Current status and therapeutic strategy of acute acalculous cholecystitis: Japanese nationwide survey in the era of the Tokyo guidelines.

PURPOSE: This study aimed to clarify the incidence, therapeutic modality, and prognosis of acute acalculous cholecystitis and to reveal its optimal treatment strategy. METHODS: As a project study of the Japanese Society for Abdominal Emergency Medicine, we performed a questionnaire survey of demographic data and perioperative outcomes of acute acalculous cholecystitis treated between January 2018 and December 2020 from 42 institutions. RESULTS: In this study, 432 patients of acute acalculous cholecystitis, which accounts for 7.04% of acute cholecystitis, were collected. According to the Tokyo guidelines severity grade, 167 (38.6%), 202 (46.8%), and 63 (14.6%) cases were classified as Grade I, II, and III, respectively. A total of 11 (2.5%) patients died and myocardial infarction/congestive heart failure was the only independent risk factor for in-hospital death. Cholecystectomy, especially the laparoscopic approach, had more preferable outcomes compared to their counterparts. The Tokyo guidelines flow charts were useful for Grade I and II severity, but in the cases with Grade III, upfront cholecystectomy could be suitable in some patients. CONCLUSIONS: The proportions of severity grade and mortality of acute acalculous cholecystitis were found to be similar to those of acute cholecystitis, and laparoscopic cholecystectomy is recommended as an effective treatment option. (UMIN000047631).

[A Resected Case of Cancer in the Ileum of the Blind Loop after an Ileotransverse Colostomy].

We report a resected case of cancer at the ileum of the blind loop. An 81-year-old male underwent an appendectomy for acute appendicitis and an ileotransverse colostomy for postoperative obstruction when he was 14 years old. He underwent radiation therapy for prostate cancer when he was 75 years old. Six years later, enhanced computed tomography revealed a 7 cm mass in the ileum of the blind loop. Colonoscopy showed wall thickening at the ileum of the blind loop, and biopsy revealed an adenocarcinoma. We performed partial resection of the ileum. The patient was discharged 17 days after surgery. Cancer at the ileum of the blind loop after an ileotransverse colostomy has rarely been reported.

Nest-Gallery Development and Caste Composition of Isolated Foraging Groups of the Drywood Termite, Incisitermes minor (Isoptera: Kalotermitidae).

An X-ray computed-tomographic examination of nest-gallery development from timbers naturally infested by foraging groups of Incisitermes minor colonies was conducted. This study documents the colonization process of I. minor to new timbers and how the isolated groups maintain their nest-gallery system. The results suggested that development of a nest-gallery within a suitable wood item is not random, but shows selection for softer substrate and other adaptations to the different timber environments. Stigmergic coordinations were expressed in dynamic changes of the nest-gallery system; indicated by fortification behavior in sealing and re-opening a tunnel approaching the outer edge of the timber, and accumulating fecal pellets in particular chambers located beneath the timber surface. The study also examines the caste composition of isolated groups to discover how I. minor sustains colonies with and without primary reproductives.

E-PASS comprehensive risk score is a good predictor of postsurgical mortality from comorbid disease in elderly gastric cancer patients.

BACKGROUND AND OBJECTIVES: The long-term prognosis of elderly gastric cancer patients is poor because of the cancer and unrelated comorbidities. We investigated the risk factors for mortality after gastrectomy to aid surgeons in deciding the correct operative procedure for elderly gastric cancer patients. METHODS: A total of 414 gastric cancer patients surgically treated between 2002 and 2012 were divided into two groups A (≥75 years) and B (<75 years). Data were collected retrospectively and analyzed using the Estimation of Physiological Ability and Surgical Stress (E-PASS) scoring system as a predictor of postoperative complications. RESULTS: Overall survival (P < 0.001), disease-specific survival (P = 0.029), and survival rate related to comorbid disease (P < 0.001) were significantly reduced in elderly patients compared with younger patients. Surgical treatment for Group A involved lesser extent of nodal resection (P < 0.001). Multivariate analysis revealed that a comprehensive risk score (CRS) ≥0.5 based on the E-PASS score (P = 0.022) and severe postoperative complication (P = 0.002) were independent risk factors for mortality from comorbid disease. CONCLUSIONS: Thus, E-PASS-based CRS was a good predictor of comorbidity-related mortality. CRS may help surgeons select elderly patients with gastric cancer for surgical or other therapies.

[A case of liver cirrhosis due to non-alcoholic steatohepatitis complicated by myotonic dystrophy].

A female in her 50s with a four-year history of myotonic dystrophy was admitted to our hospital with hematochezia. She was diagnosed with synchronous colonic cancer of the transverse and sigmoid colon, for which she underwent partial transverse and sigmoid colectomy, respectively. Postoperative respiratory failure resulted in prolonged stay in the intensive care unit. Her liver and renal function gradually deteriorated, and she eventually died from these sequelae on postoperative day 26. Intraoperative liver biopsy revealed cirrhosis arising from non-alcoholic steatohepatitis (NASH). Although myotonic dystrophy is believed to be a multisystem disease, its association with cirrhosis has not been reported in Japan. We therefore report this rare case of liver cirrhosis arising from NASH in a patient with myotonic dystrophy.

Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial.

BACKGROUND: Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting. METHODS: In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status. RESULTS: Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90% of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69%) and decreases in CA19-9 levels (89%). R0 resection was performed for 87% in resection, and the morbidity rate (40%) was acceptable. The 2-year survival rate of the total cohort was 45.7%. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017). CONCLUSIONS: NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC.

The expression of S100A4 in human pancreatic cancer is associated with invasion.

OBJECTIVES: Pancreatic cancer is one of the most lethal malignancies; its poor prognosis is strongly associated with invasion and metastasis. Expression of S100A4 has been reported to correlate with poor prognosis in various cancers. We have investigated the role of S100A4 in pancreatic cancer tumorigenesis and its clinicopathologic significance. METHODS: Protein expression of S100A4 was examined by Western blot in pancreatic cancer cell lines and a human pancreatic ductal epithelium cell line, HPDE-6. Then the expressions of S100A4, TP53, and CD133 were examined immunohistochemically in resected specimens from 83 patients with pancreatic cancer to clarify their clinicopathologic significance. Survival analyses were performed using the Kaplan-Meier method and the Mantel-Cox method. RESULTS: Forty-eight (58%) of 83 patients with pancreatic cancer positively expressed S100A4, and 50 (60%) and 29 (36%) patients positively expressed TP53 and CD133, respectively. S100A4 expression was significantly correlated with perineural invasion (P = 0.029) and invasion pattern (P = 0.001). Neither TP53 nor CD133 expression showed significant correlations with any other parameters. CONCLUSIONS: Our present results suggest that S100A4 plays an important role in the invasiveness, particularly with perineural invasion and invasion pattern, of pancreatic cancer. Development of new strategies targeting S100A4 or its downstream effectors is warranted.

Computed tomography reflected endocrine function of the pancreas.

UNLABELLED: BACKGROUNS/AIMS: There are few studies about the assessment of pancreatic function using computed tomography (CT) volumetry. In this study, we examined the correlation between CT volumetry and endocrine parameters (blood glucose and HbA1c) of the pancreas. METHODS: A total of 68 patients underwent enhanced CT for pancreatic disease from January to December in 2008. In particular, we analyzed the correlation of diabetic status and pancreatic CT parameters at 1 year after pancreatoduodenectomy in 32 patients. CT parameters including volume, volume/body weight, arterial phase density, the arterial phase to portal phase density ratio (A/P ratio) of the pancreas, and size of pancreatic duct were also analyzed. Correlation between CT parameters and diabetic status was analyzed preoperatively and postoperatively by ANOVA test. RESULTS: The preoperative diabetic status and parameters correlated well with arterial phase density (p = 0.004), A/P ratio, and pancreatic duct size (p < 0.0001). In the patients who underwent pancreatectomy, two out of 25 patients without preoperative diabetes mellitus (DM) had DM, and two out of seven patients with preoperative DM recovered from DM. Postoperative CT parameters correlated with the DM status 1 year after pancreatectomy. CONCLUSION: CT is a useful modality for evaluation of the pancreatic endocrine function and could be used for the prediction of postoperative diabetic outcome.

[Successful intervention with a longitudinal pancreaticojejunostomy for chronic pancreatitis due to obstruction of the pancreatogastrostomy after pancreatoduodenectomy].

A 50-year-old man with a cancer of the papilla of Vater underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreatogastrostomy in 2002. He began to complain of upper abdominal and back pain in April 2008. Abdominal CT scan revealed pancreatolithiasis with dilatation of the remnant main pancreatic duct. An upper intestinal endoscopy could not discern the orifice of the pancreatic duct. He was treated by transgastric EUS-guided drainage of the pancreatic duct several times, and ESWL for pancreatolithiasis. However, he had repeated pancreatitis. Surgical intervention was carried out to treat the obstructive pancreatitis in April 2009. Longitudinal pancreaticojejunostomy was performed without resection of the obstructive pancreatogastrostomy. The postoperative recovery was uneventful, and the patient remains asymptomatic after the second operation. We concluded that the longitudinal pancreaticojejunostomy is a safe and effective alternative for chronic pancreatitis after stenotic pancreatico-digestive tract anastomosis following pancreatoduodenectomy, especially for cases in which endoscopic stenting is ineffective.

Assessment of Frey procedures: Japanese experience.

BACKGROUND/PURPOSE: The Frey procedure, the coring out of the pancreatic head and longitudinal pancreaticojejunostomy, is a safe, easy, and reliable method to solve most of the problems associated with chronic pancreatitis. During long-term follow up, unexpected relapse in the pancreatic tail was encountered. The pattern of failure and the rationale for a new procedure to treat or prevent such relapse were investigated. METHODS: From 1992 to 2008, 71 patients with chronic pancreatitis underwent the Frey procedure at Tohoku University Hospital. The etiology was alcoholic in 92.6% of them, followed in incidence by idiopathic and hereditary chronic pancreatitis. In the primary operation, besides the Frey procedure, combined resection of the pancreatic tail was performed in three patients, and choledochoduodenostomy was performed in one patient. The follow-up rate was 92.9%, with a median period of 46 months. RESULTS: The incidence of early postoperative complications was 18.4%, with one reoperation for gastrointestinal bleeding from the splenic artery. Pain control was achieved in all patients and there was no operative mortality. During the long-term follow up of 62 patients with the Frey procedure, eight patients had relapse of inflammation and required reoperation. Five of these eight patients had a pseudocyst in the pancreatic tail and underwent distal pancreatectomy (DP). CONCLUSIONS: Relapse occurred in alcoholic middle-aged male patients, and in the patients with hereditary and idiopathic pancreatitis. Frey-DP and Frey-spleen-preserving DP (SPDP) procedures can be performed safely and effectively to treat the relapse and to prevent relapse in the pancreatic tail.

The PMAIP1 gene on chromosome 18 is a candidate tumor suppressor gene in human pancreatic cancer.

Frequent loss of heterozygosity on the long arm of chromosome 18 is observed in pancreatic cancer. Previous studies suggested the existence of one or more tumor-suppressor genes other than SMAD4 on chromosome 18. To identify the candidate tumor-suppressor gene(s), we compared gene expression by cDNA microarray analyses using a pancreatic cancer cell line Panc-1 and its hybrid cell lines showing suppressed cell growth after introduction of one normal copy of chromosome 18. The microarray analyses identified 38 genes on chromosome 18 that showed differential expressional levels. Among these genes, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1/APR/NOXA) was identified as one of the candidates for tumor suppressor. Expression vector-mediated introduction of PMAIP1 suppressed cell proliferation, and RNAi-mediated knockdown of PMAIP1 induced recovery of cell growth. These results suggest that PMAIP1 may play an important role in the progression of pancreatic cancer.

Elucidation of the relationship of BNIP3 expression to gemcitabine chemosensitivity and prognosis.

AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic cancer cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreatic cancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer.

A novel cancer testis antigen that is frequently expressed in pancreatic, lung, and endometrial cancers.

PURPOSE: To isolate cancer testis antigens that are expressed in pancreatic cancers and may be useful in clinical applications. EXPERIMENTAL DESIGN: To efficiently isolate cancer testis antigens, a testis cDNA library was immunoscreened (SEREX) with serum from a patient with pancreatic ductal adenocarcinoma. The expression of isolated antigens in various cancer cell lines and tissues was evaluated by reverse transcription-PCR and Northern blot analyses. The immunogenicity of the antigen in cancer patients was evaluated by detection of the IgG antibody in sera from patients with various cancers. RESULTS: Of the three clones isolated through screening of a total of 2 x 10(6) cDNA library clones, one clone (KU-CT-1) was found to be expressed in various cancers but only in testis among normal tissues, indicating that it was a novel cancer testis antigen. The KU-CT-1 gene is located on chromosome 10p12 and produces two splice variants, which encode proteins of 397 and 872 amino acids, respectively. KU-CT-1 was expressed in pancreatic cancer tissues (3 of 9, 33%), lung cancer tissues (9 of 24, 38%), and endometrial cancer tissues (7 of 11, 64%). Specific serum IgG antibodies were detected in 3 of 20 pancreatic cancer patients, 2 of 12 endometrial cancer patients, 1 of 18 colon cancer patients, and 1 of 10 prostate cancer patients but not detected in 30 healthy individuals. CONCLUSIONS: KU-CT-1 is a new cancer testis antigen that is expressed in pancreatic, lung, and endometrial cancers and may be useful for diagnosis and immunotherapy for patients with various cancers.

Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma.

BACKGROUND & AIMS: Markers to differentiate among pancreatic adenocarcinoma, chronic pancreatitis, and normal pancreas would be of significant clinical utility. This study was therefore designed to analyze the proteome of such specimens and identify new candidate proteins for differential diagnosis. METHODS: A PowerBlot analysis with more than 900 well-characterized antibodies was performed with tissue specimens from patients with chronic pancreatitis, pancreatic adenocarcinoma, and normal pancreas. Differential expression of selected proteins was confirmed on a larger scale by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry using tissue arrays. RESULTS: A total of 30 and 102 proteins showed significant deregulation between normal pancreas when compared with chronic pancreatitis and pancreatic adenocarcinoma, respectively, and although a substantial proportion were found similarly dysregulated in both chronic pancreatitis and pancreatic adenocarcinoma, several proteins were identified as potential disease-specific markers. CONCLUSIONS: A large number of proteins are differentially expressed in chronic pancreatitis and pancreatic adenocarcinoma compared with normal pancreas. Among these, expression analysis of UHRF1, ATP7A, and aldehyde oxidase 1 in combination could potentially provide a useful additional diagnostic tool for fine-needle aspirated or cytological specimens obtained during endoscopic investigations.

Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer.

PURPOSE: Although chemotherapy with gemcitabine is a common mode of treatment of pancreatic cancer, 75% of patients do not benefit from this therapy. It is likely that the sensitivity of cancer cells to gemcitabine is determined by a number of different factors. EXPERIMENTAL DESIGN: To identify genes that might contribute to resistance to gemcitabine, 15 pancreatic cancer cell lines were subjected to gemcitabine treatment. Simultaneously, gene expression profiling using a cDNA microarray to identify genes responsible for gemcitabine sensitivity was performed. RESULTS: The pancreatic cancer cell lines could be classified into three groups: a gemcitabine "sensitive," an "intermediate sensitive," and a "resistant" group. Microarray analysis identified 71 genes that show differential expression between gemcitabine-sensitive and -resistant cell lines including 27 genes relatively overexpressed in sensitive cell lines whereas 44 genes are relatively overexpressed in resistant cell lines. Among these genes, 7 genes are potentially involved in the phosphatidylinositol 3-kinase/Akt pathway. In addition to this major signaling pathway, Bcl2/adenovirus E1B 19 kDa protein interacting protein (BNIP3), a Bcl-2 family proapoptotic protein, was identified as being expressed at lower levels in drug-resistant pancreatic cancer cell lines. In an analysis of 21 pancreatic cancer tissue specimens, more than 90% showed down-regulated expression of BNIP3. When expression of BNIP3 was suppressed using small interfering RNA, gemcitabine-induced cytotoxicity in vitro was much reduced. CONCLUSIONS: These results suggest that BNIP3 and the phosphatidylinositol 3-kinase/Akt pathway may play an important role in the poor response to gemcitabine treatment in pancreatic cancer patients.

Development of immunotherapy for pancreatic cancer.

: Human tumor antigens recognized by T cells have been recently identified in various cancers, including pancreatic cancer. With the identified antigens, new immunotherapies can be developed using more efficient immunologic intervention (due to sufficient amounts of antigens in a more immunogenic form), as well as more quantitative and qualitative immunomonitoring. Various immunotherapies for patients with various cancers, including pancreatic cancer, are currently under evaluation in clinical trials. These include adoptive transfer of tumor reactive T cells and LAK cells; nonmyeloablative stem cell transplantation; active immunization with the identified tumor antigens, various tumor-derived products, dendritic cells pulsed with tumor antigens, and gene-modified tumor cells. Although these efforts in the realm of pancreatic cancer are still limited, various groups in Japan continue to be actively involved in this field of research.

Identification of bladder cancer antigens recognized by IgG antibodies of a patient with metastatic bladder cancer.

To identify tumor antigens useful for the diagnosis and treatment of patients with bladder cancer, a lambda phage cDNA library constructed from a high-grade bladder cancer cell line was screened with autologous serum from a patient with metastatic bladder cancer. Forty-eight distinct antigens were isolated. By evaluating the immunogenicity and the tissue-specific expression, KU-BL-1 and KU-BL-2 were identified as immunogenic antigens with restricted tissue expression. KU-BL-1 was found to be a putative human lipoic acid synthetase with a metal-binding site, CXXXCXXC, that was expressed in bladder cancer cell lines and most bladder cancer tissues, as well as normal bladder mucosa and testis tissues. Immunoglobulin (Ig)G antibody to KU-BL-1 was detected in 2 of 28 patients with bladder cancer, but not in 30 healthy individuals. KU-BL-2 was found to be a putative human kelch-like protein that was homologous to Drosophila kelch, with a BTB/POZ domain and kelch repeats. KU-BL-2 was expressed in bladder cancer cell lines, most bladder cancer tissues, testis and heart, but not in normal bladder mucosa. IgG antibody to KU-BL-2 was detected in 8 of 28 patients with bladder cancer, but not in 16 healthy individuals. Tumor reactive T cells were induced from peripheral blood mononuclear cells (PBMC) by stimulation with one of the HLA-A24 binding KU-BL-2 peptides. Therefore, KU-BL-1 and KU-BL-2, which showed preferential expression in bladder cancer with restricted expression in normal tissues, as well as immunogenicity in multiple patients with bladder cancer, may be useful for the development of diagnostic and therapeutic methods for patients with bladder cancer.

[Chemotherapy for pancreatic cancer].

Pancreatic cancer has one of the worst prognosis of any malignant disease. The National Registry of Japan Pancreas Society has reported that only 13% of patients achieve 5 years survival after surgical resection. The vast majority of patients present with metastatic or unresectable disease. Gemcitabine (GEM) has replaced 5-fluorouracil (5-FU)-based chemotherapy as the standard of care. GEM first generated improvements in symptom control and survival in advanced disease, spurring further research. For locally advanced disease, most recent studies have incorporated GEM into combined-modality therapy. However, subsequent trials have not demonstrated that combinations of other agents with GEM extend clinical benefits yet. Similarly, in surgically resectable disease, current trials are incorporating GEM into adjuvant therapy. According to several clinical trials it has been demonstrated that improvements in locoregional control and survival may be achieved when chemotherapy using 5-FU is added to radiation for locally advanced pancreatic cancer. The new regimen for locally advanced disease has demonstrated that the better outcome is expected by chemoradiation therapy with 5-FU followed by GEM treatment. Furthermore, one of the patients showed the significant regression of pancreas tumor, resulting in the successful surgical resection. In order to develop chemotherapy for pancreatic cancer, we are analyzing mRNA expression of pancreas cancer cell lines and examined their resistant against to GEM. One of the genes is demonstrated to be a responsible for drug sensitivity by clustering analysis.