis induced by IAHC, after a careful workup of the neoarteriovascularization of the liver., Results: These 14 cases only represented 5.8 percent of the 239 patients in whom a catheter was inserted for IAHC, and 4.2 percent of the 335 patients who had hepatectomy for carcinoma. Postoperatively, there was no mortality and no clinical hepatic insufficiency. However, ten complications occurred in eight patients (three of them resulted in reoperation). Histologic examination revealed substantial modifications of the hepatic parenchyma because of IAHC. Results concerning survival were very encouraging: five of the nine patients with metastases of the colon and rectum are free of disease, with a mean follow-up period of 36 months after the beginning of IAHC., Conclusions: The decision to perform a major hepatectomy after prolonged IAHC is difficult and must be based on an output morphologic assessment with computed tomographic portography and a careful evaluation of functional liver impairment because of IAHC (the therapeutic strategy proposed by Makuuchi for hepatectomy in patients with cirrhosis, based on indocyanine green clearance and volume to resect, is very useful for this purpose). Hepatectomy is technically difficult to perform following IAHC because of a flabby parenchyma and unusually high pressure in the small central hepatic veins. This drawback is circumvented by using techniques, such as preoperative hypertrophy of the future remaining liver, a transparenchymatous approach of vasculobiliary structures, and intermittent clamping of the hepatic pedicle or vascular isolation of the liver. Postoperative complications occurred more frequently than after major hepatectomy in other clinical settings (p < 0.05). However, as this therapeutic approach greatly increases survival, it should not be neglected by clinicians, although indications for its use are very rare.

Two 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.

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.

Gastric adenocarcinomas, even in the absence of distant metastases, have a poor prognosis which is particularly dismal when tumors are located in the cardia, in the event of locoregional lymph node involvement and/or bulky tumors. Postoperative adjuvant chemotherapy has never clearly demonstrated its efficacy on survival. Besides ongoing trials using new and more active regimens, preoperative chemotherapy has been used for unresectable cancer due to loco-regional extension and when locally advanced cancer is potentially resectable but with poor prognosis such as bulkiness, when tumors are located in the cardia and when there is tumor in the coeliac area at CAT-scan with suspected metastatic lymph nodes. In case of unresectable tumor at initial surgery five publications have reported the ability of chemotherapy to reduce the tumor volume and to allow subsequent resection of the gastric tumor in 40% to 60% of the cases. In these cases there is a clear survival advantage as the median survival reported in 2 of these studies was 12 and 18 months compared to the 4 to 6 months median survival reported in historical studies in case of unresectable cancer [17, 18]. In case of locally advanced gastric tumors some Japanese case reports have demonstrated the ability of preoperative chemotherapy to concentrate in the tumor tissue and to downstage the tumors. Four North American and European studies have demonstrated that preoperative chemotherapy is feasible, and will probably increase the resection rate. J. Ajani has reported 2 studies in which tolerance was acceptable: a major response (R) observed in 24% and 31%, the resectability rates were 72% and 77% and the median survival 15 and 16 months, respectively. Our experience is based on 30 patients treated with a combination of continuous i.v. 5-FU and CDDP. Fifteen had a tumor of the cardia, 15/30 had enlarged lymph nodes and 7/30 a linitis plastica (diffuse type). After a mean number of 3 cycles, 27/30 patients were evaluable for response. One patient achieved a CR and 14 a PR (OR rate 56%, 95% CI: 38% to 74%) but only one of those with linitis plastica responded. Twenty-eight patients underwent surgery and 23 had a macroscopically complete resection (82%). Resectability rate was higher after OR (13/15) than in nonresponding patients (4/12). Toxicity was acceptable, however grade 4 leucopenia in 5 patients and one toxicity-related death were observed. There was no increase in postoperative complications. Nine patients received postoperative chemotherapy and 3 patients with positive margins received postoperative external radiotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

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 (P < 0.02). However, the combination of diclofenac and pirarubicin was more toxic than pirarubicin alone and induced centrolobular necrosis and sclerosing cholangitis.

Right portal vein embolization (PVE) was performed in patients in need of wide hepatectomy to induce preoperative hypertrophy of the future remnant liver (FRL), which would have been insufficient for safe resection. PVE was achieved with cyanoacrylate or gelatin sponges by using a percutaneous subxiphoid approach in 10 patients with tumors in noncirrhotic liver. Surgery was performed in nine patients 17-48 days (mean, 34 days) after PVE. Computed tomographic liver volumetric studies were performed before embolization and before surgery. Clinical and biologic tolerance of PVE was excellent except in one case. Histopathologic studies showed occlusion of portal veins with minimal parenchymal ischemia in eight of nine patients. The FRL volume increased by 64%, which represented 31% of the preresection volume of the liver. Better hypertrophy was seen after cyanoacrylate embolization. The authors conclude that PVE is safe and well tolerated and induces marked hypertrophy of the unembolized parenchyma in noncirrhotic patients. This hypertrophy allows hepatectomy to be performed under safe conditions when the FRL volume is initially insufficient.

Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.

Intra-arterial hepatic chemotherapy (IAHC) with adriamycin (ADM) has not increased its therapeutic index. For our preclinical studies, we selected pirarubicin (THP), an ADM derivative with faster cellular uptake. In rabbits with VX2 tumor in the liver we compared plasmatic and cellular pharmacokinetics of ADM and THP after i.v. and IAH therapy. For ADM, there were no differences in plasma and heart concentrations, with only a slight increase in tumoral levels after IAH compared to i.v. administration; on the other hand, with IAH THP, there was important reduction in systemic exposure with a major increase in tumoral drug distribution. In the phase I study, involving nine patients with implanted catheters, the starting dose of THP was 30 mg/m2 with a 10 mg/m2 intrapatient escalation every 3 weeks in the absence of toxicity. Pharmacokinetics were compared for i.v. and IAH administration in seven patients. The limiting toxicity was neutropenia and the maximal tolerated dose (MTD) ranged from 50 to 110 mg/m2. Moderate nausea-vomiting (grade 1-2) and alopecia (grade 1) occurred at the MTD. No arterial occlusion, gastroduodenal ulcer, hepatitis, or sclerosing cholangitis were seen. In the phase II study, in colorectal cancer patients (CRC) with metastasis confined to the liver, patients were enrolled until June 1990. THP (40 min infusion every 3 weeks) was initiated at 60 mg/m2 with 10 mg/m2 increment until grade 2 hematotoxicity. The median MTD was 85 mg/m2 (range of 60-120 mg/m2), and the median number of cycles was 7 (range of 2-11) with cumulated doses from 180 to 1,030 mg/m2. Grade 2-4 neutropenia was reached in 15 patients. Other toxicities included two arterial occlusions, one episode of gastritis, but no hepatic toxicity and no heart failure. Antitumor effect (in 18 patients) included 1 CR, 5 PR, 3 MR, 6 NC, and 3 PD. The median survival was 18+ months and 1-year survival was 73% +/- 12%. Seven patients had extrahepatic progression at this time. In conclusion, besides 5-FU or Fudr, THP is active in IAHC (probably in relation with high local extraction) on CRC liver metastases usually unresponsive to ADM. It can be given in an outpatient setting with minimal toxicity.

A case of malacoplakia of the gallbladder is described. The cytoplasm of histiocytes in the gallbladder wall was filled with granules positive for periodic acid-Schiff, von Kossa's, and Perls' stains, which is highly suggestive of malacoplakia. Both local inflammation and recent neoplasia could have played a role in the histogenesis of the malacoplakia.

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.

The experience of the Institut Gustave-Roussy in the diagnosis of hepatic and pancreatic lesions by fine needle aspiration (FNA) is reported. Totals of 116 consecutive percutaneous ultrasound-guided FNAs of the liver and 27 of the pancreas were performed without complication in patients with ultrasonically suspected neoplastic lesions. In 12 cases, the material was not suitable for diagnosis. In the liver, 97 cases were correctly diagnosed and confirmed by follow-up. Immunohistologic studies were helpful in distinguishing primary liver tumors from other malignancies. One false-positive result was reported. In the pancreas, malignancy was detected in 17 cases. Cytology alone provided the correct tumor diagnosis in 15 cases: 10 primary carcinomas, 2 endocrine tumors and 3 metastases. The sensitivities of FNA in this study were 87.6% for the liver and 85% for the pancreas, similar to those reported in other series.