Zenichiro Saze

Cathepsin L is highly expressed in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that are diagnosed by c-kit staining in most cases. A lysosomal cysteine proteinase termed cathepsin L has been commonly associated with malignancy in several cancer types, but this finding has not been reported for GISTs. We analyzed the cathepsin L mRNA and protein expression in GISTs. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that cathepsin L levels were higher in GISTs than those in gastric or colorectal tumors; this finding was supported by results of the Western blot analysis. Immunohistochemistry revealed that cathepsin L was localized to the cytoplasm of GIST cells as an intense granular signal, which was not observed in the cells of leiomyoma, a mesenchymal tumor that was analyzed as a control specimen. Double immunofluorescence microscopy revealed that a portion of the granular signal colocalized with lysosome-associated membrane protein-1 (LAMP-1), which is a lysosomal marker. Moreover, immunohistochemical analysis of 43 tumor specimens revealed that 86.0% (n=37) were cathepsin-L positive, and this positivity was significantly correlated with c-kit positivity but not with other clinicopathological factors, including gender, age, region, size, mitosis and risk of recurrence. From these results, we conclude that cathepsin L is highly expressed in GISTs compared to its expression in other cancerous lesions; this identifies cathepsin-L as a new diagnostic marker for GISTs.

Activation of the sonic hedgehog pathway and its prognostic impact in patients with gastric cancer.

Background: The sonic hedgehog (SHH) signaling pathway is critical in fetal organogenesis. Activation of the SHH pathway has been associated with several types of human cancer; however, the clinical impact of SHH activation in patients with gastric cancer is still unknown. Methods: The present study included 41 patients with gastric cancer who underwent gastrectomy between 2000 and 2004. SHH, Patched-1 (PTCH1), Smoothened (SMO) and Glioma-associated oncogene-1 (GLI1) were examined immunohistochemically, and these of mRNAs from the cancer lesions were evaluated using real-time quantitative RT-PCR. Results: Immunohistological expressions of SHH-related molecules were relatively intense in cancer tissue, but no significant correlation was found with any clinicopathological factors of tumor. PTCH1 was only the molecule associated with poor prognosis of patients with differentiated type of tumor. For mRNA analysis, a significant correlation was demonstrated between certain clinicopathological factors and PTCH1, SMO or/and GLI1 mRNA levels. High levels of SHH and PTCH1 mRNA were associated with poor prognosis. Multivariate analysis demonstrated the PTCH1 mRNA level and liver metastasis as significant independent prognostic factors. Conclusions:PTCH1 expression in the SHH pathway was possibly involved in gastric cancer tumor progression, and could be a useful indicator for the prognosis of gastric cancer.

Risk Models of Operative Morbidities in 16,930 Critically Ill Surgical Patients Based on a Japanese Nationwide Database

Abstract The aim of the study was to evaluate preoperative variables predictive of lethal morbidities in critically ill surgical patients at a national level. There is no report of risk stratification for morbidities associated with mortality in critically ill patients with acute diffuse peritonitis (ADP). We examined data from 16,930 patients operated during 2011 and 2012 in 1546 different hospitals for ADP identified in the National Clinical Database of Japan. We analyzed morbidities significantly associated with operative mortality. Based on 80% of the population, we calculated independent predictors for these morbidities. The risk factors were validated using the remaining 20%. The operative mortality was 14.1%. Morbidity of any grade occurred in 40.2% of patients. Morbidities correlated with mortality, including septic shock, progressive renal insufficiency, prolonged ventilation >48 hours, systemic sepsis, central nervous system (CNS) morbidities, acute renal failure and pneumonia, and surgical site infection (SSI), were selected for risk models. A total of 18 to 29 preoperative variables were selected per morbidity and yielded excellent C-indices for each (septic shock: 0.851; progressive renal insufficiency: 0.878; prolonged ventilation >48 h: 0.849; systemic sepsis: 0.839; CNS morbidities: 0.848; acute renal failure: 0.868; pneumonia: 0.830; and SSI: 0.688). We report the first risk stratification study on lethal morbidities in critically ill patients with ADP using a nationwide surgical database. These risk models will contribute to patient counseling and help predict which patients require more aggressive surgical and novel pharmacological interventions.

Immunotherapy for esophageal squamous cell carcinoma: a review

Cancer vaccines and immune checkpoint inhibitors (ICI) have recently been employed as immunotherapies for esophageal squamous cell carcinoma (ESCC). Cancer vaccines for ESCC have yielded several promising results from investigator-initiated phase I and II clinical trials. Furthermore, a Randomized Controlled Trial as an adjuvant setting after curative surgery is in progress in Japan. On the other hand, ICI, anti-CTLA-4 mAb and anti-PD-1 mAb, have demonstrated tumor shrinkage and improved overall survival in patients with multiple cancer types. For ESCC, several clinical trials using anti-PD-1/anti-PD-L1 mAb are underway with several recent promising results. In this review, cancer vaccines and ICI are discussed as novel therapeutic strategies for ESCC.