Search

Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.Significance:GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic and epigenomic features.This article is highlighted in the In This Issue feature, p. 587

Supplementary Data from Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System

In preparing the Japanese (JPN) guidelines for the management of acute pancreatitis 2021, the committee focused the issues raised by the results of nationwide epidemiological survey in 2016 in Japan.In addition to a systematic search using the previous JPN guidelines, papers published from January 2014 to September 2019 were searched for the contents to be covered by the guidelines based on the concept of GRADE system.Thirty-six clinical questions (CQ) were prepared in 15 subject areas. Based on the facts that patients diagnosed with severe disease by both Japanese prognostic factor score and contrast-enhanced computed tomography (CT) grade had a high fatality rate and that little prognosis improvement after 2 weeks of disease onset was not obtained, we emphasized the importance of Pancreatitis Bundles, which were shown to be effective in improving prognosis, and the CQ sections for local pancreatic complications had been expanded to ensure adoption of a step-up approach. Furthermore, on the facts that enteral nutrition for severe acute pancreatitis was not started early within 48 h of admission and that unnecessary prophylactic antibiotics was used in almost all cases, we emphasized early enteral nutrition in small amounts even if gastric feeding is used and no prophylactic antibiotics are administered in mild pancreatitis.All the members of the committee have put a lot of effort into preparing the extensively revised guidelines in the hope that more people will have a common understanding and that better medical care will be spread.

Preoperative treatment is being proposed as a standard treatment for pancreatic ductal adenocarcinoma though few cases show a pathologically complete response. On the other hand, there is no consensus regarding preoperative chemotherapy for pancreatic acinar cell carcinoma (ACC). The present study described a rare case of ACC in the pancreatic head with portal vein tumor thrombosis (PVTT) treated with preoperative chemotherapy using modified FOLFIRINOX, which achieved a pathologically complete response. A 65-year-old man was referred for consideration of treatment strategy. Contrast-enhanced abdominal computed tomography revealed a pancreatic tumor and PVTT. The pancreatic tumor was diagnosed as ACC by an endoscopic ultrasound-guided fine-needle aspiration biopsy. Initially, the tumor was assessed as unresectable due to the presence of PVTT, and therefore, a chemotherapy using modified FOLFIRINOX was administered. After 14 courses of the chemotherapy, imaging studies revealed that the tumor and PVTT showed marked reduction in size; thus, the patient underwent pancreaticoduodenectomy with combined resection of the portal vein (PV). A pathological examination uncovered a complete degeneration of the primary tumor and the PV embolus without any residue of carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for 33 months after surgery. The chemotherapy using modified FOLFIRINOX could give a complete response in patients with pancreatic ACC with PVTT.

Background: Gemcitabine together with nab-paclitaxel (GnP) has been shown to improve outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). However, the predictive markers for treatment effects remain unclear. This study aimed to identify early prognostic factors in patients with PDAC receiving GnP. Patients and Methods: We analyzed 113 patients who received GnP for PDAC and evaluated the relationship between clinical factors and outcomes. Results: The median survival time (MST) was 1.2 years. In multivariate analysis, baseline carbohydrate antigen 19-9 (CA19-9) ≥747 U/ml [hazard ratio (HR)=1.9], baseline controlling nutrition status (CONUT) score ≥5 (HR=3.7) and changing rate of CA19-9 after two GnP cycles ≥0.69 (HR=3.7) were independent risk factors for poor prognosis. When examining outcomes according to pre-chemotherapeutic measurable factors (baseline CA19-9 and CONUT), the MSTs of patients with pre-chemotherapeutic zero risk factors (pre-low-risk group, n=63) and one or more risk factors (pre-high-risk group, n=50) were 1.7 and 0.65 years (p

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

A double helicene with a spiro-Si linker ( 4 ) was synthesized by four successive nucleophilic substitutions on SiCl 4 . Its ( P,P ), ( M,M ) and ( P,M ) isomers were isolated and characterized by single crystal X-ray analysis. Due to the central spirosilabi[fluorene] moiety, the two helicene units in 4 are symmetrically and nearly perpendicularly arranged. ( P,P )- 4 and ( M,M )- 4 exhibit unique optical properties attributable to the LUMO spiro-conjugation between the two sila[7]helicene units.

The controlling nutritional status (CONUT) score is a useful biomarker to evaluate undernutrition. However, there have been few reports describing the correlation between postoperative complications and the CONUT score for pancreatic cancer. Therefore, this study aimed to assess the impact of the CONUT score on the postoperative complications of pancreaticoduodenectomy (PD) in patients with pancreatic cancer. We retrospectively analyzed 206 consecutive patients with pancreatic cancer who underwent PD over a 12-year duration at our institution. The patients were divided into two groups based on preoperative CONUT scores; their clinicopathological characteristics and surgical outcomes were compared. Furthermore, we compared the CONUT score with preoperative clinical factors and several nutritional biomarkers for postoperative complications using univariate and multivariate analyses. Postoperative complications of Clavien–Dindo grade ≥ IIIa and those of Clavien–Dindo grade ≥ IIIb occurred in 29 (14.1%) and 9 (4.4%) patients, respectively. The high CONUT score (≥5) group indicated that patients with an undernutrition status had a higher postoperative complication rate, poorer relapse-free survival, and overall survival rates than the low CONUT score (≤4) group. Among preoperative clinical factors, a high CONUT score was an independent risk factor for severe postoperative complications. The CONUT score may be a useful parameter in the identification of patients undergoing pancreatic surgery who are susceptible to postoperative complications.

Background: MicroRNA-665 (miR-665), an intracellular inhibitor of pancreatic cancer (PC) cells, might be a potential biomarker to detect pancreatobiliary cancer (PBca). We sought to determine the diagnostic ability of miR-665 as a serum biomarker for PBca, and to explore the role of miR-665 in PC. Methods: This multicenter study enrolled patients with treatment-naïve PBca and healthy participants. PBca-related serum miRNAs were determined using weighted co-expression network analysis of a comprehensive serum miRNA microarray dataset in an exploratory cohort. Using various combinations of PBca-related serum miRNAs, Fisher’s linear discriminant analyses provided miRNA signatures to discriminate PBca from healthy controls. MiRNA signatures with a sensitivity/specificity (SN/SP) of ≥80/80% and high AUC in comparison with the AUC of CA19-9 were defined as the diagnostic miRNA signature in exploratory, validation and independent validation cohorts, whose accuracy was confirmed by 5-fold cross validation. Biology of the diagnostic miRNAs was evaluated using biopsy samples from liver metastasis of PC patients and human PC cells. Results: We analyzed 496 of 1487 enrolled subjects (150 healthy and 134 PBca, 50 healthy and 47 PBca, and 50 healthy and 46 PBca subjects in the exploratory, validation and independent validation cohorts, respectively). Among miRNA signatures from 82 PBca-related miRNAs, a five serum miRNA combination containing miR-665 was identified as the diagnostic miRNA signature in all three cohorts. SN/SP and AUC in the validation and independent validation cohorts were 92/88% and 0.95 (CA19-9: 81/92% and 0.94) and 87/80% and 0.91 (CA19-9: 80/98% and 0.87), respectively. In sub-population analysis for detecting 48 resectable PCs, the discriminative ability of the diagnostic miRNA signature plus CA19-9 (SN/SP: 90/78%) was superior in sensitivity to that of CA19-9 alone (60/94%). In seven PC patients with liver metastasis, high expression of intratumor miR-665 tended to correlate with high serum miR-665 level (r = 0.56) and low expression of intratumor phospho-Erk expression (r = 0.57). Transfection of miR-665 to a human PC cell led to cell growth suppression. Conclusions: This study identified the diagnostic ability of a tumor suppressor miR-665-based serum miRNA signature for PBca. For detecting resectable PC, a miR-665-based serum miRNA signature plus CA19-9 is a superior biomarker to CA19-9 alone. Citation Format: Shuichi Mitsunaga, Makoto Ueno, Masahiro Tsuda, Takamichi Kuwahara, Yukiko Takayama, Keiji Hanada, Hitoshi Yoshida, Kenji Takahashi, Kohei Nakata, Hideaki Iwama, Masafumi Ikeda, Satoshi Kobayashi, Ikuya Miki, Kazuo Hara, Ryota Higuchi, Akinori Shimizu, Tomohiro Nomoto, Hidetaka Iwamoto, Masafumi Nakamura, Etsuro Hatano, Hiroko Sudo, Satoko Takizawa, Atsushi Ochiai. Tumor suppressor miRNA-665 based serum biomarker for detecting pancreatobiliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6686.

To evaluate the surgical outcomes of patients with gallbladder cancer (GBC) with jaundice due to as-yet unelucidated prognostic factors. A total of 348 GBC patients underwent resection at our institute between 1985 and 2016. Of these, 67 had jaundice (serum total bilirubin ≥ 2 mg/dL). Preoperative biliary drainage was performed, with portal vein embolization as required. All patients underwent radical surgery. We retrospectively evaluated the outcomes, performed multivariate analysis for overall survival, and compared our findings to those reported in the literature. The 5-year survival rate of M0 (no distant metastasis) GBC patients with jaundice, who underwent resectional surgery, was 21.9%, versus 68.3% in those without jaundice (p < 0.05). Since 2000, surgical mortality in GBC patients with jaundice has decreased from 12 to 6.8%. Patients with jaundice had more advanced disease and underwent major hepatectomies and vascular resections; however, preoperative jaundice alone was not a prognostic factor. Multivariate analysis of jaundiced patients revealed that percutaneous biliary drainage (PTBD) (vis-a-vis endoscopic drainage [EBD], hazard ratio [HR] 2.82), postoperative morbidity (Clavien–Dindo classification ≥ 3, HR 2.31), and distant metastasis (HR 1.85) were predictors of poor long-term survival. The 5-year survival and peritoneal recurrence rates in M0 patients with jaundice were 16% and 44%, respectively, for patients with PTBD and 39% (p < 0.05) and 13% (p = 0.07) for those with EBD. M0 GBC patients with jaundice should undergo surgery if R0 resection is possible. Preoperative EBD may be superior to PTBD in M0 GBC patients with jaundice, although further studies are needed.

Background Minimally invasive pancreaticoduodenectomy (MIPD) has recently been safely performed by experts, and various methods for resection have been reported. This review summarizes the literature describing surgical approaches for MIPD. Methods A systematic literature search of PubMed (MEDLINE) was conducted for studies reporting robotic and laparoscopic pancreaticoduodenectomy; the reference lists of review articles were searched. Of 444 articles yielded, 23 manuscripts describing the surgical approach to dissect around the superior mesenteric artery (SMA), including hand-searched articles, were assessed. Results Various approaches to dissect around the SMA have been reported. These approaches were categorized according to the direction toward the SMA when initiating dissection around the SMA: anterior approach (two articles), posterior approach (four articles), right approach (16 articles), and left approach (three articles). Thus, many reports used the right approach. Most articles provided a technical description. Some articles showed the advantage of their method in a comparison study. However, these were single-center retrospective studies with a small sample size. Conclusions Various approaches for MIPD have been reported; however, few authors have reported the advantage of their methods compared to other methods. Further discussion is needed to clarify the appropriate surgical approach to the SMA during MIPD.

To evaluate the incidence, risk factors, management options, and outcomes of portal vein thrombosis following major hepatectomy for perihilar cholangiocarcinoma.A total of 177 perihilar cholangiocarcinoma patients who (1) underwent major hepatectomy and (2) underwent investigating the portal vein morphology, which was measured by rotating the reconstructed three-dimensional images after facilitating bone removal using Aquarius iNtuition workstation between 2002 and 2018, were included. Risk factors were evaluated using the Kaplan-Meier method and Cox proportional hazard models.Six patients developed portal vein thrombosis (3.4%) within a median time of 6.5 (range 0-22) days. Portal vein and hepatic artery resection were performed in 30% and 6% patients, respectively. A significant difference in the probability of the occurrence of portal vein thrombosis (PV) within 30 days was found among patients with portal vein resection, a postoperative portal vein angle100°, remnant portal vein diameter5.77 mm, main portal vein diameter13.4 mm, and blood loss (log-rank test, p = 0.003, p = 0.06, p0.0001, p = 0.01, and p = 0.03, respectively). Decreasing the portal vein angle and narrowing of the remnant PV diameter remained significant predictors on multivariate analysis (p = 0.027 and 0.002, respectively). Reoperation with thrombectomy was performed in four patients, and the other two patients were successfully treated with anticoagulants. All six patients subsequently recovered and were discharged between 25 and 70 days postoperatively.Narrowing of the remnant portal vein diameter and a decreased portal vein angle after major hepatectomy for perihilar cholangiocarcinoma are significant independent risk factors for postoperative portal vein thrombosis.

The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract cancers (cholangiocarcinoma, gallbladder cancer, and ampullary cancer) in 2007, then published the 2nd version in 2014.In this 3rd version, clinical questions (CQs) were proposed on six topics. The recommendation, grade for recommendation, and statement for each CQ were discussed and finalized by an evidence-based approach. Recommendations were graded as Grade 1 (strong) or Grade 2 (weak) according to the concepts of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.The 31 CQs covered the six topics: (a) prophylactic treatment, (b) diagnosis, (c) biliary drainage, (d) surgical treatment, (e) chemotherapy, and (f) radiation therapy. In the 31 CQs, 14 recommendations were rated strong and 14 recommendations weak. The remaining three CQs had no recommendation. Each CQ includes a statement of how the recommendations were graded.This latest guideline provides recommendations for important clinical aspects based on evidence. Future collaboration with the cancer registry will be key for assessing the guidelines and establishing new evidence.

Background Upfront surgery is the standard treatment for resectable invasive intraductal papillary mucinous carcinoma; however, recurrence is common. Therefore, we investigated the recurrence, surgical outcome, and preoperative prognostic factors for recurrence in patients with resectable invasive intraductal papillary mucinous carcinoma. Methods We analyzed 111 patients who underwent upfront surgery for resectable invasive intraductal papillary mucinous carcinoma between 2000 and 2017 and evaluated the relationship among clinicopathologic factors, recurrence, and outcomes. Results The 5-year recurrence-free survival and disease-specific survival rates were 61% and 74%, respectively. The median time to recurrence was 1.1 years. In multivariate analysis, carbohydrate antigen 19-9 ≥83 U/mL (hazard ratio: 2.8 and 3.1), tumor size ≥2.2 cm (hazard ratio: 3.5 and 4.7), and pathologic tubular adenocarcinoma grade 2 (hazard ratio: 3.1 and 5.2) were risk factors for a shorter recurrence-free survival and disease-specific survival, respectively. Lymph node metastasis (hazard ratio: 3.9) was also a risk factor for a shorter disease-specific survival. When examining outcomes according to preoperatively measurable factors (carbohydrate antigen 19-9 ≥83 U/mL and tumor size ≥2.2 cm), the 5-year recurrence rates in patients with none (n = 47), 1 (n = 46), and both (n = 18) risk factors were 17%, 48%, and 78%, respectively. Five-year disease-specific survival rates in patients with none, 1, and both preoperative risk factors were 95%, 69%, and 31%, respectively. Conclusion Carbohydrate antigen 19-9 ≥83 U/mL and tumor size ≥2.2 cm were independent preoperative risk factors for poor outcomes in patients with resectable invasive intraductal papillary mucinous carcinoma.

Objective The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. Summary of background data Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. Methods We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. Results Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. Conclusions Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.

To date, postoperative prognostic factors for intraductal papillary neoplasm of the bile duct (IPNB) have not been well-established. This study aimed to examine the histopathologic features and postoperative prognosis of the two IPNB subclassifications, as well as factors affecting prognosis, based on the authors’ experience at a single institution. The study enrolled 83 patients who underwent surgical resection for pathologically diagnosed IPNB at the authors’ institution. The clinicopathologic features and postoperative outcomes for these patients were examined. The study also investigated postoperative prognostic factors for IPNB using uni- and multivariate analyses. More than half of the tumors (64%) diagnosed as IPNB were early-stage cancer (UICC Tis or T1). However, none were diagnosed as benign. The multivariate analysis showed that lymph node metastasis (hazard ratio [HR], 5.78; p = 0.002) and bile duct margin status with carcinoma in situ (D-CIS; HR, 5.10; p = 0.002) were independent prognostic factors, whereas MUC6 expression showed only a marginal influence on prediction of prognosis (HR, 0.32; p = 0.07). The tumor recurrence rate and the proportion of locoregional recurrence were significantly greater among the patients with D-CIS than among those with negative bile duct margins, including those patients with low-grade dysplasia. The patients with D-CIS showed a significantly poorer prognosis than those with negative bile duct margins (5-year survival, 38% versus 87%; p = 0.0002). Evaluation of resected IPNBs showed cancer in all cases. Avoiding positive biliary stumps during surgery, including resection of carcinoma in situ, would improve the prognosis for patients with IPNB.

Combined portal vein (PV) resection is performed for pancreatic head cancer to achieve clear resection margins. This can be complicated by the formation of varices due to sinistral portal hypertension after pancreaticoduodenectomy (PD) with combined PV resection. However, clinical strategies to prevent varices formation due to sinistral portal hypertension remain controversial. Moreover, the critical vein among splenic vein (SPV), inferior mesenteric vein, left gastric vein, or middle colonic vein requiring preservation to prevent the development of varices remains unclear.We retrospectively analyzed patients with pancreatic cancer who underwent PD with combined PV resection over 18 years at our institution. Varices were evaluated using enhanced computed tomography (CT) and endoscopy. Preoperative types of porto-mesenterico-splenic confluence, venous drainage, and venous resection types were determined by operative records and CT findings.Of the 108 subjects, the incidence of postoperative varices was observed in 24.1% of cases over 5.6 months. These varices were classified into five types based on location, as pancreaticojejunostomy anastomotic (11.5%), gastrojejunostomy anastomotic (11.5%), esophageal (11.5%), splenic hilar-gastric (23.1%), and right colonic (65.4%) varices. No case of variceal bleeding occurred. Multivariate analysis showed SPV ligation as the greatest risk factor of varices (P 0.001), with a higher incidence of left-sided varices in patients with all the SPV venous drainage sacrificed (60%) than in the others (16.7%). Therefore, sacrificing all the SPV venous drainage was the only independent risk factor of varices (P = 0.049).Preservation of SPV venous drainage should be considered during SPV ligation to prevent post-PD varices.

Background Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021). Methods Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network (SIGN) methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. Results Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts. Conclusions The expert consensus on precision anatomy for MIDP has been presented as a set of recommendations based on available evidence and expert opinions. These recommendations should guide experts and trainees in performing safe MIDP and foster its appropriate dissemination worldwide.

Background: Some prognostic factors for pancreatic neuroendocrine neoplasms (PanNENs) have been reported; however, the significance of lymphatic, microvascular, and perineural invasion remains unclear. We aimed to clarify the role of these factors in PanNEN recurrence. Patients and Methods: We analyzed 138 patients who underwent curative pancreatectomy and were pathologically diagnosed with PanNEN. We evaluated the association between clinicopathological factors and the recurrence of PanNENs. Results: The numbers of patients with lymphatic, microvascular, and perineural invasion were 34 (25%), 43 (31%) and 17 (12%), respectively. Twenty-four patients (17%) had recurrences, and the 3, 5, and 10-year recurrence-free survival (RFS) rates were 88%, 84%, and 76%, respectively. The recurrence sites (with duplication) were mainly the liver (twenty-two patients), followed by the lymph nodes (seven patients), and bone (two patients). In multivariate analyses, grade 2-3 and the presence of microvascular invasion were significant risk factors for RFS (hazard ratio=7.5 and 7.9, respectively). When examining outcomes according to these factors, the 5-year RFS rates of patients with risk scores of 0, 1, and 2 were 100%, 91%, and 32%, respectively (p

We aimed to evaluate pancreatic cancer (PC) with positive peritoneal lavage cytology (CY1) outcomes following a change in adjuvant therapy.The clinicopathological data of patients with pancreatic adenocarcinoma with CY1 at 14 institutions, between 2007 and 2015, were collected and analyzed.Of the 124 eligible patients, 114 underwent macroscopically curative resection. Of the 114 patients, 80 (70%) did not have early recurrence and received postoperative chemotherapy that was S-1 in 43 (54%), gemcitabine in 31 (39%), and others in six (7%). The median overall survival was 21.0 months in S-1 and 19.2 in gemcitabine therapy (p=0.23), whereas the median relapse-free survival was 10.2 and 7.1 months (p=0.03), respectively.Following the change in adjuvant therapy, most PC patients with CY1 who underwent macroscopically curative resection received S-1; however, it was insufficient. Further development of postoperative chemotherapy is required.

BACKGROUND Socratic method, which is an educational method to promote critical thinking through a dialogue, has never been practiced in a large number of people at the academic societies. METHODS Modified Socratic method was performed for the first time as an educational seminar using an example case of moderate acute cholecystitis based on the evidence described in Tokyo Guidelines 2018. We adopted a method that Takada had been modifying for many years: the instructor first knows the degree of recognition of the audience, then the instructor gives a lecture in an easy-to-understand manner and receives questions from the audience, followed by repeated questions and answers toward a common recognition. RESULTS Using slides, video, and an answer pad, 281 participants including the audience, instructors and moderators came together to repeatedly ask and answer questions in the five sessions related to the case scenario. The recognition rate of the topic of Critical View of Safety increased significantly before vs after this method (53.0% vs 90.3%). The seminar had been successfully performed by receiving a lot of praise from the participants. CONCLUSION This educational method is considered to be adopted by many academic societies in the future as an effective educational method.

BACKGROUND Prevention of bile duct injury and vasculo-biliary injury while performing laparoscopic cholecystectomy (LC) is an unsolved problem. Clarifying the surgical difficulty using intraoperative findings can greatly contribute to the pursuit of best practices for acute cholecystitis. In this study, multiple evaluators assessed surgical difficulty items in unedited videos and then constructed a proposed surgical difficulty grading. METHODS We previously assembled a library of typical video clips of the intraoperative findings for all LC surgical difficulty items in acute cholecystitis. Fifty-one experts on LC assessed unedited surgical videos. Inter-rater agreement was assessed by Fleiss's κ and Gwet's agreement coefficient (AC). RESULTS Except for one item ("edematous change"), κ or AC exceeded 0.5, so the typical videos were judged to be applicable. The conceivable surgical difficulty gradings were analyzed. According to the assessment of difficulty factors, we created a surgical difficulty grading system (agreement probability = 0.923, κ = 0.712, 90% CI: 0.587-0.837; AC2 = 0.870, 90% CI: 0.768-0.972). CONCLUSION The previously published video clip library and our novel surgical difficulty grading system should serve as a universal objective tool to assess surgical difficulty in LC.

Objective: Morphological subtyping of intraductal papillary mucinous neoplasms of the pancreas (IPMNs) into pancreatobiliary-type, intestinal-type, or gastric-type is a prognostic factor, however, molecular foundations explaining the difference of clinical behaviors are unknown. Our research aimed to elucidate the molecular phenotypes associated with subtypes of IPMNs and establish a risk stratification model. Design: In 171 IPMNs with high-grade dysplasia (HGD) and invasive carcinoma, we analyzed protein expressions of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry, and mutations and copy number variations of KRAS and GNAS by droplet digital PCR, and analyzed the association with clinicopathological factors. Results: In HGD components of IPMNs of pancreatobiliary- (n=66), intestinal- (n=70), and gastric-type (n=35), alterations were detected respectively as follows: KRAS mutation; 98%, 62%, and 83% (P Citation Format: Yuko Omori, Yusuke Ono, Takashi Kokumai, Fumiko Date, Ryota Higuchi, Goro Honda, Yusuke Mizukami, Takanori Morikawa, Michiaki Unno, Toru Furukawa. Molecular phenotyping and risk stratification of intraductal papillary mucinous neoplasms [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A081.

Objective: We compared the pathological features and stage-matched outcomes of patients with invasive intraductal papillary mucinous carcinoma (IPMC) and invasive ductal carcinoma (IDC) of ...

BACKGROUND In Japan, strategies for preoperative management of perihilar cholangiocarcinoma (PHC) have evolved over the last decade; the operative mortality has significantly reduced to

Highlights • Obstructive jaundice due to tumor thrombus in the common bile duct with HCC is classified as icteric-type HCC. • Biliary drainage for patients with icteric-type HCC is sometimes difficult. • A staged approach with initial tumor thrombectomy followed by hepatectomy should be considered as one of the options for icteric-type HCC., Introduction Biliary drainage for patients with icteric-type hepatocellular carcinoma (HCC) is sometimes difficult, because the drainage tube makes contact with the tumor thrombus (TT) and effective drainage cannot be achieved due to hemobilia. Presentation of case We performed endoscopic naso-biliary drainage for an icteric-type HCC patient; however, the serum bilirubin level was not decreased due to bleeding from the TT. Therefore, we performed tumor thrombectomy in the bile duct and transection of the right hepatic bile duct prior to right hepatectomy. After the first operation, the bilirubin level was decreased, and liver function was recovered so that the patient could undergo right hepatectomy 4 months after the first operation. The postoperative course was uneventful after the second operation and the patient was discharged from the hospital on the 30th postoperative day. The patient is well without recurrence 10 years after surgery. Conclusion Biliary drainage is one of the key points for successful treatment of icteric-type HCC patients. A staged approach with initial tumor thrombectomy followed by hepatectomy should be considered as one of the options for icteric-type HCC.

Background This study aimed to demonstrate the diagnostic ability of 64-row multidetector computed tomography (64-row MDCT) for longitudinal superficial extension of distal cholangiocarcinoma (LSEDC). Methods Twenty-seven patients with distal cholangiocarcinoma (DC) underwent preoperative 64-row MDCT without drainage tubes. LSEDC was diagnosed using curved planar reconstruction images reconstructed from 64-row MDCT, which were compared with pathologic findings. Results LSEDC was observed in 13 patients (48%). Ten patients (37%) had enhancing nonthickened bile ducts extending continuously from the main tumor (type 1). These coincided with pathologic findings of high-grade dysplasia (HGD) in 90.0% of cases; that is, a positive predictive value (9/10). Fourteen patients (52%) had only wall thickening of the main tumor with or without enhancement (type 2). Four patients with HGD in this group were difficult to diagnose. Three patients (11%) had enhancing nonthickened bile ducts not in continuity with the main tumor (type 3). This finding revealed an inflammatory change instead of a carcinoma in the pathologic findings. The sensitivity and specificity of detecting HGD were 75% and 93% on the liver side, 33% and 100% on the duodenal side, respectively. Four patients (67%) with HGD on the liver side were overdiagnosed, and one patient (17%) was underdiagnosed. Most of the patients overdiagnosed on the liver side (3/4 or 75%) had drainage tubes inserted before the MDCT. Conclusions For DC patients without drainage tubes, the 64-row MDCT technique may be useful for diagnosing HGD depicted as LSEDC on the liver side but not as useful on the duodenal side.

The neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare but highly malignant neoplasm. We analyzed 115 cases using whole-genome/exome sequencing, transcriptome sequencing, DNA methylation assays, and/or ATAC-seq and found GIS-NECs to be genetically distinct from neuroendocrine tumors (GIS-NET) in the same location. Clear genomic differences were also evident between pancreatic NECs (Panc-NEC) and nonpancreatic GIS-NECs (Nonpanc-NEC). Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, and most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1 or MYC. Alterations of the Notch gene family were characteristic of Nonpanc-NECs. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region. This first comprehensive study of genomic alterations in GIS-NECs uncovered several key biological processes underlying genesis of this very lethal form of cancer.Significance:GIS-NECs are genetically distinct from GIS-NETs. GIS-NECs arising in different organs show similar histopathologic features and share some genomic features, but considerable differences exist between Panc-NECs and Nonpanc-NECs. In addition, Panc-NECs could be classified into two subgroups (i.e., “ductal-type” and “acinar-type”) based on genomic and epigenomic features.This article is highlighted in the In This Issue feature, p. 587

Objective We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). Background STK11 is a tumor suppressor involved in certain IPMNs, however, its significance is not well known. Methods In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKα in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. Results Consistent loss or reduction of STK11 expression was observed in 26/184 (14%) IPMNs. These STK11-aberrant IPMNs were 17/45 (38%) pancreatobiliary, 8/27 (30%) oncocytic, 1/54 (2%) gastric, and 0/58 (0%) intestinal subtypes (P = 8.5E-11), and 20/66 (30%) invasive, 6/74 (8%) high-grade, and 0/44 (0%) low-grade (P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs (P = 4.1E-06). All STK11-aberrant IPMNs were GNAS-wild-type and 96% of them were KRAS or BRAF-mutant. Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKα was downregulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs (P = 3.6E-04 overall; P = 6.1E-04 disease-free). Conclusion STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.

Background We re-analyzed data on cholangio-venous reflux from a clinical study conducted prospectively on 22 patients in 1974. Method Direct cholangiography was performed with indocyanine green (ICG) mixed into UrographinR under monitoring of intrabiliary pressure, and the participants were allocated to three groups according to whether ICG leakage into the blood, signs of infection, or both, were present. Results The intrabiliary pressure of 6 patients negative for both ICG leakage and signs of infection was approximately 19.5 (median, [range 18 to 22]) cmH2 O. In contrast, for the 5 patients positive for ICG leakage but negative for signs of infection, the intrabiliary pressure was higher (median 32.0 [range 27 to 41) cmH2 O]. The 11 patients positive for both ICG leakage and signs of infection had the highest intrabiliary pressure (median 48.0 [range 33 to 77] cmH2 O). Our analyses revealed that, as the intrabiliary pressure increased, the status of ICG leakage and signs of infection appeared in a stepwise fashion. Conclusion Our findings suggest that the tight junctions sealing the bile canaliculi deteriorated with increasing intrabiliary pressure, resulting in reflux of the biliary contents into the vascular system via paracellular pathways between hepatocytes.

Background The anatomical structure around the pancreatic head is very complex, and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD. Methods Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. Results Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection. Conclusions MIPD experts suggest to surgical trainees to perform resection based on precise anatomical landmarks for safe and reliable MIPD.

The efficacy of different types of preoperative biliary drainage for cholangiocarcinoma has been debated over the past two decades. Controversy concerning the use of percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD) still exists. This study aimed to compare the long-term outcomes between PTBD and EBD in patients with distal cholangiocarcinoma. Data of patients diagnosed with distal cholangiocarcinoma who underwent preoperative PTBD or EBD from January 1999 to December 2017 were analyzed retrospectively. Post-surgical outcomes, including the incidence of post-operative complications, peritoneal metastasis, disease-free survival, and overall survival, were analyzed. Survival analyses were also performed after propensity score matching in the PTBD and EBD groups. The incidence of post-operative complications was similar in both groups. The 5-year estimated cumulative incidences for peritoneal metastasis were 14.7% and 7.2% in the PTBD and EBD groups, respectively (p = 0.192). The 5-year disease-free survival rates were 23.7% and 47.3% in the PTBD and EBD groups, respectively (p = 0.015). In the multi-variate analysis for overall survival, PTBD was an independent poor prognostic factor. The 5-year overall survival rates were 35.9% and 56.3% in the PTBD and EBD groups, respectively (hazard ratio 1.85, confidence interval 1.05–3.26, p = 0.035). The results after propensity score matching indicated a poorer prognosis in the PTBD group, with a 5-year survival rate of 35.9% in the PTBD group vs 56.0% in the EBD group (p = 0.044). PTBD should be considered as a negative prognostic factor in distal cholangiocarcinoma patients.

Although adjuvant chemotherapy is considered a standard treatment for resected pancreatic ductal adenocarcinoma (PDAC), its utility in stage ⅠA patients is unclear. We aimed to investigate the recurrence rate, surgical outcome, prognostic factors, effectiveness of adjuvant chemotherapy, and determination of groups in whom adjuvant chemotherapy is effective in patients with stage ⅠA PDAC.We retrospectively analyzed 73 patients who underwent pancreatectomy and were pathologically diagnosed with stage ⅠA PDAC between 2000 and 2018. We evaluated the relation between clinicopathological factors, recurrence rates, and outcomes such as the recurrence-free and disease-specific survival rates (RFS and DSS, respectively).The 5-year RFS and DSS rates were 52% and 58%, respectively. In multivariate analysis, a platelet-to-lymphocyte ratio (PLR) ≥ 170, prognostic nutrition index (PNI) 47.5, and pathological grade 2 or 3 constituted risk factors for a shorter DSS (hazard ratios: 4.7, 4.6, and 4.1, respectively). Patients with 0-1 of these risk factors (low-risk group; n = 47) had significantly higher 5-year DSS rates than those with 2-3 risk factors (high-risk group; n = 26) (80% vs. 23%; P 0.001). Patients in the low-risk group showed similar 5-year RFS rates regardless of whether they received or not adjuvant chemotherapy (75% vs 70%, respectively; P = 0.49). Contrarily, high-risk patients who underwent adjuvant chemotherapy had higher 5-year RFS rates than those who did not receive adjuvant chemotherapy (32% vs 0%; P = 0.045).In stage IA PDAC, adjuvant chemotherapy seems to be effective only in a subgroup of high-risk patients.

Background Pancreatobiliary cancer is a highly aggressive tumour with a dismal prognosis. Personalised medicine represents a promising and effective therapeutic approach for this intractable disease. In this study, we aimed to establish a system for identifying and testing genotype-oriented targeted drugs for pancreatobiliary cancers by combining exome sequencing and organoid culture of primary tumours. Methods Tumour cells isolated from resected tumours were subjected to organoid cultures based on published protocols with modifications. Exome sequencing was performed on the primary tumours. Histopathological and molecular features of the primary tumours were validated in the corresponding organoids. Genotype-oriented candidate targeted drugs were identified from exome sequencing, and their efficacies were tested in the organoids. Results Organoid cultures succeeded in 30 of 54 (55.6%) cases. Six primary cancers of the biliary tract and gall bladder were subjected to exome sequencing, which revealed a variety of somatic mutations of genes involved in signalling pathways, epigenetic modifiers, genome maintenance and metabolic enzymes. Most of the organoids of these 6 cases showed identical histopathological features and genomic aberrations as those of the primary tumours. Some of the aberrations were candidates for targeted therapies. Integrin-linked kinase (ILK) was one such candidate target, and an ILK inhibitor was confirmed to suppress proliferation of patient-derived organoids. Conclusions By combining exome sequencing and organoid culture, our model enabled to identify genotype-oriented targets for personalised medicine and to test efficacies of candidate targeted drugs in the organoids. The current proof-of-concept approach could increase therapeutic opportunities for patients with pancreatobiliary cancers.