Patient reported outcomes of duodenum-preserving pancreatic head resection in chronic pancreatitis: high effectivity is impaired by prolonged non-surgical management.

BACKGROUND: Chronic pancreatitis (CP) causes suffering and socioeconomic burden. This study evaluated perioperative results and patient-reported outcomes (PRO) in CP patients treated with duodenum-preserving pancreatic head resection (DPPHR). METHODS: Data were analyzed of CP patients undergoing DPPHR between 01/2001-10/2014. PROs were measured using a specifically designed questionnaire and the EORTC QLQ-C30/PAN26. Associations between treatment variables and PROs were examined. RESULTS: Of 332 patients who received DPPHR, most (n = 251, 75.6%) underwent the Berne modification. Surgical morbidity was 21.5% (n = 71) and 90-day mortality 1.5% (n = 5). Median follow-up was 79.9 months, 5-year survival 90.5%, and 1.8% of patients developed pancreatic cancer. Of 283 patients alive, 178 (62.9%) returned questionnaires. Referral for surgery was self-initiated (38.0% of cases), by gastroenterologists (27.5%) and by general practitioners (21.1%). QoL improved in 78.7% of patients, remained stable in 12.1%, and worsened in 9.1%. Median Izbicki scores decreased from 90 to 5 points after surgery (p < 0.0001). Time from diagnosis to DPPHR was an independent, proportional predictor of a higher postoperative Izbicki score (p = 0.04). CONCLUSION: DPPHR is an effective, safe treatment for CP. A delay in surgery decreases surgical effectivity, hence CP patients should be referred to surgery early to ensure satisfactory outcomes.

Prognostic relevance of the revised R status definition in pancreatic cancer: meta-analysis.

BACKGROUND: The prognostic impact of margin status is reported with conflicting results after pancreatic cancer resection. While some studies validated an uninvolved resection margin (R0) 1 mm or more of tumour clearance, others have failed to show benefit. This systematic review and meta-analysis aimed to investigate the effects of margin definitions on median overall survival (OS). METHODS: MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for studies reporting associations between resection margins and OS between 2010 and 2021. Data regarding margin status (R0 circumferential resection margin (CRM) negative (CRM-), R0 CRM positive (CRM+), R0 direct, and R1 and OS were extracted. Hazard ratios (HRs) were pooled with a random-effects model. The risk of bias was evaluated with the Quality in Prognosis Studies (QUIPS) tool. RESULTS: The full texts of 774 studies were screened. In total, 21 studies compromising 6056 patients were included in the final synthesis. In total, 188 (24 per cent) studies were excluded due to missing margin definitions. The R0 (CRM+) rate was 50 per cent (95 per cent confidence interval (c.i.) 0.40 to 0.61) and the R0 (CRM-) rate was 38 per cent (95 per cent c.i. 0.29 to 0.47). R0 (CRM-) resection was independently associated with improved OS compared to combined R1 and R0 (CRM+; HR 1.36, 95 per cent c.i. 1.23 to 1.56). CONCLUSION: The revised R status was confirmed as an independent prognosticator compared to combined R0 (CRM+) and R1. The limited number of studies, non-standardized pathology protocols, and the varying number of margins assessed hamper comparability.

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%.

Clinical presentation and prognosis of adenosquamous carcinoma of the pancreas - Matched-pair analysis with pancreatic ductal adenocarcinoma.

INTRODUCTION: Adenosquamous carcinoma of the pancreas (ASCP) is a rare subtype of pancreatic adenocarcinoma. The aim of this study was to investigate the characteristics and outcomes of ASCP in comparison to pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: All patients with ASCP treated between December 2001 and December 2017 were identified from a prospective database. Clinicopathological and follow-up data were analyzed. A nested case-control-study with matched-pair analysis was performed to compare overall survival of ASCP and PDAC. RESULTS: Of 4009 patients undergoing surgery for pancreatic adenocarcinoma 91 patients had ASCP. Compared to PDAC ASCP were larger (4.0 vs. 3.2 cm; p < 0.0001), more frequently involved lymph nodes (88% vs. 78%; p = 0.0216), more frequently showed poor differentiation (G3: 79% vs. 36%; p < 0.0001) and more frequently were located in the pancreatic tail (19% vs. 10%; p = 0.0179). Overall median post-resection-survival was shorter in ASCP (10.8 vs. 20.5 months in PDAC; p = 0.0085), but 5-year survival rates were comparable (18.2% vs. 17.5%). After matching for the unevenly distributed prognostic factors survival after resection of ASCP and PDAC was comparable (p = 0.8301). Localization in the head or several parts of the pancreas, high CA 19-9 levels, and M1 disease were independent predictors of survival in patients with ASCP. CONCLUSION: ASCP is more aggressive with poorer differentiation and higher rates of lymph node metastases compared to PDAC. In spite of a shorter median survival, 5-year survival rates after surgical resection of about 18% can be expected in ASCP and support resection as part of a multimodal therapy as the treatment of choice in this rare cancer.

Local radicality and survival outcome of pancreatic cancer surgery.

Pancreatic cancer remains a therapeutic challenge. Surgical resection in combination with systemic chemotherapy is the only option promising long-term survival and potential cure. However, only about 20% of patients are diagnosed with tumors that are still in a resectable stage. Even after potentially curative resection and modern regimens for adjuvant chemotherapy, the majority of patients develop local and systemic recurrence resulting in median overall survival times of 28-54 months. The predominance of systemic recurrence and its impact on survival may lead to the assumption that surgical radicality and local control play only minor roles in the treatment of pancreatic cancer. This review provides an overview of the recent literature on surgical radicality and survival outcome in pancreatic cancer. The current evidence on the extent of lymphadenectomy, the prognostic impact of the extent of lymph node involvement, and the impact of the resection margin status on postresection survival are reviewed. Data from recent studies performed in the context of modern surgery and adjuvant therapy provide good evidence of a considerable impact of local radicality on survival after pancreatic cancer surgery. Surgical techniques that have been developed to refine oncological resections and to increase local control as well as resectability are highlighted. These techniques include artery-first approaches, level-3 dissection with removal of the periarterial nerve plexus, the triangle operation, and extended resections. Local radicality and quality of surgical resection remain among the most important parameters that determine the chances for survival in patients with non-metastatic pancreatic cancer.

Abdominal drainage versus no drainage after distal pancreatectomy: study protocol for a randomized controlled trial.

BACKGROUND: The placement of prophylactic intra-abdominal drains has been common practice in abdominal operations including pancreatic surgery. The PANDRA trial showed that the omission of drains following pancreatic head resection was non-inferior to intra-abdominal drainage in terms of postoperative reinterventions and superior in terms of clinically relevant pancreatic fistula rate and fistula-associated complications. The aim of the present PANDRA II trial is to evaluate the clinical outcome with versus without prophylactic drain placement after distal pancreatectomy. METHODS: The PANDRA II trial is a mono-center, randomized controlled, non-inferiority trial with two parallel study groups. In the control group at least one passive intra-abdominal drain is placed at the pancreatic resection margin. In the experimental group no drains are placed. The primary endpoint of this trial will be the Comprehensive Complication Index (CCI) measuring all postoperative complications within 90 days. Secondary endpoints are in-hospital mortality and morbidity, including the rates of postoperative pancreatic fistula, chyle leak, postpancreatectomy hemorrhage, delayed gastric emptying, reinterventions and reoperations, surgical site infection, and abdominal fascia dehiscence. Moreover, length of hospital stay, duration of intensive care unit stay, and the rate of readmission after discharge from hospital (up to day 90 after surgery) are assessed. We will need to analyze 252 patients to test the hypothesis that no drainage is non-inferior to drain placement in terms of the CCI (δ 7.5 points) in a one-sided t test with a one-sided level of significance of 2.5% and a power of 80%. DISCUSSION: The results of the PANDRA II trial will help to evaluate the effect of an omission of prophylactic intraperitoneal drainage on the rate of complications after open or minimally invasive distal pancreatectomy. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00013763 . Registered on 6 March 2018.

Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis.

BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. METHODS: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. RESULTS: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (≥ 1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P = 0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P = 0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19 months (95 CI, 15-25 months). CONCLUSIONS: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor.

Correction to: Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study.

In the original article, the institutional author the E-AHPBA DP-CAR study group was misspelled. It is correct as reflected here. The original article has also been corrected.

Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study.

BACKGROUND: Western multicenter studies on distal pancreatectomy with celiac axis resection (DP-CAR), also known as the Appleby procedure, for locally advanced pancreatic cancer are lacking. We aimed to study overall survival, morbidity, mortality and the impact of preoperative hepatic artery embolization (PHAE). METHODS: Retrospective cohort study within the European-African Hepato-Pancreato-Biliary-Association, on DP-CAR between 1-1-2000 and 6-1-2016. Primary endpoint was overall survival. Secondary endpoints were radicality (R0-resection), 90-day mortality, major morbidity, and pancreatic fistulae (grade B/C). RESULTS: We included 68 patients from 20 hospitals in 12 countries. Postoperatively, 53% of patients had R0-resection, 25% major morbidity, 21% an ISGPS grade B/C pancreatic fistula, and 16% mortality. In total, 82% received (neo-)adjuvant chemotherapy and median overall survival in 62 patients with pancreatic ductal adenocarcinoma patients was 18 months (CI 10-37). We observed no impact of PHAE on ischemic complications. CONCLUSIONS: DP-CAR combined with chemotherapy for locally advanced pancreatic cancer is associated with acceptable overall survival. The 90-day mortality is too high and should be reduced. Future studies should investigate to what extent increasing surgical volume or better patient selection can improve outcomes.

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.

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk.

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.

Human adipose tissue derived stem cells promote liver regeneration in a rat model of toxic injury.

In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC) is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20). Injection of cell culture medium performed in group 2 (n = 20) served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017), total protein (P < 0.031), glutamic oxaloacetic transaminase (P < 0.001), and lactate dehydrogenase (P < 0.04) levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.