A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Overexpression of the adhesion signaling pathway is linked to short-term survival in pancreatic ductal adenocarcinoma.

BACKGROUND AND OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is known for its unfavorable prognosis. Gaining insights into the molecular mechanisms that contribute to its progression is crucial for developing effective therapies. In this study, our objective was to investigate the molecular pathways associated with short-term survival in patients with PDAC. METHODS: Immune profiles were analyzed from both long-term survivors (n = 10) and short-term survivors (n = 10) after surgical resection. Pathway scores were calculated to compare the two groups. RESULTS: The "Adhesion" pathway emerged as the most significant pathway, exhibiting a notably higher score in the samples of short-term survivors (P < 0.009). Within this pathway, significant findings were observed in genes related to integrins and CEACAM. CONCLUSION: The role of integrins in the tumor microenvironment of pancreatic cancer is of utmost importance, as they are found to be overexpressed in short-term survivors. These findings provide valuable insights into the underlying biology of PDAC and have potential implications for the development of therapeutic strategies.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Stereotactic ablative radiotherapy or best supportive care in patients with localized pancreatic cancer not receiving chemotherapy and surgery (PANCOSAR): a nationwide multicenter randomized controlled trial according to a TwiCs design.

BACKGROUND: Significant comorbidities, advanced age, and a poor performance status prevent surgery and systemic treatment for many patients with localized (non-metastatic) pancreatic ductal adenocarcinoma (PDAC). These patients are currently treated with 'best supportive care'. Therefore, it is desirable to find a treatment option which could improve both disease control and quality of life in these patients. A brief course of high-dose high-precision radiotherapy i.e. stereotactic ablative body radiotherapy (SABR) may be feasible. METHODS: A nationwide multicenter trial performed within a previously established large prospective cohort (the Dutch Pancreatic cancer project; PACAP) according to the 'Trial within cohorts' (TwiCs) design. Patients enrolled in the PACAP cohort routinely provide informed consent to answer quality of life questionnaires and to be randomized according to the TwiCs design when eligible for a study. Patients with localized PDAC who are unfit for chemotherapy and surgery or those who refrain from these treatments are eligible. Patients will be randomized between SABR (5 fractions of 8 Gy) with 'best supportive care' and 'best supportive care' only. The primary endpoint is overall survival from randomization. Secondary endpoints include preservation of quality of life (EORTC-QLQ-C30 and -PAN26), NRS pain score response and WHO performance scores at baseline, and, 3, 6 and 12 months. Acute and late toxicity will be scored using CTCAE criteria version 5.0: assessed at baseline, day of last fraction, at 3 and 6 weeks, and 3, 6 and 12 months following SABR. DISCUSSION: The PANCOSAR trial studies the added value of SBRT as compared to 'best supportive care' in patients with localized PDAC who are medically unfit to receive chemotherapy and surgery, or refrain from these treatments. This study will assess whether SABR, in comparison to best supportive care, can relieve or delay tumor-related symptoms, enhance quality of life, and extend survival in these patients. TRIAL REGISTRATION: Clinical trials, NCT05265663 , Registered March 3 2022, Retrospectively registered.

Prophylactic abdominal drainage or no drainage after distal pancreatectomy (PANDORINA): a binational multicenter randomized controlled trial.

BACKGROUND: Prophylactic abdominal drainage is current standard practice after distal pancreatectomy (DP), with the aim to divert pancreatic fluid in case of a postoperative pancreatic fistula (POPF) aimed to prevent further complications as bleeding. Whereas POPF after pancreatoduodenectomy, by definition, involves infection due to anastomotic dehiscence, a POPF after DP is essentially sterile since the bowel is not opened and no anastomoses are created. Routine drainage after DP could potentially be omitted and this could even be beneficial because of the hypothetical prevention of drain-induced infections (Fisher, Surgery 52:205-22, 2018). Abdominal drainage, moreover, should only be performed if it provides additional safety or comfort to the patient. In clinical practice, drains cause clear discomfort. One multicenter randomized controlled trial confirmed the safety of omitting abdominal drainage but did not stratify patients according to their risk of POPF and did not describe a standardized strategy for pancreatic transection. Therefore, a large pragmatic multicenter randomized controlled trial is required, with prespecified POPF risk groups and a homogeneous method of stump closure. The objective of the PANDORINA trial is to evaluate the non-inferiority of omitting routine intra-abdominal drainage after DP on postoperative morbidity (Clavien-Dindo score ≥ 3), and, secondarily, POPF grade B/C. METHODS/DESIGN: Binational multicenter randomized controlled non-inferiority trial, stratifying patients to high and low risk for POPF grade B/C and incorporating a standardized strategy for pancreatic transection. Two groups of 141 patients (282 in total) undergoing elective DP (either open or minimally invasive, with or without splenectomy). Primary outcome is postoperative rate of morbidity (Clavien-Dindo score ≥ 3), and the most relevant secondary outcome is grade B/C POPF. Other secondary outcomes include surgical reintervention, percutaneous catheter drainage, endoscopic catheter drainage, abdominal collections (not requiring drainage), wound infection, delayed gastric emptying, postpancreatectomy hemorrhage as defined by the international study group for pancreatic surgery (ISGPS) (Wente et al., Surgery 142:20-5, 2007), length of stay (LOS), readmission within 90 days, in-hospital mortality, and 90-day mortality. DISCUSSION: PANDORINA is the first binational, multicenter, randomized controlled non-inferiority trial with the primary objective to evaluate the hypothesis that omitting prophylactic abdominal drainage after DP does not worsen the risk of postoperative severe complications (Wente etal., Surgery 142:20-5, 2007; Bassi et al., Surgery 161:584-91, 2017). Most of the published studies on drain placement after pancreatectomy focus on both pancreatoduodenectomy and DP, but these two entities present are associated with different complications and therefore deserve separate evaluation (McMillan et al., Surgery 159:1013-22, 2016; Pratt et al., J Gastrointest Surg 10:1264-78, 2006). The PANDORINA trial is innovative since it takes the preoperative risk on POPF into account based on the D-FRS and it warrants homogenous stump closing by using the same graded compression technique and same stapling device (de Pastena et al., Ann Surg 2022; Asbun and Stauffer, Surg Endosc 25:2643-9, 2011).

Dataset from a proteomics analysis of tumor antigens shared between an allogenic tumor cell lysate vaccine and pancreatic tumor tissue.

The data described was acquired as part of a clinical study with the aim to investigate the potential of tumor-reactive T-cell response as response to vaccination of pancreatic cancer patients with an allogenic tumor cell lysate vaccine (Lau et al., 2022). Proteomics analysis was carried out to identify tumor antigens that are shared between the allogeneic tumor cell lysate used for the vaccine and pancreatic ductal adenocarcinoma (PDAC) tissue samples. To this objective, cell lysates of the vaccine and of nine tissue samples were enzymatically digested and isotopically labeled with tandem mass tags (TMT) in a so-called six-plex manner (Thermo Fisher Scientific). Three pools were prepared by mixing the samples according to their TMT-labels. Subsequently, the three sample pools were fractionated into 24 fractions with high-pH reversed phase chromatography. These fractions were first analyzed on a nano-liquid chromatography (LC) system online coupled to a high-resolution Eclipse Orbitrap mass spectrometer (MS) equipped with a high-field asymmetric-waveform ion-mobility spectrometry (FAIMS) source using a data-dependent MS2 shotgun method. Overall, 126,618 unique peptide sequences, on basis of 768,638 peptide spectra matches and corresponding to 7,597 protein groups, were identified in the total sample set including 61 tumor antigens (Supplement Table S2 in Lau et al. 2022) that were prioritized by Cheever and co-workers as vaccine target antigens on basis of a series of objective criteria (Cheever et al., 2009). In the second phase of the experiment, this set of tumor antigens was targeted using a serial precursor selection (SPS) MS3 method. From this data, ion trap MS2 and Orbitrap MS3 fragment spectra were extracted for peptide identification (protein sequence database-dependent search) and relative quantification using the TMT labels, respectively. The dataset ultimately allowed the identification and quantification of 51 proteins and 163 related peptide precursors with the TMT labels (see Fig. 2B and Supplemental Fig. 8, Lau et al. 2022).

Autologous dendritic cells pulsed with allogeneic tumour cell lysate induce tumour-reactive T-cell responses in patients with pancreatic cancer: A phase I study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysate-dendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients. METHODS: In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour. RESULTS: Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-cell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months). CONCLUSION: Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens.

Appendectomy and the subsequent risk of cancer: A prospective population-based cohort study with long follow-up.

BACKGROUND: The appendix, an organ of immunological and microbiological importance, could be involved in the pathogenesis of cancers, but results are inconclusive. Our objective was to assess the association between appendectomy and the subsequent risk of cancer. METHODS: Data were obtained from the Rotterdam Study; a long-term prospective population-based study of individuals aged 55 years and older, of which the first cohort started in 1990 and included 7983 participants. Information on appendectomy was obtained through either medical interview at baseline or linkage with the national automated pathology center (PALGA). Cancer cases were pathology based. End of follow-up was January 1st, 2015. The association between appendectomy and risk of cancer was assessed using Cox proportional hazard models, adjusted for known confounders. RESULTS: Of 7135 included participants, 1373 (19.2%) had undergone an appendectomy and 1632 individuals developed cancer. After adjustment for age, sex, socioeconomic status, BMI, smoking, prevalent diabetes mellitus and alcohol intake, a history of appendectomy was associated with a significantly lower risk of cancer [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.75-0.98]. Subgroup analyses showed similar results for gastrointestinal cancer (HR 0.75, 95% CI 0.56-0.99), in particular colon cancer (HR 0.65, 95% 0.43-0.97), and cancer of the female reproductive organs (HR 0.35, 95% CI 0.15-0.80). CONCLUSION: Participants who underwent an appendectomy had a reduced risk of cancer in general after adjustment for potential confounders. Therefore, these results contradict earlier studies suggestive of an increased risk. Further research is necessary to replicate these results and reveal its underlying mechanism.

Completion pancreatectomy or a pancreas-preserving procedure during relaparotomy for pancreatic fistula after pancreatoduodenectomy: a multicentre cohort study and meta-analysis.

BACKGROUND: Despite the fact that primary percutaneous catheter drainage has become standard practice, some patients with pancreatic fistula after pancreatoduodenectomy ultimately undergo a relaparotomy. The aim of this study was to compare completion pancreatectomy with a pancreas-preserving procedure in patients undergoing relaparotomy for pancreatic fistula after pancreatoduodenectomy. METHODS: This retrospective cohort study of nine institutions included patients who underwent relaparotomy for pancreatic fistula after pancreatoduodenectomy from 2005-2018. Furthermore, a systematic review and meta-analysis were performed according to the PRISMA guidelines. RESULTS: From 4877 patients undergoing pancreatoduodenectomy, 786 (16 per cent) developed a pancreatic fistula grade B/C and 162 (3 per cent) underwent a relaparotomy for pancreatic fistula. Of these patients, 36 (22 per cent) underwent a completion pancreatectomy and 126 (78 per cent) a pancreas-preserving procedure. Mortality was higher after completion pancreatectomy (20 (56 per cent) versus 40 patients (32 per cent); P = 0.009), which remained after adjusting for sex, age, BMI, ASA score, previous reintervention, and organ failure in the 24 h before relaparotomy (adjusted odds ratio 2.55, 95 per cent c.i. 1.07 to 6.08). The proportion of additional reinterventions was not different between groups (23 (64 per cent) versus 84 patients (67 per cent); P = 0.756). The meta-analysis including 33 studies evaluating 745 patients, confirmed the association between completion pancreatectomy and mortality (Mantel-Haenszel random-effects model: odds ratio 1.99, 95 per cent c.i. 1.03 to 3.84). CONCLUSION: Based on the current data, a pancreas-preserving procedure seems preferable to completion pancreatectomy in patients in whom a relaparotomy is deemed necessary for pancreatic fistula after pancreatoduodenectomy.

Randomized clinical trial and meta-analysis of the impact of a fibrin sealant patch on pancreatic fistula after distal pancreatectomy: CPR trial.

BACKGROUND: Postoperative pancreatic fistula (POPF) remains the main cause of morbidity in patients after distal pancreatectomy. The objective of this study was to investigate whether an absorbable fibrin sealant patch could prevent POPF after distal pancreatectomy. METHODS: A multicentre, patient-blinded, parallel-group randomized superiority trial was performed in seven Dutch hospitals. Allocation was done using a computer-generated randomization list with a 1 : 1 allocation ratio and concealed varying permuted block sizes. Pancreatic stump closure with a fibrin patch was compared with standard treatment in patients undergoing distal pancreatectomy. The primary endpoint was the development of grade B/C POPF. A systematic review and meta-analysis was performed which combined the present findings with all available evidence. RESULTS: Between October 2010 and August 2017, 247 patients were enrolled. Fifty-four patients (22.2 per cent) developed a POPF, 25 of 125 patients in the patch group versus 29 of 122 in the control group (20.0 versus 23.8 per cent; P = 0·539). No related adverse effects were observed. In the meta-analysis, no significant difference was seen between the patch and control groups (19.7 versus 22.0 per cent; odds ratio 0.89, 95 per cent c.i. 0.60 to 1.32; P = 0·556). CONCLUSION: Application of a fibrin patch to the pancreatic stump does not reduce the incidence of POPF in distal pancreatectomy. Future studies should focus on alternative fistula mitigation strategies, considering pancreatic neck thickness and duct size as risk factors. Trial registration number NL5876 (Netherlands Trial Registry).

Clinical relevant pancreatic fistula after pancreatoduodenectomy: when negative amylase levels tell the truth.

Drain Amylase level are routinely determined to diagnose pancreatic fistula after Pancreatocoduodenectomy. Consensus is lacking regarding the cut-off value of amylase to diagnosis clinically relevant postoperative pancreatic fistulae (POPF). The present study proposes a model based on Amylase Value in the Drain (AVD) measured in the first three postoperative days to predict a POPF. Amylase cut-offs were selected from a previous published systematic review and the accuracy were validated in a multicentre database from 12 centres in 2 countries. The present study defined POPF the 2016 ISGPS criteria (3 times the upper limit of normal serum amylase). A learning machine method was used to correlate AVD with the diagnosis of POPF. Overall, 454 (27%) of 1638 patients developed POPF. Machine learning excluded a clinically relevant postoperative pancreatic fistulae with an AUC of 0.962 (95% CI 0.940-0.984) in the first five postoperative days. An AVD at a cut-off of 270 U/L in 2 days in the first three postoperative days excluded a POPF with an AUC of 0.869 (CI 0.81-0.90, p < 0.0001). A single AVD in the first three postoperative days may not exclude POPF after pancreatoduodenectomy. The levels should be monitored until day 3 and have two negative values before removing the drain. In the group with a positive level, the drain should be kept in and AVD monitored until postoperative day five.

Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial.

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

Effect of centralization and regionalization of pancreatic surgery on resection rates and survival.

BACKGROUND: Centralization of pancreatic surgery in the Netherlands has been ongoing since 2011. The aim of this study was to assess how centralization has affected the likelihood of resection and survival of patients with non-metastatic pancreatic head and periampullary cancer, diagnosed in hospitals with and without pancreatic surgery services. METHODS: An observational cohort study was performed on nationwide data from the Netherlands Cancer Registry (2009-2017), including patients diagnosed with non-metastatic pancreatic head or periampullary cancer. The period of diagnosis was divided into three time intervals: 2009-2011, 2012-2014 and 2015-2017. Hospital of diagnosis was classified as a pancreatic or non-pancreatic surgery centre. Analyses were performed using multivariable logistic and Cox regression models. RESULTS: In total, 10 079 patients were included, of whom 3114 (30.9 per cent) were diagnosed in pancreatic surgery centres. Between 2009-2011 and 2015-2017, the number of patients undergoing resection increased from 1267 of 3169 (40.0 per cent) to 1705 of 3566 (47.8 per cent) (P for trend < 0.001). In multivariable analysis, in 2015-2017, unlike the previous periods, patients diagnosed in pancreatic and non-pancreatic surgery centres had a similar likelihood of resection (odds ratio 1.08, 95 per cent c.i. 0.90 to 1.28; P = 0.422). In this period, however, overall survival was higher in patients diagnosed in pancreatic surgery than in those diagnosed in non-pancreatic surgery centres (hazard ratio 0.92, 95 per cent c.i. 0.85 to 0.99; P = 0.047). CONCLUSION: After centralization of pancreatic surgery, the resection rate for patients with pancreatic head and periampullary cancer diagnosed in non-pancreatic surgery centres increased and became similar to that in pancreatic surgery centres. Overall survival remained higher in patients diagnosed in pancreatic surgery centres.

A phase II study of stereotactic radiotherapy after FOLFIRINOX for locally advanced pancreatic cancer (LAPC-1 trial): Long-term outcome.

PURPOSE: To report the long-term outcome of a multicenter phase II study with FOLFIRINOX followed by stereotactic body radiotherapy (LAPC-1 trial) in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Patients with histological confirmation of LAPC inoperable at diagnosis were enrolled. Induction therapy with 8 cycles of FOLFIRINOX was administered. If no disease progression was found after chemotherapy, patients received stereotactic body radiotherapy (SBRT) at a total dose of 40 Gy in 5 fractions. RESULTS: In LAPC-1 trial, 50 patients were included, but due to disease progression in 11 patients under chemotherapy, 39 patients received stereotactic SBRT after FOLFIRINOX treatment. In whole population, the 1- and 3-year overall survival (OS) were 62% and 10%, respectively. Median follow-up was 13 months. The SBRT group had median OS of 18 months (95% CI 13.2-21.5) versus 5 months (95% CI 4.1-6.7) in non-SBRT group (p<0.001). After chemoradiotherapy, seven patients underwent surgery achieving a radical resection. Patients who underwent surgery had a 3-years OS of 43% compared to 6.5% in the unresected group (p=0.03). Four patients developed grade ≥ 3 adverse events during SBRT. CONCLUSIONS: Long-term survival has been found in patients with LAPC underwent FOLFIRINOX followed by SBRT. This approach increased the probability of a radical surgery. The resected patients achieved a significant better survival compared to unresected group.

Two cases of Hemosuccus pancreaticus after stereotactic radiotherapy to the pancreas: A case study.

Hemosuccus Pancreaticus (HP) is a very rare upper gastro-intestinal haemorrhagic event whose causes can be aneurismal lesions, acute and chronic pancreatic inflammatory conditions, and pancreatic masses. We present 2 cases of patients who underwent stereotactic radiotherapy for pancreatic lesions who manifested signs of HP after treatment. Two male patients were diagnosed with an inoperable locally advanced pancreatic cancer and underwent 8 cycles of chemotherapy followed by stereotactic radiotherapy to the pancreatic lesion delivering 40Gy in 8 fractions. The first patient complained of melena and had a necrotic tumoural mass with a new aneurysmal bulge 3 months after the SBRT. A stent was placed in the aneurysmal lesion, however, a few days later, the bleeding occurred again and the patient died. The other patient had local tumour progression 12 months after SBRT with a pancreatic mass eroding the near vessels. He developed a fast and massive bleeding. HP may occur after SBRT. Inflammation of the tumour mass can lead to erosion of the vessels with subsequent bleeding. The radiotherapy treatment may have contributed to the HP genesis. The treatment is complex and consists of the placement of a stent or surgery.

Systematic review of functional outcome and quality of life after total pancreatectomy.

BACKGROUND: Surgeons have traditionally been reluctant to perform total pancreatectomy because of concerns for brittle diabetes and poor quality of life (QoL). Several recent studies have suggested that outcomes following total pancreatectomy have improved, but a systematic review is lacking. METHODS: A systematic review was undertaken of studies reporting on outcomes after total pancreatectomy for all indications, except chronic pancreatitis. PubMed, EMBASE (Ovid), and Cochrane Library were searched (2005-2018). Endpoints included functional outcome and QoL. RESULTS: A total of 21 studies, including 1536 patients, fulfilled the eligibility criteria. During a median follow-up of 20·8 (range 1·5-96·0) months, 18·6 per cent (45 of 242 patients) were readmitted for endocrine-related morbidity, with associated mortality in 1·6 per cent (6 of 365 patients). No diabetes-related mortality was reported in studies including only patients treated after 2005. Symptoms related to exocrine insufficiency were reported by 43·5 per cent (143 of 329 patients) during a median follow-up of 15·9 (1·5-96·0) months. Overall QoL, reported by 102 patients with a median follow-up of 28·6 (6·0-66·0) months, using the EORTC QLQ-C30 questionnaire, showed a moderately reduced summary score of 76 per cent, compared with a general population score of 86 per cent (P = 0·004). CONCLUSION: Overall QoL after total pancreatectomy is affected adversely, in particular by the considerable impact of diarrhoea that requires better treatment. There is also room for improvement in the management of diabetes after total pancreatectomy, particularly with regards to prevention of diabetes-related morbidity.

ANTECEDENTES: Los cirujanos tradicionalmente se han mostrado reacios a realizar una pancreatectomía total (total pancreatectomy, TP) debido a la preocupación por la aparición de diabetes lábil y la mala calidad de vida (quality of life, QoL). Varios estudios recientes han sugerido que el resultado de la TP ha mejorado, sin embargo no existe una revisión sistemática. MÉTODOS: Se ha realizado una revisión sistemática de los estudios que incluían los resultados después de una TP efectuada para todas las indicaciones, excepto para una pancreatitis crónica. Se realizaron búsquedas en PubMed, Embase (Ovid) y Cochrane Library (2005-2018). Los resultados principales eran el resultado funcional y la calidad de vida. RESULTADOS: En total, 21 estudios cumplieron los criterios de elegibilidad, incluyendo 1.536 pacientes que se habían sometido a una TP. Durante una mediana de seguimiento de 20,8 meses (rango 1,5-96,0), el 18,6% de los pacientes (45 de 242) fueron reingresados por morbilidad relacionada con la función endocrina, con una mortalidad asociada del 1,6% (6 de 365 pacientes). No hubo mortalidad relacionada con la diabetes en los estudios que incluyeron solo aquellos pacientes tratados después de 2005. Se observaron síntomas relacionados con insuficiencia exocrina en un 43,5% de los pacientes (143 de 329) durante una mediana de seguimiento de 15,9 meses (rango 1,5-96,0). La calidad de vida global, informada para 102 pacientes con una mediana de seguimiento de 28,6 meses (rango 6,0-66,0) utilizando el cuestionario EORTC QLQ-C30, mostró una puntuación sumatoria moderadamente reducida del 76% en comparación con la puntuación del 86% para la población general (P = 0,004). CONCLUSIÓN: Es necesario seguir mejorando el manejo de la diabetes después de la TP, sobre todo en lo que respecta a la prevención de la morbilidad relacionada con la diabetes. La calidad de vida global se ve afectada después de la TP y, especialmente, el impacto de la diarrea es considerable y requiere mejorar este aspecto en el futuro.