Tumor location, clinicopathological features, and perioperative and prognostic outcomes in patients who underwent pancreatic resection following neoadjuvant chemoradiotherapy for resectable pancreatic cancer: A retrospective study.

BACKGROUND: /Objective: Preoperative treatment of resectable pancreatic ductal adenocarcinoma (PDAC) is gaining popularity worldwide. However, the characteristics of tumors located in the pancreatic head (Ph), or those in the body or tail (Pbt), after surgery following neoadjuvant chemoradiotherapy (NACRT) remain unclear. This study aimed to evaluate and compare the clinicopathological features, perioperative outcomes, and prognosis of patients with resectable PDAC who underwent NACRT followed by curative pancreatic resection, focusing on distinguishing between Ph and Pbt PDACs. METHODS: We included 107 patients with resectable PDAC who underwent curative resection following NACRT between 2009 and 2023. Clinicopathological features, perioperative and prognostic outcomes, recurrence patterns, and prognoses were compared between Ph and Pbt PDAC groups. RESULTS: Tumors were found in the Ph and Pbt in 64 and 43 patients, respectively. Albumin levels and lymphocyte-to-monocyte ratios after NACRT were significantly lower in the Ph group than in the Pbt group. The Pbt group showed significantly higher rates of positive peritoneal lavage cytology and serosal, arterial, and portal vein invasion than the Ph group did. Overall and recurrence-free survival were similar between the two groups. The most common site of initial postoperative recurrence was the lung only in both groups; however, the rate of peritoneal dissemination only was significantly higher in the Pbt group than in the Ph group. CONCLUSIONS: The prognoses based on tumor locations in the Ph and Pbt after surgery following NACRT are similar. Following the resection of resectable Pbt PDAC, the possibility of peritoneal dissemination recurrence should be considered.

A combined score for predicting clinically relevant postoperative pancreatic fistula based on inflammatory parameters and drainage fluid culture results on postoperative day 3.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatic resection can lead to severe postoperative complications. POPF is defined based on postoperative day (POD) 3 drainage fluid amylase level. POPF correlates with inflammatory parameters as well as drainage fluid bacterial infection. However, a standardized model based on these factors for predicting CR-POPF remains elusive. We aimed to identify inflammatory parameter- and drainage fluid culture-related risk factors for CR-POPF on POD 3 after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Data from 351 patients who underwent PD or DP between 2013 and 2022 at a single institution were retrospectively analyzed. Risk factors for CR-POPF were investigated using multivariate analyses, and a prediction model combining the risk factors for CR-POPF was developed. RESULTS: Of the 351 patients, 254 and 97 underwent PD and DP, respectively. Multivariate analyses revealed that drainage fluid amylase level ≥722 IU/L, culture positivity, as well as neutrophil count ≥5473/mm3 on POD 3 were independent risk factors for CR-POPF in PD group. Similarly, drainage fluid, amylase level ≥500 IU/L, and culture positivity on POD 3 as well as pancreatic thickness ≥11.1 mm were independent risk factors in the DP group. The model for predicting CR-POPF achieved the maximum overall accuracy rate when the number of risk factors was ≥2 in both the PD and DP groups. CONCLUSIONS: Inflammatory parameters on POD 3 significantly influence the risk of CR-POPF onset after pancreatectomy. The combined models based on these values can accurately predict the risk of CR-POPF after pancreatectomy.

Tumor-to-blood pool ratio of 18F-fluorodeoxyglucose-positron emission tomography's standardized uptake value as a useful parameter indicating malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasm compared to the international Fukuoka guidelines: a retrospective cohort study from surgical resections.

BACKGROUND: Identifying malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging, but the standardized uptake value (SUV) obtained from 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT has the potential to become a valuable parameter for differentiation. This study aimed to assess the effectiveness of SUV of FDG-PET/CT in distinguishing low-grade dysplasia (LGD), high-grade dysplasia (HGD), and intraductal papillary mucinous carcinoma (IPMC) within BD-IPMNs. METHODS: We assessed 58 patients with confirmed BD-IPMN undergoing surgery between 2008 and 2022. Receiver operating characteristic curves were plotted using the tumor-to-blood pool ratio (TBR) of FDG-PET/CT in two scenarios: one considering HGD + IPMC as positive and the other considering only IPMC as positive. RESULTS: In the cohort of 58 cases, there were 39 females, and the median age was 71 years. The median TBR value was 1.45 (range, 0.35-25.44). The TBRs exhibited a significant correlation with each histopathology (p < 0.001). Furthermore, in the multivariate analysis, TBR was independently significant in both scenarios, with HGD + IPMC defined as malignant (p = 0.001) and with only IPMC defined as malignant (p = 0.024). CONCLUSIONS: TBR might have the potential to serve as a valuable parameter for indicating malignant transformation in pancreatic BD-IPMNs.

Efficacy of neoadjuvant chemoradiotherapy followed by pancreatic resection for older patients with resectable and borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The benefit of preoperative treatment followed by pancreatic resection in older patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this retrospective analysis of prospectively collected data, we evaluated the significance and safety of preoperative treatment followed by curative resection for older PDAC patients. METHODS: We evaluated 122 patients with resectable and borderline resectable PDAC who received neoadjuvant chemoradiotherapy (NACRT) followed by curative resection between 2009 and 2019. Changes in the prognostic nutritional indices during NACRT, surgical outcomes, and prognosis were compared between older (≥75 years, n = 44) and younger patients (<75 years, n = 78). RESULTS: The completion rate, adverse event rate, changes in prognostic nutritional indices during NACRT, and prognosis were similar between the groups. In multivariate analysis, an elevated C-reactive protein/albumin ratio (CRP/Alb) ≥ 33.1% during NACRT (p = 0.035) and no postoperative adjuvant chemotherapy (p = 0.041) were identified as significant predictors of overall survival. CONCLUSIONS: NACRT followed by pancreatic resection could be safely performed in older patients, with a similar prognosis as that of younger patients, despite an increased frequency of postoperative complications. Elevated CRP/Alb during NACRT and no postoperative adjuvant chemotherapy were poor prognostic factors for older patients.

Prediction of local tumor control and recurrence-free survival in patients with pancreatic cancer undergoing curative resection after neoadjuvant chemoradiotherapy.

BACKGROUND AND OBJECTIVES: There is little data on the correlation between the reduction in fluorodeoxyglucose positron emission tomography (FDG-PET) radioactive accumulation and carbohydrate antigen 19-9 (CA19-9) levels with pathological tumor responses (PTRs) and prognosis after neoadjuvant chemoradiotherapy (NACRT) for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was a retrospective analysis of prospectively collected data from 102 patients with resectable (R-) and borderline resectable (BR-) PDAC who received NACRT, followed by curative resection. Data were prospectively collected and compared between the responders and nonresponders to NACRT. RESULTS: Patients with 60% or more reduction in maximum standardized uptake value (SUVmax) on FDG-PET, with 75% or more reduction in CA19-9 levels, or with 50%-100% of tumor cells destroyed due to NACRT had significantly better recurrence-free survival (RFS) than each of the nonresponders (p = 0.028, <0.001, and 0.022, respectively). The reduction rates of SUVmax and CA19-9 levels were correlated with PTR. The combined evaluation of these biomarkers reflected RFS. CONCLUSIONS: Reduction rates of FDG uptake and CA19-9 levels were preoperative predictors of pathological response to NACRT. These biomarkers of local response had prognostic value in R-PDAC and BR-PDAC. The combined evaluation of these biomarkers allowed for reliable prediction of RFS after surgery.

Tumor metabolic alterations after neoadjuvant chemoradiotherapy predict postoperative recurrence in patients with pancreatic cancer.

OBJECTIVE: We investigated the metabolic changes in pancreatic ductal adenocarcinoma to identify the mechanisms of treatment response of neoadjuvant chemoradiation therapy. METHODS: Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with pancreatic ductal adenocarcinoma who underwent curative-intent surgery. Sixty-two patients received neoadjuvant chemoradiation therapy and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue was performed by capillary electrophoresis-mass spectrometry. RESULTS: Capillary electrophoresis-mass spectrometry detected 90 metabolites for analysis among more than 500 ionic metabolites quantified. There were significant differences in 27 tumor metabolites between the neoadjuvant chemoradiation therapy and control groups. There were significant differences in eight metabolites [1-MethylnNicotinamide, Carnitine, Glucose, Glutathione (red), N-acetylglucosamine 6-phosphate, N-acetylglucosamine 1-phosphate, UMP, Phosphocholine] between good responder and poor responder for neoadjuvant chemoradiation therapy. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the neoadjuvant chemoradiation therapy group. Microarray confirmed marked gene suppression of choline transporters [CTL1-4 (SLC44A1-44A4)] in pancreatic ductal adenocarcinoma tissue of neoadjuvant chemoradiation therapy group. CONCLUSION: The present study identifies several important metabolic consequences and potential neoadjuvant chemoradiation therapy targets in pancreatic ductal adenocarcinoma. Choline metabolism is one of the key pathways involved in recurrence of the patients with pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation therapy.

Ampullary carcinoma of the duodenum: current clinical issues and genomic overview.

Ampullary carcinomas of the duodenum are uncommon. Moreover, the diversity in the clinical outcomes of these patients makes it difficult to interpret previous studies and clinical trial results. The difficulty in proper staging of ampullary carcinomas, especially with regard to the T category of the tumor in the TNM system, reflects the anatomic complexity and non-uniform histopathologic subtypes. One major reason for this difficulty in interpretation is that the tumors may arise from any of the three epithelia (duodenal, biliary, or pancreatic) that converge at this location. Generally, ampullary carcinomas are classified into intestinal and pancreaticobiliary types based on morphology and immunohistochemical features. While many studies have described their specific characteristics and clinical impact, the prognostic value of these subtypes is controversial. In recent years, whole-exome sequencing analyses have advanced our understanding of the genomic overview of ampullary carcinoma. Gene mutations serve as prognostic and predictive biomarkers for this disease. Therefore, basic knowledge of the genomic profile of ampullary carcinomas is required for surgeons to understand how best to apply precision medicine as well as surgery and adjuvant therapies. This review provides an overview of the current basic and clinical issues of ampullary carcinoma.

[Case of Solitary Liver Metastasis of Breast Cancer Showing Minimal Differentiation from Intrahepatic Cholangiocarcinoma].

A 75-year-old woman presented to our department with a liver tumor. She had undergone left total mastectomy and axillary lymph node dissection for left breast cancer at the age of 67 years. Subsequently, she had taken an aromatase inhibitor. A follow-up abdominal echo revealed a 50 mm tumor in the liver. Based on examinations, she was diagnosed with an intrahepatic cholangiocarcinoma. She underwent laparoscopic lateral segment hepatectomy. Pathological diagnosis showed liver metastasis of the breast cancer. After surgery, she received hormonal therapy. After 5 months, multiple brain metastases appeared. She died 15 months after the liver operation.

Immunohistochemically Detected Expression of ATRX, TSC2, and PTEN Predicts Clinical Outcomes in Patients With Grade 1 and 2 Pancreatic Neuroendocrine Tumors.

OBJECTIVE: The goal of this retrospective study was to clarify the clinical implications of immunohistochemically detected protein expression for genes that are frequently mutated in pancreatic neuroendocrine tumors (PNETs). BACKGROUND: The clinical management of PNETs is hindered by their heterogenous biological behavior. Whole-exome sequencing recently showed that 5 genes (DAXX/ATRX, MEN1, TSC2, and PTEN) are frequently mutated in PNETs. However, the clinical implications of the associated alterations in protein expression remain unclear. METHODS: We collected Grade 1 and 2 (World Health Organization 2017 Classification) primary PNETs samples from 100 patients who underwent surgical resection. ATRX, DAXX, MEN1, TSC2, and PTEN expression were determined immunohistochemically to clarify their relationships with prognosis and clinicopathological findings. RESULTS: Kaplan-Meier analysis indicated that loss of TSC2 (n = 58) or PTEN (n = 37) was associated with significantly shorter overall survival, and that loss of TSC2 or ATRX (n = 41) was associated with significantly shorter recurrence-free survival. Additionally, loss of ATRX or TSC2 was significantly associated with nodal metastasis. In a multivariate analysis, combined loss of TSC2 and ATRX (n = 31) was an independent prognostic factor for shorter recurrence-free survival (hazard ratio 10.1, 95% confidence interval 2.1-66.9, P = 0.003) in G2 PNETs. CONCLUSIONS: Loss of ATRX, TSC2, and PTEN expression might be useful as a method of clarifying the behavior and clinical outcomes of Grade 1 and 2 PNETs in routine clinical practice. Combined loss of TSC2 and ATRX had an especially strong, independent association with shorter recurrence-free survival in patients with G2 PNETs. Loss of pairs in ATRX, TSC2, or PTEN would be useful for selecting the candidate for postoperative adjuvant therapy.

Laparoscopic hand-sewn esophagojejunal anastomosis in laparoscopic proximal gastrectomy for early gastric cancer.

PURPOSE: In Asian countries, proximal gastrectomy is a standard treatment option for early primary gastric cancer located in the upper third of the stomach. However, laparoscopic proximal gastrectomy (LPG) is not widely employed due to the technical difficulty of laparoscopic esophagojejunal anastomosis. Therefore, we began performing laparoscopic hand-sewn esophagojejunal anastomosis. In this report, we describe the technique of this method and the short-term surgical outcomes. METHODS: Between February 2016 and June 2020, 18 patients underwent LPG with double-tract reconstruction at our institution. Laparoscopic hand-sewn esophagojejunal anastomosis was attempted for all patients. RESULTS: The median operative time for the 18 patients was 431 min (range: 301-549 min), and the estimated blood loss was 100 mL (range: 0-1524 mL). The median time for the hand-sewn esophagojejunostomy was 42 min (range: 26-81 min). Only one case was converted to open surgery after the reconstruction due to bleeding from an artery of the lesser curvature. No anastomotic leakage was observed in any patients (0/18, 0 %); however, two patients developed anastomotic stenosis (2/18, 11%). The mean length of postoperative hospital stay was 10 days (range: 8-28 days). CONCLUSION: The laparoscopic hand-sewn esophagojejunal anastomosis in LPG is a simple, cost-effective, and safe procedure. We believe that our method is a feasible choice. However, careful and longer follow-up of more patients is necessary to determine the advantages of our method.

Early gastric cancer with an Adachi type VI (group 26) vascular anomaly diagnosed preoperatively and treated by laparoscopic surgery: a case report.

BACKGROUND: It is important to understand the branching pattern of the celiac artery for a safe surgery. Various branching anomalies of the celiac artery were classified by Adachi in 1928. In Adachi's classification, type VI (group 26) is a rare anatomical anomaly (0.4%) that requires care when carrying out a surgery in gastric cancer patients with this anomaly. Herein, we reported a case treated successfully with laparoscopic distal gastrectomy with D1+ lymph node dissection for early gastric cancer. CASE PRESENTATION: An 84-year-old female was referred to our division for an additional surgical treatment for early gastric cancer that was resected by endoscopic submucosal dissection. A three-dimensional computed tomography angiography revealed an angioplany of the common hepatic artery branching from the left gastric artery. According to Adachi's classification, the anomaly of this patient corresponded to type VI (group 26). Preoperative anatomical information of this rare anomaly helped us to safely perform a laparoscopic distal gastrectomy and lymph node dissection with common hepatic artery preservation. The patient had an uneventful postoperative course and was discharged on postoperative day 11. CONCLUSIONS: We consider that Group 26 anomalies require the most precise anatomical understanding among Adachi classification type VIs, since it affects hepatic blood flow and can cause serious complications. In this time, we reported a successful case to perform laparoscopic distal gastrectomy with safety and accuracy by preoperative understanding of the precise vascular anatomy.

Changes and prognostic impact of inflammatory nutritional factors during neoadjuvant chemoradiotherapy for patients with resectable and borderline resectable pancreatic cancer.

BACKGROUND: Inflammatory nutritional factors, such as the neutrophil/lymphocyte ratio (NLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), and C-reactive protein/albumin (CRP/Alb) ratio, have prognostic values in many types of cancer. In this study, the prognostic values of inflammatory nutritional scores were evaluated in the patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemoradiotherapy (NACRT). METHODS: A total of 49 patients who underwent pancreatectomy after NACRT from September 2009 to May 2016 were enrolled. The NACRT consisted of hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) delivered 5 days/week for 2 weeks before pancreatectomy. Inflammatory nutritional scores were determined before and after NACRT in this series. RESULTS: The median NLR increased after NACRT (from 2.067 to 3.302), with statistical difference (p < 0.001). In multivariate analysis, high pre-NACRT mGPS (2 or 1; p = 0.0478) and significant increase in CRP/Alb ratio after NACRT (≧ 0.077; p = 0.0036) were associated with shorter overall survival. All patients were divided into two groups according to the ΔCRP/Alb ratio after NACRT: the group with high ΔCRP/Alb ratio (≧ 0.077) and the group with low ΔCRP/Alb ratio (< 0.077). The group with high ΔCRP/Alb ratio after NACRT (n = 13) not only had higher post-NACRT CRP levels (p < 0.001) but also had lower post-NACRT Alb levels (p = 0.002). Patients in the group with high ΔCRP/Alb ratio lost more body weight during NACRT (p = 0.03). CONCLUSION: In addition to pre-NACRT mGPS, ΔCRP/Alb after NACRT could provide prognostic value in the patients with PDAC treated by NACRT.

Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC.

Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.

The predictors and patterns of the early recurrence of pancreatic ductal adenocarcinoma after pancreatectomy: the influence of pre- and post- operative adjuvant therapy.

BACKGROUND: The perioperative factors predicting or influencing early pancreatic ductal adenocarcinoma recurrence are unclear. This study attempted to identify the predictive factors for early pancreatic ductal adenocarcinoma recurrence post-pancreatectomy and the influence of pre- and post- operative adjuvant therapy. METHODS: One hundred and fifteen patients undergoing curative resection for pancreatic ductal adenocarcinoma between 2000 and 2016 at our institution were retrospectively analyzed. Patients were divided into two groups: those who did (n = 34) and did not (n = 81) experience a recurrence within 6 months postoperatively. RESULTS: Multivariate analyses demonstrated postoperative CA19-9 de-normalization, no postoperative adjuvant chemotherapy, and serosal invasion were independent risk factors for early recurrence (P < 0.001, P = 0.001, and P = 0.010, respectively). A subgroup analysis showed patients with (n = 51) and without (n = 64) preoperative chemoradiotherapy had different predictors. Although postoperative adjuvant chemotherapy was not a significant indicator in patients with preoperative chemoradiotherapy, CA19-9 de-normalization and no postoperative adjuvant chemotherapy were significant indicators in patients without preoperative chemotherapy. Preoperative chemotherapy strongly prevented early local recurrence while postoperative adjuvant chemotherapy prevented early distant recurrence. CONCLUSIONS: CA19-9 de-normalization was an important predictor of early recurrence of pancreatic ductal adenocarcinoma. Although postoperative adjuvant chemotherapy was an important preventive measure against early recurrence, particularly for distant recurrence, preoperative chemoradiotherapy could strongly prevent the early local recurrence of pancreatic ductal adenocarcinoma. These perioperative adjuvant therapies could have a complementary relationship.

Pure laparoscopic pancreas parenchymal dissection using CUSA for distal pancreatectomy.

Although stapler dissection and closure is commonly used for laparoscopic distal pancreatectomy (LDP), it is risky in patients with thick pancreatic parenchyma or titanium allergy. We performed laparoscopic pancreatic parenchymal dissection with cavitron ultrasonic surgical aspirator (CUSA) successfully in a patient with titanium allergy. Slinging the pancreas with nylon tape delineates the surgical plane. Pancreatic parenchyma was transected by CUSA in an almost bloodless field. Pancreatic duct branches and vessels were adequately exposed and dissected with a vessel sealing system. The main pancreatic duct was closed with Hem-O-lock. CUSA is an alternative to stapler dissection during LDP in select patients.

18F-fluorodeoxyglucose positron emission tomography to indicate conversion surgery in patients with initially unresectable locally advanced pancreatic cancer.

OBJECTIVE: Advances in chemotherapy and chemoradiotherapy have enabled conversion of initially unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) to a resectable disease. However, definitive criteria for conversion surgery have not been established. We evaluated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to indicate conversion surgery in patients with primary UR-LA PDAC. METHODS: Twenty consecutive patients with UR-LA PDAC underwent chemoradiation or chemotherapy followed by assessment with FDG-PET. We defined PET responders (standardized uptake value <3.0) with marked reduction (>80%) of carbohydrate antigen 19-9 as potential candidates for conversion surgery. Outcomes were compared with those of the patients with resectable (R; n = 94) and borderline resectable (BR; n = 37) PDAC. RESULTS: Eight of the 20 patients (40%) were considered PET responders with marked reduction of CA19-9 and received conversion surgery (UR-LAR) 3-9 months (median, 5 months) after the initiation of therapy. Complete resection (R0) was achieved in 7 of 8 patients (87.5%) with UR-LAR. There was no significant difference in R0 rates, morbidity, or mortality among the UR-LAR, R and BR groups. The overall survival (OS) curve was better in the UR-LAR group than in the group that did not receive surgery. There was no significant difference in OS between the UR-LAR and the R or BR groups. CONCLUSIONS: FDG-PET could be a potential indicator for conversion surgery in patients with primary UR-LA PDAC and may help in selecting patients who qualify for complete surgical resection and have a promising prognosis.

A Prospective Phase II Trial of Neoadjuvant S-1 with Concurrent Hypofractionated Radiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The ideal neoadjuvant treatment protocol for patients with pancreatic cancer (PDAC) remains unclear. We evaluated the efficacy and safety of neoadjuvant hypofractionated chemoradiotherapy with S-1 for patients with resectable (R) and borderline resectable (BR) PDAC. METHODS: Eligibility criteria included patients with R and BR PDAC, performance status 0-1, and age 20-85 years. Hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) was delivered 5 days/week for 2 weeks prior to pancreatectomy. RESULTS: Fifty-seven patients were enrolled in this study, including 33 R and 24 BR [19 BR tumors with portal vein contact (BR-PV) and 5 BR tumors with arterial contact (BR-A)]. The total rates of protocol treatment completion and resection were 91% (50/57) and 96% (55/57), respectively. Seven patients failed to complete S-1 due to cholangitis (n = 5) or neutropenia (n = 2). The most common grade 3 toxicities [Common Terminology Criteria for Adverse Events (CTCAE) version 4.0] were anorexia (7%), nausea (5%), neutropenia (4%), and leukopenia (4%). No patient experienced grade 4 toxicity. Pathologically negative margins (R0) were achieved in 54 of 55 patients (98%) who underwent pancreatectomy. Pathological response was classified as Evans grade I in 8 patients (15%), IIa in 31 patients (56%), IIb in 14 patients (25%), III in 1 patient (2%), and IV in 1 patient (2%), and operative morbidity (Clavien-Dindo grade IIIb or less) was observed in 4 patients (8%). The 1- and 2-year overall survival (OS) rates were 91 and 83% in R patients, respectively, and 77 and 58% in BR patients, respectively (p = 0.03). CONCLUSION: Neoadjuvant S-1 with concurrent hypofractionated radiotherapy is tolerable and appears promising for patients with R and BR PDAC.

Phenotypic characterization and clinical outcome in ampullary adenocarcinoma.

BACKGROUND: Although various features of ampullary adenocarcinoma have been reported, the impact of genetic alterations and rare subtypes on clinical outcome remains unclear. METHODS: We determined the expression of proteins, including MUC1, MUC2, p53, p16, Smad/Dpc4, and ß-catenin, and genetic mutations such as KRAS, BRAF, and GNAS mutations in 69 patients with ampullary adenocarcinoma to clarify their relationships with clinicopathological findings and subtypes. RESULTS: Kaplan-Meier survival analysis indicated that abnormal p53 labeling was significantly associated with a shorter overall survival. MUC1-positive and MUC2-negative expressions were significantly associated with lymphatic invasion, pancreatic invasion, lymph node metastasis, and advanced UICC stage. The KRAS mutation was significantly associated with large tumor size and pancreatic invasion. There were 35 intestinal (50%), 15 pancreatobiliary (22%), and 11 mixed subtype (16%) tumors. Patients with the mixed subtype showed significantly poor outcome. The invasiveness of the mixed subtype was similar to that of the pancreatobiliary subtype; moreover, the mixed subtype showed a high incidence of abnormal ß-catenin immunolabeling (73%). CONCLUSIONS: Protein expression and genetic mutation are clinically associated with the characteristics of ampullary adenocarcinoma. The mixed subtype may have a distinct tumor nature as compared to other two major subtypes. J. Surg. Oncol. 2016;114:119-127. © 2016 Wiley Periodicals, Inc.

Factors predicting survival and pathological subtype in patients with ampullary adenocarcinoma.

BACKGROUND: Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes. METHODS: Medical records were reviewed for 86 patients who underwent curative resection for ampullary adenocarcinoma between 2000 and 2012 at 12 principal hospitals in Kagawa, Japan. RESULTS: Resection was most common among 75-79-year-old patients. Actuarial 1-, 3-, and 5-year postoperative survival rates for ampullary adenocarcinoma were 90%, 72.3%, and 69.1%, respectively. Preoperative biliary drainage; serum CA19-9 and total bilirubin levels; pathological grade; perineural, vascular, pancreatic, and duodenal invasion; nodal metastasis; UICC-T stage; and pancreatobiliary subtype were predictors of poor survival. An elevated serum CA19-9 level; an elevated total bilirubin level; lymphatic, vascular, perineural, and pancreatic invasion; and advanced overall tumor stage were more common in patients with pancreatobiliary-type tumors than in patients with intestinal-type tumors. Additionally, pathologic subtype analysis showed that each subtype had distinct prognostic factors. CONCLUSIONS: Preoperative elevated serum CA19-9 and total bilirubin levels are prognostic factors for ampullary adenocarcinoma, and are both associated with pancreatobiliary-type tumors. Surgeons should be aware of these factors because pancreatobiliary-type adenocarcinoma is aggressively invasive and is associated with poor survival.