The Revised R Status is an Independent Predictor of Postresection Survival in Pancreatic Cancer After Neoadjuvant Treatment.

OBJECTIVE: To investigate the oncological outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) who had an R 0 or R 1 resection based on the revised R status (1 mm) after neoadjuvant therapy (NAT). BACKGROUND: The revised R status is an independent prognostic factor in upfront-resected PDAC; however, the significance of 1 mm margin clearance after NAT remains controversial. METHODS: Patients undergoing pancreatectomy after NAT for PDAC were identified from 2 prospectively maintained databases. Clinicopathological and survival data were analyzed. The primary outcomes were overall survival (OS), recurrence-free survival (RFS), and pattern of recurrence in association with R 0 >1 mm and R 1 ≤1 mm resections. RESULTS: Three hundred fifty-seven patients with PDAC were included after NAT and subsequent pancreatic resection. Two hundred eight patients (58.3%) received FOLFIRINOX, 41 patients (11.5%) received gemcitabine-based regimens, and 299 individuals (83.8%) received additional radiotherapy. R 0 resections were achieved in 272 patients (76.2%) and 85 patients (23.8%) had R 1 resections. Median OS after R 0 was 41.0 months, compared with 20.6 months after R 1 resection ( P = 0.002), and even longer after additional adjuvant chemotherapy ( R 0 44.8 vs R1 20.1 months; P = 0.0032). Median RFS in the R 0 subgroup was 17.5 months versus 9.4 months in the R 1 subgroup ( P < 0.0001). R status was confirmed as an independent predictor for OS ( R 1 hazard ratio: 1.56, 95% CI: 1.07-2.26) and RFS ( R 1 hazard ratio: 1.52; 95% CI: 1.14-2.0). In addition, R 1 resections were significantly associated with local but not distant recurrence ( P < 0.0005). CONCLUSIONS: The revised R status is an independent predictor of postresection survival and local recurrence in PDAC after NAT. Achieving R 0 resection with a margin of at least 1 mm should be a primary goal in the surgical treatment of PDAC after NAT.

The relationship of hospital and surgeon volume indicators and post-operative outcomes in pancreatic surgery: a systematic literature review, meta-analysis and guidance for valid outcome assessment.

BACKGROUND: Available evidence on the volume-outcome relationship after pancreatic surgery is limited due to the narrow focus of interventions, volume indicators and outcomes considered as well as due to methodological differences of the included studies. Therefore, we aim to evaluate the volume-outcome relationship following pancreatic surgery following strict study selection and quality criteria, to identify aspects of methodological variation and to define a set of key methodological indicators to consider when aiming for comparable and valid outcome assessment. METHODS: Four electronic databases were searched to identify studies on the volume-outcome relationship in pancreatic surgery published between the years 2000-2018. Following a double-screening process, data extraction, quality appraisal, and subgroup analysis, results of included studies were stratified and pooled using random effects meta-analysis. RESULTS: Consistent associations were found between high hospital volume and both postoperative mortality (OR 0.35, 95% CI: 0.29-0.44) and major complications (OR 0.87, 95% CI: 0.80-0.94). A significant decrease in the odds ratio was also found for high surgeon volume and postoperative mortality (OR 0.29, 95%CI: 0.22-0.37). DISCUSSION: Our meta-analysis confirms a positive effect for both hospital and surgeon volume indicators for pancreatic surgery. Further harmonization (e.g. surgery types, volume cut-offs/definition, case-mix adjustment, reported outcomes) are recommended for future empirical studies.

A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer.

OBJECTIVE: Molecular taxonomy of tumours is the foundation of personalised medicine and is becoming of paramount importance for therapeutic purposes. Four transcriptomics-based classification systems of pancreatic ductal adenocarcinoma (PDAC) exist, which consistently identified a subtype of highly aggressive PDACs with basal-like features, including ΔNp63 expression and loss of the epithelial master regulator GATA6. We investigated the precise molecular events driving PDAC progression and the emergence of the basal programme. DESIGN: We combined the analysis of patient-derived transcriptomics datasets and tissue samples with mechanistic experiments using a novel dual-recombinase mouse model for Gata6 deletion at late stages of KRasG12D-driven pancreatic tumorigenesis (Gata6LateKO). RESULTS: This comprehensive human-to-mouse approach showed that GATA6 loss is necessary, but not sufficient, for the expression of ΔNp63 and the basal programme in patients and in mice. The concomitant loss of HNF1A and HNF4A, likely through epigenetic silencing, is required for the full phenotype switch. Moreover, Gata6 deletion in mice dramatically increased the metastatic rate, with a propensity for lung metastases. Through RNA-Seq analysis of primary cells isolated from mouse tumours, we show that Gata6 inhibits tumour cell plasticity and immune evasion, consistent with patient-derived data, suggesting that GATA6 works as a barrier for acquiring the fully developed basal and metastatic phenotype. CONCLUSIONS: Our work provides both a mechanistic molecular link between the basal phenotype and metastasis and a valuable preclinical tool to investigate the most aggressive subtype of PDAC. These data, therefore, are important for understanding the pathobiological features underlying the heterogeneity of pancreatic cancer in both mice and human.

Long-Term Follow-Up after Surgery for Chronic Pancreatitis: A Bicentric Retrospective Experience.

INTRODUCTION: The impact of surgery on nutritional status, pancreatic function, and symptoms of patients affected by chronic pancreatitis (CP) has not been unequivocally determined. This study aimed to evaluate clinical follow-up after surgery for CP in an Italian-Austrian population. MATERIALS AND METHODS: Patients operated for CP at two high-volume centers between 2000 and 2018 were analyzed. The following parameters were compared between the pre- and postoperative period: nutritional status, endocrine and exocrine pancreatic functions, and chronic pain. RESULTS: Overall, 186 patients underwent surgery for CP. Among these, 68 (40%) answered a specific follow-up questionnaire. The body mass index showed a significant increase between pre- and postoperative assessments (21.1 vs. 22.5 p = 0.003). Furthermore, a 60% decrease in the prevalence of chronic pain (81 vs. 21%, p < 0.001) was observed. On the contrary, both exocrine and endocrine pancreatic functions pointed toward a worsening after surgery, with consistent higher rates of patients presenting with diabetes mellitus, as well as patients requiring insulin therapy and oral intake of pancreatic enzymes. The analysis of body composition performed on 40 (24%) patients with a complete imaging pack revealed no significant change in the nutritional status after surgery. DISCUSSION/CONCLUSION: Despite the good results observed in terms of pain relief, the surgical approach led to a consistent worsening of the global pancreatic function. No significant influence of surgery on the nutritional status of patients was detected.

Reproducibility of improvements in patient-reported functional ability following functional capacity evaluation.

BACKGROUND: Performance of functional capacity evaluation (FCE) may affect patients, self-efficacy to complete physical activity tasks. First evidence from a diagnostic before-after study indicates a significant increase of patient-reported functional ability. Our study set out to test the reproducibility of these results. METHODS: Patients with musculoskeletal trauma and an unclear return to work prognosis were recruited in a trauma rehabilitation center in Lower Austria. We included patient cohorts of three consecutive years (2016: n = 161, 2017: n = 140; 2018: n = 151). Our primary outcome was patient-reported functional ability, measured using the Spinal Function Sort (SFS). SFS scores were assessed before and after performing an FCE to describe the change in patient-reported functional ability (cohort study). We investigated whether the change in SFS scores observed after performing an FCE in our first cohort could be replicated in subsequent cohorts. RESULTS: Demographic data (gender, age and time after trauma) did not differ significantly between the three patient cohorts. Correlation analysis showed highly associated before and after SFS scores in each cohort (2016: rs = 0.84, 95% CI: 0.79 to 0.89; 2017: rs = 0.85, 95% CI: 0.81 to 0.91; 2018: rs = 0.86, 95% CI: 0.82 to 0.91). Improvements in SFS scores were consistent across the cohorts, with overlapping 95% confidence intervals (2016: 14.8, 95% CI: 11.3 to 18.2; 2017: 14.8, 95% CI: 11.5 to 18.0; 2018: 15.2, 95% CI: 12.0 to 18.4). Similarity in SFS scores and SFS differences were also supported by non-significant Kruskal-Wallis H tests (before FCE: p = 0.517; after FCE: p = 0.531; SFS differences: p = 0.931). CONCLUSIONS: A significant increase in patient-reported functional ability after FCE was found in the original study and the results could be reproduced in two subsequent cohorts.

Surgery for chronic pancreatitis: the comparison of two high-volume centers reveals lack of a uniform operative management.

PURPOSE: Many aspects of surgical therapy for chronic pancreatitis (CP), including the correct indication and timing, as well as the most appropriate operative techniques, are still a matter of debate in the surgical community and vary widely across different centers. The aim of the present study was to uncover and analyze these differences by comparing the experiences of two specialized surgical units in Italy and Austria. METHODS: All patients operated for CP between 2000 and 2018 at the two centers involved were included in this retrospective analysis. Data regarding the clinical history and the pre- and perioperative surgical course were analyzed and compared between the two institutions. RESULTS: Our analysis showed a progressive decrease in the annual rate of pancreatic surgical procedures performed for CP in Verona (no. = 91) over the last two decades (from 3% to less than 1%); by contrast, this percentage increased from 3 to 9% in Vienna (no. = 77) during the same time frame. Considerable differences were also detected with regard to the timing of surgery from the first diagnosis of CP - 4 years (IQR 5.5) in the Austrian series vs two (IQR 4.0) in the Italian series -, and of indications for surgery, with a 12% higher prevalence of groove pancreatitis among patients in the Verona cohort. CONCLUSION: The comparison of the surgical attitude towards CP between two surgical centers proved that a consistent approach to this pathology still is lacking. The identification of common guidelines and labels of surgical eligibility is advisable in order to avoid interinstitutional treatment disparities.

Correction to: The Prognostic Index Independently Predicts Survival in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Resection.

In the original article there are errors in the authors' affiliations.

The Prognostic Index Independently Predicts Survival in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Resection.

BACKGROUND: Cancer-related inflammation is associated with tumour proliferation, maintenance and dissemination. It therefore impacts pancreatic cancer survival. The goal of this study was to examine the Prognostic Index (PI) as a prognostic biomarker for survival in patients with pancreatic ductal adenocarcinoma (PDAC). In addition, we explored factors known to interact with the immune and inflammation cascade that might interfere with the PI's strength for prognostication. METHODS: Patients with PDAC undergoing resection were analysed retrospectively. The PI was calculated from preoperatively derived C-reactive protein levels and white blood count. Data were subject to correlation and survival analysis. RESULTS: Of 357 patients, 235 (65.8%) patients had a PI 0, 108 (30.3%) PI 1, and 14 (3.9%) PI 2. Median (quartiles) survival with a high PI (group 1 + 2) was 13.2 months (7.7-27.0), compared with 18.7 months (10.2-35.4) with a low PI (group 0; p = 0.012). The PI proved to be an independent prognostic factor for cancer-specific survival (p = 0.003) adjusted for conventional prognostic factors. Prognostic strength was influenced by the presence of a bile stent (p = 0.032). CONCLUSIONS: The PI is a strong and solid independent prognostic tool for survival in patients with PDAC undergoing resection. Preoperative survey of inflammatory activity as provided by the use of a biomarker like the PI may help to identify those patients at risk of a poor prognosis.

Objective and subjective comparison of virtual monoenergetic vs. polychromatic images in patients with pancreatic ductal adenocarcinoma.

OBJECTIVES: The aim of this study was to assess the objective and subjective image characteristics of monoenergetic images (MEI[+]), using a noise-optimized algorithm at different kiloelectron volts (keV) compared to polyenergetic images (PEI), in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective, institutional review board-approved study included 45 patients (18 male, 27 female; mean age 66 years; range, 42-96 years) with PDAC who had undergone a dual-energy CT (DECT) of the abdomen for staging. One standard polyenergetic image (PEI) and five MEI(+) images in 10-keV intervals, ranging from 40 to 80 keV, were reconstructed. Line-density profile analysis, as well as the contrast-to-noise ratio (CNR) of the tumor, the signal-to-noise ratio (SNR) of the regular pancreas parenchyma and the tumor, and the CNR of the three main peripancreatic vessels, was calculated. For subjective quality assessment, two readers independently assessed the images using a 5-point Likert scale. Reader reliability was evaluated using an intraclass correlation coefficient. RESULTS: Line-density profile analysis revealed the largest gradient in attenuation between PDAC and regular tissue in MEI(+) at 40 keV. Low-keV MEI(+)reconstructions at 40 and 50 keV increased CNR and SNR compared to PEI (40 keV: CNR 46.8 vs. 7.5; SNRPankreas 32.5 vs. 15.7; SNRLesion 13.5 vs. 8.6; p < 0.001). MEI(+) at 40 keV and 50 keV were consistently preferred by the observers (p < 0.05), showing a high intra-observer 0.937 (0.92-0.95) and inter-observer 0.911 (0.89-0.93) agreement. CONCLUSION: MEI(+) reconstructions at 40 keV and 50 keV provide better objective and subjective image quality compared to conventional PEI of DECT in patients with PDAC. KEY POINTS: • Low-keV MEI(+) reconstructions at 40 and 50 keV increase tumor-to-pancreas contrast compared to PEI. • Low-keV MEI(+) reconstructions improve objective and subjective image quality parameters compared to PEI. • Dual-energy post-processing might be a valuable tool in the diagnostic workup of patients with PDAC.

Impact of Functional Capacity Evaluation on Patient-Reported Functional Ability: An Exploratory Diagnostic Before-After Study.

Introduction Work capacity in patients with orthopedic trauma and long-lasting inactivity is significantly reduced. Functional capacity evaluation (FCE) is a diagnostic approach for developing recommendations for a return to work and further occupational rehabilitation when the ability to carry out previous job demands is uncertain. However, FCE may also have direct effects on the patients' appraisal of their functional ability. Our study therefore evaluated the change in patient-reported functional ability after the performance of an FCE. Methods We performed a diagnostic before-after study in 161 consecutively recruited patients with trauma who were referred for FCE at the end of an interdisciplinary inpatient rehabilitation program in Austria. Patients completed the Spinal Function Sort to assess patient-reported functional ability both prior to the FCE and after completing it. Results Patient-reported functional ability (0-200 points) improved by 14.8 points (95% CI 11.3-18.2). The number of participants who rated their functional ability below their functional capacity as observed by the FCE decreased from 82.6 to 64.6% by about 18 percentage points. Conclusions The performance of the FCE in patients with trauma was associated with an improvement of patient-reported functional ability. The performance of an FCE in trauma rehabilitation may possibly have a direct therapeutic effect on the patient by allowing a more realistic appraisal of the ability to perform relevant work activities.

Quantifying changes in innate immune function following liver transplantation for chronic liver disease.

BACKGROUND: Liver transplantation (LT) offers patients with cirrhosis long-term survival, however many die from sepsis whilst awaiting LT. The liver's role in innate immunity may be key to improving outcomes, but the immune effects of LT have not been quantified. METHODS: Innate immune capacity was assessed by clearance of 99mTc-Albumin nanospheres in patients with chronic liver failure before and after LT. RESULTS: Twenty-eight patients with chronic liver disease on the LT waiting list entered the study during the twelve-month study period and nine patients underwent LT and completed the study protocol. One patient developed hepatic artery thrombosis in <7 days and was excluded from the study. Innate immune function was significantly impaired in patients with chronic liver disease on the LT waiting list and this was directly correlated with MELD score. LT normalised innate immune function by day 1 post LT with further improvement occurring by day 7 post LT. Donor liver weight was the only factor correlated with innate immune function at day 1 post LT but this effect was negated by day 7 post LT. CONCLUSION: Recognising the immune effects of LT may facilitate treatment of cirrhosis and inform development of extracorporeal liver support systems.

Preparing for prospective clinical trials: a national initiative of an excellence registry for consecutive pancreatic cancer resections.

BACKGROUND: Despite significant improvements in perioperative mortality as well as response rates to multimodality treatment, results after surgical resection of pancreatic adenocarcinoma with respect to long-term outcomes remain disappointing. Patient recruitment for prospective international trials on adjuvant and neoadjuvant regimens is challenging for various reasons. We set out to assess the preconditions and potential to perform perioperative trials for pancreatic cancer within a well-established Austrian nationwide network of surgical and medical oncologists (Austrian Breast & Colorectal Cancer Study Group). METHODS: From 2005 to 2010 five high-volume centers and one medium-volume center completed standardized data entry forms with 33 parameters (history and patient related data, preoperative clinical staging and work-up, surgical details and intraoperative findings, postoperative complications, reinterventions, reoperations, 30-day mortality, histology, and timing of multimodality treatment). Outside of the study group, in Austria pancreatic resections are performed in three "high-volume" centers (>10 pancreatic resections per year), three "medium-volume" centers (5­10 pancreatic resections per year), and the rest in various low-volume centers (<5 pancreatic resections per year) in Austria. Nationwide data for prevalence of and surgical resections for pancreatic adenocarcinoma were contributed by the National Cancer Registry of Statistics of Austria and the Austrian Health Institute. RESULTS: In total, 492 consecutive patients underwent pancreatic resection for ductal adenocarcinoma. All postoperative complications leading to hospital readmission were treated at the primary surgical department and documented in the database. Overall morbidity and pancreatic fistula rate were 45.5 % and 10.1 %, respectively. Within the entire cohort there were 9.8 % radiological reinterventions and 10.4 % reoperations. Length of stay was 16 days in median (0­209); 12 of 492 patients died within 30 days after operation, resulting in a 30-day mortality rate of 2.4 %. Seven of the total 19 deaths (36.8 %) occurred after 30 days, during hospitalization at the surgical department, resulting in a hospital mortality rate of 3.9 % (19/492). With a standardized histopathological protocol, there were 70 % (21/30) R0 resections, 30 % (9/30) R1 resections, and no R2 resections in Vienna and 62.7 % (32/51) R0 resections, 35.3 % (18/51) R1 resections, and 2 % (1/51) R2 resections in Salzburg. Resection margin status with nonstandardized protocols was classified as R0 in 82 % (339/411), R1 in 16 % (16/411), and R2 in 1.2 % (5/411). Perioperative chemotherapy was administered in 81.1 % of patients (8.3 % neoadjuvant; 68.5 % adjuvant; 4.3 % palliative); chemoradiotherapy (1.6 % neoadjuvant; 3 % adjuvant; 0.2 % palliative), in 4.9 % of patients. The six centers that contributed to this registry initiative provided surgical treatment to 40 % of all Austrian patients, resulting in a median annual recruitment of 85 (51­104) patients for the entire ABCSG-group and a median of 11.8 (0­38) surgeries for each individual department. CONCLUSIONS: Surgical quality data of the ABCSG core pancreatic group are in line with international standards. With continuing centralization the essential potential to perform prospective clinical trials for pancreatic adenocarcinoma is given in Austria. Several protocol proposals aiming at surgical and multimodality research questions are currently being discussed

Prognostic impact of resection margin status on survival after neoadjuvant treatment for pancreatic cancer: systematic review and meta-analysis.

BACKGROUND: A greater than 1 mm tumour-free resection margin (R0 >1 mm) is a prognostic factor in upfront-resected pancreatic ductal adenocarcinoma. After neoadjuvant treatment (NAT); however, the prognostic impact of resection margin (R) status remains controversial. METHODS: Randomised and non-randomised studies assessing the association of R status and survival in resected pancreatic ductal adenocarcinoma after NAT were sought by systematic searches of MEDLINE, Web of Science and CENTRAL. Hazard ratios (HR) and their corresponding 95% CI were collected to generate log HR using the inverse-variance method. Random-effects meta-analyses were performed and the results presented as weighted HR. Sensitivity and meta-regression analyses were conducted to account for different surgical procedures and varying length of follow-up, respectively. RESULTS: Twenty-two studies with a total of 4929 patients were included. Based on univariable data, R0 greater than 1 mm was significantly associated with prolonged overall survival (OS) (HR 1.76, 95% CI 1.57-1.97; P<0.00001) and disease-free survival (DFS) (HR 1.66, 95% CI 1.39-1.97; P<0.00001). Using adjusted data, R0 greater than 1 mm was significantly associated with prolonged OS (HR 1.65, 95% CI 1.39-1.97; P<0.00001) and DFS (HR 1.76, 95% CI 1.30-2.39; P=0.0003). Results for R1 direct were comparable in the entire cohort; however, no prognostic impact was detected in sensitivity analysis including only partial pancreatoduodenectomies. CONCLUSION: After NAT, a tumour-free margin greater than 1 mm is independently associated with improved OS as well as DFS in patients undergoing surgical resection for pancreatic cancer.

Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma.

The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched ("Tumor") and stroma cell enriched ("Stroma") regions within human PDAC tissue samples. By comparing those regions, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (p = 0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm² exhibited significantly shorter overall survival (p = 0.036). Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.

Liver failure after major liver resection: risk assessment by using preoperative Gadoxetic acid-enhanced 3-T MR imaging.

PURPOSE: To determine if gadoxetic acid-enhanced magnetic resonance (MR) imaging with measurement of relative liver enhancement (RLE) on hepatobiliary phase images can allow preoperative assessment of the risk of liver failure after major liver resection. MATERIALS AND METHODS: The local institutional review committee approved this retrospective analysis and waived written informed consent. The study included 73 patients (39 men; median age, 64.4 years) who underwent gadoxetic acid-enhanced 3-T MR imaging before resection of three or more liver segments. RLE was calculated as the ratio of signal intensity measurements of the liver parenchyma before and 20 minutes after intravenous administration of gadoxetic acid. RLE was assessed in each liver segment and the mean value of all segments was used for analysis. Posthepatectomy liver failure was defined according to the "50-50 criteria" (ie, prothrombin time <50% and serum bilirubin >50 µmol/L on postoperative day 5) and the International Study Group of Liver Surgery (ISGLS) classification. The association of RLE and liver failure was tested with univariate and multivariate logistic regression analysis. In addition to RLE, the latter also included demographic, clinical, operative, and histologic variables. RESULTS: Patients with liver failure according to the 50-50 criteria (n = 3) had significantly lower RLE (54.5%) than those without (125.6%) (P = .009). According to ISGLS criteria, RLE was 112.5% in patients with grade A liver failure (n = 20), 88.4% in patients with grade B (n = 7), 41.7% (n = 2) in patients with grade C, and 136.5% (P < .001) in those without liver failure. In a logistic regression analysis, RLE was inversely related to the probability of liver failure according to the 50-50 (P = .02) and ISGLS (P < .001) criteria. In a multivariate analysis, RLE was independently associated with a higher probability of liver failure according to ISGLS classification (P = .003). CONCLUSION: Gadoxetic acid-enhanced MR imaging can help with the assessment of the risk for liver failure after major liver resection.

Prognostic significance of mean corpuscular volume in patients with pancreatic ductal adenocarcinoma and multimodal treatment.

AIM OF THE STUDY: Mean corpuscular volume (MCV) has shown mounting evidence as a prognostic indicator in a number of malignancies. The aim of this study was to examine the prognostic potential of pretherapeutic MCV among patients with pancreatic ductal adenocarcinoma (PDAC) who underwent upfront resection or resection after neoadjuvant treatment (NT). PATIENTS AND METHODS: Consecutive patients with PDAC who underwent pancreatic resection between 1997 and 2019 were included in this study. Neoadjuvantly treated patients' serum MCV was measured before NT and before surgery. In patients undergoing upfront resection serum MCV was measured before surgery. Median MCV values were used as cut-off to distinguish high from low MCV values. RESULTS: Five hundred and forty-nine (438 upfront resected and 111 neoadjuvantly treated) patients were included in this study. Multivariate analysis revealed, that high MCV before and after NT, were independent negative prognostic factors for overall survival (P<0.01, respectively). Furthermore, the median MCV value from before to after NT increased significantly (P<0.001, Wilcoxon signed-rank test) and was (P=0.03, Wilcoxon rank sum test) associated with tumor response to NT. CONCLUSION: High MCV is an independent adverse prognostic factor in patients with resectable neoadjuvantly treated PDAC and may qualify as useful indicator to help physicians to provide personalized prognostication.

Smoking impairs the effect of neoadjuvant FOLFIRINOX on postresection survival in pancreatic cancer.

INTRODUCTION: Smoking plays an important role in carcinogenesis, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about the association between smoking status and prognosis in resected PDAC. METHODS: All patients who underwent resection for PDAC were identified from two prospective institutional databases. Clinicopathologic data as well as demographics including smoking status were extracted. Survival analysis and multivariable Cox regression modelling was performed. Restricted cubic splines were used for linear data to define cut-off points. RESULTS: Out of 848 patients, 357 (42.1%) received neoadjuvant treatment (NAT), 491 upfront resection (57.9%), and 475 (56%) adjuvant therapy. The median overall survival (OS) was 27.8 months, 36.1 months, and 23.0 months for the entire cohort, after NAT and upfront resection. 464 patients were never smokers (54.7%), 250 former smokers (29.5%), and 134 active smokers (15.8%). In the multivariable model, the interaction of neoadjuvant FOLFIRINOX and active smoking was associated with the highest risk for decreased OS (harzard ratio (HR) 2.35; 95% confidence interval 1.13-4.90) and strongly mitigated the benefit of FOLFIRNOX (HR 0.40; 95% CI 0.25-0.63). Adjusted median OS in NAT patients with FOLFIRINOX was not reached for never and former smokers, compared to 26.2 months in active smokers. Based on the model, a nomogram was generated to illustrate the probability of 5-year survival after PDAC resection. CONCLUSION: The present study confirms that neoadjuvant FOLFIRINOX is associated with excellent survival and demonstrates that active smoking reduces its benefit. The nomogram can assist in daily clinical practice and emphasises the importance of smoking cessation in patients with PDAC, especially prior to NAT with FOLFIRINOX.

NeoGemTax: gemcitabine and docetaxel as neoadjuvant treatment for locally advanced nonmetastasized pancreatic cancer.

BACKGROUND: About 30% of patients with pancreatic cancer suffer from locally advanced nonmetastatic carcinoma at the time of diagnosis. We conducted a prospective phase II clinical trial using neoadjuvant chemotherapy, consisting of gemcitabine and docetaxel, to assess the rate of complete radical resection and overall survival. METHODS: Gemcitabine (900 mg/m2) and docetaxel (35 mg/m2) were given on days 1, 8, and 15 of a 28-day cycle. Two cycles were administered for a preoperative treatment duration of 8 weeks. Patients experiencing tumor regression or stable disease and improved performance status subsequently underwent surgical exploration and pancreatic resection, if feasible. All patients were followed postoperatively to assess long-term survival. RESULTS: A total of 25 patients were eligible and included in the intent-to-treat and evaluable population. Thirteen patients had unresectable disease at inclusion and 12 patients had borderline resectable pancreatic cancer. Finally, 8 of 25 (32%) patients underwent resection after neoadjuvant chemotherapy; 7 (87%) of these patients had R0 resection. The median overall survival of patients who underwent resection was 16 months (95% confidence interval [CI], 8-24 months) compared to 12 months (95% CI, 8-16 months) for those without resection (p=0.276). The median recurrence-free survival rate after resection was 12 months (95% CI, 2-21 months). CONCLUSIONS: NeoGemTax was safe and resection was feasible in a number of patients after systemic neoadjuvant treatment. Further randomized clinical trials are needed to identify novel multimodal regimens that would be able to increase the percentage of patients undergoing curative pancreatic cancer surgery despite advanced tumor stage at the time of diagnosis.

[Surgery for periampullary pancreatic cancer]. / Chirurgie periampullärer Pankreaskarzinome.

Periampullary neoplasms are a heterogeneous group of different tumor entities arising from the periampullary region, of which pancreatic ductal adenocarcinoma (PDAC) is the most common subgroup with 60-70%. As typical for pancreatic adenocarcinomas, periampullary pancreatic cancer is characterized by an aggressive growth and early systemic progression. Due to the anatomical location in close relationship to the papilla of Vater symptoms occur at an earlier stage of the disease, so that treatment options and prognosis are overall more favorable compared to pancreatic carcinomas at other locations. Nevertheless, the principles of treatment for periampullary pancreatic cancer are not substantially different from the standards for pancreatic cancer at other locations. A potentially curative approach for non-metastatic periampullary pancreatic cancer is a multimodal therapy concept, which includes partial pancreatoduodenectomy as a radical oncological resection in combination with a systemic adjuvant chemotherapy. As a result, long-term survival can be achieved in patients with favorable prognostic factors. In addition, with the continous development of surgery and systemic treatment potentially curative treatment concepts for advanced initially nonresectable tumors were also established, after completion of neoadjuvant treatment. This article presents the current surgical principles of a radical oncological resection for periampullary pancreatic cancer in the context of a multimodal treatment concept with an outlook for future developments of treatment.