Surgical interpretation of the WHO subclassification of intrahepatic cholangiocarcinoma: a narrative review.

Intrahepatic cholangiocarcinoma (iCCA) has been subclassified by its gross morphology into the mass-forming (MF), periductal-infiltrating (PI), and intraductal growth (IG) types and their combinations. This classification correlates well with clinical features; for example, MF-iCCA has less lymph-node metastasis and a better prognosis than PI-iCCA. According to the recently accumulated evidence from histological investigations, the WHO classification endorsed a subclassification scheme in which iCCA cases are classified into small- and large-duct types. Small-duct iCCA is considered to originate from septal or smaller bile ducts and is characterized by less frequent lymph-node metastasis, a favorable prognosis, and an MF appearance. Large-duct iCCA arises around the second branch of the biliary tree and has more aggressive biology and distinct genetic abnormalities. According to the practice guidelines for iCCA from the Liver Cancer Study Group of Japan and the National Comprehensive Cancer Network, upfront surgery is recommended for iCCA without distant metastasis regardless of the morphological subtype, based on clinical experience. In consideration of the biological heterogeneity of iCCA, the treatment strategy for iCCA needs to be reconsidered based on the WHO subtypes.

Utility of plasma D-dimer for diagnosis of venous thromboembolism after hepatectomy.

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of hepatectomy. The use of postoperative prophylactic anticoagulation in patients who have undergone hepatectomy is controversial because of the risk of postoperative bleeding. Therefore, we hypothesized that monitoring plasma D-dimer could be useful in the early diagnosis of VTE after hepatectomy. AIM: To evaluate the utility of monitoring plasma D-dimer levels in the early diagnosis of VTE after hepatectomy. METHODS: The medical records of patients who underwent hepatectomy at our institution between January 2017 and December 2020 were retrospectively analyzed. Patients were divided into two groups according to whether or not they developed VTE after hepatectomy, as diagnosed by contrast-enhanced computed tomography and/or ultrasonography of the lower extremities. Clinicopathological factors, including demographic data and perioperative D-dimer values, were compared between the two groups. Receiver operating characteristic curve analysis was performed to determine the D-dimer cutoff value. Univariate and multivariate analyses were performed using logistic regression analysis to identify significant predictors. RESULTS: In total, 234 patients who underwent hepatectomy were, of whom (5.6%) were diagnosed with VTE following hepatectomy. A comparison between the two groups showed significant differences in operative time (529 vs 403 min, P = 0.0274) and blood loss (530 vs 138 mL, P = 0.0067). The D-dimer levels on postoperative days (POD) 1, 3, 5, 7 were significantly higher in the VTE group than in the non-VTE group. In the multivariate analysis, intraoperative blood loss of > 275 mL [odds ratio (OR) = 5.32, 95% confidence interval (CI): 1.05-27.0, P = 0.044] and plasma D-dimer levels on POD 5 ≥ 21 µg/mL (OR = 10.1, 95%CI: 2.04-50.1, P = 0.0046) were independent risk factors for VTE after hepatectomy. CONCLUSION: Monitoring of plasma D-dimer levels after hepatectomy is useful for early diagnosis of VTE and may avoid routine prophylactic anticoagulation in the postoperative period.

Efficacy of S-1 Adjuvant Chemotherapy for Resected Biliary Tract Cancer: A Retrospective Propensity-Matched Analysis.

INTRODUCTION: Surgical resection is considered an effective cure for biliary tract cancer (BTC); however, the prognosis is unsatisfactory despite improved surgical techniques and perioperative management. The recurrence rate remains high even after curative resection. The efficacy of adjuvant chemotherapy in pancreatic and gastric cancers has been previously reported, and the feasibility of adjuvant therapy with S-1 has recently been reported in patients with resected BTC. We aimed to retrospectively investigate the effects of adjuvant chemotherapy with S-1 on resected advanced BTC. METHODS: We included data from 438 BTC patients who underwent resection between 2001 and 2020. After excluding patients with pTis-pT1 (n = 112) and other exclusion criteria, 266 patients were included in the analysis. RESULTS: After propensity score matching, 48 patients received S-1 adjuvant chemotherapy (S-1 group), and 48 patients received non-S1 adjuvant chemotherapy or underwent surgery alone (Non-S-1 group). The patients in the S-1 group had significantly better overall survival (OS) than those in the non-S-1 group (MST 51 vs 37 months, hazard ratio [HR]:.54, 95% confidence interval [CI]:.30-.98, P = .04). The S-1 group had a significantly better recurrence-free survival (RFS) than the non-S-1 group (94 vs 21 months, HR: .57, 95% CI: .33-.97, P = .03). Subgroup analyses for OS and RFS exhibited the benefits of S-1 in patients aged <75 years and in patients with primary sites of extrahepatic and perineural invasion and curability of R0. DISCUSSION: S-1 adjuvant therapy is promising for improving the postoperative survival of patients with resected advanced BTC, positive nerve invasion, and R0 resection.

Wnt Signaling Stimulates Cooperation between GREB1 and HNF4α to Promote Proliferation in Hepatocellular Carcinoma.

Wnt signaling is known to maintain two cell states, hepatocyte differentiation and proliferation, in hepatocellular carcinoma (HCC). On the other hand, activation of Wnt signaling in colon cancer promotes uncontrollable stereotypic proliferation, whereas cells remain undifferentiated. To elucidate the unique mode of Wnt signaling in HCC, we comprehensively investigated HCC-specific Wnt pathway target genes and identified GREB1. Wnt signaling induced expression of GREB1 coupled with HNF4α and FOXA2, master transcription factors that maintain hepatic differentiation. Moreover, GREB1 was enriched at the regulatory region of atypical HNF4α target genes, including progrowth genes, thereby stimulating HCC proliferation. Therefore, GREB1 acts as a unique mediator of versatile Wnt signaling in HCC progression, bridging the roles of the Wnt pathway in differentiation and proliferation. SIGNIFICANCE: GREB1 is a liver cancer-specific Wnt signaling target gene that induces an oncogenic shift of HNF4α, a putative tumor suppressor, and may represent a therapeutic target in Wnt-activated hepatocellular carcinoma.

Gastric Carcinoma With Sebaceous Differentiation and SALL4 Expression.

A sebaceous carcinoma is rarely seen in extracutaneous sites. We present a 75-year-old man who was admitted with epigastralgia and melena. Endoscopic examination revealed an ulcer on the posterior wall of the gastric antrum, and distal gastrectomy was performed. Histopathological examination revealed thin to thick trabeculae of polygonal cells with scattered foci of foamy cells, whereas Sudan 3 staining showed lipid vacuoles. Immunohistochemistry was positive for both p40 and SALL4. After considering these findings, we suggest sebaceous differentiation as the diagnosis. To the best of our knowledge, this is the first case of gastric carcinoma with sebaceous differentiation.

Prognostic Impact of Malnutrition Diagnosed by the GLIM Criteria for Resected Extrahepatic Cholangiocarcinoma.

BACKGROUND/AIM: Recently, the Global Leadership Initiative on Malnutrition (GLIM), which includes the world's leading clinical nutrition societies, proposed the first global diagnostic criteria for malnutrition. However, the association between malnutrition diagnosed by the GLIM criteria and prognosis in patients with resected extrahepatic cholangiocarcinoma (ECC) remains unknown. This study aimed to investigate the predictive validity of the GLIM criteria for the prognosis of patients with resected ECC. PATIENTS AND METHODS: Between 2000 and 2020, 166 patients who underwent curative-intent resection for ECC were retrospectively analyzed. Prognostic significance of preoperative malnutrition diagnosed by the GLIM criteria was investigated using a multivariate Cox proportional hazards model. RESULTS: Eighty-five (51.2%) and 46 (27.7%) patients were diagnosed with moderate and severe malnutrition, respectively. Increased malnutrition severity tended to be correlated with increased lymph node metastasis rate (p-for-trend=0.0381). The severe malnutrition group had worse 1-, 3-, and 5-year overall survival rates than the normal (without malnutrition) group (82.2% vs. 91.2%, 45.6% vs. 65.1%, 29.3% vs. 61.5%, respectively, p=0.0159). In multivariate analysis, preoperative severe malnutrition was an independent predictor for poor prognosis (hazard ratio=1.68, 95% confidence interval=1.06-2.66, p=0.0282), along with intraoperative blood loss >1,000 ml, lymph node metastasis, perineural invasion, and curability. CONCLUSION: Severe preoperative malnutrition diagnosed by the GLIM criteria was associated with poor prognosis in patients who underwent curative-intent resection for ECC.

Diagnostic usefulness of SpyGlass in intracholecystic papillary neoplasm with pancreaticobiliary maljunction: a case report and comparison with conventional gallbladder cancer with pancreaticobiliary maljunction.

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is one of the precursors of gallbladder cancer defined in the 2010 World Health Organization classification of tumors. We herein report ICPN with pancreaticobiliary maljunction (PBM), which is a high-risk factor for biliary cancer. CASE PRESENTATION: A 57-year-old female presented with abdominal pain. Computed tomography showed a swollen appendix and gallbladder nodules with bile duct dilatation. Endoscopic ultrasonography revealed a gallbladder tumor spreading into the cystic duct confluence accompanying PBM. Based on papillary tumors around the cystic duct detected using the SpyGlass DS II Direct Visualization System (SpyGlass DS), ICPN was suspected. We performed extended cholecystectomy, extrahepatic bile duct resection, and appendectomy with a diagnosis of ICPN and PBM. The pathological diagnosis was ICPN (90 × 50 mm) with high-grade dysplasia spreading into the common bile duct. The absence of residual cancer in the resected specimen was pathologically confirmed. P53 staining was totally negative in both the tumor and normal epithelium. The overexpression of CTNNB1 was not observed. CONCLUSIONS: We encountered a patient with a very rare gallbladder tumor, ICPN with PBM. SpyGlass DS contributed to a precise assessment of the extent of the tumor as well as a qualitative diagnosis.

Neoplastic Progression in Intraductal Papillary Neoplasm of the Bile Duct.

CONTEXT.­: Intraductal papillary neoplasm of the bile duct (IPNB) is classified into types 1 and 2 based on criteria proposed in 2019. Recent studies investigated the clinicopathologic and molecular features of IPNB, which contributed to a more detailed understanding of this undercharacterized neoplasm. OBJECTIVE.­: To summarize driver gene mutations, radiologic tumor evolution, and a potentially unique pattern of tumor progression in IPNB. DATA SOURCES.­: Data were derived from a literature review and personal clinical and research experiences. CONCLUSIONS.­: In contrast to de novo cholangiocarcinoma, type 1 IPNB often has mutations in APC, CTNNB1, STK11, and GNAS. These molecular features are shared with intraductal papillary mucinous neoplasm of the pancreas; however, the frequencies of individual gene abnormalities differ between these 2 neoplasms. A radiologic review of sequential images suggested that type 1 IPNB is a slow-growing neoplasm, with an ∼1-cm increase in size every 2 to 3 years, and remains in a noninvasive state for many years. A similar papillary neoplasm may develop in the biliary tree years after the complete surgical resection of IPNB. The second neoplasm has the same genetic abnormalities as the first neoplasm, indicating intrabiliary implantation rather than multifocal lesions. In contrast to type 1 IPNB, most cases of type 2 IPNB have invasive malignancy at the initial presentation. Type 2 IPNB shares many clinicopathologic and molecular features with de novo cholangiocarcinoma, questioning the distinctness of this tumor entity. The molecular mechanisms underlying malignant transformation in IPNB warrant further study.

DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness.

Hepatocellular carcinoma (HCC) is the most prevalent malignant liver neoplasm. Despite the advances in diagnosis and treatment, the prognosis of HCC patients remains poor. Cytoskeleton-associated membrane protein 4 (CKAP4) is a receptor of the glycosylated secretory protein Dickkopf-1 (DKK1), and the DKK1-CKAP4 axis is activated in pancreatic, lung, and esophageal cancer cells. Expression of DKK1 and CKAP4 has been examined in HCC in independent studies that yielded contradictory results. In this study, the relationship between the DKK1-CKAP4 axis and HCC was comprehensively examined. In 412 HCC cases, patients whose tumors were positive for both DKK1 and CKAP4 had a poor prognosis compared to those who were positive for only one of these markers or negative for both. Deletion of either DKK1 or CKAP4 inhibited HCC cell growth. In contrast to WT DKK1, DKK1 lacking the CKAP4 binding region did not rescue the phenotypes caused by DKK1 depletion, suggesting that binding of DKK1 to CKAP4 is required for HCC cell proliferation. Anti-CKAP4 Ab inhibited HCC growth, and its antitumor effect was clearly enhanced when combined with lenvatinib, a multikinase inhibitor. These results indicate that simultaneous expression of DKK1 and CKAP4 is involved in the aggressiveness of HCC, and that the combination of anti-CKAP4 Ab and other therapeutics including lenvatinib could represent a promising strategy for treating advanced HCC.

[A Case of Ampullary Carcinoma with Celiac Axis Stenosis That Underwent Pancreaticoduodenectomy and Arterial Reconstruction].

A 72-year-old male patient presented with obstructive jaundice and was diagnosed with ampullary carcinoma. Contrast- enhanced computed tomography(CT)showed stenosis of the common hepatic artery and dilatation of the pancreaticoduodenal arcade(PDA)due to celiac axis stenosis(CAS)at the origin, suggesting that hepatic artery blood flow was supplied from the superior mesenteric artery via the PDA. Since calcification of the arterial wall was observed at the origin of the celiac artery(CA), the cause of the CAS was diagnosed as atherosclerotic. An intraoperative gastroduodenal artery(GDA) clamp test showed no obvious decrease in hepatic arterial blood flow. However, because of concerns about the postoperative patency of the CA, an inferior pancreaticoduodenal artery-GDA bypass using the left great saphenous vein and subtotal stomach-preserving pancreaticoduodenectomy were performed. The postoperative course was uneventful. When pancreaticoduodenectomy is performed in patients with atherosclerotic CAS, this arterial reconstruction method can be considered as an option.

A good surgical field for para-aortic nodal dissection in gastric cancer by the Cattell-Braasch maneuver.

PURPOSE: Gastric cancer patients with para-aortic lymph node metastases may achieve long-term survival with radical gastrectomy and para-aortic lymph nodal dissection (PAND) following neoadjuvant therapy. We introduced the Cattell-Braasch maneuver to facilitate safe and complete PAND for advanced gastric cancer with extensive lymph node metastases. METHODS: Between January 2014 and March 2020, 7 patients with highly advanced gastric cancer received preoperative chemotherapy followed by radical gastrectomy and PAND using the Cattell-Braasch maneuver. This maneuver consists of mobilization of the right hemi-colon and the total small intestine. RESULTS: Five patients received preoperative chemotherapy for para-aortic lymph node metastases and 2 for bulky lymph node metastases around the supra-pancreatic area. All patients received S-1 + cisplatin therapy, and one was additionally treated with paclitaxel chemotherapy followed by nivolumab. After chemotherapy, 2 patients with para-aortic lymph node metastases achieved down-staging on imaging tests. Total gastrectomy with PAND by the Cattell-Braasch maneuver was performed on all patients and was accompanied by splenectomy (n = 5) and distal pancreatectomy (n = 1). Pathological assessments revealed that 3 patients had para-aortic lymph node metastases, and the median number of retrieved para-aortic lymph nodes was 16. Three patients without para-aortic lymph node metastasis survived for more than 5 years without recurrence. CONCLUSION: The Cattell-Braasch maneuver provides a good surgical field and is useful for complete PAND for gastric cancer.

Aggressive behavior of anaplastic undifferentiated carcinoma arising from the hilar bile duct.

BACKGROUND: Undifferentiated carcinoma of the biliary tree is extremely rare, and biliary undifferentiated carcinoma mostly originates from the gallbladder. We herein present a case of anaplastic undifferentiated carcinoma of the hilar bile duct and reviewed the literature. CASE PRESENTATION: The patient was an 81-year-old male with obstructive jaundice. Contrast-enhanced computed tomography (CT) showed a protruded tumor located at the hepatic hilum. Obstructive jaundice was relieved by endoscopic drainage. Endoscopic biopsy revealed carcinoma without glandular differentiation, and the patient was diagnosed with resectable hilar undifferentiated carcinoma. During the 5-week preoperative examination, the tumor increased in size from 23 to 45 mm. Left hemi-hepatectomy and extrahepatic bile duct resection were performed, and there were no postoperative complications. Histological findings demonstrated that the tumor was mainly composed of non-cohesive polygonal neoplasms with pleomorphic nuclei, and was diagnosed as anaplastic undifferentiated carcinoma of the common hepatic duct (T2a N0 M0 Stage II). One month after surgery, the patient was readmitted to our hospital with pyrexia due to cholangitis, and liver nodules suggestive of multiple liver metastases were detected by CT. Three months after surgery, the patient died of multiple liver metastases. CONCLUSIONS: This is the first case report of undifferentiated cholangiocarcinoma with anaplastic features. Anaplastic undifferentiated carcinoma of the hilar bile duct showed preoperative rapid growth and early relapse despite a cancer-negative surgical margin.

Epigenetic upregulation of TET2 is an independent poor prognostic factor for intrahepatic cholangiocarcinoma.

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Anatomical change of SMV branches after the Cattell Braasch maneuver facilitates safe resection around the uncinated process in pancreatoduodenectomy.

BACKGROUND: The aims of the present study were to demonstrate the anatomical change of superior mesenteric vein (SMV) branches and to show how the Cattell Braasch maneuver facilitates a safer ligation of these venous branches during a pancreatoduodenectomy (PD). METHODS: Between January 2010 and December 2019, 97 patients with peripancreatic tumors underwent pancreatectomy. We retrospectively reviewed preoperative triple-phase enhanced computed tomography (CT) images and analyzed variations in SMV branches. Anatomical changes in SMV branches after the Cattell Braasch technique were observed using our operation video and illustrations. RESULTS: The first jejunal vein (J1v) in 75% of patients ran posterior to the superior mesenteric artery (SMA), while the remainder (25%) ran anterior to it. The inferior pancreatoduodenal vein (IPDV) was preoperatively detected in 91% of patients. The IPDV drained into the J1v in 74% of patients and into the SMV in 37%. After the Cattell Braasch maneuver, the J1v which ran posterior to the SMA now was found to lie to the right anterolateral side the SMA and the visualization of both the J1v and the IPDV were much more clearly visualized. CONCLUSIONS: The most frequent venous variation was the IPDV draining into the J1v posterior to the SMA. After the Cattell Braasch maneuver, the IPDV was now located to the right anterolateral anterior aspect of the SMA which facilitates its visualization and should allow a safer ligation.

A case report of a gastrobronchial fistula and lung abscess caused by leakage from the staple line of a gastric tube after esophagectomy for esophageal cancer.

BACKGROUND: Gastrobronchial fistulas are rare, but life-threatening, complications of esophagectomy. They are caused by anastomotic leakage and mainly occur around anastomotic sites. In the present paper, we report a rare case of leakage from the staple line of a gastric tube after esophagectomy for esophageal cancer, which was successfully treated using an intercostal muscle flap and lung resection. CASE PRESENTATION: A 61-year-old male underwent subtotal esophagectomy with regional lymphadenectomy for esophageal cancer. The sutures along the staple line of the gastric tube failed 11 days after surgery, and a pulmonary abscess was also found on imaging. The abscess did not heal after conservative treatment; therefore, right lower lobectomy, gastrobronchial fistula resection, primary closure, and patching of the leaking portion of the gastric tube with an intercostal muscle flap were performed 9 months after the first operation. The patient's postoperative course was uneventful, and he was discharged on the 354th day. CONCLUSIONS: We experienced a case involving a gastrobronchial fistula caused by leakage from the staple line of a gastric tube and successfully treated it by performing right lower lobectomy and patching the leak with an intercostal muscle flap.

An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping.

This study aimed to establish an immunohistochemical panel useful for subclassification of intrahepatic cholangiocarcinoma (iCCA) into small- and large-duct types. Fifty surgical cases of iCCA consisting of small- (n = 31) and large-duct types (n = 19) were examined. To imitate liver needle biopsies, tissue microarrays were constructed using three tissue cores (2 mm in diameter) obtained from one representative paraffin block of each case. Immunostaining for C-reactive protein (CRP), N-cadherin, tubulin beta-III (TUBB3), neural cell adhesion molecule (NCAM), and S100 calcium binding protein P (S100P) was conducted. Most cases of small-duct iCCA were immunoreactive to CRP and N-cadherin, whereas expressions of these markers were markedly less common in large-duct iCCA (CRP, 97% vs. 5%, P < 0.001; N-cadherin, 87% vs. 16%, P < 0.001). TUBB3 and NCAM were also more frequently expressed in small-duct iCCA (65% vs. 32%, P = 0.006; 58% vs. 5%, P < 0.001), but their sensitivities were lower than those of CRP and N-cadherin. S100P was more commonly expressed in large-duct iCCA than in small-duct iCCA (95% vs. 29%, P < 0.001), and diffuse expressions were observed in 17 of 19 cases of large-duct iCCA (90%). All cases with a CRP+/S100P- immunophenotype were of small-duct type, whereas all but one case with a CRP-/S100P+ immunophenotype were of large-duct type. Of 10 cases with a double-positive or double-negative immunophenotype, 7 were appropriately classified based on immunoreactivity to N-cadherin. In conclusion, CRP, N-cadherin, and S100P form a useful immunohistochemical panel for iCCA subclassification, and correct subclassification was possible in 92% of cases based on a proposed, simple algorithm.

Neuroendocrine carcinoma and mixed neuroendocrine‒non-neuroendocrine neoplasm of the stomach: a clinicopathological and exome sequencing study.

The gene mutation profiles of gastric neuroendocrine neoplasms are incompletely understood. The purpose of this study was to characterize the molecular pathology of poorly differentiated neuroendocrine carcinoma (NEC) and mixed neuroendocrine‒non-neuroendocrine neoplasm (MiNEN) of the stomach. Surgical cases of gastric NEC (n = 7) and MiNEN (n = 6) were examined by clinical review, immunohistochemistry, microsatellite instability (MSI) analysis and whole-exome sequencing. NEC cases consisted of small- (n = 2) and large-cell types (n = 4). All cases of MiNEN were histologically composed of large-cell type NEC and tubular adenocarcinoma. Whole-exome sequencing analysis detected recurrent mutations in TP53 in 8 cases (62%), and they were more frequently observed in MiNEN than in NEC (100% vs. 29%). Frameshift mutations of APC were observed in two cases of MiNEN. One case of large-cell type NEC had a frameshift mutation with loss of heterozygosity in RB1. The other mutated genes (e.g., ARID1 and KRAS) were detected in a single case each. A high level of MSI was confirmed in one case of MiNEN, which harbored mutations in two well-differentiated neuroendocrine tumor (NET)-related genes (MEN1 and ATRX1). In cases of MiNEN, two histological components shared mutations in TP53, APC and ZNF521, whereas alterations in CTNNB1, KMT2C, PTEN and SPEN were observed in neuroendocrine components only. In conclusion, TP53 is a single, frequently mutated gene in gastric NEC and MiNEN, and alterations in other genes are less common, resembling the mutation profiles of gastric adenocarcinomas. Gene mutations frequently observed in well-differentiated NET were uncommon but not entirely exclusive.

Bochdalek hernia in an adult: two case reports and a review of perioperative cardiopulmonary complications.

BACKGROUND: Bochdalek hernia in an adult is very rare and often needs an immediate surgical repair for the herniation. Although its etiology and surgical techniques have frequently been reported, perioperative complications, especially cardiopulmonary problems, remain unknown. We reported two adults with Bochdalek hernia and reviewed the published literatures with a focus on these issues. CASE PRESENTATION: We experienced two adult cases of Bochdalek hernia with gastrointestinal strangulation. One case had massive herniation of the stomach, colon, spleen, and pancreas in the left chest, causing repeated vomiting. The other had a right-side hernia with strangulation of the colon. We successfully performed emergency repairs of these diaphragmatic hernias without any postoperative complications. CONCLUSIONS: Our literature review revealed that life-threatening cardiopulmonary complications, such as empyema or cardiac arrest caused by the tamponade effect of the herniated viscera, sometimes occurred in patients with Bochdalek hernia. These complications were found in Bochdalek hernia with gastrointestinal strangulation.

Biliary intraductal tubule-forming neoplasm: a whole exome sequencing study of MUC5AC-positive and -negative cases.

AIMS: Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear, although some pathologists may classify these as 'intraductal papillary neoplasms of the bile duct (IPNBs) of gastric type'. This study aimed to elucidate genetic features of biliary intraductal tubular neoplasms. METHODS AND RESULTS: Six resected cases of biliary intraductal neoplasm with >70% tubular configuration were characterised by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n = 2) and -positive cases (n = 4). The intraductal tumours consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n = 2), perihilar (n = 1) and distal bile ducts (n = 1). In an exome-sequencing study, MUC5AC-negative cases harboured mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas. CONCLUSIONS: This exome-sequencing study suggested that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.