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Background: Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care., Methods: In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups., Results: Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59)., Conclusions: The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis., Competing Interests: Disclosure SK reports honoraria (self) from Merck, Amgen, Roche, Sanofi, Aventis, Servier and Lilly; honoraria (institution) from Merck, Amgen, Roche and Lilly; advisory/consultancy roles with Merck, Amgen, Roche, Sanofi, Aventis, Servier and Lilly; research grants/funding (self) from Merck, Bristol Myers Squibb, Roche and Lilly; research grants/funding (institution) from Merck and Lilly; and travel/accommodation expenses from Merck, Amgen, Roche, Sanofi, Aventis, Servier, Pierre Fabre and Lilly. MW reports honoraria from Amgen, Boehringer Ingelheim, Novartis, Roche and Takeda; and received research funding from Bristol Myers Squibb and Takeda. JTS reports honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Immunocore, Roche and Servier. His institution receives research funding from Bristol Myers Squibb, Celgene, Roche. He holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work. MS reports compensated consultancy from Amgen, AstraZeneca, BIOCAD, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi and Takeda; honoraria for continuing medical education presentations from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen and Novartis; and received research funding to his institution from AstraZeneca and Bristol Myers Squibb. All other authors have declared no conflicts of interest. Data sharing De-identified datasets analyzed in this study are available from the corresponding author upon reasonable request., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: In metastatic esophagogastric adenocarcinoma (EGA), the addition of programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes in selected patient populations., Objective: To investigate the efficacy of trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive EGA., Design, Setting, and Participants: This phase 2 multicenter, outpatient, randomized clinical trial with 2 experimental arms compared with historical control individually was conducted between March 2018 and May 2020 across 21 German sites. The reported results are based on a median follow-up of 14.3 months. Patients with previously untreated, metastatic ERBB2-positive (local immunohistochemistry score of 3+ or 2+/in situ hybridization amplification positive) EGA, adequate organ function, and eligibility for immunotherapy were included. Data analysis was performed from June to September 2021., Interventions: Patients were randomized to trastuzumab and nivolumab (1 mg/kg × 4/240 mg for up to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 mg/kg × 4 for up to 12 weeks) (ipilimumab arm)., Main Outcomes and Measures: The primary end point was survival improvement with a targeted increase of the 12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) to 70% in each arm., Results: A total of 97 patients were enrolled, and 88 were randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in the ipilimumab arm, respectively, with a higher incidence of autoimmune-related AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy analyses showed strong correlation of early cell-free DNA increase with shorter progression-free and overall survival and emergence of truncating and epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment., Conclusions and Relevance: In this randomized clinical trial, trastuzumab, nivolumab, and FOLFOX showed favorable efficacy compared with historical data and trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm yielded similar OS compared with the ToGA regimen., Trial Registration: ClinicalTrials.gov Identifier: NCT03409848.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8 + T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC., (© 2022. The Author(s).)

Background: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles., Patients and Methods: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment., Results: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021)., Conclusion: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients., Clinical Trial Information: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242., (Copyright © 2020. Published by Elsevier Ltd.)

Introduction: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia., Methods: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed., Results: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13)., Conclusion: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The risk for multicentricity of pancreatic adenocarcinoma remains unclear and the question whether pancreaticoduodenectomy represents sufficient oncological treatment for patients with ductal adenocarcinoma of the head of the pancreas needs further investigation., Patients and Methods: Clinicopathological data of patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2005 and 2015 were assessed and the incidence of tumor multicentricity among patients who required salvage pancreatectomy within 90 postoperative days was evaluated., Results: Pancreaticoduodenectomy was performed in 1,005 patients. Sixty-two patients (6%) suffered a major postoperative complication (pancreatic fistula/anastomotic leak/bleeding) after resection of the head of the pancreas, requiring salvage pancreatectomy. Histological examination of the pancreatic remnant in patients with ductal adenocarcinoma (n=19) revealed multicentric carcinoma in two patients, resulting in an incidence of 11% for tumor multicentricity. Preoperative cross-sectional imaging failed to identify tumor multicentricity in these patients. Additionally, two patients with pancreatic intraepithelial neoplasia and two with neuroendocrine tumor were identified., Conclusion: The incidence of previously undetected multicentric adenocarcinoma among patients undergoing salvage pancreatectomy in our study was surprisingly high. This finding suggests that the role of total pancreatectomy for pancreatic head cancer, as well as the current strategies for postoperative tumor surveillance, should be re-evaluated in order to provide the best oncological approach and prolonged survival for patients with ductal adenocarcinoma., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: With increasing numbers of therapeutic options in inoperable pancreatic cancer (PAC), patients tend to receive more than just a first line (FL) therapy., Methods: All patients who started FL for PAC at our institution (1997-2012) were retrospectively studied to identify patient's and treatment characteristics. Significant parameters in regard to second-line (SL) related survival were looked for as the basis for a prognostic model. This score was validated in a patient cohort from the CONKO-003 study., Results: Two hundred eighty of 521 (53.7%) patients received SL therapy, median overall survival (OS) from the beginning of SL (OS2) was 5.1 months. Significant more SL patients had undergone surgery, a higher Karnofsky performance state (KPS) and a duration of FL longer than 4 months.Prognostic factors impacting OS2 were KPS, carbohydrate antigen 19-9 levels at start of SL and the duration of FL. These 3 factors establish a prognostic score--validated in CONKO-003--for SL patients with 3 subgroups: "good" (median OS2, 9.3 months), "intermediate" (median OS2, 7.1 months), "poor" prognosis (median OS2, 3.8 months; P < 0.001)., Conclusions: Among patients with PAC, more than 50% receive SL therapy. Our prognostic model identifies 3 subgroups and can identify patients with a maximum benefit of SL therapy.

Objectives: Pancreatoduodenectomy is feasible also in patients with locally advanced pancreatic adenocarcinoma (PA) nowadays. Data on risk and survival analysis of palliative pancreatic resections followed by gemcitabine-based chemotherapy (Cx) are limited., Methods: Between 2000 and 2009, a total of 45 patients had primary cytoreductive surgery (cS) (pancreaticoduodenectomy or total pancreatectomy) followed by gemcitabine-based Cx (cS + Cx) for advanced PA. We matched 1:1 the cS + Cx group with 45 contemporaneous patients who primarily started palliative gemcitabine-based Cx for age, sex, performance status, and body mass index. Overall, survival was evaluated., Results: Local R0 and R1 resection in metastatic patients was achieved in 27% and 27%, respectively. The R2 resection status without distant metastasis resulted in 33%, whereas 13% showed a local R2 status with additional metastasis (M1). Median overall survival was 10.4 months after cytoreductive pancreatic surgery and consecutive gemcitabine-based Cx versus 7.2 months after upfront gemcitabine-based Cx (P = 0.009). Median survival for R0/M1 patients was 14.4 months and 11.0 months for R2/M0 patients, whereas the median survival for R1/M1 and for R2/M1 patients was 7.3 months and 6.1 months, respectively., Conclusions: Individual patients with advanced PA had a significantly longer overall survival after palliative pancreaticoduodenectomy followed by Cx than patients in a matched control group who underwent primarily palliative Cx.

Background and Objectives: The continuous progress in treatment options for pancreatic adenocarcinoma has lead to a re-evaluation of prognostic markers. In this study the prognostic relevance of DNA Index and classical histopathological parameters with regard to disease-free (DFS) and overall survival (OS) was analyzed within the CONKO-001 patient population., Methods: One hundred forty three fresh-frozen paraffin-embedded tissue samples of the resected tumor specimen of the CONKO-001 patient population were available for DNA index analysis to evaluate its impact on patient outcome., Results: Median DFS (7.3 vs. 14.3 months; P = 0.004) and median OS (16.6 vs. 29.2 months; P = 0.011) were significantly decreased in patients with a high DNA index (>1.4). Multivariate analysis revealed both DNA index (DFS: P = 0.002; OS: P = 0.019) and tumor grading (DFS: P = 0.004; OS: P = 0.004) as individual prognostic markers for DFS and OS. The following prognostic subgroups were identified: good (low DNA Index + G1/2 tumor grading), intermediate (low DNA Index + G3 tumor grading or high DNA Index + G1/2 tumor grading), poor (high DNA Index + G3 tumor grading)., Conclusion: The DNA index/tumor grading constellation may serve as a helpful guide for personalized treatment recommendations for adjuvant therapy of patients with pancreatic adenocarcinoma., (© 2015 Wiley Periodicals, Inc.)

Background: Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients., Methods: CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome., Results: High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival., Conclusions: Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy.

Background: Long-term survival (LTS) in patients (pts) with pancreatic cancer is still uncommon, little data is available to identify long-term survivors. The CONKO-001 study, which established gemcitabine after resection as adjuvant therapy, may provide data to answer this question., Methods: CONKO-001 pts with an overall survival ≥5 years were compared to those who survived <5 years. Central re-evaluation of primary histology was performed. Univariate analysis with the χ(2) -test identified qualifying factors. Logistic regression was used to investigate the influence of these covariates on LTS., Results: Of the evaluable 354 CONKO-001 pts, 54 (15%) with an overall survival ≥5 years were identified. It was possible to obtain tumor specimens of 39 pts (72%). Histological re-evaluation confirmed adenocarcinoma in 38 pts, 1 showed a high-grade neuroendocrine tumor. Univariate analysis for all 53 LTS pts with adenocarcinoma compared to the remaining 300 non-LTS pts revealed as relevant active treatment, tumor grading, tumor size, lymph nodes. No significance could be demonstrated for resection margin, sex, age, Karnofsky performance status, CA 19-9 at study entry. In multivariate analysis, tumor grading, active treatment, tumor size, lymph node involvement were independent prognostic factors for LTS., Conclusion: Long-term survival can be achieved in adenocarcinoma of the pancreas., (© 2013 Wiley Periodicals, Inc.)

Background and Objective: The indication for medical venous thrombosis prophylaxis in ambulatory cancer patients is still under discussion. To provide more data on this topic we conducted an analysis in ambulatory patients with advanced pancreatic adenocarcinoma, reflecting a patient cohort at high risk of symptomatic venous thromboembolism (sVTE)., Patients and Methods: Data from 312 consecutively recruited patients of the CONKO-004 trial were analysed according to predefined parameters and additionally with respect to established scores. To focus on patients with highest risk of sVTE unvaried and multivariate analyses were conducted., Results: The global analyses had educed a number needed to treat (NNT) by medical thrombosis prophylaxis of 12 patients to prevent one sVTE. The modified score model did not provide further clinical benefit. However, the regression model can identify single parameters with a trend to higher risk of sVTE or higher risk of severe bleeding. Most of the parameters do not have enough power to be significant, but they can support clinical decisions., Conclusion: These data suggest that medical thrombosis prophylaxis should be performed in patients with advanced pancreatic cancer at least for the initial 3 months of first line chemotherapy., (© Georg Thieme Verlag KG Stuttgart · New York.)