Takehisa Hiraoka

Effect of arterial administration of high-molecular-weight anticancer agent SMANCS with lipid lymphographic agent on hepatoma: a preliminary report.

A clinical evaluation of arterial infusion of high-molecular-weight antitumor agent SMANCS dissolved in lipid lymphographic agent (thiodol) in 44 patients with mostly unresectable hepatoma is described. The treatment regimen demonstrated significant merits both therapeutically and diagnostically. Marked antitumor effects were shown in the decreased serum alpha-fetoprotein levels (86% of cases) and tumor size (95% of cases), and in survival period and histological findings. Furthermore, there was increased diagnostic sensitivity using CT scan, plain X-rays or ultrasound. The procedure of selective arterial administration of 3-4 mg of SMANCS in 3-4 ml of ethiodol per dose was simple to perform and was required only once every 3-4 weeks. Both ethiodol and the drug accumulated more selectively in tumor than in any other tissues and their activity remained for more than 3 weeks. Only minimal side-effects were associated with SMANCS and ethiodol during this study.

Pancreatic Cancer Registry in Japan: 20 years of experience.

Abstract: The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Long-term survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).

Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer

In six adult patients with nonresectable liver cancer, as well as in mature New Zealand white rabbits with implanted VX2 carcinoma in the liver, the artery feeding the hepatic lobe with the malignant lesion was ligated, and an oily contrast medium (Lipiodol Ultra‐Fluid) was injected into the hepatoproximal lumen of the ligated artery of the liver with carcinoma. The oily contrast medium was detected in all the branches of the artery injected, and thereafter was found only in tumor tissue for 7 days experimentally and for 16 months clinically. Taking advantage of this phenomenon, the therapeutic effect of the injection of an oily anticancer drug (bleomycin oil suspension) into the hepatoproximal lumen of the ligated hepatic artery was investigated in rabbits with VX2 carcinoma of the liver. The mean concentration level of bleomycin in the tumor tissue was 2.4 ± 0.4 μg/g 1 week after the injection of bleomycin oil suspension (1.5 mg potency/kg) in three rabbits. However, its concentration level in nontumorous tissue of the liver was undetectably low in two rabbits, but 0.6 μg/g in the third rabbit. The group of rabbits receiving an injection of bleomycin oil suspension into the ligated artery had a significantly longer mean survival time than those of the experimental group receiving an injection of saline solution of bleomycin into the ligated artery as well as the three other groups treated (P < 0.02, N = 5 for each group). It may be concluded that an oily anticancer drug injected into the hepatoproximal lumen of the ligated hepatic artery can intensify the anticancer effects of a ligation of the hepatic artery for liver cancer. Cancer 52:2193‐2200, 1983.

The prognostic significance of lymph node metastasis and intrapancreatic perineural invasion in pancreatic cancer after curative resection

To investigate the prognostic factors of pancreatic cancer, a retrospective analysis of 193 patients who underwent curative resection was conducted. Of the 193 patients, 38 (20%) survived for more than 5 years, the 5-year survival rates for stages I, II, III, and IV disease being 41%, 17% 11%, and 6%, respectively. According to a multivariate analysis, lymph node metastasis, intrapancreatic perineural invasion, and portal vein invasion were significant prognostic factors. Subsequently, a subgroup analysis concerning nodal metastasis and intrapancreatic perineural invasion was performed in 126 patients with records of these histological findings. In the group of patients without nodal metastasis, the 5-year survival rate for those without perineural invasion was 75%, whereas that for those with perineural invasion was 29%, the difference in survival of these subgroups being significant (P<0.02). In the group of patients with nodal metastasis, the 5-year survival rate for those without perineural invasion was 17%, while that for those with perineural invasion was 10%. The most favorable 5-year survival of 89% was observed in the subgroup of patients with stage I disease without perineural invasion. Thus, pancreatic adenocarcinoma categorized by the combination of these independent types of biological behavior showed 5-year survival rates ranging from very high to low, indicating that these two factors play an important role in the prognosis of this disease.

Production, characterization, and interspecies reactivities of monoclonal antibodies against human class A macrophage scavenger receptors

Class A macrophage scavenger receptor (SR-A) is one of the major receptors of macrophages and plays important roles in atherogenesis and host defense mechanisms. To assess the role of SR-A, monoclonal antibodies were generated by immunizing SR-A-deficient mice with a recombinant protein of human type I SR-A as immunogen. Four antibodies (SRA-C6, SRA-D10, SRA-E5, and SRA-F8) were confirmed to be specific for SR-A by Western blot analysis. In early atherosclerotic lesions, these antibodies recognized scattered macrophages in intima and foamy macrophages in the periphery of atheromatous cores. Interestingly, foamy macrophages in the core lesion were only weakly stained. In other organs, the antibodies recognized tissue macrophages such as alveolar macrophages, Kupffer cells in the liver, red pulp macrophages in the spleen, sinus macrophages in lymph nodes, and interstitial macrophages in various organs. Perivascular macrophages in the brain (Mato cells) were also positive for these antibodies. Freshly isolated blood monocytes were negative; however, they became positive for these antibodies after 1 day in culture. At 3-5 days in culture, the reaction intensity became stronger along their differentiation towards macrophages. Dendritic cells such as interdigitating cells of lymphoid tissues and epidermal Langerhans cells were invariably negative. In the reaction with animal tissues, each antibody showed a unique reaction pattern. Among four antibodies, SRA-E5 recognized SR-A molecules in all animal species examined, including rats and mice. These antibodies will be useful tools for the study of SR-A in atherogenesis and various other pathological conditions in humans and animal species.

A human homolog of Drosophila warts tumor suppressor, h-warts, localized to mitotic apparatus and specifically phosphorylated during mitosis

We identified a human homolog of Drosophila warts tumor suppressor gene, termed h‐warts, which was mapped at chromosome 6q24‐25.1. The h‐warts protein has a serine/threonine kinase domain and is localized to centrosomes in interphase cells. However, it becomes localized to the mitotic apparatus, including spindle pole bodies, mitotic spindle, and midbody, in a highly dynamic manner during mitosis. Furthermore, h‐warts is specifically phosphorylated in cells at mitotic phase, most likely by Cdc2 kinase. These findings suggest that h‐warts functions as a component of the mitotic apparatus and is involved in proper progression of mitosis.

Combination of intraoperative radiation with resection of Cancer of the pancreas

SummaryThe utility of intraoperative radiation therapy (IORT) as an adjuvant to the surgical resection of pancreatic cancer was studied. In 1976, as our first trial with this combined therapy, we applied IORT with 30 Gy of electron beam with 8 MeV to 15 patients to prevent local recurrence around the celiac axis and superior mesenteric artery after standard pancreatectomy. However, the combined therapy did not show an improvement in survival rate as compared to that of 19 patients with standard operation alone. Autopsies of three patients with the combined therapy did not show involved lymph nodes in the radiation field, but did show local recurrence around the aorta outside the radiation field.By comparison, we performed extended operation without IORT on nine patients, with almost complete dissection of the lymph nodes around the aorta, from the diaphragm to the level of the inferior mesenteric artery. This extended surgery did not improve survival time, and autopsy showed local recurrence in spite of the dissection of lymph nodes.Therefore, since 1984, we have performed IORT with a dose of 30 Gy, 9 MeV, and an extended radiation field from the diaphragm above to the inferior mesenteric artery below, following extended operation on 14 patients. The five-year cumulative survival rate of these cases was 33.3%. Four autopsies showed improvement of local control rate. No radiation-related complications were noticed postoperatively in patients who underwent extended IORT following pancreatectomy. We were encouraged to continue this approach for the cure of pancreatic cancer.

Small mass lesions in cirrhosis: Transition from benign adenomatous hyperplasia to hepatocellular carcinoma?

Abstract Ten patients with cirrhosis, in whom small mass lesions were detected by imaging techniques and histological diagnosis of the resected specimens was difficult, are described. There were 17 grossly discrete lesions measuring 10 × 8 mm to 27 × 22 mm. Four were compatible with so‐called adenomatous hyperplasia showing no histological features of malignancy, and eight were equivocal as to whether they were benign or malignant. The other five lesions (in four patients) were hepatocellular carcinoma, co‐existing with apparently benign lesions. The eight equivocal lesions were eventually judged to be highly differentiated hepatocellular carcinomas. These benign‐appearing lesions, found by advanced imaging in patients with cirrhosis, create a serious problem in regions where primary liver cancer is endemic among cirrhotics, and hepatic resection is the preferred treatment.

Vascular encasement by pancreatic cancer : Correlation of CT findings with Surgical and pathologic results

Purpose The purpose of this study was to correlate thin-slice high-resolution helical CT findings of arterial and venous involvement in pancreatic cancers with surgical and histopathologic results. Method Forty-eight patients with pancreatic cancer underwent preoperative thin-slice high-resolution helical CT, followed by surgical dissection of the pancreatic vessels during curative or palliative surgery. Major vessels running within 1 cm from the tumor margin were evaluated. CT appearance was graded on a 0–4 scale (0: none, 1: <24%, 2: 25–49%, 3: 50–74%, 4: 75–100%) by circumferential contiguity of tumor to vessels. Resected specimens were available from 26 patients. Results Surgical correlation of CT findings was available in 89 veins and 83 arteries, and both surgical and histologic correlation was available for 42 veins and 29 arteries. At surgical observation, 29 of 35 veins (82.9%) evaluated as CT grade 3 or 4 were found to be involved, whereas only 18 of 30 arteries (60%) evaluated as CT grade 3 or 4 were proved to be involved. On microscopic observation, tumor invasion to the portal venous systems was confirmed in 15 of 42 (35.7%) vessels, and this invasion was depicted as from CT grades 1 to 4. In arteries, tumor invasion was seen in 3 of 29 vessels (10.3%), all of which were graded as 3 or 4 by CT. Conclusion The grading system of vascular invasion should differ between arteries and veins. Involvement of the venous system exceeding one-half circumference of the vessels (grade 3 or 4) was suggestive of vascular invasion; however, this criterion was not always satisfactory for the evaluation of tumor invasion in the arterial system.

Loss of alveolar basement membrane type IV collagen α3, α4, and α5 chains in bronchioloalveolar carcinoma of the lung

Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct α(IV) chains. This study investigated for the first time the expression of these six α(IV) chains immunohistochemically, using α(IV) chain‐specific monoclonal antibodies, in normal lung and in small (less than 2 cm in diameter) adenocarcinoma of the lung with a bronchioloalveolar growth pattern at the periphery. Small adenocarcinomas were histopathologically classified into three subtypes: bronchioloalveolar carcinoma (BAC) without collapse, BAC with collapse, and adenocarcinoma with bronchioloalveolar features. In normal lung, alveolar BM was composed of α1(IV)/α2(IV) chains and α3(IV)/α4(IV)/α5(IV) chains. In non‐collapsed areas of BAC, alveolar BM was composed of linear α1(IV)/α2(IV) chains and discontinuous α3(IV)/α4(IV)/α5(IV) chains. In collapsed areas of BAC, alveolar BM was composed of linear and thick α1(IV)/α2(IV) chains only, because of the complete loss of α3(IV)/α4(IV)/α5(IV) chains. In invasive areas of adenocarcinoma with bronchioloalveolar features, α1(IV)/α2(IV) chains around the cancer cell nests were disrupted, in addition to the complete loss of α3(IV)/α4(IV)/α5(IV) chains. In conclusion, during the process of stromal invasion of lung adenocarcinoma, type IV collagen of alveolar BM is remodelled from the complete type, composed of α1(IV)/α2(IV)/α3(IV)/α4(IV)/α5(IV) chains, to the incomplete type, composed of only α1(IV)/α2(IV) chains, before the disruption of α1(IV)/α2(IV) chains. These findings may help to clarify the molecular mechanisms of cancer invasion. Copyright