Completion Pancreatectomy After Pancreatoduodenectomy: Who Needs It?

OBJECTIVE: The objective of this study was to identify the indications for and report the outcomes of completion pancreatectomy (CPLP) in the postoperative course after pancreatoduodenectomy (PD). BACKGROUND: CPLP may be considered or even inevitable for damage control after PD. METHODS: A prospectively maintained database of all patients undergoing PD between 2001 and 2019 was searched for patients who underwent CPLP in the postoperative course after PD. Baseline characteristics, perioperative details, and outcomes of CPLP patients were analyzed and specific indications for CPLP were identified. RESULTS: A total of 3953 consecutive patients underwent PD during the observation period. CPLP was performed in 120 patients (3%) after a median of 10 days following PD. The main indications for CPLP included postpancreatectomy acute necrotizing pancreatitis [n=47 (39%)] and postoperative pancreatic fistula complicated by hemorrhage [n=41 (34%)] or associated with uncontrollable leakage of the pancreatoenteric anastomosis [n=23 (19%)]. The overall 90-day mortality rate of all 3953 patients was 3.5% and 37% for patients undergoing CPLP. CONCLUSIONS: Our finding that only very few patients (3%) need CPLP suggests that conservative, interventional, and organ-preserving surgical measures are the mainstay of complication management after PD. Postpancreatectomy acute necrotizing pancreatitis, uncontrollable postoperative pancreatic fistula, and fistula-associated hemorrhage are highly dangerous and represent the main indications for CPLP after PD.

A Pretreatment Prognostic Score to Stratify Survival in Pancreatic Cancer.

OBJECTIVE: The aim of this study was to develop and validate a pretreatment prognostic score in pancreatic cancer (PDAC). BACKGROUND: Pretreatment prognostication in PDAC is important for treatment decisions but remains challenging. Available prognostic tools are derived from selected cohorts of patients who underwent resection, excluding up to 20% of patients with exploration only, and do not adequately reflect the pretreatment scenario. METHODS: Patients undergoing surgery for PDAC in Heidelberg from July 2006 to June 2014 were identified from a prospective database. Pretreatment parameters were extracted from the database and the laboratory information system. Parameters independently associated with overall survival by uni- and multivariable analyses were used to build a prognostic score. A contemporary cohort from Verona was used for external validation. RESULTS: In 1197 patients, multiple pretreatment parameters were associated with overall survival by univariable analyses. American Society of Anesthesiology classification, carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen, C-reactive protein, albumin, and platelet count were independently associated with survival and were used to create the Heidelberg Prognostic Pancreatic Cancer (HELPP)-score. The HELPP-score was closely associated with overall survival (median survival between 31.3 and 4.8 months; 5-year survival rates between 35% and 0%) and was able to stratify survival in subgroups with or without resection as well as in CA19-9 nonsecretors. In the resected subgroup the HELPP-score stratified survival independently of pathological prognostic factors. The HELPP-score was externally validated and was superior to CA19-9 in both the development and validation cohorts. CONCLUSION: The HELPP-score is a readily available prognostic tool based on pretreatment routine parameters to stratify survival in PDAC independently of resection status and pathological tumor stage.

Actual Five-year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma: Who Beats the Odds?

OBJECTIVE: To determine actual five-year survival (5YS) rates associated with a strategy of upfront surgery and adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The rate of actual 5YS in PDAC remains controversial. Available data is restricted to cohorts acquired over several decades and series of resection after patient selection by neoadjuvant therapy. METHODS: All patients undergoing upfront resection for resectable and borderline-resectable PDAC from 10/2001 to 12/2011 were identified from a prospective database. Actual overall survival was assessed after a follow-up of at least 5 years. Uni- and multivariable logistic regression analyses were performed. RESULTS: Median survival of 937 patients was 22.1 months. The actual 5YS rate was 17.0% (n = 159) including 89 (9.5%) patients without evidence of disease >5 years after resection. 5YS rates in patients with or without adjuvanttherapy were 18.8% vs. 12.2%, respectively. Tumorgrading, number of positive lymph nodes, a context of intraductal papillary mucinous neoplasia, and vascular resections were independently associated with 5YS. Patient-related parameters and CA 19-9 levels were associated with observed survival up to 3 years, but lost relevance thereafter. The extent of lymph node involvement was the strongest predictor of 5YS. Patients with pN0R0 had a 5YS rate of 38.2%. in patients with exclusively favorable factors the observed 5YS rate was above 50%. CONCLUSIONS: This is the largest series of long-term survivors with histologically confirmed PDAC. With upfront resection and adjuvant therapy an actual overall 5YS rate of 18.8% can be expected. in favorable subgroups actual 5YS is above 50%.

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

Refined prognostic staging for resected pancreatic cancer by modified stage grouping and addition of tumour grade.

BACKGROUND: With changes in T and N categories the 8th edition of the AJCC/UICC TNM staging system for pancreatic cancer resulted in improved prognostic staging, but inconsistencies were observed with specific stage groups. Tumour grading remains disregarded in prognostic staging. We aimed to validate the current staging system and to investigate the possibility of further optimization by integration of grading. METHODS: 1946 patients undergoing upfront surgical resection for pancreatic adenocarcinoma from 10/2001 to 12/2015 were identified from a prospective institutional database. Survival analyses based on the 8th UICC TNM edition were performed and rare TNM subgroups were reallocated based on survival. The impact of tumour grade on stage-specific survival was assessed and a TNMG staging system was developed. RESULTS: The 8th UICC staging system accurately stratified prognosis except for comparable survival in stages IB (pT2N0M0) and IIA (pT3N0M0). Regrouping of pT3N0M0 and pT1N1M0 to IB and of pT1N2M0 to II resulted in a modified staging system with higher consistency. High tumour grade (G3&G4 vs G1&G2) was associated with a significantly shorter survival in all new stage groups except for stage IV modified UICC. A TNMG-based prognostic stage grouping in which high tumour grade results in grouping with tumours of the next higher pTNM-stage resulted in improvement of prognostication in non-metastatic pancreatic cancer. CONCLUSIONS: The 8th edition of the UICC TNM staging system leaves room for improvement. A TNMG staging system with adjustments in group-allocation of specific rarely occurring pTNM subgroups and integration of tumour grade results in improved prognostic stratification.

The Outcome of Ex Vivo TIL Expansion Is Highly Influenced by Spatial Heterogeneity of the Tumor T-Cell Repertoire and Differences in Intrinsic In Vitro Growth Capacity between T-Cell Clones.

PURPOSE: During our efforts to develop tumor-infiltrating lymphocyte (TIL) therapy to counter the devastating recurrence rate in patients with primary resectable pancreatic ductal adenocarcinoma (PDA), we found that PDA TILs can readily be expanded in vitro and that the majority of resulting TIL cultures show reactivity against the autologous tumor. However, the fraction of tumor-reactive T cells is low. We investigated to which extent this was related to the in vitro expansion. EXPERIMENTAL DESIGN: We compared the clonal composition of TIL preparations before and after in vitro expansion using T-cell receptor (TCR) deep sequencing. Our findings for PDA were benchmarked to experiments with melanoma TILs. RESULTS: We found that the TIL TCR repertoire changes dramatically during in vitro expansion, leading to loss of tumor- dominant T-cell clones and overgrowth by newly emerging T-cell clones that are barely detectable in the tumor. These changes are primarily driven by differences in the intrinsic in vitro expansion capacity of T-cell clones. Single-cell experiments showed an association between poor proliferative capacity and expression of markers related to antigen experience and dysfunction. Furthermore, we found that spatial heterogeneity of the TIL repertoire resulted in TCR repertoires that are greatly divergent between TIL cultures derived from distant tumor samples of the same patient. CONCLUSIONS: Culture-induced changes in clonal composition are likely to affect tumor reactivity of TIL preparations. TCR deep sequencing provides important insights into the factors that govern the outcome of in vitro TIL expansion and thereby a path toward optimization of the production of TIL preparations with high therapeutic efficacy.See related commentary by Lozano-Rabella and Gros, p. 4177.

"Heidelberg Standard Examination" - Final year students' experiences with a handbook and instructional videos to improve medical competence in conducting physical examinations.

Background: The physical examination (PE) of patients is a core competence in almost all medical disciplines. The teaching materials "Heidelberger Standard Examination", consisting of a handbook and accompanying videos, were developed with the objective of providing medical students with an innovative faculty-wide teaching and examination standard to sustainably advance students' PE competences during medical training. Methods: In a "mixed-method approach" comprising both quantitative and qualitative measures, our study examined Heidelberg University Hospital final year (FY) medical students' use and evaluation of the individual teaching material components. Therefore, 92 FY students completed quantitative evaluation measures and ten FY students took part in individual 30-minute semi-structured interviews. Results: Of the sample of n=77 students, who had completed the clinical part of their studies at Heidelberg University Hospital, 97.4% (n=75) had used the handbook and 35.0% (n=27) the accompanying videos. The teaching materials were evaluated via the common German six-point school grading system with an average mark of 1.35±0.5 for the handbook and a mark of 2.15±1.0 for the accompanying videos. Further, our results show that FY students especially valued the "Heidelberg Standard Examination" handbook as a guide and general reference work and felt the materials improved their self-perceived PE competence. Although FY students saw the accompanying video material as helpful, it was less frequently used, indicating further development potential. Overall, results reveal that FY students perceive the "Heidelberg Standard Examination" teaching program to contribute to the improvement of the quality of their PE training.