Kazue Morishima

Phlegmonous gastritis after endoscopic submucosal dissection for early gastric cancer

A 74-year-old man with diabetic nephropathy developed epigastric pain and high fever after endoscopic submucosal dissection (ESD) for early gastric cancer. Gastroscopy, endoscopic ultrasonography and computed tomography showed ulceration with a purulent lake, thickened entire gastric mucosal layers suggesting focal abscess formation, leading to the diagnosis of phlegmonous gastritis. He underwent total gastrectomy as an emergency. Histological findings of the resected specimen showed severe inflammatory cell infiltration and multiple focal abscess formation spreading to the entire gastric wall. In patients with poorer general conditions, phlegmonous gastritis should be considered as a serious complication after ESD, indicating a requirement of antibiotic prophylaxis.

The HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) synergizes with cisplatin and induces apoptosis in cisplatin-resistant esophageal squamous cell carcinoma cell lines via the Akt/XIAP pathway.

Although cisplatin (CDDP) is a key drug in the treatment of esophageal squamous cell carcinoma (ESCC), acquired chemoresistance remains a major problem. Combination therapy may represent one strategy to overcome this resistance. Heat shock protein 90 (HSP90) is known to be overexpressed in several types of cancer cells, and its inhibition by small molecules, either alone or in combination, has shown promise in the treatment of solid malignancies. In the present study, we evaluated the synergistic effects of combining CDDP with the HSP90 inhibitor 17-N-allylamino-17-demethoxy geldanamycin (17-AAG) on two CDDP-resistant human esophageal squamous cancer cell lines, KYSE30 and KYSE150. The results obtained demonstrated the synergistic inhibitory effects of CDDP and 17-AAG on the growth of KYSE30 and KYSE150 cells. Cell growth and cell number were more effectively reduced by the combined treatment with CDDP and 17-AAG than by the treatment with either CDDP or 17-AAG alone. Western blotting revealed that the combined action of CDDP and 17-AAG cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3, which demonstrated that the reduction in both cell growth and cell number was mediated by apoptosis. Time-course experiments showed that reduction in X-linked inhibitor of apoptosis protein (XIAP) and phosphorylated Akt were concomitant with apoptosis. The results of the present study demonstrate that 17-AAG synergizes with CDDP and induces apoptosis in CDDP-resistant ESCC cell lines, and also that modulation of the Akt/XIAP pathway may underlie this synergistic effect. Combination therapy with CDDP and an HSP90 inhibitor may represent a promising strategy to overcome CDDP resistance in ESCC.

A case of mixed adenoneuroendocrine carcinoma of the gallbladder arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction.

A 54‐year‐old Japanese woman was referred with a gallbladder tumor. Based on the results of the computed tomography scan, endoscopic retrograde cholangiopancreatography, and magnetic resonance cholangiopancreatography, a mucin‐producing neoplasm of the gallbladder associated with pancreaticobiliary maljunction was diagnosed. Extended cholecystectomy, extrahepatic bile duct resection, and choledochojejunostomy were performed, and she remains free of recurrence 24 months after resection. Histopathological examination revealed that the papillary component of the lesion was an intracystic papillary neoplasm with diverse characteristics of pancreaticobiliary epithelium and intestinal epithelium including mucin. In this component, most of the papillary lesion was a high‐grade intraepithelial neoplasm, but also showed slight invasion into the muscular layer. The nodular component consisted of both poorly differentiated biliary type adenocarcinoma and large cell neuroendocrine carcinoma. We report a rare case of a mixed adenoneuroendocrine carcinoma arising from an intracystic papillary neoplasm associated with pancreaticobiliary maljunction. As for the histogenesis of this tumor, based on the histopathologic appearance, transdifferentiation from poorly differentiated biliary type adenocarcinoma to large cell neuroendocrine carcinoma is considered the most possible histogenesis of this tumor.

A clinicopathological and immunohistochemical study of gastric cancer with squamous cell carcinoma components: A clinically aggressive tumor

OBJECTIVE:  Adenosquamous carcinoma originating in the stomach is an unusual neoplasm with few existing histological studies. This study was aimed to gain insight into the histogenetic and clinicopathological characteristics of gastric cancer with squamous cell carcinoma (SCC) components.

Recurrent Cholangitis by Biliary Stasis Due to Non-Obstructive Afferent Loop Syndrome After Pylorus-Preserving Pancreatoduodenectomy: Report of a Case

We report a 71-year-old man who had undergone pylorus-preserving pancreatoduodenectomy (PPPD) using PPPD-IV reconstruction for cholangiocarcinoma. For 6 years thereafter, he had suffered recurrent cholangitis, and also a right liver abscess (S5/8), which required percutaneous drainage at 9 years after PPPD. At 16 years after PPPD, he had been admitted to the other hospital because of acute purulent cholangitis. Although medical treatment resolved the cholangitis, the patient was referred to our hospital because of dilatation of the intrahepatic biliary duct (B2). Peroral double-balloon enteroscopy revealed that the diameter of the hepaticojejunostomy anastomosis was 12 mm, and cholangiography detected intrahepatic stones. Lithotripsy was performed using a basket catheter. At 1 year after lithotripsy procedure, the patient is doing well. Hepatobiliary scintigraphy at 60 minutes after intravenous injection demonstrated that deposit of the tracer still remained in the upper afferent loop jejunum. Therefore, we considered that the recurrent cholangitis, liver abscess, and intrahepatic lithiasis have been caused by biliary stasis due to nonobstructive afferent loop syndrome. Biliary retention due to nonobstructive afferent loop syndrome may cause recurrent cholangitis or liver abscess after hepaticojejunostomy, and double-balloon enteroscopy and hepatobiliary scintigraphy are useful for the diagnosis of nonobstructive afferent loop syndrome.

Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma

The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.

Participation of Surgical Residents Does Not Adversely Affect the Outcome of Inguinal Hernia Repair in an Integrated Teaching Program

OBJECTIVE The Lichtenstein inguinal hernia repair is commonly performed and suitable for teaching basic surgical skills. The objective of this study is to evaluate the feasibility of this procedure for surgical training, particularly in regard to patient outcomes. DESIGN Retrospective case review after introduction of an integrated teaching program. SETTING University teaching hospital. PARTICIPANTS The Lichtenstein inguinal hernia repair is the standard procedure for adult primary unilateral inguinal hernia since 2003 at Jichi Medical University. We introduced an integrated teaching system of lectures, skill training. and videos to teach the skills for Lichtenstein inguinal hernia repair to residents and junior faculty in 2003. Cases were retrospectively divided into 4 groups based on the experience of the operating surgeon; junior residents (PGY 1-2, group A), senior residents (PGY 3-5, group B), junior faculty (PGY 6-10, group C), and senior faculty (PGY 11 or more, group D). Background, perioperative factors, and outcomes were evaluated among the groups. RESULTS A total of 246 elective inguinal hernia repairs (group A: 136, group B: 49, group C: 42, group D: 19) were performed. There was a significant difference in the frequency of concomitant diseases (p = 0.012) and anticoagulant therapy (p = 0.031). Average operating time was 80.7 ± 24.9, 72.6 ± 20.8, 63.5 ± 22.0, and 54.7 ± 27.9 (min ± SD) in groups A, B, C, and D, respectively, with a significant difference between groups A and D (p < 0.001). No significant differences were observed in estimated blood loss (p = 0.216) or morbidity (p = 0.294). CONCLUSIONS The Lichtenstein inguinal hernia repair can be safely performed by residents and junior faculty with the appropriate supervision of senior faculty without any disadvantage to patients. This integrated teaching program for Lichtenstein inguinal hernia repair is effective and feasible for training residents and junior faculty.

Living donor liver transplantation from an asymptomatic donor with mild coagulation factor IX deficiency: Report of a case

The use of donors with coagulation FIX deficiency is controversial, and there are no current protocols for peri‐transplant management. We herein describe the first reported case of a pediatric LDLT from an asymptomatic donor with mild coagulation FIX deficiency. A 32‐yr‐old female was evaluated as a donor for her 12‐month‐old daughter with biliary atresia. The donors pretransplant coagulation tests revealed asymptomatic mild coagulation FIX deficiency (FIX activity 60.8%). Freeze‐dried human blood coagulation FIX concentrate was administered before the dissection of the liver and 12 h afterwards by bolus infusion (40 U/kg) and was continued on POD 1. The bleeding volume at LDLT was 590 mL. On POD 1, 3, 5, and 13, the coagulation FIX activity of the donor was 121.3%, 130.6%, 114.6%, and 50.2%, respectively. The donors post‐transplant course was uneventful, and the recipient is currently doing well at 18 months after LDLT. The FIX activity of the donor and recipient at nine months after LDLT was 39.2% and 58.0%, respectively. LDLT from donors with mild coagulation FIX deficiency could be performed effectively and safely using peri‐transplant short‐term coagulation FIX replacement and long‐term monitoring of the plasma FIX level in the donor.

Partial duplication of MSH2 spanning exons 7 through 14 in Lynch syndrome

BackgroundLynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is the most common form of hereditary colorectal cancer, and is associated with a high incidence of multiple primary neoplasms in various organs.MethodsA 79-year-old woman (patient 1) diagnosed with ascending colon cancer had a history of previous carcinomas of the uterus, stomach, uroepithelial tract, and colon. One year later, she developed a brain tumor (glioblastoma). A 54-year-old female (patient 2) was diagnosed with endometrial cancer and sigmoid colon cancer. Both patients underwent genetic evaluations independently.ResultsNo mutations were found in an exon-by-exon analysis of genomic DNA by polymerase chain reaction (PCR) and reverse transcription (RT)-PCR. However, multiplex ligation-dependent probe amplification (MLPA) identified genomic duplication spanning from exon 7 to exon 14 of the MSH2 gene in both patients. Due to the presence of this characteristic gene duplication, their pedigrees were investigated further, and these showed that they are paternal half-sisters, consistent with paternal inheritance.ConclusionLarge genomic duplication from intron 6 through intron 14 in MSH2 is a very rare cause of Lynch syndrome and is difficult to identify with conventional methods. MLPA may be an alternative approach for detecting large-scale genomic rearrangements.

Abstract 1495: Role of stromal fibroblasts in the progression of esophageal squamous cell carcinoma

Objectives: The prevalence of esophageal squamous-cell carcinoma (ESCC) is high in Asia, including Japan. Cancer results from the accumulated effects of many genetic alterations. However, the microenvironment of cancer cells has recently been shown to strongly influence the biologic properties of cancer. In this study, we focused on interrelations between cancer and fibroblasts, the main component of cancer stroma. Methods: We purchased 22 cell lines of esophageal squamous-cell carcinoma from RIKEN Cell Bank and the Japanese Collection of Research Bioresources. For fibroblasts we used human esophageal fibroblasts isolated from surgical specimens. To examine interactions between esophageal squamous-cell carcinoma and fibroblasts, the following in vitro experiments were performed: 1) cell proliferation assays; 2) cell migration assays; 3) 3-dimensional organotypic culture; and 4) time-lapse cinematography of 3-dimentional culture. For in vivo experiments, cancer cells and fibroblasts were co-transplanted subcutaneously in NOD/SCID mice to assess the effects of fibroblasts on tumorigenicity. We also retrospectively analyzed 97 ESCC patients to study the relationship between tumor stroma and pathological findings. Results: Fibroblast culture supernatant increased the cell count in 14 of 22 cell lines. The stimulating effect of fibroblast supernatant could be explained by various growth factors and cytokines; HGF and IL-6 stimulated the proliferation of 6 and 5 cancer cell lines, respectively, while FGF1, FGF7, and FGF10 increased cell proliferation of 7, 6, and 6 cancer cell lines, respectively. When the MET inhibitor PHA-665752 was added to the fibroblast culture supernatant, the culture supernatant-induced proliferation of was abrogated in 2 cell lines. Among 10 cell lines whose proliferation was induced by FGFs, addition of FGFR inhibitor PD-173074 to the fibroblast culture supernatant abrogated the effect of the culture supernatant in 4 cell lines. In migration assays, the presence of fibroblasts significantly increased the migration of cancer cells in 3 of 6 representative cell lines. In organotypic culture, stromal invasion was seen only in presence of fibroblasts. Time-lapse cinematography confirmed that clusters of cancer cells progressively migrated towards the fibroblast meshwork. In vivo tumor growth was promoted by co-injection of fibroblasts in 13 of 22 cancer cell lines. In clinicopathological study, the extent of stromal fibrosis was significantly related to depth of invasion and venous invasion of tumor cells. Conclusion: In many esophageal cancer cell lines, cell proliferation was promoted by the presence of fibroblasts both in vivo and in vitro. The stimulatory effect of fibroblast could be accounted for by various growth factors and cytokines, such as HGF, interleukin-6 and/or FGFs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1495. doi:1538-7445.AM2012-1495