[A Case of Primary Gastric Adenocarcinoma with Enteroblastic Differentiation(GAED)].

Gastric adenocarcinoma with enteroblastic differentiation(GAED)is a rare disease that is classified as a special type in the 15th edition Japanese Classification of Gastric Carcinoma. GAED is considered to have a poor prognosis. We report about a 76-year-old man with GAED who presented with complaints of poor appetite and weight loss. He was suspected of having gastric cancer based on ultrasonography and computed tomography findings and was referred to our hospital by his home doctor. Upper gastrointestinal endoscopy revealed a gastric cancer in the lesser curvature of the gastric antrum. Distal gastrectomy was performed. Histopathology showed a moderately differentiated adenocarcinoma with a clear cytoplasm. Immunostaining was positive for Sal-like protein 4(SALL4)and negative for α-fetoprotein(AFP). The patient was diagnosed as having GAED. Vascular and lymphatic invasion were not observed. He was discharged on the 9th day after surgery. At 5 months postoperatively, he was treated with adjuvant chemotherapy, and no recurrence was noted. GAED is a rare disease with a poor prognosis. We report this case and discuss relevant literature.

[A case report of distal gastrectomy with thrombectomy after NAC for Gastric cancer].

This is a case report of gastric cancer with a tumor embolus in the portal vein of a 76-year-old male. Both computed tomography (CT) and upper gastrointestinal endoscopy were performed. The diagnosis was gastric cancer with an accompanying tumor embolus in the portal vein, specifically in the superior mesenteric vein. After neoadjuvant chemotherapy, a distal gastrectomy, and thrombectomy were performed. Upon pathological examination, the main tumor was diagnosed as adenocarcinoma, and the embolus was confirmed to extend from the main tumor into the superior mesenteric vein. Upon immunostaining examination, neither the embolus nor main tumor expressed alpha-fetoprotein (AFP), but both expressed carcinoembryonic antigen (CEA). Gastric cancer with a tumor embolus in the portal vein is considered an incurable disease. However, with no other non-curative factor than portal vein embolus, it is possible that gastrectomy with thrombectomy can result in a good prognosis. On the other hand, it is extremely difficult to improve the prognosis of gastric cancer with both tumor embolus in the portal vein and liver metastasis.

[A case of advanced signet ring cell carcinoma of the appendix that responded to S-1 and docetaxel].

A 68-year-old man was admitted to our hospital after testing positive in a fecal occult blood test. He was subsequently diagnosed with advanced signet ring cell carcinoma of the appendix with disseminated peritoneal disease and ascites. Weekly chemotherapy with S-1 was commenced, and after three courses, the tumor shrunk in size and the ascites decreased. Two more courses were administered;however, disease progression was noted because of increasing ascites. The chemotherapy regimen was changed to weekly docetaxel, and after two courses, further tumor shrinkage and a decrease in ascites were noted. The disease course of this patient suggests that S-1 and docetaxel were effective against signet ring cell carcinoma of the appendix. Here we report this case and discuss the relevant literature.

[A case of advanced gastric cancer with esophageal invasion treated by neoadjuvant S-1/CDDP chemotherapy].

A 75-year-old man was found, by endoscopic examination, to have type 2 advanced gastric adenocarcinoma with esophageal invasion in the cardia. Endoscopy and other modalities revealed observable esophageal invasion. To minimize surgical intervention, we treated him with S-1 and cisplatin as neoadjuvant therapy. Treatment was as follows: S-1(80mg/m2)was administered orally for 3 weeks followed by 2 weeks of rest, and cisplatin(60mg/m2)was administered by intravenous drip on day 8. Two courses of treatment resulted in marked shrinkage of the primary lesion and improvement of the esophageal invasion. Total gastrectomy with splenectomy, and D2 lymph node dissection were performed with an adequately long proximal margin, without thoracotomy. Pathological efficacy was Grade 2. At present, 1 year after the operation, the patient presents no evidence of a recurrence. We concluded that through neoadjuvant chemotherapy for advanced gastric cancer with esophageal invasion, thoracotomy could be avoided, thereby reducing risks associated with surgery.

Nonclinical safety profile of tolvaptan.

PURPOSE: In the present study, the nonclinical safety profile of tolvaptan was evaluated. METHODS: A series of safety pharmacology and toxicology studies were performed in vitro and in mice, rats, dogs, rabbits and guinea pigs. RESULTS: In safety pharmacological studies, tolvaptan had no adverse effects on the central nervous, somatic nervous, autonomic nervous, smooth muscle, respiratory and cardiovascular, or digestive systems. In general toxicity studies, a single dose of tolvaptan up to 2,000 mg/kg was not lethal in rats and dogs. Tolvaptan did not cause any target organ toxicity in rats after treatment for 26 weeks or in dogs after treatment for 52 weeks at oral doses of up to 1,000 mg/kg/day. The toxicities observed in the present studies were generally attributable to the exaggerated pharmacological action of tolvaptan. In reproductive and developmental toxicity studies in rats, fertility was not affected. Suppressed viability or growth observed in the prenatal and postnatal progeny occurred at the maternally toxic dose of 1,000 mg/kg/day. In rabbits, tolvaptan showed teratogenicity at 1,000 mg/kg/day, a dose that was maternally toxic causing abortion. Tolvaptan was not genotoxic or carcinogenic, and did not induce phototoxicity, antigenicity or immunotoxicity. CONCLUSION: Nonclinical toxicity that precludes the safe administration of tolvaptan to humans was not observed. However, appropriate cautions should be taken in women of childbearing potential.

[Successful withdrawal from disseminated intravascular coagulation caused by disseminated carcinomatosis of bone marrow originated from gastric cancer treated by sequential therapy consisting of MTX and 5-FU and palliative radiotherapy].

A 5 8-year-old man with severe back pain caused by multiple vertebral metastases developed disseminated intravascular coagulation(DIC). We adopted palliative radiotherapy(8 Gy/1 day)for palliation of his back pain as initial treatment. Afterwards, we started sequential chemotherapy consisting of methotrexate(MTX)and 5-fluorouracil(5-FU). After two courses, DIC was resolved, and the patient was discharged in fair condition after five more courses of MTX and 5-FU therapy.

[An effective case of gemcitabine therapy with post-operative peritoneal recurrence of intrahepatic cholangiocarcinoma].

The patient was a 53-year-old man who had undergone left hepatectomy due to intrahepatic cholangiocarcinoma in August 2007. Pathologically, the tumor was diagnosed as a cholangiocellular carcinoma (T2, N0, M0, Stage II). Ascites appeared about one year after surgery and control was difficult using diuretics. Since abdominal CT revealed peritoneal recurrence with massive ascites, we conducted chemotherapy using gemcitabine (GEM) in September 2008. In the outpatient setting, GEM at a dose of 1, 000 mg/body was administered once a week with a 1-week rest as 1 course. The response was assessed as a complete response (CR) because abdominal CT after 7 courses of chemotherapy showed the disappearance of both ascites and the peritoneal nodules. An adverse effect for GEM was grade 3 anemia, but we could continue the chemotherapy until September 2009. At present, CR has been observed, and one year and three months have passed since the peritoneal reccurrence.

Lymphotoxin-alpha polymorphisms and the risk of endometrial cancer in Japanese subjects.

OBJECTIVE: To test the association of endometrial cancer with the lymphotoxin-alpha (LTalpha) C804A and A252G polymorphisms, a hospital-based incident case-control study was performed in Japanese subjects. METHODS: The cases comprised 110 endometrial cancer patients, and the controls were 220 age-matched cancer-free females. RESULTS: The LTalpha C804A and A252G polymorphisms were in complete linkage disequilibrium. We performed conditional logistic regression analysis adjusted for age, which revealed that the LTalpha 252AG and 804CA variant genotypes were associated with a significantly reduced risk of endometrial cancer (OR=0.51, 95% CI=0.31-0.86, P=0.011). Being homozygous of the LTalpha 252G and 804A alleles was not associated with the risk of endometrial cancer. However, the presence of at least one variant LTalpha allele was associated with a significantly lower risk of endometrial cancer (OR=0.54, 95% CI=0.33-0.87, P=0.012). After adjusting for potential confounders (body mass index, age at menarche, parity, hypertension, diabetes mellitus, family history of endometrial cancer, hormone replacement therapy, smoking status, and alcohol consumption), the risk of endometrial cancer was significantly lower both in carriers of one variant allele and in carriers of either one or two of the variant alleles (OR=0.47, 95% CI=0.26-0.85, P=0.017; OR=0.50, 95% CI=0.28-0.89, P=0.019; respectively). CONCLUSION: The results suggest that these LTalpha polymorphisms play an important role in the tumorigenesis of endometrial cancer.

ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase.

Placental leucine aminopeptidase (P-LAP), a type-II transmembrane protease responsible for oxytocin degradation during pregnancy, is converted to a soluble form through proteolytic cleavage. The goal of this study was to determine the nature of the P-LAP secretase activity. The hydroxamic acid-based metalloprotease inhibitors GM6001 and ONO-4817 as well as the TNF-alpha protease inhibitor-2 (TAPI-2) reduced P-LAP release, while tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, which are matrix metalloproteinase inhibitors, had no effect on P-LAP release in Chinese hamster ovary (CHO) cells stably overexpressing P-LAP, thus indicating possible involvement of ADAM (a disintegrin and metalloproteinase) members in P-LAP shedding. Furthermore, overexpression of ADAM9 and ADAM12 increased P-LAP release in P-LAP-CHO transfectants. Immunohistochemical analysis in human placenta demonstrated strong expression of ADAM12 in syncytiotrophoblasts, while little expression of ADAM9 was detected throughout the placenta. Our results suggest ADAM members, at least including ADAM12, are involved in P-LAP shedding in human placenta.

Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer. Association with tumor grade and CA-125.

Adipocyte-derived leucine aminopeptidase (A-LAP) is a novel zinc-metallopeptidase involved in angiotensin II (AngII) metabolism, cell migration and antigen presentation. These functions are implicated in the progression of cancer, whereas A-LAP expression and involvement have not been studied in any type of cancer. We investigated the expression of A-LAP in endometrial cancer as well as its association with angiogenesis and clinicopathological features. Immunohistochemical staining of 58 endometrial endometrioid adenocarcinoma specimens revealed that 37 were A-LAP immunoreactive. We also found that A-LAP staining correlated with histological tumor grade in a significant and reverse manner. In addition, serum CA-125 levels in patients with A-LAP positive cancers were significantly higher. However, contrary to our hypothesis that A-LAP suppresses angiogenic activity via AngII metabolism, A-LAP expression was not associated with the microvessel count determined by CD34 immunostaining. Our results suggest that A-LAP is involved in endometrial cancer cell growth and differentiation. However, further studies, especially of the biological roles of A-LAP, are required to confirm this notion.

Ultrastructural localization of aminopeptidase A/angiotensinase and placental leucine aminopeptidase/oxytocinase in chorionic villi of human placenta.

AIMS: Membrane-bound aminopeptidases in human placenta are thought to be involved in maintaining homeostasis during pregnancy by metabolizing bioactive peptides such as oxytocin and angiotensin at the interface between the fetus and mother. Because determining the precise localization of these enzymes is required to support this notion, we investigated the ultrastructural localization of two principal enzymes, aminopeptidase A (APA; EC 3.4.11.7)/angiotensinase and placental leucine aminopeptidase (P-LAP; EC 3.4.11.3)/oxytocinase in human first trimester and full-term placenta. METHODS: Immunohistochemical analysis using anti-P-LAP and anti-APA antibodies was performed on ultrathin frozen sections of fixed human placental villi. RESULTS: Transmission immunoelectron microscopy revealed that both enzymes were expressed on the surface of apical microvilli of syncytiotrophoblast cells and, to a lesser extent, on the basal infoldings. The location of the two enzymes did not vary between the first trimester and full-term placenta sections, while the staining intensities were slightly enhanced in full-term villi. CONCLUSIONS: Our observation that P-LAP and APA are present on the microvilli, which is a site of interaction between the mother and fetus, suggests possible involvement of these enzymes in cleaving peptide hormones from the fetus and mother in order to regulate bioactivity.