Predicting lymph node metastasis using preoperative parameters in patients with T1 ampulla of vater cancer.

BACKGROUND: Lymph node (LN) metastasis is an established prognostic factor for patients with surgically resected ampulla of Vater (AoV) cancer. The standard procedure for radical resection, including removal of regional LNs, is pancreaticoduodenectomy (PD); however, local excision has been considered as an alternative option for patients in the early stage cancer with significant comorbidities. In the present study, we elucidated the preoperative factors associated with LN metastasis to determine the appropriate surgical extent for T1 AoV cancer. METHODS: We included patients who underwent surgery for T1 AoV cancer at Samsung Medical Center and Severance Hospital between 2000 and 2019. Risk factors were analyzed to identify the preoperative parameters associated with LN metastasis or regional LN recurrence during follow-up. Finally, using the identified risk factors, a prediction model was constructed. RESULTS: Among 342 patients, 311 patients underwent PD, whereas 31 patients underwent transduodenal ampullectomy. Fourty-eight patients had LN metastasis according to pathology report, and two patients presented with regional LN recurrence. Age, carbohydrate antigen 19 - 9 (CA 19 - 9), and tumor differentiation were identified as factors associated with the increased risk of LN metastasis or regional LN recurrence. The area under the curve of the prediction model with these three factors was 0.728. CONCLUSION: Our newly developed prediction model using age, CA 19 - 9, and tumor differentiation can help select patients who require PD over local excision. Nevertheless, additional in-depth analysis is warranted to select appropriate surgical extent for patients with presumed T1 AoV cancer.

Laparoscopic versus open pancreaticoduodenectomy for ampullary cancer: A retrospective study.

INTRODUCTION: Studies comparing laparoscopic pancreaticoduodenectomy (LPD) with open pancreaticoduodenectomy (OPD) for ampullary carcinoma (AC) are limited. This study aimed to compare short- and long-term outcomes between LPD and OPD for AC. METHODS: This study included patients with AC who underwent pancreaticoduodenectomy (PD) with curative intention at Ogaki Municipal Hospital from April 2008 to March 2023. RESULTS: Fifty-five patients underwent LPD (n = 26) or OPD (n = 29). There were no significant differences in the demographics between the two groups. The LPD group had a significantly longer operative time (268 vs. 225 min), less blood loss (125 vs. 450 mL), and shorter postoperative hospital stay (18 vs. 23 days) than the OPD group. There was no significant difference in the morbidity ratio. Fewer lymph nodes were harvested in the LPD group than OPD group (9.5 vs. 16.0), but there were no significant differences in lymph node metastasis or pathological stages. There were no significant differences in overall survival (OS) or recurrence-free survival (RFS). The 3- and 5-year OS rates in the LPD group and the OPD group were 63.0% and 54%, 64.8%, and 61.2%, respectively. The 3- and 5-year RFS rates were 57.4% and 57.4%, 58.1%, and 54.4%, respectively. CONCLUSIONS: LPD for AC had short- and long-term outcomes comparable with those of OPD. LPD could be considered the standard treatments for AC because of less blood loss and a shorter hospital stay.

Risk factors for recurrent biliary obstruction following endoscopic biliary stenting in patients with unresectable ampullary cancer: A multicenter retrospective study.

OBJECTIVES: Unresectable ampullary cancer (AC) is a rare disease entity. The risk factors for recurrent biliary obstruction (RBO) following endoscopic biliary stenting (EBS) for unresectable AC remain unknown. In this study we aimed to evaluate the cumulative RBO rate and to identify risk factors for RBO following palliative EBS in patients with unresectable AC. METHODS: This multicenter retrospective observational study enrolled consecutive patients with unresectable AC who had undergone palliative EBS between April 2011 and December 2021. The cumulative rate of and risk factors for RBO following palliative EBS were evaluated via multivariate analysis. RESULTS: The study analysis comprised 107 patients with a median age of 84 years (interquartile range 79-88 years). Plastic stents (PSs) and self-expandable metal stents (SEMSs) were placed in 53 and 54 patients, respectively. Functional success was accomplished in 104 (97.2%) patients. Of these, RBO occurred in 62 (59.6%) patients, with obstruction and complete/partial migration occurring in 47 and 15 patients, respectively. The median time to RBO was 190 days. Multivariate analysis showed that PS was associated with a higher rate of RBO compared to SEMS (hazard ratio [HR] 2.48; P < 0.01) and that the presence of common bile duct stones/sludge immediately after EBS was an independent risk factor for RBO (HR 1.99; P = 0.04). CONCLUSIONS: The use of SEMS compared to PS during EBS reduced the time to RBO in patients with unresectable AC. Common bile duct stones/sludge immediately after EBS was a risk factor for RBO.

Identification of patients at high risk for recurrence in carcinoma of the ampulla of Vater: Analysis in 460 patients.

Aim: Carcinoma of the ampulla of Vater (CAV) shows a favorable prognosis compared to that with the other periampullary tumors, while some cases have a poor prognosis. The aims of the present study are to clarify the clinicopathological factors associated with poor recurrence-free survival (RFS) in patients with CAV after curative resection and to validate the usefulness of adjuvant chemotherapy (AC). Patients: The study design is a multicenter retrospective cohort study. Patients with CAV who underwent pancreaticoduodenectomy between January 2008 and December 2020 at 26 hospitals were analyzed. The 30 clinicopathological factors were evaluated. A propensity score matching (PSM) was used to compare between patients with and without AC. Results: Finally, 460 patients were analyzed. Median duration of follow-up was 47.2 months. Twenty-one prognostic factors associated with poor RFS were identified by univariate analysis. In multivariate analysis, aged ≥71, tumor diameter ≥12 mm, pT2 or higher stage (pT≥2), portal vein invasion (PV+), venous invasion(V+), and node positive disease (pN+) were independent prognostic factors for poor RFS. Out of 80 patients who received AC, 63 patients were assigned to analysis for PSM. The results showed no beneficial effect of AC on RFS. The preoperative factors potentially predicting pT≥2, V+, and/or N+ were at least one of following; (1) CA19-9 > 37 IU/mL, (2) ulcerative or mixed type appearance, (3) except for well-differentiated tumor, or (4) except for intestinal subtype of histology. Conclusions: Aged ≥71, tumor diameter ≥12 mm, pT≥2, PV+, V+, and pN+ were independent prognostic factors for poor RFS in patients with CAV. An additional therapeutic strategy may be desirable in CAV patients at high risk for recurrence.

Advanced Adenosquamous Carcinoma of the Ampulla of Vater Treated with Adjuvant Chemotherapy after Pancreaticoduodenectomy.

Introduction: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is rare. The prognosis is generally worse in patients undergoing resection of ASC of the AmV than in those undergoing resection of adenocarcinoma of the AmV because the former shows early recurrence after surgery. A treatment strategy for ASC of the AmV has not been established, and the efficacy of adjuvant chemotherapy after curative resection is unclear. Given the paucity of data, we report a case of ASC of the AmV that was curatively resected and treated with adjuvant chemotherapy. Case Presentation: A 66-year-old man presented with pruritus and anorexia. Contrast-enhanced computed tomography revealed a tumor measuring 1.6 cm in diameter located at the AmV and distal bile duct. Biopsy revealed adenocarcinoma of the AmV. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination contradictorily revealed ASC of the AmV and lymph node metastases. The postoperative course of the patient was uneventful, and he was discharged on day 25. The patient underwent S-1 adjuvant chemotherapy for 6 months and did not exhibit any postoperative recurrence for a follow-up duration of 28 months. Conclusion: Although treatment strategy for ASC of the AmV has not been established, our case shows that surgery followed by S-1 adjuvant chemotherapy could improve prognosis of patients with such tumors. However, further research is required to determine the efficacy of adjuvant chemotherapy and treatment strategies for resectable ASC of the AmV.

Whipple's cephalic pancreaticoduodenectomy versus pyloric-preserving pancreaticoduodenectomy. Retrospective study.

INTRODUCTION: Controversy exists in the literature as to the best technique for pancreaticoduodenectomy (PD), whether pyloric preservation (PP-CPD) or Whipple's technique (with antrectomy [W-CPD]), the former being associated with a higher frequency of delayed gastric emptying (DGE). METHODS: Retrospective and comparative study between PP-CPD technique (n = 124 patients) and W-CPD technique (n = 126 patients), in patients who were operated for tumors of the pancreatic head and periampullary region between the period 2012 and 2023. RESULTS: Surgical time was longer, although not significant, with the W-CPD technique. Pancreatic and peripancreatic tumor invasion (p = 0.031) and number of lymph nodes resected (p < 0.0001) reached statistical significance in W-CPD, although there was no significant difference between the groups in terms of lymph node tumor invasion. Regarding postoperative morbimortality (medical complications, postoperative pancreatic fistula [POPF], hemorrhage, RVG, re-interventions, in-hospital mortality, Clavien-Dindo complications), ICU and hospital stay, no statistically significant differences were observed between the groups. During follow-up, no significant differences were observed between the groups for morbidity and mortality at 90 days and survival at 1, 3 and 5 years. Binary logistic regression analysis for DGE showed that binary relevant POPF grade B/C was a significant risk factor for DGE. CONCLUSIONS: Postoperative morbidity and mortality and long-term survival were not significantly different with PP-CPD and W-CPD, but POPF grade B/C was a risk factor for DGE grade C.

Association between Cholecystectomy and the Incidence of Pancreaticobiliary Cancer after Endoscopic Choledocholithiasis Management.

(1) Background: Previous studies have raised concerns about a potential increase in pancreaticobiliary cancer risk after cholecystectomy, but few studies have focused on patients who undergo cholecystectomy after receiving endoscopic retrograde cholangiopancreatography (ERCP) for choledocholithiasis. This study aims to clarify cancer risks in these patients, who usually require cholecystectomy, to reduce recurrent biliary events. (2) Methods: We conducted a nationwide cohort study linked to the National Health Insurance Research Database, the Cancer Registry Database, and the Death Registry Records to evaluate the risk of pancreaticobiliary cancers. All patients who underwent first-time therapeutic ERCP for choledocholithiasis from 2011 to 2017 in Taiwan were included. We collected the data of 13,413 patients who received cholecystectomy after endoscopic retrograde cholangiopancreatography and used propensity score matching to obtain the data of 13,330 patients in both the cholecystectomy and non-cholecystectomy groups with similar age, gender, and known pancreaticobiliary cancer risk factors. Pancreaticobiliary cancer incidences were further compared. (3) Results: In the cholecystectomy group, 60 patients had cholangiocarcinoma, 61 patients had pancreatic cancer, and 15 patients had ampullary cancer. In the non-cholecystectomy group, 168 cases had cholangiocarcinoma, 101 patients had pancreatic cancer, and 49 patients had ampullary cancer. The incidence rates of cholangiocarcinoma, pancreatic cancer, and ampullary cancer were 1.19, 1.21, and 0.3 per 1000 person-years in the cholecystectomy group, all significantly lower than 3.52 (p < 0.0001), 2.11 (p = 0.0007), and 1.02 (p < 0.0001) per 1000 person-years, respectively, in the non-cholecystectomy group. (4) Conclusions: In patients receiving ERCP for choledocholithiasis, cholecystectomy is associated with a significantly lower risk of developing pancreaticobiliary cancer.

Prognostic value of nodal staging classification and number of examined lymph nodes among patients with ampullary cancer.

BACKGROUND: Metastatic disease in the regional lymph nodes (LNs) is a strong indicator of worse outcomes among patients after curative-intent resection of ampullary cancer (AC). This study aimed to ascertain the threshold number of examined LNs (ELNs) for AC to compare the prognosis accuracy of various nodal classification schemes relative to long-term prognosis. METHODS: Patients who underwent pancreatoduodenectomy (PD) for AC (2004-2019) were identified using the National Cancer Database. Locally weighted regression scatter plot smoothing (LOWESS) curves were used to ascertain the optimal cut point for ELNs. The accuracy of the American Joint Committee on Cancer N classification, LN ratio, and log odds transformation (LODDS) ratio to stratify patients relative to survival was examined. RESULTS: Among 8127 patients with AC, 67% were male with a median age of 67 years (IQR, 59-74). Tumors were most frequently classified as T3 (34.9%), followed by T2 (30.6%); T1 (12.9%) and T4 (17.6%) were less common. LN metastasis was identified in 4606 patients (56.7%). Among patients with nodal disease, 37.0% and 19.7% had N1 and N2 disease, respectively. The LOWESS curves identified an inflection cutoff point in the hazard of survival at 20 ELNs. The survival benefit of 20 ELNs was more pronounced among patients without LN metastasis vs patients with N1 disease (median overall survival [OS]: 54.1 months [IQR, 45.9-62.1] in ≥20 ELNs vs 39.0 months [IQR, 35.8-42.2] in <20 ELNs; P < .001) or N2 disease (median OS: 22.5 months [IQR, 18.9-26.2] in ≥20 ELNs vs 25.4 months [IQR, 23.3-27.6] in <20 ELNs; P < .001). When comparing the 4 different N classification schemes, the LODDS classification scheme yielded the highest predictive ability. CONCLUSIONS: Evaluation of a minimum of 20 LNs was needed to stratify patients with AC relative to the prognosis and to minimize stage migration. The LODDS nodal classification scheme had the highest prognostic accuracy to differentiate survival among patients after PD for AC.

Establishment and characterization of DPC-X4: a novel mixed-type ampullary cancer cell line.

Mixed-type ampullary cancer is a distinct subtype of ampullary cancer that manifests a merging of the biological characteristics of both intestinal and pancreaticobiliary subtypes. The absence of established cell lines specific to this subtype has resulted in a concomitant scarcity of research on its tumorigenic mechanisms and the development of novel therapeutic modalities. The present study achieved the successful establishment of a novel mixed-type ampullary cancer cell line, designated DPC-X4 through primary culture techniques. Subsequent analyses pertaining to phenotypic characteristics, molecular profiling, biomarker identification, and histological features validated the DPC-X4 cell line as a potent model for delineating the pathogenesis of mixed-type ampullary cancer and facilitating the development of new pharmacological agents. This newly established cell line was subjected to continuous cultivation for 1 year, with stable passaging for over 50 generations. Notably, the DPC-X4 cell line manifested typical morphological features associated with epithelial tumors. Furthermore, the population doubling time for the DPC-X4 cell line was determined at 70 h. Short tandem repeat (STR) analysis confirmed that the DPC-X4 cell line exhibited a high genetic concordance with the primary tumor from the patient. Karyotypic profiling indicated an abnormal sub-triploid karyotype, with representative karyotypes of 57, XXY inv (9), 14p + , 15p + , der (17), + mar. The DPC-X4 cell line demonstrated a high capacity for efficient organoid formation under suspension culture conditions. In addition, the subcutaneous inoculation of DPC-X4 cells into NXG mice led to the formation of xenografted tumors. The results of drug sensitivity testing indicated that DPC-X4 cells were sensitive to paclitaxel and resistant to oxaliplatin, 5-fluorouracil, and gemcitabine. Immunohistochemistry revealed positive expression of CK7, CK19, and CK20 in DPC-X4 cells, while CDX2 demonstrated negative expression. In addition, positive expression of E-cadherin and vimentin was identified in DPC-X4 cells, with a proliferation index indicated by Ki-67 at 70%. The findings of our study establish DPC-X4 as a novel mixed-type ampullary cancer cell line, which can serve as a potential experimental model for exploring the pathogenesis of ampullary cancer and the development of therapeutic drugs.

Survival and surgical outcomes of robotic versus open pancreatoduodenectomy for ampullary cancer: A propensity score-matching comparison.

BACKGROUND/OBJECTIVE: Robotic pancreaticoduodenectomy in ampullary cancer has never been studied. This study aimed to clarify the feasibility and justification of robotic pancreaticoduodenectomy in ampullary cancer in terms of surgical risks, and oncologic and survival outcomes. METHODS: A propensity score-matching comparison of robotic and open pancreaticoduodenectomy based on seven factors commonly used to predict the survival outcomes in ampullary cancer patients. RESULTS: A total of 147 patients were enrolled, of which 101 and 46 underwent robotic and open pancreaticoduodenectomies, respectively. After propensity score-matching with a 2:1 ratio, 88 and 44 patients in the robotic and open pancreaticoduodenectomy groups were included. The operation time was of no significant difference after matching. The median intraoperative blood loss was much less in those who underwent robotic pancreaticoduodenectomy, both before (median, 120 vs. 320 c.c. P < 0.001) and after (100 vs. 335 mL P < 0.001) score-matching. There were no significant differences in terms of surgical risks, including surgical mortality, surgical morbidity, Clavien-Dindo severity classification, postoperative pancreatic fistula, delayed gastric emptying, post-pancreatectomy hemorrhage, chyle leak, bile leak, and wound infection, both before or after score-matching. The survival outcomes were also similar between the two groups, regardless of matching. CONCLUSIONS: Robotic pancreaticoduodenectomy for ampullary cancer is not only technically feasible and safe without increasing surgical risks, but also oncologically justifiable without compromising surgical radicality and survival outcomes.

Incidence and risk factors for recurrence of ampullary adenomas after endoscopic papillectomy: Comparative analysis of familial adenomatous polyposis and sporadic ampullary adenomas in an international multicenter cohort.

OBJECTIVES: Endoscopic papillectomy (EP) is a minimally invasive therapy for the management of ampullary adenomas (AA). We conducted this multicenter study to assess the incidence of and factors related to the recurrence of AA after EP in patients with familial adenomatous polyposis (FAP) compared to sporadic AA. METHODS: We included patients who underwent EP for AA at 10 tertiary hospitals. Adenomatous tissue at the resection site at the time of surveillance endoscopies was considered recurrent disease. RESULTS: In all, 257 patients, 100 (38.9%) with FAP and 157 (61%) patients with sporadic AA, were included. Over a median of 31 (range, 11-61) months, recurrence occurred in 48/100 (48%) of patients with FAP and 58/157 (36.9%) with sporadic AA (P = 0.07). Two (2%) FAP patients and 10 (6.3%) patients with sporadic AA underwent surgery for recurrence. On multivariable regression analysis, the recurrence in FAP was higher than in sporadic patients after the first year of follow-up. AA size (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.001, 1.056), periampullary extension (HR 2.5, 95% CI 1.5, 4.01), and biliary duct dilation (HR 2.04, 95% CI 1.2, 3.4) increased the risk, while en bloc resection (HR 0.6, 95% CI 0.41, 0.9) decreased the risk of recurrence. CONCLUSION: Recurrence rates are high after EP. Most recurrences in sporadic patients occur within the first year of follow-up, but after the first year of follow-up in patients with FAP. Recurrences are higher with larger adenomas, biliary duct dilation, and periampullary extensions, and may be mitigated by en bloc resection. These factors should be considered in decision-making with the patients.

Combined analytical approach empowers precise spectroscopic interpretation of subcellular components of pancreatic cancer cells.

The lack of specific and sensitive early diagnostic options for pancreatic cancer (PC) results in patients being largely diagnosed with late-stage disease, thus inoperable and burdened with high mortality. Molecular spectroscopic methodologies, such as Raman or infrared spectroscopies, show promise in becoming a leader in screening for early-stage cancer diseases, including PC. However, should such technology be introduced, the identification of differentiating spectral features between various cancer types is required. This would not be possible without the precise extraction of spectra without the contamination by necrosis, inflammation, desmoplasia, or extracellular fluids such as mucous that surround tumor cells. Moreover, an efficient methodology for their interpretation has not been well defined. In this study, we compared different methods of spectral analysis to find the best for investigating the biomolecular composition of PC cells cytoplasm and nuclei separately. Sixteen PC tissue samples of main PC subtypes (ductal adenocarcinoma, intraductal papillary mucinous carcinoma, and ampulla of Vater carcinoma) were collected with Raman hyperspectral mapping, resulting in 191,355 Raman spectra and analyzed with comparative methodologies, specifically, hierarchical cluster analysis, non-negative matrix factorization, T-distributed stochastic neighbor embedding, principal components analysis (PCA), and convolutional neural networks (CNN). As a result, we propose an innovative approach to spectra classification by CNN, combined with PCA for molecular characterization. The CNN-based spectra classification achieved over 98% successful validation rate. Subsequent analyses of spectral features revealed differences among PC subtypes and between the cytoplasm and nuclei of their cells. Our study establishes an optimal methodology for cancer tissue spectral data classification and interpretation that allows precise and cognitive studies of cancer cells and their subcellular components, without mixing the results with cancer-surrounding tissue. As a proof of concept, we describe findings that add to the spectroscopic understanding of PC.

Minimally invasive versus open pancreatoduodenectomy for pancreatic and peri-ampullary neoplasm (DIPLOMA-2): study protocol for an international multicenter patient-blinded randomized controlled trial.

BACKGROUND: Minimally invasive pancreatoduodenectomy (MIPD) aims to reduce the negative impact of surgery as compared to open pancreatoduodenectomy (OPD) and is increasingly becoming part of clinical practice for selected patients worldwide. However, the safety of MIPD remains a topic of debate and the potential shorter time to functional recovery needs to be confirmed. To guide safe implementation of MIPD, large-scale international randomized trials comparing MIPD and OPD in experienced high-volume centers are needed. We hypothesize that MIPD is non-inferior in terms of overall complications, but superior regarding time to functional recovery, as compared to OPD. METHODS/DESIGN: The DIPLOMA-2 trial is an international randomized controlled, patient-blinded, non-inferiority trial performed in 14 high-volume pancreatic centers in Europe with a minimum annual volume of 30 MIPD and 30 OPD. A total of 288 patients with an indication for elective pancreatoduodenectomy for pre-malignant and malignant disease, eligible for both open and minimally invasive approach, are randomly allocated for MIPD or OPD in a 2:1 ratio. Centers perform either laparoscopic or robot-assisted MIPD based on their surgical expertise. The primary outcome is the Comprehensive Complication Index (CCI®), measuring all complications graded according to the Clavien-Dindo classification up to 90 days after surgery. The sample size is calculated with the following assumptions: 2.5% one-sided significance level (α), 80% power (1-ß), expected difference of the mean CCI® score of 0 points between MIPD and OPD, and a non-inferiority margin of 7.5 points. The main secondary outcome is time to functional recovery, which will be analyzed for superiority. Other secondary outcomes include post-operative 90-day Fitbit™ measured activity, operative outcomes (e.g., blood loss, operative time, conversion to open surgery, surgeon-reported outcomes), oncological findings in case of malignancy (e.g., R0-resection rate, time to adjuvant treatment, survival), postoperative outcomes (e.g., clinically relevant complications), healthcare resource utilization (length of stay, readmissions, intensive care stay), quality of life, and costs. Postoperative follow-up is up to 36 months. DISCUSSION: The DIPLOMA-2 trial aims to establish the safety of MIPD as the new standard of care for this selected patient population undergoing pancreatoduodenectomy in high-volume centers, ultimately aiming for superior patient recovery. TRIAL REGISTRATION: ISRCTN27483786. Registered on August 2, 2023.

Cephalic pancreatoduodenectomy in octogenarian patients with pancreatic tumors.

INTRODUCTION: Current literature supports the claim that performing a cephalic pancreaticoduodenectomy (CPD) as treatment for pancreatic cancer (PC) is associated with an increase in median survival, both in octogenarian (≥80 years) patients as well as younger patients. METHODS: This is a retrospective and comparative trial, comparing results for CPD performed on 30 patients ≥80 years with PC and 159 patients <80 years. RESULTS: The patients in the octogenarian group showed a significantly higher rate of preoperative cardiovascular morbidity and a more aggressive tumoral behaviour, including more significant preoperative anemia, jaundice and levels of CA 19-9, higher vascular and neural invasion, and a lower rate of R0 resection despite using the same surgical technique. There were no significant differences in terms of postoperative complications. Postoperative mortality was similar in both groups (3.3% in octogenarians vs 3.1% in patients <80 years). Mortality during follow-up was mainly due to tumour recurrence, cardiovascular complications and COVID-19 in 2 elderly patients. Actuarial survival at 1, 3 and 5 years was significantly larger for patients <80 years old, as compared to octogenarians (85.9%, 61.1% and 39.2% versus 72.7%, 28.9% and 9.6%, respectively; P = 0.001). The presence of a pancreatic fistula and not using external Wirsung stenting were significantly associated with 90-day postoperative mortality after a CPD. CONCLUSIONS: Morbidity and mortality post-CPD is similar in octogenarians and patients younger than 80, although long-term survival is shorter due to more aggressive tumours and comorbidities associated with older age.

Current progress in perioperative chemotherapy for biliary tract cancer.

Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%-30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S-1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S-1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S-1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.

The prognostic role of epidermal growth factor receptor mutation in completely resected ampullary adenocarcinoma.

The aim of this study is to make a differential diagnosis and prognosis of the ampullary adenocarcinoma subtypes. We also investigated the role of prognostic markers PD-1 and PD-L1, and epidermal growth factor receptor (EGFR). Local or locally advanced stage ampullary adenocarcinoma patients who had undergone pancreaticoduodenectomy at the time of diagnosis were included. MUC1, MUC2, MUC5AC, CDX2, CK7, CK20, PD-1, and PDL-1 were analysed immunohistochemically, and EGFR was analysed by real-time polymerase chain reaction. According to histopathological and immunohistochemical evaluation, we found 27 patients as pancreatobiliary type and 56 patients as intestinal type adenocarcinoma. The median survival of patients with intestinal and pancreatobiliary type adenocarcinoma was 23 months and 76 months ( p = 0.201), respectively. When the survival of PD1-positive ( n = 23) and PD-L1-positive ( n = 18) patients were compared with the patients with negative staining ( n = 60, n = 65), no significant difference was found. Epidermal growth factor receptor mutation was detected in a total of 6 patients, and 5 of these 6 mutations were shown in intestinal type tumours and one in a pancreatobiliary type tumour. A significant difference was determined in terms of overall survival for the patients with EGFR mutations compared to those without ( p = 0.008). In conclusion, we could reveal the prognostic significance of EGFR mutation, which is also a target molecule.

The Optimal Cutoff Value of Tumor Markers for Prognosis Prediction in Ampullary Cancer.

BACKGROUND: Carbohydrate antigen 19-9 (CA 19-9) is a representative tumor marker used for the diagnosis of pancreatic and biliary tract cancers. There are few published research results that can be applied to actual clinical practice for ampullary cancer (AC) alone. This study aimed to demonstrate the relationship between the prognosis of AC and the level of CA 19-9, and to determine the optimal thresholds. METHODS: Patients who underwent curative resection (pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD)) for AC at the Seoul National University Hospital between January 2000 and December 2017 were enrolled. To determine the optimal cutoff values that could clearly stratify the survival outcome, the conditional inference tree (C-tree) method was used. After obtaining the optimal cutoff values, they were compared to the upper normal clinical limit of 36 U/mL for CA 19-9. Results In total, 385 patients were enrolled in this study. The median value of the tumor marker CA 19-9 was 18.6 U/mL. Using the C-tree method, 46 U/mL was determined to be the optimal cutoff value for CA 19-9. Histological differentiation, N stage, and adjuvant chemotherapy were significant predictors. CA 19-9 36 U/mL had marginal significance as a prognostic factor. In contrast, the new cutoff value, CA 19-9 46 U/mL, was found to be a statistically significant prognostic factor (HR: 1.37, p = 0.048). CONCLUSIONS: The new cutoff value of CA 19-9 46 U/mL may be used for evaluating the prognosis of AC. Therefore, it may be an effective indicator for determining treatment strategies such as surgical treatments and adjuvant chemotherapy.

Multimodal treatment with curative intent in a germline BRCA2 mutant metastatic ampullary adenocarcinoma: a case report.

BACKGROUND: Cancers of the Vater ampulla (ampullary cancers, ACs) account for less than 1% of all gastrointestinal tumors. ACs are usually diagnosed at advanced stage, with poor prognosis and limited therapeutic options. BRCA2 mutations are identified in up to 14% of ACs and, differently from other tumor types, therapeutic implications remain to be defined. Here, we report a clinical case of a metastatic AC patient in which the identification of a BRCA2 germline mutation drove a personalized multimodal approach with curative-intent. CASE PRESENTATION: A 42-year-old woman diagnosed with stage IV BRCA2 germline mutant AC underwent platinum-based first line treatment achieving major tumor response but also life-threatening toxicity. Based on this, as well as on molecular findings and expected low impact of available systemic treatment options, the patient underwent radical complete surgical resection of both primary tumor and metastatic lesions. Following an isolated retroperitoneal nodal recurrence, given the expected enhanced sensitivity to radiotherapy in BRCA2 mutant cancers, the patient underwent imaging-guided radiotherapy leading to long-lasting complete tumor remission. After more than 2 years, the disease remains radiologically and biochemically undetectable. The patient accessed a dedicated screening program for BRCA2 germline mutation carriers and underwent prophylactic bilateral oophorectomy. CONCLUSIONS: Even considering the intrinsic limitations of a single clinical report, we suggest that the finding of BRCA germline mutations in ACs should be taken into consideration, together with other clinical variables, given their potential association with remarkable response to cytotoxic chemotherapy that might be burdened with enhanced toxicity. Accordingly, BRCA1/2 mutations might offer the opportunity of personalizing treatment beyond PARP inhibitors up to the choice of a multimodal approach with curative-intent.

Spatial Alignment of Organoids Tracking Subclonal Chemotherapy Resistance in Pancreatic and Ampullary Cancer.

Pancreatic and ampullary cancers remain highly morbid diseases for which accurate clinical predictions are needed for precise therapeutic predictions. Patient-derived cancer organoids have been widely adopted; however, prior work has focused on well-level therapeutic sensitivity. To characterize individual oligoclonal units of therapeutic response, we introduce a low-volume screening assay, including an automated alignment algorithm. The oligoclonal growth response was compared against validated markers of response, including well-level viability and markers of single-cell viability. Line-specific sensitivities were compared with clinical outcomes. Automated alignment algorithms were generated to match organoids across time using coordinates across a single projection of Z-stacked images. After screening for baseline size (50 µm) and circularity (>0.4), the match efficiency was found to be optimized by accepting the diffusion thresholded with the root mean standard deviation of 75 µm. Validated well-level viability showed a limited correlation with the mean organoid size (R = 0.408), and a normalized growth assayed by normalized changes in area (R = 0.474) and area (R = 0.486). Subclonal populations were defined by both residual growth and the failure to induce apoptosis and necrosis. For a culture with clinical resistance to gemcitabine and nab-paclitaxel, while a therapeutic challenge induced a robust effect in inhibiting cell growth (GΔ = 1.53), residual oligoclonal populations were able to limit the effect on the ability to induce apoptosis (GΔ = 0.52) and cell necrosis (GΔ = 1.07). Bioengineered approaches are feasible to capture oligoclonal heterogeneity in organotypic cultures, integrating ongoing efforts for utilizing organoids across cancer types as integral biomarkers and in novel therapeutic development.

Estimation of the organ of origin of peri-ampullary malignancy by preoperative CT scan.

BACKGROUND: Tumors occurring within the pancreatic head commonly arise from the pancreas, duodenal ampulla, distal bile duct, or duodenum. However, they are difficult to distinguish on standard preoperative imaging. PURPOSE: To assess the ability of specialist reporting of preoperative computed tomography (CT) scans to determine the organ of origin of pancreatic cancer (PC). MATERIAL AND METHODS: Blinded re-reporting of preoperative imaging from five hospitals was undertaken of a consecutive cohort of 411 patients undergoing surgery for PC between January 2006 and May 2014. Radiological identification of tumor site was determined by the presence of the main tumor bulk within the pancreatic head parenchyma and estimation of the pathological organ of origin of the PC was based on all the reported features. RESULTS: Each pathological tumor type was noted to have distinct radiological features. Localization of a visible tumor within the pancreatic parenchyma was seen most commonly in PC (92%) than other tumor types (P < 0.0001). Local invasion into the duodenum was a characteristic feature seen in 79% of patients with ampullary tumors and isolated dilation of the bile duct without dilation of the pancreatic duct was seen most commonly in patients with ampullary or bile duct cancer. In the assessment of tumor origin, good agreement (kappa = 0.6, 0.51-0.68) was noted between the consensus radiology opinion and the final histology result. Overall accuracy was greatest for ampullary cancer (88.1%) and lowest for PC (83.2%). CONCLUSION: Radiological assessment of preoperative imaging provides a high degree of accuracy in predicting the organ of origin of peri-ampullary cancer.