OBJECTIVE:To provide a composite endpoint in pancreatic surgery. BACKGROUND:Single endpoints in prospective and randomized studies have become impractical due to their low frequency and the marginal benefit of new interventions. METHODS:Data from prospective studies were used to develop (n=1273) and validate (n=544) a composite endpoint based on postoperative pancreatic fistula, postpancreatectomy hemorrhage, as well as reoperation and reinterventions. All patients had pancreatectomies of different extents. The association of the developed PAncreatic surgery Composite Endpoint (PACE) with prolonged length of hospital stay >75th percentile and mortality was assessed. A single-institution database was used for external validation (n=2666). Sample size calculations were made for single outcomes and the composite endpoint. RESULTS:In the internal validation cohort, the PACE demonstrated an area under the curve of 78.0%, a sensitivity of 90.4%, and a specificity of 67.6% in predicting a prolonged length of hospital stay. In the external cohort, the area under the curve was 76.9%, a sensitivity of 73.8%, and a specificity of 80.1%. The 90-day mortality rate was significantly different for patients with a positive versus a negative PACE both in the development and internal validation cohort (5.1% vs 0.9%; P < 0.001), as well as in the external validation cohort (8.5% vs 1.2%, P < 0.001). The PACE enabled sample size reductions of up to 80.5% compared to single outcomes. CONCLUSIONS:The PACE performed well in predicting prolonged hospital stays and can be used as a standardized and clinically relevant endpoint for future prospective trials enabling lower sample sizes and therefore improved feasibility compared to single outcome parameters.

Purpose: The differentiation of mass-forming chronic pancreatitis (MFCP) and pancreatic ductal adenocarcinomas (PDAC) based on conventional imaging methods like ultrasound, CT and MRI is frequently not possible. Here, we applied static (60 minutes post injection) and dynamic PET/CT with 68Gallium-labelled Fibroblast Activated Protein Inhibitors (68Ga-FAPI-PET/CT) in 26 preoperative, treatment-naive patients with unclear pancreatic masses to evaluate its potential diagnostic value for MFCP and PDAC. Methods: 26 Patients underwent static and dynamic 68 Ga-FAPI-PET/CT as well as dedicated fundamental (US) and contrast-enhanced ultrasonography (CEUS) before surgical resection or biopsy of pancreatic masses and subsequent histological analyses. Static parameters (SUVmax and SUVmean and target to background ratios) were generated from VOIs of pancreatic masses. Time activity curves and dynamic parameters were extracted from dynamic PET data. Results: Histology revealed 12 PDAC, 2 high-grade IPMN and 12 MFCP. We observed higher 68Ga-FAPI-uptake in PDACs (average SUVmax/mean 18.09 +/- 5.5 / 10.55 +/- 2.97) than in MFCP (average SUVmax/mean 11.55 +/- 3.88 / 6.83 +/- 2.20). In dynamic PET-imaging, PDAC and MFCP showed differential time activity curves and the average time to peak was markedly longer for PDAC (1094 +/- 945 seconds ) than for MFCP (449 seconds +/- 203). In ROC curves, static and dynamic imaging parameters showed higher sensitivity and specificity than laboratory parameters, CT- and US-size. Conclusion: 68Ga-FAPI-PET/CT displays the fibrotic activity of MFCP. Static and dynamic 68Ga-FAPI-PET/CT should be considered, when clinical parameters and other imaging methods are not able to distinguish between PDAC and MFCP.

Background: After resection of pancreatic ductal adenocarcinoma (PDAC) 8 out of 10 patients will relapse within two years. Despite the lack of harmonized guidelines, data point towards benefit for structured postoperative follow-up with CT imaging during the first years after resection. Preliminary data on PET scan with the novel tracer FAPI (fibroblast activation protein inhibitor) showed high tumor-associated tracer uptakes and image contrasts in PDAC.

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP.DesignGenome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples.ResultsMachine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma.ConclusionThe success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer.

Clinical/methodological issue Diagnostic and clinical relevance of pancreas divisum. Standard radiological methods Ultrasonography (US), magnetic resonance cholangiopancreatography (MRCP), magnetic resonance imaging (MRI), computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP). Performance Pancreas divisum is an anatomic variation of pancreatic duct system with an incidence in general population of about 10%. It can become symptomatic in approximately 5% of patients. MRI with MRCP is the method of choice to diagnose pancreas divisum. Achievements MRCP is equal to ERCP in diagnosing pancreas divisum in routine clinical practice as it is noninvasive, offers the possibility to evaluate the adjacent tissues and has almost no contraindications. Practical recommendations It is important to be familiar with the anatomy of the pancreatic duct system in order to plan interventional procedures for symptomatic patients in due time.

Background Marginal ulcer is a well-known complication after pancreatoduodenectomy. In light of increasing long-term survival after pancreatoduodenectomy, the identification of risk factors and preventive strategies are of utmost importance. We assessed the incidence, clinical impact, and potential risk factors of marginal ulcer after pancreatoduodenectomy. Methods A prospectively maintained database of patients undergoing pancreatoduodenectomy was analyzed retrospectively. Univariate and bivariate competing-risk Cox regression analyses were performed to identify risk factors for marginal ulcer. Results Two hundred and fifty-five consecutive patients underwent pancreatoduodenectomy. The median follow-up was 35.7 months. Marginal ulcer was diagnosed in 19 patients (7.5%), and the median time from pancreatoduodenectomy to marginal ulcer diagnosis was 450 days. Thirteen of these 19 patients presented with abdominal pain, melena, or anemia. In all these 13 patients, marginal ulcer resolved with proton pump inhibitor therapy and endoscopic surveillance. Six patients with marginal ulcer presented with an acute abdomen and underwent emergency laparotomy for marginal ulcer perforation and peritonitis. There was no marginal ulcer-related mortality. Univariate and bivariate competing-risk analyses showed an increased risk for marginal ulcer with discontinuation of proton pump inhibitor therapy, smoking, alcohol intake, and the use of non-steroidal anti-inflammatory drugs. Discontinuation of proton pump inhibitor therapy was an independent risk factor for marginal ulcer development. Conclusion Marginal ulcer is a relevant long-term complication after pancreatoduodenectomy that occurs more frequently after proton pump inhibitor therapy is discontinued. Based on our data, permanent use of proton pump inhibitor after pancreatoduodenectomy is strongly recommended especially for those patients who smoke, consume alcohol, or use non-steroidal anti-inflammatory drugs.

BackgroundThe purpose of this study is to compare the performance of three-dimensional magnetic resonance cholangiopancreatography (3D-MRCP) with non-MRCP T2-weighted magnetic resonance imaging (MRI) sequences for diagnosis of pancreas divisum (PD).MethodsThis is a retrospective study of 342 consecutive patients with abdominal MRI including 3D-MRCP. 3D-MRCP was a coronal respiration-navigated T2-weighted sequence with 1.5mm slice thickness. Non-MRCP T2-weighted sequences were (1) a coronal inversion recovery sequence (TIRM) with 6mm slice thickness and (2) a transverse single shot turbo spin echo sequence (HASTE) with 4mm slice thickness. For 3D-MRCP, TIRM, and HASTE, presence of PD and assessment of evaluability were determined in a randomized manner. A consensus read by two radiologists using 3D-MRCP, non-MRCP T2-weighted sequences, and other available imaging sequences served as reference standard for diagnosis of PD. Statistical analysis included performance analysis of 3D-MRCP, TIRM, and HASTE and testing for noninferiority of non-MRCP T2-weighted sequences compared with 3D-MRCP.ResultsThirty-three of 342 patients (9.7%) were diagnosed with PD using the reference standard. Sensitivity/specificity of 3D-MRCP for detecting PD were 81.2%/69.7% (p<0.001). Sensitivity/specificity of TIRM and HASTE were 92.5%/93.9 and 98.1%/97.0%, respectively (p<0.001 each). Grouped sensitivity/specificity of non-MRCP T2-weighted sequences were 99.8%/91.0%. Non-MRCP T2-weighted sequences were non-inferior to 3D-MRCP alone for diagnosis of PD. 20.2, 7.3%, and 2.3% of 3D-MRCP, TIRM, and HASTE, respectively, were not evaluable due to motion artifacts or insufficient duct depiction.ConclusionsNon-MRCP T2-weighted MRI sequences offer high performance for diagnosis of PD and are noninferior to 3D-MRCP alone.Trial registrationNot applicable.

ImportanceThe patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.ObjectiveTo define patterns of recurrence after adjuvant chemotherapy and the association with survival.Design, Setting, and ParticipantsProspectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.InterventionsRandomization to adjuvant gemcitabine or gemcitabine plus capecitabine.Main Outcomes and MeasuresOverall survival, recurrence, and sites of recurrence.ResultsOf the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03).Conclusions and RelevanceThere were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.Trial RegistrationClinicaltrials.gov Identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

Die Früherkennung des Pankreaskarzinoms ist problematisch. Die Abdomensonografie ist mit jährlich > 10 Untersuchungen/100 Einwohner die häufigste Bildgebung. Als Nachteile werden Untersucherabhängigkeit und fehlende Reproduzierbarkeit postuliert, die Darstellbarkeit des Pankreas wegen „Luftüberlagerung“ verneint. Systematische Daten zur Nativsonografie existieren nicht.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two‐sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (OR dom ) = 1.78, 95% confidence interval (CI) = 1.26–2.52, p = 1.19 × 10 −3 and OR dom = 1.74, 95% CI = 1.15–2.63, p = 8.57 × 10 −3 , respectively). Neither mutation was significantly associated with risk of developing early‐onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non‐genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high‐risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

BACKGROUND Improving quality of life (QoL) is an important treatment goal in pancreatic cancer patients. Although the beneficial effects of exercise on QoL are well understood, few studies have investigated more aggressive cancers such as pancreatic cancer. METHODS Within a randomized trial, we assessed the efficacy of 6-month resistance training on physical functioning (primary outcome) and further QoL-related outcomes. 65 pancreatic cancer patients were assigned to home-based training, supervised training, or a usual care control group. Analysis-of-covariance models on changes from baseline to 6 and 3 months were ap- plied. RESULTS 47 patients completed the intervention period. After 6 months, no effects of resistance training were observed. However, after 3 months, explorative analyses showed significant between-group mean differences (MD) in favor for resistance training for physical functioning (pooled group: MD=11.0; p=0.016; effect size[ES]=0.31), as well as for global QoL (MD=12.1; p=0.016; effect size=0.56), and other outcomes, such as sleep problems and fatigue. Multiple imputation analyses yielded similar results. Home-based and supervised training performed similarly. CONCLUSION This first randomized resistance training trial in pancreatic cancer patients indicated clinically relevant improve- ments in QoL after 3 but not after 6 months. Given the severity of pancreatic cancer, exercise recommendations may already commence at surgery.

Antecedentes: Las guías clínicas actuales recomiendan efectuar la orquidopexia para el tratamiento de la criptorquidia a los 12 meses de edad, a pesar de que no hay adherencia universal a esta recomendación. El objetivo de esta revisión sistemática y metaanálisis fue comparar los resultados de las orquidopexias realizadas antes y después del año de edad. Métodos: Se realizó una búsqueda en Medline y Embase (septiembre 2015) usando términos relacionados con criptorquidia, orquidopexia y resultados de interés. Los estudios se consideraron elegibles para su inclusión cuando comparaban orquidopexia <1 años de edad (tempranas) con orquidopexia ≥1 año de edad (tardía) y presentaban datos relativos al objetivo primario (atrofia testicular) u objetivos secundarios (potencial de fertilidad, complicaciones postoperatorias, malignización). Se excluyeron los estudios cuando >50% de los niños presentaban testículos intraabdominales o cuando la población de estudio incluía niños con alteraciones de la diferenciación sexual. Se identificaron estudios adicionales a partir de las referencias bibliográficas. Se buscaron datos no publicados en el estudio ORCHESTRA de los autores. Resultados: Se identificaron 15 estudios elegibles a partir de 1.387 artículos. No se observaron diferencias en la tasa de atrofia entre la orquidopexia temprana y tardía (RR 0,64, i.c. del 95% 0,25-1,66, n = 912 testículos). El volumen testicular fue mayor (0,06 ml más, i.c. del 95% 0,01-0,10 ml, n = 346 testículos) y hubo más espermatogonias por túbulo (0,47 más, i.c. del 95% 0,31-0,64; n = 382 testículos) en niños sometidos a orquidopexia temprana, sin diferencias en la tasa de complicaciones (RR 0,68, i.c. del 95% 0,27-1,68, n = 426 testículos). Ningún estudio incluía datos de las tasas de malignidad. Conclusión: Las tasas de atrofia y de complicaciones no parecen ser diferir entre la orquidopexia temprana o tardía, y el potencial de fertilidad podría ser mejor tras la orquidopexia temprana. La imprecisión de los datos disponibles limita la rotundidad de estas conclusiones.

The vast majority of presumed branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are referred to a surveillance program due to the relatively low risk of malignancy. We aim to evaluate all available data from observational studies focused on the risks of BD-IPMN progression and malignancy to provide vital insights into its management in clinical practice.A comprehensive search was conducted at PubMed, Cochrane, Web of Science and Embase for observational studies published before January 1st, 2020. The progression of BD-IPMN was defined as the development of worrisome features (WFs) or high-risk stigmata (HRS) during surveillance. Overall malignancy was defined as all malignancies, such as malignant IPMN, concomitant pancreatic ductal adenocarcinoma (PDAC) and other malignancies, including BD-IPMN with high-grade sec. Baltimore consensus 2015 or BD-IPMN with high-grade dysplasia (carcinoma in situ) sec. WHO 2010. A meta-analysis was performed to investigate the presence of a mural nodule as a possible predictor of malignancy.Twenty-four studies were included, with a total of 8941 patients with a presumed BD-IPMN. The progression rate was 20.2%, and 11.8% underwent surgery, 29.5% of whom showed malignancy at the final pathology. Of those, 78% had malignant IPMNs, and 22% had concomitant pancreatic cancer. Overall, 0.5% had distant metastasis. The meta-analysis showed that the risk of malignancy in the presence of a mural nodule >5 mm had a RR of 5.457 (95% CI 1.404–21.353), while a nonenhancing mural nodule or an enhancing mural nodule < 5 mm had a RR of 5.286 (95% CI 1.805–15.481) of harboring malignancy.Most presumed BD-IPMNs entering surveillance do not become malignant. Of those submitted to surgery, concomitant PDAC adds to the overall risk of detecting malignancy.

Background: Given the poor prognosis and high symptom burden of pancreatic cancer, preservation of quality of life (QoL), physical functioning and minimization of adverse treatment effects are important treatment goals in pancreatic cancer patients. Even though exercise has proven to provide health benefits, including improvements in QoL, in patients with various cancer types, studies are rare for more aggressive cancer types like pancreatic cancer. Therefore, we conducted a randomized controlled trial to assess the efficacy of a 6-month resistance training (RT) on QoL in pancreatic cancer patients. Methods: Sixty-five pancreatic cancer patients, mostly stage IIb after tumor resection and during chemotherapy, were assigned to one of two progressive RT groups (supervised or home-based) or to usual care for 6 months. The primary outcome, the physical functioning subscale of the EORTC QLQ-C30, and other QoL-related outcomes were assessed before the intervention, after 3 and 6 months. Results: Forty-seven patients (mean age: 60.5 years, 53.2% males) completed the intervention period. After 6 months, no between-group differences were observed. However, after 3 months, intention-to-treat analyses showed significant between-group mean differences (MD) in favor for the pooled RT group for physical functioning (MD = 12.0; p = 0.010), as well as for overall QoL (MD = 12.5; p = 0.014), and several other secondary outcomes (cognitive functioning, insomnia, physical fatigue, and reduced activity). Both modes of delivery, supervised and home-based resistance-training, showed similar effects. Overall mean training adherence rate was 66.5%, with a steady decrease over the 6-month intervention period. Conclusions: This was the first randomized controlled RT intervention trial in pancreatic cancer patients. The findings showed clinically relevant improvements in QoL after 3 but not 6 months. Given the severity of pancreatic cancer and the importance of maintaining QoL, patients should be timely advised to perform exercise. Future research needs to focus on prolonging the positive mid-term effects, possibly through improving training adherence. Clinical trial identification: NCT01977066. Legal entity responsible for the study: German Cancer Research Center. Funding: German Cancer Aid (Foundation). Disclosure: All authors have declared no conflicts of interest.

BACKGROUND:Estimation of the risk of malignancy in intraductal papillary mucinous neoplasia (IPMN) of the pancreas is a clinical challenge. Several routinely used clinical factors form the basis of the current consensus guidelines. This study aimed to determine the predictive values of the most commonly assessed risk factors.METHODS:A meta-analysis of individual risk factors of malignancy in IPMN was performed. Contingency tables were derived from these data, and sensitivity, specificity, negative and positive predictive values, and diagnostic odds ratios (DOR) were determined. Hierarchical summary receiver operating characteristic (HSROC) curves for each factor were calculated and the respective area under the curve (AUC) was assessed.RESULTS:A total of 3443 studies were screened initially. Analysis of recent literature revealed 60 studies with 13 relevant risk factors including clinical, serological and radiological parameters. The largest area under the HSROC curve was found for weight loss (0·84) and jaundice/raised bilirubin level (0·80), followed by increased carcinoembryonic antigen (CEA) (0·79) or carbohydrate antigen (CA) 19-9 (0·78) levels. The most sensitive factors were patient age (71 per cent) and mural nodules (65 per cent), and jaundice/raised bilirubin level (97 per cent) and increased CEA level (95 per cent) were most specific. None of the analysed factors reached a positive or negative level of prediction beyond 90 per cent.CONCLUSION:None of the established criteria safely distinguishes malignant from non-malignant lesions.

The management of cystic pancreatic lesions fundamentally depends on knowing the cyst type and the risk or presence of malignancy. Only serous cystic neoplasms (SCN) are generally benign lesions, while mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN) as the most common cystic lesion and solid-pseudopapillary neoplasm (SPN) show different risk profiles for the development of invasive cancer. Once a cystic lesion is detected, the clinical decision is necessary if an upfront resection with the inherent morbidity of pancreatic surgery should be performed or if an observational management can be preferred. Whereas these strategies are clearly defined for certain cystic lesions including SCN, MCN, and SPN, the management of IPMN, especially with regard to the branch-duct type, remains partly controversial, and current guidelines differ with regard to indications for surgery and/or surveillance. The present chapter gives an overview on the different types of pancreatic cystic neoplasms and current diagnostic modalities. Furthermore, the indications for surgery, the variety of surgical resections, and the surveillance/follow-up strategies are discussed in the light of the current literature and guidelines.