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Aims Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a recently recognized pancreatic tumor entity. Here we aimed to determine the most important features with a systematic review coupled with an integrated statistical approach. Methods and results PubMed, SCOPUS, and Embase were searched for studies reporting data on pancreatic ITPN. The clinicopathological, immunohistochemical, and molecular data were summarized. Then a comprehensive survival analysis and a comparative analysis of the molecular alterations of ITPN with those of pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) from reference cohorts (including the International Cancer Genome Consortium- ICGC dataset and The Cancer Genome Atlas, TCGA program) were conducted. The core findings of 128 patients were as follows: (i) Clinicopathological parameters: pancreatic head is the most common site; presence of an associated adenocarcinoma was reported in 60% of cases, but with rare nodal metastasis. (ii) Immunohistochemistry: MUC1 (>90%) and MUC6 (70%) were the most frequently expressed mucins. ITPN lacked the intestinal marker MUC2; unlike IPMN, it did not express MUC5AC. (iii) Molecular landscape: Compared with PDAC/IPMN, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, GNAS, and RNF43 were less altered in ITPN (P < 0.001), whereas MCL amplifications, FGFR2 fusions, and PI3KCA mutations were commonly altered (P < 0.001). (iv) Survival analysis: ITPN with a "pure" branch duct involvement showed the lowest risk of recurrence. Conclusion ITPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for the enrichment of potential targets for precision oncology.

The phosphorous balance is clinically important in increasing the long-term outcomes and preventing complications of end-stage renal disease. Sevelamer is a phosphate binder used widely to regulate hyperphosphatemia. On the other hand, gastrointestinal side effects increase with increasing sevelamer intake. A 29-year-old male with end-stage renal disease of IgA nephropathy on maintenance hemodialysis was admitted for diffuse alveolar bleeding and pneumonia. He presented with a low-grade fever and watery diarrhea tinged with blood. Initially, a Clostridioides difficile-associated diarrhea treatment was started with positive findings of Clostridioides difficile toxin and culture. Despite this, there was no improvement in the symptoms even with the appropriate antibiotic treatment. Computed tomography of the abdomen and pelvis revealed an occlusive mass in the rectum and secondary obstructive changes in the sigmoid colon. The initial suspicion was a malignancy or fungal infection. Sigmoidoscopy with a biopsy identified the mass as a lump of mucous material with the entire lumen covered with exudate. The subsequent histopathology examination revealed a colonic mucosal injury and characteristic ''fish scale"-like sevelamer crystals in the exudate. The diagnosis of a sevelamer-induced rectal ulcer was made. We report this case of a sevelamer-associated rectal ulcer of the sigmoid.

Epigenetic alterations are increasingly recognized as important contributors to the development and progression of pancreatic ductal adenocarcinoma. 5-hydroxymethylcytosine (5hmC) is an epigenetic DNA mark generated through the ten-eleven translocation (TET) enzyme-mediated pathway and is closely linked to gene activation. However, the timing of alterations in epigenetic regulation in the progression of pancreatic neoplasia is not well understood. In this study, we hypothesized that aberrant expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) and subsequent global 5hmC alteration are linked to early tumorigenesis in the pancreas. Therefore, we evaluated alterations of 5hmC and TET1 levels using immunohistochemistry in pancreatic neoplasms (n = 380) and normal ducts (n = 118). The study cohort included representation of the full spectrum of precancerous lesions from low- and high-grade pancreatic intraepithelial neoplasia (n = 95), intraductal papillary mucinous neoplasms (all subtypes, n = 129), intraductal oncocytic papillary neoplasms (n = 12), and mucinous cystic neoplasms (n = 144). 5hmC and TET1 were significantly downregulated in all types of precancerous lesion and associated invasive pancreatic ductal adenocarcinomas compared with normal ductal epithelium (all p < 0.001), and expression of 5hmC positively correlated with expression of TET1. Importantly, downregulation of both 5hmC and TET1 was observed in most low-grade precancerous lesions. There were no clear associations between 5hmC levels and clinicopathological factors, thereby suggesting a common epigenetic abnormality across precancerous lesions. We conclude that downregulation of 5hmC and TET1 is an early event in pancreatic tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Owing to an increased number of colonoscopy screenings, the incidence of diagnosed rectal neuroendocrine tumors (NETs) has also increased. Tumor size is one of the most frequently regarded factors when selecting treatment; however, it may not be the determinant prognostic variable. We aimed to evaluate oncological outcomes according to the treatment modality based on the size of rectal NETs. A retrospective analysis was performed on patients who were treated for rectal NETs between March 2000 and January 2016 at the Asan Medical Center, Seoul, Korea. Patients who underwent endoscopic removal, local surgical excision, and radical resection were included. The primary outcome was recurrence-free survival (RFS). Data were specified and analyzed following the 2019 World Health Organization classification (WHO). A total of 644 patients were categorized under three groups according to the treatment modality used: endoscopic removal (n = 567), surgical local excision (n = 56), and radical resection (n = 21). Of a total of 35 recurrences, 27 were local, whereas eight were distant. The RFS rate did not differ significantly between the treatment groups in the same tumor-size group ( $$\le$$ 1 cm group: P = .636, 1–2 cm group: P = .160). For T1 tumors, RFS rate was not different between local excision and radical resection ( $$\le$$ 1 cm group: P = .452, 1–2 cm group: P = .700). Depth of invasion, a high Ki-67 index, and margin involvement were confirmed as independent risk factors for recurrence. Among patients treated with endoscopic removal, endoscopic biopsy was a significant factor for worse RFS (P

Indocyanine green (ICG) has been used in clinical practice for more than 40 years and its safety and preferential accumulation of ICG in tumors has been reported for various tumor types, including colon cancer. However, reports on the clinical assessments of ICG-based molecular endoscopy imaging for pre-cancerous lesions are scarce. Therefore, we determined the percent visualization ability of ICG endoscopy in colitis-associated colon cancer using 30 lesions from an animal model and 16 patient tissues. ICG could detect 100% of carcinoma, 90% adenoma, and 57.1% dysplasia, with little background signal at 30 min after injection via real-time fluorescence endoscopy. Correlation analysis of ICG fluorescence intensity and cancer specific molecules revealed a positive correlation of ICG with c-Met and iNOS (r > 0.5). A high level of iNOS expression increased the cellular nitric oxide in cancer cells than that in normal cells, which was related to the inhibition of drug efflux via ABCB1 transporter down regulation resulted to delayed retention of intracellular ICG. These findings highlight the feasibility of ICG as a detector of pre-cancerous lesions in real-time fluorescence endoscopy and suggest that the mechanism of ICG retention in cancer cells is related with intracellular nitric oxide concentration.

Context.— Although several neuroendocrine cell types constitute gastroenteropancreatic neuroendocrine tumors (NETs), the clinical and prognostic implications of the expression of multiple peptide hormones have not been comprehensively evaluated in rectal NETs. Objective.— To identify the clinicopathologic characteristics and prognostic impact of peptide hormone expression. Design.— We evaluated the expression of peptide YY (PYY), glucagon, somatostatin, serotonin, insulin, and gastrin using immunolabeling in 446 endoscopically or surgically resected rectal NETs. Results.— PYY, glucagon, serotonin, somatostatin, insulin, and gastrin were expressed in 261 of 389 (67.1%), 205 of 446 (46.0%), 36 of 446 (8.1%), 33 of 446 (7.4%), 2 of 446 (0.4%), and 1 of 446 cases (0.2%), respectively. Immunoreactivity to any peptide hormone was present in 345 of 446 cases (77.4%). Tumors expressing serotonin or somatostatin were associated with lymphovascular invasion, chromogranin A expression, and shorter disease-free survival (DFS). Rectal NETs were classified as L-cell, enterochromaffin-cell, D-cell, null-expression, or mixed-expression type based on peptide hormonal expression status. Patients with D-cell NET had the shortest DFS (10-year DFS, 54.5%), followed by those with enterochromaffin-cell NET (89.5%), null expression (97.0%), L-cell NET (99.6%), and mixed-expression NET (100%; P < .001). Multivariable analyses revealed that somatostatin expression was an independent indicator of poor prognosis with respect to DFS in rectal NETs (P = .001). Conclusions.— Somatostatin expression is a poor prognostic indicator in patients with rectal NETs. Therefore, additional peptide hormonal immunolabeling, including somatostatin, serotonin, and PYY, in rectal NETs can provide more information regarding DFS.

Extranodal extension (ENE) is an established prognostic factor in several gastrointestinal cancers. However, the prognostic impact remains unclear. Here, we investigated the prognostic implications of ENE in patients with surgically resected pancreatic cancer.We retrospectively reviewed 476 surgically resected pancreatic head cancer patients who consecutively underwent upfront pancreaticoduodenectomy for pathologically confirmed pancreatic ductal adenocarcinoma between January 2009 and December 2013. We compared the disease-free survival (DFS) rates of the patients according to ENE status.Among the 476 patients, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; LN+/ENE-, 7 months; LN+/ENE+, 6 months; P .001). In addition, even in the same N stage, patients with ENE had lower DFS rates than those without ENE (N0, 13 months; N1/ENE- 8 months; N1/ENE+, 7 months; N2/ENE-, 7 months; N2/ENE+, 4 months, P .001). However, there was no significant difference in survival rates between patients in the N1/ENE+ group and those in the N2/ENE- group. Additionally, ENE was an independent prognostic factor for pancreatic cancer.Extranodal extension significantly predicted a poor prognosis among patients with pancreatic head cancer, especially those with nodal metastasis. Therefore, ENE should be considered a prognostic factor in future editions of the staging system.

Epithelioid hemangioendothelioma (EHE) is a rare borderline vascular tumor. Due to its rarity and protean behavior, the optimal treatment of hepatic EHE has not yet been standardized. This single-center study describes outcomes in patients with hepatic EHE who underwent living donor liver transplantation (LDLT).The medical records of patients who underwent LDLT for hepatic EHE from 2007 to 2016 were reviewed.During 10-year period, four patients, one man and three women, of mean age 41.3±11.1 years, underwent LDLT for hepatic EHE. Based on imaging modalities, these patients were preoperatively diagnosed with EHE or hepatocellular carcinoma, with percutaneous liver biopsy confirming that all four had hepatic EHE. The tumors were multiple and scattered over entire liver, precluding liver resection. Blood tumor markers were not elevated, except that CA19-9 and des-γ-carboxy prothrombin was slightly elevated in one patient. Mean model for end-stage liver disease score was 10.8±5.7. All patients underwent LDLT using modified right liver grafts, with graft-recipient weight ratio of 1.11±0.19, and all recovered uneventfully after LDLT. One patient died due to tumor recurrence at 9 months, whereas the other three have done well without tumor recurrence, resulting in 5-year disease-free and overall patient survival rates of 75% each. The patient with tumor recurrence was classified as a high-risk patient based on the original and modified hepatic EHE-LT scoring systems.LDLT can be an effective treatment for patients with unresectable hepatic EHEs that are confined within the liver and absence of macrovascular invasion and lymph node metastasis.

Background Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and fine-needle biopsy (FNB) are the current standard of care for sampling pancreatic and peripancreatic masses. Recently, a 22G EUS-FNB needle with Franseen geometry was developed, and this device was also introduced in a 25G platform. We compared the performance of the 25G and 22G Franseen needles for EUS-guided sampling of pancreatic and peripancreatic solid masses. Methods We conducted a parallel-group randomized non-inferiority trial at a tertiary-care center from November 2018 to May 2019. The primary outcome was the quality of the histologic core assessed using the Gerke score. The optimal histologic core is indicated by a Gerke score of 4 or 5, which enables optimal histologic interpretation. The overall diagnostic accuracy and adverse event rate were also evaluated. Results 140 patients were enrolled and randomized (1:1) to the 25G and 22G groups. Tissue acquisition by EUS-FNB was successful in all patients. The optimal histologic core procurement rate was 87.1 % (61/70) for the 25G needle vs. 97.1 % (68/70) for the 22G; difference −10 % (95 % confidence interval −17.35 % to −2.65 %). High quality specimens were more frequently obtained in the 22G group than in the 25G group (70.0 % [49/70] vs. 28.6 % [20 /70], respectively; P Conclusions The 25G Franseen needle was inferior to the 22G needle in histologic core procurement. Therefore, for cases in which tissue architecture is pivotal for diagnosis, a 22G needle, which procures relatively higher quality specimens than the 25G needle, should be used.

Backgrounds/aims Hepatic inflammatory pseudotumor (HIPT) is a rare disease characterized by chronic infiltration of inflammatory cells and area of fibrosis. The objective of this retrospective observational study was to investigate clinicopathological features and outcomes of patients who underwent hepatic resection (HR) for HIPT. Methods From 2009 to 2018, seven patients with HIPT underwent HR, accounting for 0.06% of 11,979 adults who underwent HR at our center. Results These seven patients included five men and two women. Their mean age was 62.3±11.6 years. In four patients with hepatitis B virus (HBV)-associated liver cirrhosis or chronic hepatitis, liver masses were suspected of hepatocellular carcinoma (HCC) or combined HCC-cholangiocarcinoma based on imaging studies. In three patients without HBV infection, two patients were suspected of HCC, for whom liver biopsy was not performed. One patient was suspected of liver abscess or HIPT, for whom percutaneous liver biopsy was performed and the mass was diagnosed with HIPT. However, this patient underwent HR owing to abdominal pain. No patient presented with abnormally elevated levels of alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, or CA19-9. During a mean follow-up period of 76.4±34.8 months, no patient experienced recurrence of HIPT. Conclusions HIPT, a rare form of liver disease, is often misdiagnosed as malignant liver tumor. Active histological diagnosis is warranted for patients with suspected HIPT to avoid unnecessary operation. HR can be indicated in case of diagnostic ambiguity of HIPT or under a clinical diagnosis of malignant liver tumor.

One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This “evolutionary view” creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.

Solid pseudopapillary neoplasms (SPNs) of the pancreas have low malignant potential. However, malignant SPNs are not fully understood.To evaluate risk factors affecting malignant potential, the clinicopathologic features of 375 surgically resected SPNs were compared.Fifty (13.3%) had malignant histologic features. Twenty-seven and 22 had perineural and lymphovascular invasions, respectively. Adjacent organ invasion was noted in 9 cases. Recurrence occurred in 8 cases. The median recurrence time after surgical resection was 67 months and was associated with a higher pT category (P = 0.001), lymphovascular invasion (P 0.001), and synchronous metastasis (P 0.001). SPN patients with malignant histologic features had worse recurrence-free survival (RFS; 10-year survival rate, 73.2%) than those without malignant histologic features (96.3%; P = 0.01). Patients with a higher pT category (P = 0.04), synchronous metastasis (P 0.01), and lymphovascular invasion (P 0.01) had worse RFS. Lymphovascular invasion (P = 0.042) and a higher T category (P = 0.002) were poor prognostic factors for recurrence.Lymphovascular invasion and a higher T category were worse prognostic factors for recurrence in SPN patients with malignant histologic features. For SPN patients with malignant histologic features, a longer follow-up may be required.

Backgrounds/aims Hepatocellular adenomas (HCA) are rare benign liver tumors with the potential of malignant transformation and risk of bleeding. We investigated the clinicopathological features and outcomes of HCA in 19 patients who underwent surgical resection. Methods This retrospective observational study included 19 patients who underwent hepatic resection during a 9-year period from 2011 to 2019. Results The incidence of HCA was 0.18% of all hepatic resection cases during the study period. The mean age of the patients was 34.3±9.6 years, and 12 patients (63.2%) were female. Abdominal pain was present as initial clinical manifestation in 5 patients and the other 14 patients had no specific symptoms. HCA was diagnosed in 7 out of 8 patients who underwent liver biopsy. R0 resection was performed in 18 patients (94.7%) and laparoscopic liver resection was performed in 11 patients (57.9%). The mean tumor size was 5.6±3.6 cm and 17 patients had a single tumor. Immunohistochemical analysis of the resected tumor specimens revealed hepatocyte-nuclear-factor-1α mutated HCA in 2 (10.5%), β-catenin-mutated HCA in 2 (10.5%), inflammatory HCA in 12 (63.2%) and unclassified HCA in 3 (15.8%). There were no pathognomonic findings in the preoperative liver imaging studies among these four groups. Currently, all patients are alive with a mean follow-up period of 40.1±26.3 months. One patient showed residual tumors after incomplete resection. Conclusions Surgical resection may be indicated if imaging studies show diagnostic ambiguity, growing tumor or symptomatic mass. Because of the risk of tumor recurrence and malignant transformation, long-term follow-up is necessary.

BackgroundCancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing.MethodsTo overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method.ResultsNintedanib blocked the platelet-derived growth factor receptor β (PDGFRβ) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRβ+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes.ConclusionOur strategy against PDGFRβ+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.

Anorectal malignant melanoma (ARMM) is a rare disease with poor prognosis. Determining ARMM prognosis precisely is difficult due to the lack of proper assessment techniques. Immunotherapy has proven effective against cutaneous malignant melanoma and may show efficacy in ARMM. Herein, we assessed the immune profile of ARMM to identify possible prognostic biomarkers. Twenty-two ARMM formalin-fixed and paraffin-embedded samples were evaluated using an nCounter® PanCancer Immune Profiling Panel. Validation was performed through immunohistochemical staining for CD3, CD8, Foxp3, CD68, CD163, and PD-L1. RNA analysis revealed significantly decreased scores for pathways involved in cell regulation and function, as well as chemokines, in recurrent patients compared to nonrecurrent patients. In cell-type profiling, the recurrent cases displayed significantly low tumor infiltrating lymphocyte (TIL) scores. Recurrence/death prediction models were defined using logistic regression and showed significantly lower scores in recurrent and deceased patients (all, P

Lymphovascular invasion (LVI) is a high-risk feature guiding decision making for adjuvant chemotherapy. We evaluated the prognostic importance and reliability of LVI as an adjuvant chemotherapy indicator in 1634 patients with pT3N0 colorectal cancer treated with curative radical resection between 2012 and 2016. LVI and perineural invasion (PNI) were identified in 382 (23.5%) and 269 (16.5%) patients, respectively. In total, 772 patients received adjuvant chemotherapy. The five-year recurrence-free survival (RFS) and OS rates were 92% and 94.8%, respectively. Preoperative obstruction, PNI, and positive margins were significantly associated with RFS and OS; however, adjuvant chemotherapy and LVI were not. Pathologic slide central reviews of 242 patients using dual D2-40 and CD31 immunohistochemical staining was performed. In the review cohort, the diagnosis of LVI and PNI was changed in 82 (33.9%) and 61 (25.2%) patients, respectively. Reviewed LVI, encompassing small vessel invasion, lymphatic invasion, and large vessel invasion, was not an independent risk factor associated with OS but was related to RFS. The prognostic importance of LVI and adjuvant chemotherapy was not defined because LVI may be underrecognized in pathologic diagnoses using hematoxylin and eosin staining slides only, leading to low recurrence rate predictions. Using LVI as a guiding factor for adjuvant chemotherapy requires further consideration.

Accurate assessment of pancreatic ductal adenocarcinoma (PDAC) resectability after neoadjuvant therapy (NAT) is crucial. Recently, the NCCN introduced criteria for resection of PDAC following NAT.We analyzed 127 patients who underwent NAT and pancreatectomy for PDAC between January 2010 and March 2020. CT-determined resectability according to the NCCN guideline and CA 19-9 level was evaluated before and after NAT. Diagnostic performance of the NCCN criteria for margin-negative (R0) resection was investigated and compared with CT alone.R0 resection was achieved in 104 (81.9%) patients. After NAT, there were 30 (23.6%) resectable, 90 (70.9%) borderline resectable, and seven (5.5%) locally advanced tumors. Significantly decreased or stable CA 19-9 levels were noted in 114 (89.8%) patients. The sensitivity and specificity of the NCCN criteria were 87.5% (91/104) and 21.7% (5/23), respectively, which were significantly different from CT including only resectable PDAC (26.9% [28/104] and 91.3% [21/23]; P .001), but less prominently different from CT including resectable and borderline resectable PDAC (95.2% [99/104]; P = .022 and 8.7% [2/23]; P = .375).The NCCN criteria for resection following NAT showed high sensitivity and low specificity for predicting R0 resection. It had supplementary benefit over CT alone, mainly in preventing underestimation of R0 resection.

Large duct pattern of pancreatic ductal adenocarcinomas (PDACs) comprises occasional large cancer glands (0.5 mm in size), along with conventional smaller cancer glands. They histologically mimic intraductal papillary mucinous neoplasms. However, the clinicopathologic significance of PDACs with predominant large duct pattern (PLDP) has not been systematically evaluated. A total of 41 cases of PDACs with PLDP, which were defined as irregularly-shaped cancer glands0.5 mm in size occupied50% of tumor volume, were enrolled and their clinicopathological, immunohistochemical, and targeted exome-wise mutational characteristics were compared with 298 conventional PDACs. PDACs with PLDP had cancers with larger tumor sizes (P = 0.025), which were more frequently well to moderately differentiation (P 0.001), with less lymphovascular invasion (P = 0.013) and had a higher T category (P = 0.023) than conventional PDACs. Immunohistochemically, PDACs with PLDP showed similar abnormal p53 (61%) and SMAD4 (59%) expression patterns as conventional PDACs. In addition, PDACs with PLDP showed diffuse MUC1 (88%), MUC5AC (100%), MUC6 (66%), and focal MUC2 (20%) expressions. More frequent ROS1 mutations were observed in PDACs with PLDP. PDAC patients with PLDP had a better overall and recurrence-free survival (OS and RFS; median, 42 and 34 months) than that of patients with conventional PDACs (34 and 16 months) as per univariate (P = 0.037 and P = 0.001) and multivariate (P = 0.031 and P = 0.034) analyses. PDACs with PLDP showed mutational patterns similar to those of conventional PDACs. They had unique histologic features and longer OS and RFS compared to those of conventional PDACs. Therefore, PDACs with PLDP could be considered a histologic subtype of PDACs.

Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs.Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (HE)-stained slides.Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps .05).Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.

Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

We aimed to assess the ability of CT-determined resectability, as defined by a recent version of NCCN criteria, and associated CT findings to predict margin-negative (R0) resection in patients with PDAC after neoadjuvant FOLFIRINOX chemotherapy. Sixty-four patients (36 men and 28 women; mean age, 58.8 years) with borderline resectable or unresectable PDAC who received neoadjuvant FOLFIRINOX were evaluated retrospectively. CT findings were independently assessed by two abdominal radiologists according to NCCN criteria (version 3. 2019). Tumor resectability was classified as resectable, borderline resectable, or unresectable, and change in resectability was classified as regression, stability, or progression. The associations of R0 resection rate with CT-determined resectability and change in resectability categories were evaluated, as were the sensitivity and specificity of NCCN criteria for R0 resection. Factors associated with R0 resection were identified by logistic regression analysis. R0 resection rate did not differ significantly among the resectable, borderline resectable, or unresectable PDAC (67–73%, p = 0.95) or among PDAC with regression, stability, or progression (56–77%, p = 0.39). The sensitivity and specificity for R0 resection were 67% and 37%, respectively, for resectability (resectable/borderline vs. unresectable) and 80% and 21%, respectively, for changes in resectability (regression/stable vs. progression). Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with R0 resection (p = 0.01). CT-determined resectability after neoadjuvant FOLFIRINOX chemotherapy was relatively insensitive and non-specific for predicting R0 resection. Low-contrast enhancement of soft tissue contacting artery may increase the ability of CT to predict R0 resection. • Margin-negative resection rate of pancreatic cancer following FOLFIRINOX therapy did not differ among each resectability (67–73%, p = 0.95) based on NCCN criteria or changes in resectability categories (56–77%, p = 0.39). • The sensitivity and specificity for margin-negative resection were 67% and 37% for resectability (resectable/borderline vs. unresectable) and 80% and 21% for changes in resectability (regression/stable vs. progression). • Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with margin-negative resection (p = 0.01).

Background IPNB is very rare disease and most previous studies on IPNB were case series with a small number due to low incidence. The aim of this study is to validate previously known clinicopathologic features of intraductal papillary neoplasm of bile duct (IPNB) based on the first largest multicenter cohort. Methods Among 587 patients previously diagnosed with IPNB and similar diseases from each center in Korea, 387 were included in this study after central pathologic review. We also reviewed all preoperative image data. Results Of 387 patients, 176 (45.5%) had invasive carcinoma and 21 (6.0%) lymph node metastasis. The 5-year overall survival was 80.9% for all patients, 88.8% for IPNB with mucosal dysplasia, and 70.5% for IPNB with invasive carcinoma. According to the “Jang & Kim's modified anatomical classification,” 265 (68.5%) were intrahepatic, 103 (26.6%) extrahepatic, and 16 (4.1%) diffuse type. Multivariate analysis revealed that tumor invasiveness was a unique predictor for survival analysis. (p = 0.047 [hazard ratio = 2.116, 95% confidence interval 1.010–4.433]). Conclusions This is the first Korean multicenter study on IPNB through central pathologic and radiologic review process. Although IPNB showed good long-term prognosis, relatively aggressive features were also found in invasive carcinoma and extrahepatic/diffuse type.

BACKGROUND The prevalent location and incidence of intraductal papillary neoplasm of the bile duct (IPNB) and invasive carcinoma associated with them have varied markedly among studies due to differences in diagnostic criteria and tumor location. METHODS IPNBs were classified into two types: Type 1 IPNB, being histologically similar to intraductal papillary mucinous neoplasm of the pancreas, and Type 2 IPNB, having a more complex histological architecture with irregular papillary branching or foci of solid-tubular components. Medical data were evaluated. RESULTS Among 694 IPNB patients, 520 and 174 had Type 1 and Type 2, respectively. The levels of AST, ALT, ALP, T. Bil, and CEA were significantly higher in patients with Type 2 than in those with Type 1. Type 1 IPNB was more frequently located in the intrahepatic bile duct than Type 2, whereas Type 2 was more frequently located in the distal bile duct than Type 1 IPNB (P

Purpose The current standard chemotherapy for advanced biliary tract cancer (BTC) has limited benefit, and novel therapies need to be investigated. Materials and MethodsIn 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. ResultsBetween 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.

Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P

Acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MAcNECs) of the pancreas are extremely rare carcinomas with a significant component with acinar differentiation. To date, the clinicopathological behaviours of these neoplasms remain unclear. In this study, we evaluated the histopathological and molecular characteristics of 20 ACCs and 13 MAcNECs and compared them to a cohort of 269 well-differentiated pancreatic neuroendocrine tumours (PanNETs). Compared to PanNETs, both ACCs and MAcNECs had an advanced pT classification (p

Objectives Histopathologic characteristics of choledochal cysts and their clinical implications have not been previously comprehensively studied. Methods Smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated. Results Mean patient age was 23.3 ± 19.8 years, with male:female ratio of 0.3. Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%). Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P 20 years vs ≤20 years), suggesting that chronic irritation in association with developmental anomalies involves tumorigenesis from choledochal cysts. Conclusion Smooth muscle distribution pattern of choledochal cyst may predict postoperative complication, raising clinical implications of smooth muscle patterns in postoperative management of choledochal cysts.

The diagnosis of small intestinal adenocarcinoma (SIAC) is usually determined at an advanced stage due to non-specific symptoms and the difficulty of exploring the small intestine. Therefore, the majority of SIAC patients have limited chemotherapeutic options. Until recently, the development of novel and effective therapies for SIAC have been limited owing to the low number of samples that have been collected and the low incidence of SIAC. Immunotherapies are becoming a focus. However, in SIAC, only a few studies to identify immunotherapy-responsive subgroups and their prognostic indicators have been reported. In the present study, we categorise primary SIAC into four types of tumour immune microenvironments and propose a strategy for identifying patient subgroups that are most likely to be immunotherapy-responsive. Formalin-fixed, paraffin-embedded tissue samples of a multicentre cohort of patients with SIAC (n=195) were collected using tissue microarrays. Immunohistochemical (IHC) stains for PD-L1, PD-1, and CD8 were performed, and microsatellite instability was evaluated using an IHC stain. Tumour microenvironment immune type (TMIT) I [PD-L1-positive tumour cells and CD8-high tumour-infiltrating lymphocytes (TILs)] and TMIT III (PD-L1-positive tumour cells and CD8-low TILs) show the best and worse prognoses, respectively. PD-L1 expression was significantly associated with high microsatellite instability (MSI) status. CD8-high TILs were positively correlated with PD-1-high TILs and high MSI. The TMIT I subgroup demonstrated a more patent CD8/PD-L1/PD-1 signalling pathway compared to other TMITs. Therefore, the TMIT I subgroup can be expected to have an effective response to immune checkpoint inhibitor therapies in SIAC. Such classification of SIACs into four immune types can be useful in predicting the prognosis of patients and the identification of immunotherapy-responsive subgroups.

PURPOSE The most recent 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNENs) has refined the three-tiered 2010 scheme by separating grade 3 pancreatic neuroendocrine tumors (G3 PanNETs) from poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). However, differentiating between G3 Pan- NETs and PanNECs is difficult in clinical practice. Materials and Methods Eighty-two surgically resected PanNENs were collected from 16 institutions and reclassified according to the 2017 WHO classification based on the histological features and proliferation index (mitosis and Ki-67). Immunohistochemical stains for ATRX, DAXX, retinoblastoma, p53, Smad4, p16, and MUC1 were performed for 15 high-grade PanNENs. RESULTS Re-classification resulted in 20 G1 PanNETs (24%), 47 G2 PanNETs (57%), eight G3 well-differentiated PanNETs (10%), and seven poorly differentiated PanNECs (9%). PanNECs showed more frequent diffuse nuclear atypia, solid growth patterns and apoptosis, less frequent organoid growth and regular vascular patterns, and absence of low-grade PanNET components than PanNETs. The Ki-67 index was significantly higher in PanNEC (58.2%± 15.1%) compared to G3 PanNET (22.6%±6.1%, p < 0.001). Abnormal expression of any two of p53, p16, MUC1, and Smad4 could discriminate PanNECs from G3 PanNETs with 100% specificity and 87.5% sensitivity. CONCLUSION Histological features supporting the diagnosis of PanNECs over G3 PanNETs were the absence of a low-grade PanNET component in the tumor, the presence of diffuse marked nuclear atypia, solid growth pattern, frequent apoptosis and markedly increased proliferative activity with homogeneous Ki-67 labeling. Immunohistochemical stains for p53, p16, MUC1, and Smad4 may be helpful in distinguishing PanNECs from G3 PanNETs in histologically ambiguous cases, especially in diagnostic practice when only small biopsied tissues are available.

Pancreatic neuroendocrine tumors (PanNETs) are frequently detected on endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens. The conventional methods for evaluating the Ki-67 labeling index (Ki67LI) in EUS-FNAB specimens are laborious, and their results are difficult to interpret. More practical and easy methods for evaluating the Ki67LI in PanNETs from EUS-FNAB specimens is increasing in need.We used double Ki-67 and synaptophysin (double Ki-Syn) antibody cocktail; Ki67LI, total Ki-67 positive cells, and total tumor cells were counted and compared with those detected on conventional single Ki-67 immunostaining (single Ki-67) of 96 PanNETs [Grade 1 (G1), 68 cases (71%); G2, 26 (27%); G3, 2 (2%)] from EUS-FNAB specimens.The tumor grading between double Ki-Syn and single Ki-67 immunolabeling was highly concordant (correlation, 0.95; Fisher's exact test, P 0.001). Seven EUS-FNAB specimens (7%) had discrepant results, of which 2 were removed through surgical resection and showed the same tumor grade as that detected on double Ki-Syn immunolabeling. Fifty-four specimens (56%) had higher Ki-67 positive tumor cell counts on single Ki-67 immunolabeling. Sixty-two specimens (65%) had higher total tumor cell counts on double Ki-Syn immunolabeling. The number of specimens with less than 500 total counted tumor cells were significantly reduced when double Ki-Syn immunolabeling was applied [P = 0.046; single Ki-67, 17 specimens (18%); double Ki-Syn, 9 specimens (9%)].Double Ki-Syn immunolabeling enables the accurate counting of the number of proliferating tumor cells without including inflammatory and contaminant epithelial cells compared with single Ki-67 immunolabeling in PanNETs from EUS-FNAB specimens.

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4 fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz-Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCH family genes and ERBB2, fusions involving RET and ERBB2, and RB1 disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53 mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCA alterations, ERBB2 and RET fusions, and ERBB2 amplification are novel targets in precision oncology. The TP53 mutation status can be used as a prognostic biomarker., This study is supported by Associazione Italiana Ricerca sul Cancro (AIRC IG n. 26343); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017); Fondazione Italiana Malattie Pancreas (FIMP-Ministero Salute J38D19000690001); Italian Ministry of Health (RF CO-2019-12369662: CUP: B39C21000370001).

Context.— The roles of the gallbladder and cystic duct (CD) invasions in distal bile duct carcinoma (DBDC) have not been well elucidated. Objective.— To define the characteristics and prognostic significance of gallbladder or CD invasions in patients with DBDC. Design.— Organ invasion patterns with clinicopathologic features were assessed in 258 resected DBDCs. Results.— CD invasions (N = 31) were associated with frequent concomitant pancreatic and/or duodenal invasions (23 of 31, 74%) and showed stromal infiltration (16 of 31, 52%) and intraductal cancerization (15 of 31, 48%) patterns. In only 2 cases, invasions with intraductal cancerization were observed in the gallbladder neck. Conversely, all pancreatic (N = 175) and duodenal (83) invasions developed through stromal infiltration. CD invasions were associated with larger tumor size (P = .001), bile duct margin positivity (P = .001), perineural invasions (P = .04), and higher N categories (P = .007). Patients with pancreatic or duodenal invasions had significantly lower survival rates than those without pancreatic (median, 31.0 versus 93.9 months) or duodenal (27.5 versus 56.8 months, P < .001, both) invasions. However, those with gallbladder or CD invasions did not have different survival times (P = .13). Patients with concomitant gallbladder/CD and pancreatic/duodenal invasions demonstrated significantly lower survival rates than those without organ invasions (P < .001). Conclusions.— Gallbladder invasions were rare in DBDCs as neck invasions with intraductal cancerization. CD invasions occurred by stromal infiltrations and intraductal cancerization, whereas all pancreatic and duodenal invasions had stromal infiltration patterns. Gallbladder and/or CD invasions did not affect survival rates of patients with DBDC, while pancreatic and duodenal invasions affected survival rates. Therefore, these differences in survival rates may originate from the different invasive patterns of DBDCs.

Context.— Pancreatic neuroendocrine tumors (PanNETs) are heterogeneous tumors with a wide range of malignant potential. Therefore, identification of prognostic factors is essential. Objective.— To systematically assess the significance of tumor border, a well-known prognostic indicator in other cancers, in PanNETs. Design.— We evaluated the macroscopic growth pattern (expansile [Exp] versus infiltrative [Inf]) and the microscopic tumor border (pushing [Pus] versus Inf) of 203 surgically resected PanNETs and compared them with other clinicopathologic factors. Results.— Based on macroscopic growth pattern, 83 cases had Exp patterns whereas 84 had Inf patterns. According to microscopic tumor border, 122 PanNETs had Pus borders whereas 81 had Inf borders. Combining macroscopic growth pattern and microscopic tumor border, 65 PanNETs had Exp/Pus, 34 had Inf/Pus, 18 had Exp/Inf, and 50 had Inf/Inf status. PanNETs with Inf/Inf status were associated with higher tumor grade, pT classification, and American Joint Committee on Cancer stage grouping; lymph node metastasis; and lymphovascular and perineural invasions (all P < .001). Patients with PanNET having Inf/Inf status had significantly shorter overall survival (OS) and recurrence-free survival (RFS; all P < .001). Further, using multivariate analysis, Inf/Inf status was identified as an independent poor prognostic factor of OS (P = .02) and RFS (P = .03). Conclusions.— In summary, combined Inf/Inf status was observed in approximately 25% of PanNETs and was associated with aggressive biological behavior and short OS and RFS. Therefore, assessing combined macroscopic growth pattern and microscopic tumor border can provide additional information regarding survival and recurrence in PanNET patients.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p &lt, 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p &lt, 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Context.— A standardized detailed surgical pathology report is the cornerstone of gastric cancer management. Objective.— To guide management and prognostication for patients with gastric carcinomas globally, the International Collaboration on Cancer Reporting aimed to produce an evidence-based international pathology reporting data set with a panel of globally recognized expert pathologists and clinicians. Design.— Based on published guidelines/data sets for gastric carcinomas, a working draft was developed by the chair of the expert panel of pathologists and clinicians. The draft was then circulated to the panel and discussed in a series of teleconferences and email communications until consensus was achieved. The draft data set was uploaded on the International Collaboration on Cancer Reporting Web site for public comment. The data set was reviewed in consideration of the feedback, and a final version was approved by the panel. Results.— This data set was developed for gastrectomy specimens for primary gastric carcinomas, including neuroendocrine carcinomas and mixed neuroendocrine-nonneuroendocrine neoplasms. Well-differentiated neuroendocrine tumors, nonepithelial malignancies, and secondary tumors were excluded from this data set. The final data set contains 15 core (required) elements and 8 noncore (recommended) elements. A commentary is provided for each element. Conclusions.— The International Collaboration on Cancer Reporting has published freely available, evidence-based data sets for gastric cancer reporting. Standardized reporting has been shown to improve patient care and facilitates data exchange and analysis for quality assurance, cancer epidemiology, and clinical and basic research.

The direct esterification reaction between 3-mercaptopropionic acid (3-MPA) and trimethylolpropane (TMP) was conducted in the presence of various catalyst concentrations of p-toluenesulfonic acid (p-TSA) to examine the optimized synthetic conditions needed to produce high-purity trimethylolpropane-tris(3-mercaptopropionate) (TMPMP). The purity of the desired TMPMP and uncompleted side-product reduced as the acid catalyst concentration in this esterification reaction increased while the generation of thioester-based side-product increased. The equivalent ratio between epoxy and the manufactured TMPMP was maintained at 1 : 1 to monitor the curing behavior of the thiol–epoxy click reaction using the DSC technique. The thermal features of the base-catalyzed TMPMP-cured epoxy resin were assessed according to the purity of the TMPMP curing agent.

BackgroundGallbladder cancer (GBC) has a poor prognosis. Although complete surgical resection is the only successful approach for improving survival, additional therapeutic modalities are required for recurrent or surgically unresectable GBCs.Materials and MethodsTo determine the expression status of HER2 and the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2, immunohistochemical staining of MMR proteins and HER2 was carried out in 216 surgically resected GBCs. HER2 labeling was scored by adopting a scoring system for gastric carcinomas. Tissues scoring 0 to 2+ were defined as HER2 negative, whereas those scoring 3+ were regarded as HER2-positive. In addition, silver in situ hybridization and microsatellite instability (MSI) analysis were conducted to confirm HER2 amplification and MSI, respectively.ResultsThree of 216 GBCs (1.3%) showed MMR protein deficiency. All three observed MSI cases exhibited dual loss of MSH2 and MSH6 protein expression. However, no cases showed loss of either MLH1 or PMS2 expression. No association was observed between MMR protein deficiency and other clinicopathological factors. HER2 amplification was noted in 30 (13.9%) GBCs and associated with Crohn-like lymphoid reaction (P = 0.023). No survival difference was observed based on HER2 overexpression or HER2 amplification status.ConclusionMMR protein deficiency and HER2 overexpression were observed in a small subset (1.3% and 13.9%, respectively) of GBCs without simultaneous occurrence of deficient MMR protein expression and HER2 overexpression. The presence of Crohn-like lymphoid reaction may help identify cases with HER2 amplification, by using hematoxylin-stained slides. Although the proportion of MMR protein-deficient- and HER2-overexpressing GBCs was small, applying immunotherapy to MMR protein-deficient GBCs and herceptin to HER2-overexpressing GBCs may provide alternative treatment options for patients with GBC.

The response to preoperative chemoradiotherapy (PCRT) is correlated with oncologic outcomes in patients with locally advanced rectal cancer. Accurate prediction of PCRT response before surgery can provide crucial information to aid clinicians in further treatment planning. This study aimed to develop an evaluation tool incorporating a genetic biomarker and magnetic resonance imaging (MRI) to improve the assessment of response in post-CRT patients with locally advanced rectal cancer. A total of 198 patients who underwent PCRT followed by surgical resection for locally advanced rectal cancer between 2010 and 2016 were included in this study. Each patient’s response prediction index (RPI) score, a multigene biomarker developed in our previous study, and magnetic resonance tumor regression grade (mrTRG) score were added to create a new predictive value for pathologic response after PCRT, called the combined radiation prediction value (cRPV). Based on the new value, 121 and 77 patients were predicted to be good and poor responders, respectively, showing significantly different cRPV values (p = 0.001). With an overall predictive accuracy of 84.8%, cRPV was superior to mrTRG and RPI for the prediction of pathologic chemoradiotherapy response (mrTRG, 69.2%, RPI, 77.3%). In multivariate analysis, cRPV was found to be the sole predictor of tumor response (odds ratio, 32.211, 95% confidence interval, 14.408–72.011, p = 0.001). With its good predictive value for final pathologic regression, cRPV may be a valuable tool for assessing the response to PCRT before surgery.

Small rectal neuroendocrine tumors (NETs) can be treated using cap-assisted endoscopic mucosal resection (EMR-C), which requires additional effort to apply a dedicated cap and snare. We aimed to evaluate the feasibility of a simpler modified endoscopic mucosal resection (EMR) technique, so-called anchored snare-tip EMR (ASEMR), for the treatment of small rectal NETs, comparing it with EMR-C. We retrospectively evaluated 45 ASEMR and 41 EMR-C procedures attempted on small suspected or established rectal NETs between July 2015 and May 2020. The mean (SD) lesion size was 5.4 (2.2) mm and 5.2 (1.7) mm in the ASEMR and EMR-C groups, respectively (p = 0.558). The en bloc resection rates of suspected or established rectal NETs were 95.6% (43/45) and 100%, respectively (p = 0.271). The rates of histologic complete resection of rectal NETs were 94.1% (32/34) and 88.2% (30/34), respectively (p = 0.673). The mean procedure time was significantly shorter in the ASEMR group than in the EMR-C group (3.12 [1.97] vs. 4.13 [1.59] min, p = 0.024). Delayed bleeding occurred in 6.7% (3/45) and 2.4% (1/41) of patients, respectively (p = 0.618). In conclusion, ASEMR was less time-consuming than EMR-C, and showed similar efficacy and safety profiles. ASEMR is a feasible treatment option for small rectal NETs.

BACKGROUND AND AIMS Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown. METHODS To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC. RESULTS Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P

Purpose In biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential new therapeutic targets and predictive biomarkers. Methods Targeted exome sequencing was performed for 124 patients with BTC [gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44]. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease. Results Genetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88). Conclusions A subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.

AIMS Mucinous cystic neoplasms (MCNs) of the pancreas are cystic neoplasms lined by mucinous lining epithelium (MLE) with associated ovarian-type stroma. Although a non-MLE (NMLE) can be observed in some MCNs, whether cystic neoplasms with ovarian-type stroma and NMLE should be classified as MCNs or separately designated is debated. METHODS AND RESULTS To test this, NMLEs were defined as flat or cuboidal epithelial cells without intracytoplasmic mucin. A total of 112 MCNs were reviewed, and the epithelium was classified as NMLE or MLE. A total of 110 females and two males with a mean age of 46.5 ± 12.3 years were included in this study. At least focal NMLE was noted in 76.8% (86/112) of MCNs. The mean percentage of the neoplastic epithelium that was NMLE in these 86 cases was 46%. NMLE was predominant (>50%) in 38.4% (43/112) of cases. MCNs with NMLE were smaller (42 ± 21 mm) than those with MLE (60 ± 36 mm, P

AIMS To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P