佐田 尚宏

BACKGROUND: Lynch 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. METHODS: A 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. RESULTS: No 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. CONCLUSION: Large 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.

We present three patients with T2 acinar cell carcinomas (ACC) (two of which were small) and discuss their clinical and pathological features. Case 1: A 34 year-old woman had a 2.6 cm iso- or hyperdense tumor. Enucleation was performed but final diagnosis was ACC and a pylorus preserving pancreaticoduodenectomy was performed. Case 2: A 35 year-old woman was found to have a 4.5 cm hypervascular tumor in the tail of the pancreas. Distal pancreatectomy was performed. Case 3: A 61 year-old man suffered from acute pancreatitis and was found to have an encapsulated 2.5 cm hypervascular tumor in the head of pancreas. Pylorus-preserving pancreaticoduodenectomy was performed. These three patients with T2 ACCs had common characteristics including well-demarcated exophytic tumors with slow and limited progress, distinctively different from large ACCs and pancreatic ductal adenocarcinomas. ACCs are important in the differential diagnosis of homogeneously or heterogeneously enhancing small pancreatic tumors. Copyright (c) 2013, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

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 frequeney 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. (J Surg 69:605-610. (C) 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

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. METHODS: From January 2001 to June 2010 a total of 1735 patients underwent a resection of gastric cancer. Histopathologically, eight patients had adenocarcinoma containing SCC components, in which the proportion of SCC components was above 25% of the total tumor mass in four patients. The immunohistochemical and clinicopathological characteristics of these eight patients were analyzed. RESULTS: The median survival duration was 22 months. Adenocarcinoma was present at the superficial layer of all tumors and SCC was primarily present at sites with deep invasion. Immunohistochemically, adenocarcinoma components were positive for cytokeratin (CK) 8/18/19 and CK7 in all cases. SCC components were positive for carcinoembryonic antigen and CK7 in more than 60% of patients. Expression patterns of p53 product were identical in both components. SCC components were positive for 34βE12 and adenocarcinoma components were negative for 34βE12 in all patients. CONCLUSIONS: SCC components are derived from squamous metaplasia in a pre-existing adenocarcinoma. A gastric adenocarcinoma with SCC components is associated with various patterns of metastasis and both SCC and adenocarcinoma components have the potential for metastasis. Gastric cancer with SCC components is a clinically aggressive tumor.

Strangulation of the gallbladder by the omentum is extremely rare. We report what to our knowledge is only the second documented case of strangulation of a floating gallbladder by the lesser omentum. A 61-year-old Japanese woman presented to a local hospital after the sudden onset right upper quadrant pain. Her clinical features suggested a gallbladder volvulus, and the patient was referred to our hospital for investigation and treatment. Ultrasonography and computed tomography showed no cholecystolithiasis, but the fundus and body of the gallbladder were markedly swollen without wall thickening, whereas the neck of the gallbladder was normal. A narrowed, twisted area was seen between the body and neck of the gallbladder. Based on these findings, gallbladder volvulus was diagnosed and she underwent emergency laparoscopic cholecystectomy. The fundus and body of the gallbladder were grossly necrotic. The narrowest part of the gallbladder was tightly strangulated by the lesser omentum, but the gallbladder neck was normal. Histopathologic examination of the resected gallbladder showed ischemic changes in the wall of the fundus and body. This case highlights that the clinical features and imaging findings of a gallbladder strangulated by the lesser omentum are similar to those of gallbladder volvulus and that a positive outcome is dependent on a correct diagnosis and prompt surgical management.

INTRODUCTION: Laparoscopic splenectomy using pneumoperitoneum has been performed since 1992. The gasless abdominal wall-lifting method for laparoscopic splenectomy was introduced as an alternative. This retrospective study was undertaken to compare results using the two techniques. METHODS: Between 1995 and 2010, 54 patients underwent laparoscopic splenectomy at a single institution; 30 underwent the procedure using the gasless technique and 24 using pneumoperitoneum. There were no significant differences between the two groups regarding age, sex or BMI, but more patients underwent concurrent operations in the pneumoperitoneum group. The abdominal wall-lift system with subcutaneous K-wires was used for the gasless method. RESULTS: Intraoperative blood loss was similar in the two groups (193.0 ± 196.7 mL gasless, 217.3 ± 296.6 mL pneumoperitoneum; P > 0.05), but operative time (182.1 ± 92.1 min, 135.1 ± 46.1 min; P < 0.05), and resected spleen weight (306.1 ± 297.7 g, 138 ± 81.0 g; P < 0.05) were significantly different. In the gasless group, additional procedures included conversion (n = 1), mini-laparotomy (n = 2), and CO(2) insufflation (n = 2). Excluding the concurrent living-related kidney donor patients, hospital stay was similar (6.9 ± 2.5 days, 6.3 ± 2.0 days, P > 0.05). CONCLUSION: Although gasless laparoscopic splenectomy is feasible, there are disadvantages, particularly the restricted operative working space in some patients. These results suggest that either technique may be used on an individual basis in patients undergoing laparoscopic splenectomy.

OBJECTIVE: Although studies have been conducted to identify factors that attract students to a career in surgery, the relative importance of factors that attract students to a particular training program remains unknown. Comparative data between countries may provide insights and ultimately provide guidance to program directors as they seek to attract the best applicants to their program. DESIGN: Blinded written survey, scored 1-5 on a list of 26 factors divided into 3 categories, including educational factors, lifestyle factors, and other. SETTING: Jichi Medical University, Japan and the David Geffen School of Medicine at University of California Los Angeles. PARTICIPANTS: Japan residents (N = 125), Japan Medical Students (N = 68), United States Residents (N = 99), and United States Students (N = 55). RESULTS: All 4 groups surveyed judged faculty quality among the most important factors, with educational program quality, clinical experience and perceptions of resident happiness also rated among the most important. A comparison of factors consistent with lifestyle and factors consistent with the educational program found significantly (p &lt; 0.05) higher scores for educational factors by 3 groups surveyed. CONCLUSIONS: Resident applicants are most interested in training program factors related to the quality of the educational program and the faculty. Issues such as salary, vacation, night call, location, or benefits are considered less important. The results in Japan and the United States were remarkably similar despite major differences in the educational system and debt load at the time of graduation. Program directors should communicate the value of those factors considered important by applicants as part of the recruitment process. (J Surg 69: 167-172. (C) 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

BACKGROUND: Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection. METHODS: We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1) using a newly developed matrix-assisted laser desorption/ionization (oMALDI) QqTOF (quadrupole time-of-flight) mass spectrometry (MS) system. RESULTS: We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z), unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z), and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36×10(-21), P = 4.35×10(-14), and P = 1.83×10(-24) (Mann-Whitney U-test); area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103) and Cohort 3 (n = 163)] and a prospective cohort [Cohort 4 (n = 833)] collected from 8 medical institutions in Japan and Germany. CONCLUSIONS: We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer.

INTRODUCTION: Uterine rupture is a life-threatening condition both to mothers and fetuses. Its early diagnosis and treatment may save their lives. Previous myomectomy is a high risk factor for uterine rupture. Intestinal adhesion due to previous myomectomy may also prevent early diagnosis of uterine rupture. CASE PRESENTATION: A 38-year-old primiparous non-laboring Japanese woman with a history of myomectomy was admitted in her 34th week due to lower abdominal pain. Although the pain was slight and her vital signs were stable, computed tomography revealed massive fluid collection in her abdominal cavity, which led us to perform a laparotomy. Uterine rupture had occurred at the site of the previous myomectomy; however, the small intestine was adhered tightly to the rupture, thus masking it. The baby was delivered through a low uterine segment transverse incision. The ruptured uterine wall was reconstructed. CONCLUSION: Intestinal adhesion due to a prior myomectomy occluded a uterine rupture, possibly masking its symptoms and signs, which may have prevented early diagnosis.

BACKGROUND: To decrease the incidence of internal hernia after laparoscopic gastric bypass, current recommendations include closure of mesenteric defects. Laparoscopic gastric resection is used increasingly for the treatment of gastric cancer, but the incidence of internal hernia in the treated patients has not been studied. METHODS: This study retrospectively reviewed 173 patients who underwent laparoscopic resection for gastric cancer at one institution, including distal and total gastric resections with antecolic Roux-en-Y reconstruction. RESULTS: An internal hernia occurred in 4 (7%) of 58 patients whose jejunojejunal mesenteric defect was not closed a mean of 326 days after surgery. All the patients underwent reoperation with reduction and repair of the hernia. In 115 subsequent cases, with closure of the mesenteric defect, internal hernias did not occur (0/115 cases; p < 0.05). CONCLUSION: Based on the current recommendations for patients undergoing bariatric surgery, closure of this potential hernia defect is mandatory after laparoscopic gastrectomy with a Roux-en-Y reconstruction for gastric cancer.

BACKGROUND: The aim of this study was to identify a new plasma biomarker for use in early detection of colorectal cancer. METHODS: Using the combination of hollow fiber membrane (HFM)-based low-molecular weight protein enrichment and two-dimensional image converted analysis of liquid chromatography and mass spectrometry (2DICAL), we compared the plasma proteome of 22 colorectal cancer patients with those of 21 healthy controls. An identified biomarker candidate was then validated in two larger cohorts [validation-1 (n = 210) and validation-2 (n = 113)] using a high-density reverse-phase protein microarray. RESULTS: From a total of 53,009 mass peaks, we identified 103 with an area under curve (AUC) value of 0.80 or higher that could distinguish cancer patients from healthy controls. A peak that increased in colorectal cancer patients, with an AUC of 0.81 and P value of 0.0004 (Mann-Whitney U test), was identified as a product of the PLIN2 gene [also known as perilipin-2, adipose differentiation-related protein (ADRP), or adipophilin]. An increase in plasma adipophilin was consistently observed in colorectal cancer patients, including those with stage I or stage II disease (P < 0.0001, Welch's t test). Immunohistochemical analysis revealed that adipophilin is expressed primarily in the basal sides of colorectal cancer cells forming polarized tubular structures, and that it is absent from adjacent normal intestinal mucosae. CONCLUSIONS: Adipophilin is a plasma biomarker potentially useful for the detection of early-stage colorectal cancer. IMPACT: The combination of HFM and 2DICAL enables the comprehensive analysis of plasma proteins and is ideal for use in all biomarker discovery studies.

We report two cases of carcinoid tumor of the gallbladder. Case 1 was a 59-year-old woman who presented with epigastric pain. Abdominal ultrasonography and computed tomography (CT) revealed a 16 mm polypoid lesion in the neck of the gallbladder. Tumor markers were within normal limits. Open cholecystectomy was performed with a preoperative diagnosis of early cancer of the gallbladder. Case 2 was a 45-year-old man. A polyp in the gallbladder was incidentally detected on annual checkup. Ultrasound and CT showed an 18 mm protruding lesion in the neck of the gallbladder. Laparoscopic cholecystectomy was performed and the tumor diagnosed as a carcinoid tumor based on the findings of funicular and tubular cells in the lamina propria mucosa, homogeneous nuclei, basophilic cytoplasm, and positive staining with chromogranin A and synaptophysin. The postoperative course of both patients was uneventful, with no recurrence at 44 and 41 months after surgery. In this literature review of 39 cases, classical carcinoid of the gallbladder has a favorable postoperative outcome. Of cases reviewed, 60% are located in the neck of the gallbladder and 50% have a polypoid shape.

The patient is a 61-year-old man who had previously undergone an extended thymectomy for myasthenia gravis. Endoscopic examination during a routine follow-up visit revealed early gastric cancer in the proximal portion of the stomach. To undergo resection the patient received general and epidural anesthesia. The conditions were unfavorable for laparoscopic-assisted surgery because he had a body mass index of 33 and muscle relaxants could not be used. Pneumoperitoneum was induced with carbon dioxide, and the abdominal wall was lifted. An adequate working space was secured in the upper abdomen and proximal gastrectomy was successfully performed.

BACKGROUND: Esophagectomy after gastric reconstruction leads to significant weight loss. Ghrelin is known to stimulate appetite and cause weight increase. The objective of this study is to examine the relationship of serum ghrelin levels and weight loss in patients after esophagectomy for cancer. METHODS: Twenty-two patients underwent esophagectomy including gastric reconstruction. Serum ghrelin levels and weight were measured preoperatively and then postoperatively for 12 months in all patients. A questionnaire assessed appetite, amount of food eaten, satisfaction, and frequency of eating. RESULTS: Preoperatively, the mean serum ghrelin level was 67.9 ± 42.6 (fmol/mL ± SD), and at 1, 3, 6, and 12 months after surgery were 43.4 ± 28.1, 51.5 ± 32.2, 67.1 ± 50.9, and 84.9 ± 43.1, respectively. Compared with preoperative values, the mean body mass index decreased by 1.9 ± 1.5, 2.3 ± 1.8, 2.1 ± 2.3, 2.4 ± 2.7 at 1, 3, 6, and 12 months after surgery. While appetite score showed a decrease at 1 month (1.6 ± 0.92), appetite increased by 12 months postoperatively (2.7 ± 1.0) and showed a strong positive correlation (r = 0.743) with serum ghrelin levels. There were no significant differences in ghrelin levels when patients were stratified by disease stage, recurrence, or administration of adjuvant chemotherapy. CONCLUSIONS: Esophagectomy resulted in temporary reduction of ghrelin levels, but while levels returned to normal 3 months later, weight loss persisted at 12 months. Further study is needed to elucidate the mechanisms of persistent weight loss and design therapeutic interventions to recover the weight lost.

The development of a new plasma biomarker for early detection would be necessary to improve the overall outcome of colorectal cancer. Here we report the identification and validation of the ninth component of complement (C9) as a novel plasma biomarker for colorectal cancer by cutting-edge proteomic technologies. Plasma proteins were enzymatically digested into a large array of peptides, and the relative quantity of a total of 94,803 peptide peaks was compared between 31 colorectal cancer patients and 59 age/sex-matched healthy controls using 2D image-converted analysis of liquid chromatography and mass spectrometry. The selected biomarker candidates were validated in 345 subjects (115 colorectal cancer patients and 230 age/sex-matched healthy controls) using high-density reverse-phase protein microarrays. Plasma levels of Apo AI and C9 in colorectal cancer patients significantly differed from healthy controls with P values of 7.94×10(-4) and 1.43×10(-12) (Student's t-test), respectively. In particular, C9 was elevated in patients with colorectal cancer, including those with stage-I and -II diseases (P=3.01×10(-3) and P=1.13×10(-5) , respectively). Although the significance of the present study must be validated in an independent clinical study, the increment of plasma C9 may be applicable to the early detection of colorectal cancer.

BACKGROUND: Early detection is essential to improve the outcome of patients with pancreatic cancer. A noninvasive and cost-effective diagnostic test using plasma/serum biomarkers would facilitate the detection of pancreatic cancer at the early stage. METHODS: Using a novel combination of hollow fiber membrane-based low-molecular-weight protein enrichment and LC-MS-based quantitative shotgun proteomics, we compared the plasma proteome between 24 patients with pancreatic cancer and 21 healthy controls (training cohort). An identified biomarker candidate was then subjected to a large blinded independent validation (n = 237, validation cohort) using a high-density reverse-phase protein microarray. RESULTS: Among a total of 53,009 MS peaks, we identified a peptide derived from CXC chemokine ligand 7 (CXCL7) that was significantly reduced in pancreatic cancer patients, showing an area under curve (AUC) value of 0.84 and a P value of 0.00005 (Mann-Whitney U test). Reduction of the CXCL7 protein was consistently observed in pancreatic cancer patients including those with stage I and II disease in the validation cohort (P < 0.0001). The plasma level of CXCL7 was independent from that of CA19-9 (Pearson's r = 0.289), and combination with CXCL7 significantly improved the AUC value of CA19-9 to 0.961 (P = 0.002). CONCLUSIONS: We identified a significant decrease of the plasma CXCL7 level in patients with pancreatic cancer, and combination of CA19-9 with CXCL7 improved the discriminatory power of the former for pancreatic cancer. IMPACT: The present findings may provide a new diagnostic option for pancreatic cancer and facilitate early detection of the disease.

We report an extremely rare case of solitary liver metastasis from papillary thyroid carcinoma. A 56-year-old woman referred for a lung-cancer screening-detected liver tumor. Her medical history included right thyroid lobectomy for papillary carcinoma 18 years earlier and total thyroidectomy for adenoma-tous goiter 2 years thereafter. Blood tests showed markedly-elevated preoperative serum thyroglobulin. Computed tomography (CT) showed a lateral hepatic tumor with a central scar and capsule-like structure. Contrast medium enhanced the lesion in the early phase, with washout in the late phase. Magnetic resonance imaging (MRI) showed lesions in the left seventh rib and first lumbar vertebra in the same phase as the liver tumor. Whole-body bone scintigraphy showed increased tracer uptake in the sixth thoracic vertebra and seventh rib, yielding a diagnosis of solitary liver tumor with multiple bone metastases. The liver tumor was suspected of being hepatocellular carcinoma and liver metastases from thyroid cancer. The liver tumor was resected concomitant to lateral segmentectomy with rib biopsy. Histo-pathologically, both lesions were papillary thyroid carcinoma metastases. © 2011 The Japanese Society of Gastroenterological Surgery.

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients' prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.

CONTEXT: Although surgical resection is the only curative therapeutic option for recurrent or metachronous pancreatic carcinomas, most such cancers are beyond surgical curability. We herein report on two rare cases of remnant pancreatectomy used to treat recurrent or metachronous pancreatic carcinomas. CASE REPORTS: CASE#1 A 65-year-old male developed weight loss and diabetes mellitus 83 months after a pylorus-preserving pancreaticoduodenectomy followed by two years of adjuvant chemotherapy (5-fluorouracil plus leucovorin plus mitomycin C) for a pancreatic carcinoma in the head of the pancreas (stage IA). An abdominal CT scan revealed a 3 cm tumor in the remnant pancreas which appeared as a 'hot' nodule on FDG-PET. A remnant distal pancreatectomy was performed and a pancreatic carcinoma similar in profile to the primary lesion (stage IIB) was confirmed pathologically. CASE#2 A 67-year-old male showed increased CA 19-9 levels 25 months after a distal pancreatectomy for a pancreatic carcinoma in the body of the pancreas (stage IA). An abdominal CT scan revealed a cystic lesion in the cut end of the pancreas which appeared as a 'hot' nodule on FDG-PET. A remnant proximal pancreatectomy with duodenectomy was performed and a metachronous pancreatic carcinoma (stage III) was confirmed pathologically. CONCLUSION: Remnant pancreatectomy can be considered a treatment option for recurrent or metachronous pancreatic carcinomas. FDG-PET can play a key role in detecting remnant pancreatic carcinomas.

Gallbladder cancer (GBC) is a highly fatal malignancy in humans. Genetic alterations in KRAS or TP53 as well as overexpression of ERBB2 have been shown to contribute to the development of certain types of GBC. However, many cases of GBC do not harbor such genetic changes, with other transforming events awaiting discovery. We here tried to identify novel cancer-promoting genes in GBC, with the use of a retroviral cDNA expression library. A retroviral cDNA expression library was constructed from a surgically resected clinical specimen of GBC, and was used to infect 3T3 fibroblasts in a focus formation assay. cDNA incorporated into the transformed foci was rescued by PCR. One such cDNA was found to encode free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor for short-chain fatty acids. The oncogenic potential of FFAR2 was confirmed both in vitro with the focus formation assay and by evaluation of cell growth in soft agar as well as in vivo with a tumorigenicity assay in nude mice. The isolated FFAR2 cDNA had no sequence alterations, suggesting that upregulation of FFAR2 expression may contribute to malignant transformation. Indeed, all of quantitative RT-PCR, in situ hybridization, and immunohistochemical analyses showed that the amount of FFAR2 mRNA and its protein product was increased in digestive tract cancer specimens. Furthermore, short-chain fatty acids potentiated the mitogenic action of FFAR2 in 3T3 cells. Our data thus, for the first time, implicate FFAR2 in carcinogenesis of the digestive tract.

To identify novel cancer-promoting genes in biliary tract cancer (BTC), we constructed a retroviral cDNA expression library from a clinical specimen of BTC with anomalous pancreaticobiliary duct junction (APBDJ), and used the library for a focus formation assay with 3T3 fibroblasts. One of the cDNAs rescued from transformed foci was found to encode Indian hedgehog homolog (IHH). The oncogenic potential of IHH was confirmed both in vitro with the focus formation assay and in vivo with a tumorigenicity assay in nude mice. The isolated IHH cDNA had no sequence alterations, suggesting that upregulation of IHH expression may contribute to malignant transformation. Quantitation of IHH mRNA among clinical specimens has revealed that the expression level of IHH in BTC with APBDJ is higher than that in BTC without APBDJ and than in non-cancerous biliary tissues. Our data thus implicate a direct role of IHH in the carcinogenesis of BTC with APBDJ.

A 65-year-old man underwent a total gastrectomy and distal pancreatectomy for acinar cell carcinoma of the pancreas. Multiple metastatic liver lesions were found one year postoperatively. He was treated with S-1 chemotherapy over 34 months, and the tumors significantly reduced in size without severe side effects. Four years after surgery, the liver metastases increased in size, associated with pain especially in the right upper quadrant. We then performed right hepatectomy. Peritoneal dissemination and multiple lung metastases were found 8 months after liver resection. Acinar cell carcinoma of the pancreas is a rare and highly malignant tumor, and there are few reports regarding treatment with chemotherapy. Herein, we report a case with multiple liver metastases which were controlled by systemic chemotherapy using S-1.

Gastrectomy reduces food intake and body weight (BW) hampering recovery of physical conditions. It also reduces plasma levels of stomach-derived orexigenic ghrelin. This study explored changes in orexigenic ghrelin system in rats receiving total gastrectomy with Billroth II (B-II) or Roux-en-Y (R-Y) method. Feeding and BW were reduced by gastrectomy and subsequently recovered to a greater extent with R-Y than B-II while plasma ghrelin decreased similarly. At postoperative 12th week, ghrelin contents increased in the duodenum and pancreas, plasma ghrelin levels increased upon fasting, and ghrelin injection promoted feeding but not in earlier periods. In summary, gastrectomized rats partially recover feeding and BW, in a reconstruction-dependent manner. At 12th week, ghrelin is upregulated in extra-stomach tissues, plasma ghrelin levels are physiologically regulated, and orexigenic effect of exogenous ghrelin is restored. This time-related recovery of ghrelin system may provide a strategy for promoting feeding, BW, and thereby physical conditions in gastrectomized patients.

Plasma proteome analysis requires sufficient power to compare numerous samples and detect changes in protein modification, because the protein content of human samples varies significantly among individuals, and many plasma proteins undergo changes in the bloodstream. A label-free proteomics platform developed in our laboratory, termed "Two-Dimensional Image Converted Analysis of Liquid chromatography and mass spectrometry (2DICAL)," is capable of these tasks. Here, we describe successful detection of novel prolyl hydroxylation of alpha-fibrinogen using 2DICAL, based on comparison of plasma samples of 38 pancreatic cancer patients and 39 healthy subjects. Using a newly generated monoclonal antibody 11A5, we confirmed the increase in prolyl-hydroxylated alpha-fibrinogen plasma levels and identified prolyl 4-hydroxylase A1 as a key enzyme for the modification. Competitive enzyme-linked immunosorbent assay of 685 blood samples revealed dynamic changes in prolyl-hydroxylated alpha-fibrinogen plasma level depending on clinical status. Prolyl-hydroxylated alpha-fibrinogen is presumably controlled by multiple biological mechanisms, which remain to be clarified in future studies.

We reviewed the clinicopathological characteristics of 14 patients who underwent resection of basaloid squamous carcinoma (BSC) of the esophagus. The mean age was 65.3 years, and all patients were male. Seven patients had superficial BSCs and 7 had advanced BSCs. BSCs were associated with high rates of lymph node metastases and venous invasion. With regard to immunohistochemistry, the rate of cyclin D1 expression was higher (13/14), and the preservation rate of E-cadherin expression was lower (4/14), than that seen in ordinary esophageal squamous cell carcinoma. Squamous cell carcinoma components were most often found at sites of lymph node metastases, whereas basaloid components predominated at sites of hematogenous metastases in 4 patients, including lung, brain, and liver. Seven of the 9 patients with stage I or II disease are alive without recurrence. All patients with stage III or IV tumors developed recurrent disease. Primary tumors responded well in 3 patients who received preoperative chemotherapy (5-fluorouracil plus cisplatin) and/or radiotherapy, but further studies are needed to clarify the role of chemoradiotherapy. We believe that control of the hematogenous spread of basaloid components may lead to improved outcomes in patients with esophageal BSC.