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Background/Aims: Endoscopic papillectomy (EP) is increasingly used as an alternative to surgery for managing benign ampullary neoplasms. However, post-EP resection margins are often positive or indeterminate, and there is no consensus on the management of ampullary adenomas with positive or indeterminate margins after EP. This study was designed to compare the longterm outcomes between resected margin-negative (RMN) and resected margin-positive/indeterminate (RMPI) groups and to identify factors associated with clinical outcomes. Methods: This retrospective analysis included patients with ampullary adenoma without evidence of adenocarcinoma who underwent EP between 2004 and 2016. The RMN and RMPI groups were compared for recurrence rates and recurrence-free duration during a mean followup duration of 71.7±39.8 months. Factors related to clinical outcomes were identified using multivariate analysis. Results: Of the 129 patients who underwent EP, 82 were in the RMN group and 47 were in the RMPI group. The RMPI group exhibited a higher recurrence rate compared to the RMN group (14.6% vs 34.0%, p=0.019). However, the recurrence-free duration was not significantly different between the groups (34.7±32.6 months vs 36.2±27.4 months, p=0.900). Endoscopic treatment successfully managed recurrence in both groups (75% vs 75%). Submucosal injection was a significant risk factor for residual lesions (hazard ratio, 4.11; p=0.009) and recurrence (hazard ratio, 2.57; p=0.021). Conclusions: Although ampullary adenomas with positive or indeterminate margins after EP showed a higher rate of recurrence at long-term follow-up, endoscopic treatment was effective with favorable long-term outcomes. Submucosal injection prior to resection was associated with increased risk of recurrence and residual lesions. [ABSTRACT FROM AUTHOR]

Background/Aims: Although gastric neuroendocrine tumors (NETs) are uncommon neoplasms, their prevalence is increasing. The clinical importance of the World Health Organization (WHO) classification of gastric NETs, compared with NETs in other organs, has been underestimated. This study aimed to systematically evaluate the clinical and pathologic characteristics of gastric NETs based on the 2019 WHO classification and to assess the survival outcomes of patients from a single-center with a long-term follow-up. Methods: The medical records of 427 patients with gastric NETs who underwent endoscopic or surgical resection between January 2000 and March 2020 were retrospectively reviewed. All specimens were reclassified according to the 2019 WHO classification. The clinicopathologic characteristics, treatment, and oncologic outcomes of 139 gastric NETs were analyzed. Results: The patients’ median age was 53.0 years (interquartile range [IQR], 46.0 to 63.0 years). The median follow-up period was 36.0 months (IQR, 15.0 to 63.0 months). Of the patients, 92, 44, and 3 had grades 1, 2, and 3 NETs, respectively. The mean tumor size significantly increased as the tumor grade increased (p=0.025). Patients with grades 2 and 3 gastric NETs more frequently had lymphovascular invasion (29.8% vs 10.9%, p=0.005) and deeper tissue invasion (8.5% vs 0%, p=0.012) than those with grade 1 tumors. The overall disease-specific survival rate was 100%. Two patients with grades 2-3 gastric NETs experienced extragastric recurrence. Conclusions: Although gastric NETs have an excellent prognosis, grade 2 or grade 3 gastric NETs are associated with a larger size, deeper invasion, and extragastric recurrence, which require active treatment. [ABSTRACT FROM AUTHOR]

Purpose There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). Materials and Methods Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or postoperation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. Results Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, including ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. Conclusion Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of patients with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker. [ABSTRACT FROM AUTHOR]

Background: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. Methods: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. Results: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. Conclusion: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT. [ABSTRACT FROM AUTHOR]

The major challenges in pancreatic ductal adenocarcinoma (PDAC) management are local or distant metastasis and limited targeted therapeutics to prevent it. To identify a druggable target in tumor secretome and to explore its therapeutic intervention, we performed a liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based proteomic analysis of tumors obtained from a patient-derived xenograft model of PDAC. Galectin-3 binding protein (Gal-3BP) is identified as a highly secreted protein, and its overexpression is further validated in multiple PDAC tumors and primary cells. Knockdown and exogenous treatment of Gal-3BP showed that it is required for PDAC cell proliferation, migration, and invasion. Mechanistically, we revealed that Gal-3BP enhances galectin-3–mediated epidermal growth factor receptor signaling, leading to increased cMyc and epithelial-mesenchymal transition. To explore the clinical impact of these findings, two antibody clones were developed, and they profoundly abrogated the metastasis of PDAC cells in vivo. Altogether, our data demonstrate that Gal-3BP is an important therapeutic target in PDAC, and we propose its blockade by antibody as a therapeutic option for suppressing PDAC metastasis. [ABSTRACT FROM AUTHOR]

Purpose This study aimed to evaluate the real-world efficacy of immune checkpoint inhibitors (ICIs), and to identify clinicolaboratory factors to predict treatment outcomes in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving ICIs. Materials and Methods Sixty patients with metastatic or unresectable ESCC treated with nivolumab (n=48) or pembrolizumab (n=12) as ≥ second-line treatment between 2016 and 2019 at Asan Medical Center were included. Results The median age of the patients was 68 years (range, 52 to 76 years), and 93.3% were male. Most patients had metastatic disease (81.7%) and had been previously treated with fluoropyrimidines, platinum, and taxane. In 53 patients with measurable disease, the overall response rate and disease control rate were 15.1% and 35.8%, respectively. With a median follow-up duration of 16.0 months, the median progression-free survival (PFS) and overall survival (OS) were 1.9 months (95% confidence interval [CI], 1.54 to 2.19) and 6.4 months (95% CI, 4.77 to 8.11), respectively. After multivariate analysis, recent use of antibiotics, low prognostic nutrition index (< 35.93), high Glasgow Prognosis Score (≥ 1) at baseline, and ≥ 1.4-fold increase in neutrophil-to-lymphocyte ratio after one cycle from baseline were significantly unfavorable factors for both PFS and OS. Younger age (< 65 years) was a significant factor for unfavorable PFS and hyponatremia (< 135 mmol/L) for unfavorable OS. Conclusion The use of ICIs after the failure of chemotherapy showed comparable efficacy in patients with advanced ESCC in real practice; this may be associated with host immune-nutritional status, which could be predicted by clinical and routine laboratory factors. [ABSTRACT FROM AUTHOR]

Purpose The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. Materials and Methods A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. Results The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. Conclusion The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin. [ABSTRACT FROM AUTHOR]

Purpose The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated. Materials and Methods In this prospective cohort study, programmed death ligand-1 (PD-L1)--positive BTC patients who progressed on first-line gemcitabine plus cisplatin were enrolled. Pembrolizumab 200 mg was administered intravenously every 3 weeks. Results Between May 2018 and February 2019, 40 patients were enrolled. Pembrolizumab was given as second-line (47.5%) or ≤ third-line therapy (52.5%). The objective response rate was 10% and 12.5% by Response Evaluation Criteria in Solid Tumor (RECIST) v1.1 and immune-modified RECIST (imRECIST) and median duration of response was 6.3 months. Among patients with progressive disease as best response, one patient (1/20, 5.0%) achieved complete response subsequently. The median progression-free survival (PFS) and overall survival (OS) were 1.5 months (95% confidence interval [CI], 0.0 to 3.0) and 4.3 months (95% CI, 3.5 to 5.1), respectively, and objective response per imRECIST was significantly associated with PFS (p < 0.001) and OS (p=0.001). Tumor proportion score ≥ 50% was significantly associated with higher response rates including the response after pseudoprogression (vs. < 50%; 37.5% vs. 6.5%; p=0.049). Conclusion Pembrolizumab showed modest anti-tumor activity in heavily pretreated PD-L1--positive BTC patients. In patients who showed objective response, durable response could be achieved. [ABSTRACT FROM AUTHOR]

Purpose The 8th edition of gallbladder cancer staging in the American Joint Committee on Cancer (AJCC) staging system changed the T and N categories. Materials and Methods In order to validate the new staging system, a total of 348 surgically resected gallbladder cancers were grouped based on the 8th edition of the T and N categories and compared with patients' survival. Results Significant differences were noted between T1b-T2a (p=0.003) and T2b-T3 (p < 0.001) tumors, but not between Tis-T1a, T1a-T1b, and T2a-T2b tumors. However, significant survival differences were observed both by the overall and pair-wise (T1-T2, T2-T3) comparisons (all, p < 0.001) without dividing T1/T2 subcategories. When cases with ≥ 6 examined lymph nodes were evaluated, significant survival differences were observed among the entire comparison (p < 0.001) and pair-wise comparisons of N0-N1 (p=0.001) and N1-N2 (p=0.039) lesions. When cases without nodal dissection (NX) were additionally compared, significant survival differences were observed between patients with N0-NX (p=0.001) and NX-N1 (p < 0.001) lesions. Conclusion The T category in the 8th edition of the AJCC staging system did not completely stratify the prognosis of patients with gallbladder cancer. Modification by eliminating T subcategories can better stratify the prognosis. In contrast, the N category clearly determines patients' survival with ≥ 6 examined lymph nodes. The survival time in patients of gallbladder cancers without nodal dissection is between N0 and N1 cases. Therefore, close postoperative followed up is recommended for those patients. [ABSTRACT FROM AUTHOR]

Background/Aims: Type 2 autoimmune pancreatitis (AIP) has been considered extremely rare in East Asia. This study aimed to clarify the prevalence, clinical characteristics and radiological findings of type 2 AIP highlighting patients presenting as acute pancreatitis in a single center. Methods: Type 2 AIP patients were classified according to International Consensus Diagnostic Criteria. Radiological findings were compared between type 2 AIP presenting as acute pancreatitis and gallstone pancreatitis. Results: Among 244 patients with AIP, 27 (11.1%) had type 2 AIP (definite, 15 [55.5%] and probable 12 [44.5%]). The median age of patients with type 2 AIP was 29 years (interquartile range, 20 to 39 years). Acute pancreatitis was the most common initial presentation (n=17, 63%) while obstructive jaundice was present in only one patient. Ulcerative colitis (UC) was associated with type 2 AIP in 44.4% (12/27) of patients. Radiological pancreatic imaging such as delayed enhancement of diffusely enlarged pancreas, homogeneous enhancement of focal enlargement/ mass, absent/minimal peripancreatic fat infiltration or fluid collection, and multifocal main pancreatic duct narrowings were helpful for differentiating type 2 AIP from gallstone pancreatitis. During follow-up (median, 32.3 months), two patients (2/25, 8%) experienced relapse. Conclusions: In South Korea, type 2 AIP is not as rare as previously thought. Overall, the clinical profile of type 2 AIP was similar to that of Western countries. Type 2 AIP should be considered in young UC patients with acute pancreatitis of uncertain etiology. [ABSTRACT FROM AUTHOR]

Purpose T category of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for distal bile duct carcinoma (DBDC) was changed to include tumor invasion depth measurement, while the N category adopted a 3-tier classification system based on the number of metastatic nodes. Materials and Methods To validate cancer staging, a total of 200 surgically resected DBDCs were staged and compared according to the seventh and eighth editions. Results T categories included T1 (n=37, 18.5%), T2 (n=114, 57.0%), and T3 (n=49, 24.5%). N categories included N0 (n=133, 66.5%), N1 (n=50, 25.0%), and N2 (n=17, 8.5%). Stage groupings included I (n=33, 16.5%), II (n=150, 75.0%), and III (n=17, 8.5%). The overall 5-year survival rates (5-YSRs) of T1, T2, and T3 were 59.3%, 42.4%, and 12.2%, respectively. T category could discriminate patient survival by both pairwise (T1 and T2, p=0.011,T2 and T3, p < 0.001) and overall (p < 0.001) comparisons. The overall 5-YSRs of N0, N1, and N2 were 47.3%, 17.0%, and 14.7%, respectively. N category could partly discriminate patient survival by both pairwise (N0 and N1, p < 0.001,N1 and N2, p=0.579) and overall (p < 0.001) comparisons. The overall 5-YSRs of stages I, II, and III were 59.0%, 35.4%, and 14.7%, respectively. Stages could distinguish patient survival by both pairwise (I and II, p=0.002,II and III, p=0.015) and overall (p < 0.001) comparisons. On multivariate analyses, T and N categories (p=0.014 and p=0.029) and pancreatic invasion (p=0.006) remained significant prognostic factors. Conclusion The T and N categories of the eighth edition AJCC staging system for DBDC accurately predict patient prognosis. [ABSTRACT FROM AUTHOR]

Purpose Pancreatic cancer associated double primary tumors are rare and their clinicopathologic characteristics are not well elucidated. Materials and Methods Clinicopathologic factors of 1,352 primary pancreatic cancers with or without associated double primary tumors were evaluated. Results Of resected primary pancreatic cancers, 113 (8.4%) had associated double primary tumors, including 26 stomach, 25 colorectal, 18 lung, and 13 thyroid cancers. The median interval between the diagnoses of pancreatic cancer and associated double primary tumors was 0.5 months. Overall survival (OS) of pancreatic cancer patients with associated double primary tumors was longer than those with pancreatic cancer only (median, 23.1 months vs. 17.0 months; p=0.002). Patients whose pancreatic cancers were resected before the diagnosis of metachronous tumors had a better OS than patients whose pancreatic cancer resected after the diagnosis of metachronous tumors (48.9 months and 13.5 months, p=0.001) or those whose pancreatic cancers were resected synchronously with non-pancreas tumors (19.1 months, p=0.043). The OS of pancreatic cancer patients with stomach (33.9 months, p=0.032) and thyroid (117.8 months, p=0.049) cancers was significantly better than those with pancreas cancer only (17.0 months). Conclusion About 8% of resected pancreatic cancers had associated double primary tumors, and those from the colorectum, stomach, lung, and thyroid were common. Patients whose pancreatic cancer was resected before the diagnosis of metachronous tumors had better OS than those resected after the diagnosis of metachronous tumors or those resected synchronously. [ABSTRACT FROM AUTHOR]

Background/Aims α-Synucleinopathy in the brain is the neuropathological hallmark of Parkinson's disease (PD). However, the functional impact of α-synucleinopathy in the enteric nervous system remains unknown. We aim to evaluate the association between gastrointestinal (GI) dysfunction and α-synuclein (αSYN) pathology in the stomach and colon of PD patients and controls, as well as to investigate the association between the αSYN pathology in GI tract and future PD risk. Methods A total of 35 PD patients and 52 neurologically intact subjects were enrolled in this study. Endoscopic biopsies were performed, and then immunohistochemical staining for αSYN was performed. All subjects completed the validated Rome III questionnaire for the assessment of GI symptoms. The association between GI symptoms and the αSYN pathology in GI mucosa was evaluated. Incident PD cases were assessed during a median follow-up of 46 months. Results The proportion of self-reported constipation and functional constipation through the Rome III questionnaire was significantly higher in PD patients than in controls (P < 0.001 and P = 0.015). However, no significant association was found between the αSYN pathology in the stomach and colon mucosa and constipation, as well as other GI symptoms including dyspepsia symptoms and abdominal discomfort or pain, regardless of the presence or absence of clinical PD (P > 0.05). No incident PD cases were diagnosed during study period. Conclusions Our present study suggests that the deposition of αSYN in the mucosal enteric nervous system may not be reflected by functional impairment of the affected segment of the gut. [ABSTRACT FROM AUTHOR]

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between CT imaging findings and DPC4 gene expression and to determine the prognostic value of DPC4 gene expression to predict overall survival in patients with pancreatic ductal adenocarcinoma. Methods: Between January and December 2011, we retrospectively analyzed 163 pancreatic ductal adenocarcinomas in 163 patients who had undergone surgical resection (mean age = 61.8 years; range = 35–81 years). We divided the study patients into two groups according to DPC4 gene expression: DPC4-expression or DPC4-non-expression group. The CT findings were analyzed by two reviewers. The associations between the CT imaging findings and DPC4 gene expression were evaluated using univariate analysis and multivariate logistic regression analysis. Overall survival was compared according to the DPC4 gene expression (DPC4-expression vs DPC4-non-expression) using Kaplan–Meier analysis and log-rank testing. To avoid bias, subgroup analyses of CT findings in T3 tumour and overall survival in patients with T3 tumour and R0 resection were performed. Results: Between DPC4-expression group (n = 75) and DPC4-non-expression group (n = 88), three CT findings (i.e., tumour margin, peripancreatic infiltration, and the presence of background intraductal pancreatic mucinous neoplasm) were significantly different in univariate analysis. Of these, a well-defined tumour margin was significantly associated with DPC4-expression tumour (adjusted odds ratio = 2.06; p = 0.032) in multivariate analysis. Of the total 163 patients, the mean overall survival of the DPC4-expression group was significantly longer than that of the DPC4-non-expression group (30.0 vs 22.0 months; p = 0.049). Of the 150 T3 tumours, the presence of well-defined tumour margins was also a significant CT finding (adjusted odd ratio = 2.00; p = 0.044) in multivariate analysis. However, of 131 patients with T3 tumour and R0 resection, the overall survival period of the DPC4-expression group was not significantly different from that of the DPC4-non-expression group (24.0 vs 22.0 months; p = 0.240). Conclusion: The presence of well-defined tumour margins on CT was significantly linked with DPC4-expression tumour. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinomas are among the most malignant neoplasms and have very poor prognosis. Our understanding of various cancers has recently improved the survival of patients with cancer, except for pancreatic cancers. Establishment of primary cancer cell lines of pancreatic ductal adenocarcinomas will be useful for understanding the molecular mechanisms of this disease. Methods: Eighty-one surgically resected pancreatic ductal adenocarcinomas were collected. Six novel pancreatic cancer cell lines, AMCPAC01-06, were established and histogenetic characteristics were compared with their matched tissues. The clinicopathologic and molecular characteristics of the cell lines were investigated by KRAS and TP53 sequencing or SMAD4 and p53 immunohistochemistry. Xenografts using AMCPAC cell lines were established. Results: From the 81 pancreatic ductal adenocarcinomas, six (7.4% success rate) patient-derived primary cell lines were established. The six AMCPAC cell lines showed various morphologies and exhibited a wide range of doubling times. AMCPAC cell lines contained mutant KRAS in codons 12, 13, or 61 and TP53 in exon 5 as well as showed aberrant p53 (5 overexpression and 1 total loss) or DPC4 (all 6 intact) expression. AMCPAC cell lines demonstrated homology for the KRAS mutation and p53 expression compared with matched primary cancer tissues, but showed heterogeneous DPC4 expression patterns. Conclusions: The novel AMCPAC01-06 cell lines established in this study may contribute to the understanding of pancreatic ductal adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background: Acinar cell carcinoma represents only 1-2% of exocrine pancreatic neoplasms. On exceptionally rare occasions, primary acinar cell carcinoma can occur in ectopic locations. Herein, we report a case of pure pancreatic-type acinar cell carcinoma arising in the stomach. Case presentation: A 54-year-old male presented with a gastric submucosal mass detected by endoscopic examination. Laparoscopic wedge resection was performed. Macroscopically, the 2.7 cm yellowish mass was located in the submucosa of the stomach. Microscopically, the tumor was well circumscribed and had a homogeneous acinar architecture. The tumor cells were small and had a minimal amount of cytoplasm. The nuclei of the tumor cells were round to oval with finely dispersed chromatin. The tumor cells were strongly positive for α1-antitrypsin, chymotrypsin, and α1-antichymotrypsin immunostaining, consistent with pancreatic exocrine differentiation. There was no clinical or radiologic evidence of primary pancreatic or head and neck tumors. After surgical resection of the tumor, there was no recurrence or metastasis during 33 months follow-up. Conclusion: In this report, we have presented a rare case of primary pure pancreatic-type acinar cell carcinoma arising in the stomach and suggest that it could be helpful if the pathologist were aware that pancreatic-type acinar cell carcinoma could arise in the stomach as a polypoid submucosal tumor in the routine diagnostic field of gastric endoscopy. [ABSTRACT FROM AUTHOR]

Purpose: Although the mutation status of KRAS is highly concordant in primary and metastatic lesions, it has not been generalized to other major pathway genes. Materials and Methods: In this study, 41 genes were evaluated and the mutational profiles were compared in 46 colorectal cancer patients with paired surgical specimens of primary and metastatic lesions: synchronous (n=27) and metachronous (n=19) lesions. A high-throughput mass spectrometry- based genotyping platform validated by orthogonal chemistry, OncoMap v.4.4, was used to evaluate the formalin-fixed, paraffin-embedded surgical specimens. The patients' demographics, tumor characteristics, and microsatellite instability status were analyzed by a retrospective chart review. Results: In this study, with OncoMap, mutations were identified in 80.4% of patients with the following frequency: KRAS (39.1%), TP53 (28.3%), APC (28.3%), PIK3CA (6.5%), BRAF (6.5%), and NRAS (4.3%). Although 19.6% (9/46) of the patients showed no gene mutations, 43.5% (20/46) and 37.0% (17/46) had mutations in one and two or more genes, respectively. The synchronous and metachronous lesions showed similar mutational profiles. Paired samples between primary and metastatic tumors differed in 7.4% (2/27) and 10.5% (2/19) for synchronous and metachronous according to OncoMap. Conclusion: These findings indicate the major pathway genes, including KRAS, TP53, APC, PIK3CA, BRAF, and NRAS, are often concordant between the primary and metastatic lesions regardless of the temporal relationship of metastasis. [ABSTRACT FROM AUTHOR]

Background: This study analyzes the clinicopathologic and radiologic characteristics of malignant serous cystic neoplasm (SCN) of the pancreas through systematic review and an institutional case report. Methods: A comprehensive literature search was performed in the MEDLINE database to identify studies on malignant SCNs of the pancreas that had detailed clinicopathologic and radiologic information. A computerized systematic search of our institutional database was also performed to identify cases of malignant SCN for addition to the systematic review. Using the final included cases, we analyzed the clinicopathologic and radiologic features of malignant SCNs of the pancreas. Results: A review of 136 candidate articles identified 26 studies with 26 cases that had detailed clinical information. Our institutional data search added one case. The systematic review of the 27 cases revealed that primary tumors (mean diameter 10.2 ± 4.0 cm) mainly involved the body and tail of the pancreas (n = 16) and frequently invaded adjacent organs (n = 19). Distant metastases occurred in 14 patients (synchronous, n = 5; metachronous, n = 8; both, n = 1), most commonly in the liver (n = 13). Imaging features of malignant SCNs of the pancreas were identical to the benign counterpart, except local invasion or distant metastases. The prognosis was excellent in that 17 were alive at the time of writing with a median follow-up period of 2 years. Conclusions: The malignant potential of SCNs of the pancreas should be considered in the diagnosis and management of patients with pancreatic SCNs. [ABSTRACT FROM AUTHOR]

As mast cells have been highlighted in the pathogenesis of diarrhea-predominant irritable bowel syndrome, a new term "mastocytic enterocolitis" was suggested by Jakate and colleagues to describe an increase in mucosal mast cells in patients with chronic intractable diarrhea and favorable response to treatment with antihistamines. Although it is not an established disease entity, two cases have been reported in the English medical literature. Here, for the first time in Asia, we report another case of chronic intractable diarrhea caused by gastrointestinal mastocytosis. The patient was a 70-year-old male with chronic intractable diarrhea for 3 months; the cause of the diarrhea remained obscure even after exhaustive evaluation. However, biopsy specimens from the jejunum were found to have increased mast cell infiltration, and the patient was successfully treated with antihistamines. [ABSTRACT FROM AUTHOR]

Background Vascular endothelial growth factor (VEGF) is a critical pro-angiogenic factor, found in a number of cancers, and a target of therapy. It is typically assessed by immunohistochemistry (IHC) in clinical research. However, IHC is not a quantitative assay and is rarely reproducible. We compared VEGF levels in colon cancer by IHC and a quantitative immunoassay on proteins isolated from formalin fixed, paraffin embedded tissues. Results VEGF expression was studied by means of a well-based reverse phase protein array (RPPA) and immunohistochemistry in 69 colon cancer cases, and compared with various clinicopathologic factors. Protein lysates derived from formalin fixed, paraffin embedded tissue contained measurable immunoreactive VEGF molecules. The VEGF expression level of well differentiated colon cancer was significantly higher than those with moderately and poorly differentiated carcinomas by immunohistochemistry (P = 0.04) and well-based RPPA (P = 0.04). VEGF quantification by well-based RPPA also demonstrated an association with nodal metastasis status (P = 0.05). In addition, the normalized VEGF value by well-based RPPA correlated (r = 0.283, P = 0.018). Furthermore, subgroup analysis by histologic type revealed that adenocarcinoma cases showed significant correlation (r = 0.315, P = 0.031) between well-based RPPA and IHC. Conclusions The well-based RPPA method is a high throughput and sensitive approach, is an excellent tool for quantification of marker proteins. Notably, this method may be helpful for more objective evaluation of protein expression in cancer patients. [ABSTRACT FROM AUTHOR]

Aims Due to the rarity of small intestine adenocarcinoma (SIAC), estimating the prognosis for patients with surgically resected SIAC is difficult. Overexpression of S100A4 has been linked to worse patient survival in several malignant neoplasms, but its significance in SIAC has not been determined. Methods S100A4 protein expression was assessed in 197 surgically resected SIAC cases and compared with clinicopathological factors, including patient survival. Results A progressive increase in S100A4 labelling was observed in normal intestinal epithelium, adenoma and adenocarcinoma (p<0.001), and 50 SIAC cases (26.2%) showed strong S100A4 expression. Patients with SIAC with strong S100A4 expression had a higher pT classification ( p=0.05), as well as increased lymph node metastasis (p=0.009) and perineural invasion (p=0.002). Patients with SIAC with strong S100A4 expression had significantly worse survival (median survival, 21 months) than those with weak/no S100A4 expression (42.5 months) by univariable ( p=0.04) and multivariable ( p=0.01) analyses. Conclusions S100A4 overexpression is observed in a subset of SIACs, is associated with advanced disease and can be used as a prognostic indicator of poor prognosis in patients with SIAC. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association of microsatellite instability (MSI) with clinicopathologic features and oncologic outcomes in patients with poorly differentiated colorectal cancer (PD). Methods: Study patients were divided into well-differentiated colorectal cancer (WD) and PD, which were compared according to histologic differentiation and MSI status. Results: Among 1,941 patients, PD was more frequent among microsatellite-unstable tumors (23.6%) than among microsatellite-stable (MSS) tumors (4.2%, P < .001). Patients with PD had worse 4-year overall survival rates than patients with WD (78.6% vs 88.2%, P = 0.010). Compared with MSS-PD tumors, MSI-PD tumors were characterized by right-colon predilection, larger size, and infrequent lymph node metastasis (P < .001 to P = .007). Conclusions: The clinicopathologic characteristics of PD were closely associated with those of MSI. The outcomes of MSI-PD tumors were better than those of MSS-PD tumors, but this finding did not reach statistical significance. [ABSTRACT FROM AUTHOR]

Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and β-catenin, we performed immunohistochemistry for E-cadherin and β-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant β-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant β-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant β-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant β-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC. [ABSTRACT FROM AUTHOR]

Background: Small intestinal adenocarcinomas (SACs) are rare malignancies of the alimentary tract with uncertain carcinogenesis. Methods: We investigated the expression of deleted in pancreatic cancer 4 (DPC4) in 188 cases of surgically resected SACs, using tissue microarray technology. Results: Twenty-four of the 188 tumors showed complete loss of Smad4/DPC4 expression in cytoplasm (score, 0; 12.8%). Eighty-four and 31 cases were moderately and strongly positive, respectively (score, 2 and 3; 44.7% and 16.5%, respectively) and 49 cases were focally or weakly stained (score, 1; 29.1%). Immunohistochemistry analysis showed that the expression of Smad4/DPC4 was related to an increased risk of lymphatic invasion but not to other clinicopathological features of the tumors (tumor location, differentiation, growth pattern, T stage, direct invasion, vascular invasion, and nodal metastasis). There was no significant association between Smad4/DPC4 expression and patient survival. Conclusions: The present research is the first study to evaluate Smad4/DPC4 expression in a large sample of SACs with clinicopathologic correlation. Future studies should focus on the immunohistochemical and molecular characteristics of SACs to clarify their tumorigenesis. [ABSTRACT FROM AUTHOR]

Purpose: Cancer associated stromal fibroblasts (CAFs) undergo transcriptional and phenotypic changes that contribute to tumor progression, but the mechanisms responsible for these changes are not well understood. Aberrant DNA methylation is an important cause of transcriptional alterations in cancer cells but it is not known how important DNA methylation alterations are to CAF behavior. Experimental Design: We used Affymetrix exon arrays to compare genes induced by the DNA methylation inhibitor 5-azadC in cultured pancreatic cancer associated fibroblasts, pancreatic control fibroblasts and pancreatic cancer cell lines. Results: We found that pancreatic CAFs and control pancreatic fibroblasts were less responsive to 5-aza-dC-mediated gene reactivation than pancreatic cancer cells (mean+/-SD of genes induced ≥5-fold was 9±10 genes in 10 pancreatic CAF cultures, 17±14 genes in 3 control pancreatic fibroblast cultures, and 134±85 genes in 4 pancreatic cancer cell lines). We examined differentially expressed genes between CAFs and control fibroblasts for candidate methylated genes and identified the disintegrin and metalloprotease, ADAM12 as hypomethylated and overexpressed in pancreatic CAF lines and overexpressed in fibroblasts adjacent to primary pancreatic adenocarcinomas. Conclusions: Compared to pancreatic cancer cells, few genes are reactivated by DNMT1 inhibition in pancreatic CAFs suggesting these cells do not harbor many functionally important alterations in DNA methylation. CAFs may also not be very responsive to therapeutic targeting with DNA methylation inhibitors. [ABSTRACT FROM AUTHOR]

Background: The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries. Objectives: To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth. Design, Setting, and Patients: From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review. Main Outcome Measures: Tumor depth and overall survival. Results: Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P>.05 for all). Median survival was associated with the invasion depth of the tumor (⩾5 mm vs <5 mm): 18 months vs 30 months (P=.01). On multivariate analysis, tumor depth remained predictive of disease-specific death (hazard ratio,1.70; P=.03). Conclusions: The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome. [ABSTRACT FROM AUTHOR]

Abstract  Intraductal papillary neoplasm of bile duct (IPNB) is one of the precursor lesions of cholangiocarcinoma. Although hepatolithiasis has been extensively studied in its association with IPNBs, there had been no comprehensive study of IPNBs with Clonorchis sinensis infection. Twelve IPNBs were selected from 20 surgically resected cholangiocarcinomas, positive for C. sinensis tests (60%) and compared with eight IPNBs, selected from 51 resected cholangiocarcinomas, negative for C. sinensis tests (16%), by histologic and immunohistochemical studies of mucin core proteins and cytokeratin panels. The predominant immuno-phenotype of IPNB cases with Clonorchiasis was pancreatobiliary type (MUC1+/MUC2-/CDX2-; 9/12 cases), while that of IPNB cases with negative for C. sinensis was intestinal type (MUC1-/MUC2+/CDX2+; 6/8; p = 0.04). The prevalence of IPNBs was higher when patients with cholangiocarcinoma had Clonorchiasis. IPNBs with Clonorchiasis tended to have a more pancreatobiliary phenotype, which suggests IPNBs with Clonorchiasis may have a different tumorigenesis pathway from IPNBs with other etiologies. [ABSTRACT FROM AUTHOR]