Is surgical resection justified for pancreatic ductal adenocarcinoma with distant abdominal organ metastasis? A position paper by experts in pancreatic surgery at the Joint Meeting of the International Association of Pancreatology (IAP) & the Japan Pancreas Society (JPS) 2022 in Kyoto.

Pancreatic ductal adenocarcinoma (PDAC) is a typical refractory malignancy, and many patients have distant organ metastases at diagnosis, such as liver metastasis and peritoneal dissemination. The standard treatment for unresectable PDAC with distant organ metastasis (UR-M) is chemotherapy, but the prognosis remained poor. However, with recent dramatic developments in chemotherapy, the prognosis has gradually improved, and some patients have experienced marked shrinkage or disappearance of their metastatic lesions. With this trend, attempts have been made to resect a small number of metastases (so-called oligometastases) in combination with the primary tumor or to resect the primary and metastatic tumor in patients with a favorable response to anti-cancer treatment after a certain period of time (so-called conversion surgery). An international consensus meeting on surgical treatment for UR-M PDAC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of the Japan Pancreas Society (JPS) in Kyoto in July 2022. The presenters showed their indications for and results of surgical treatment for UR-M PDAC and discussed their advantages and disadvantages with the experts. Although these reports were limited to a small number of patients, findings suggest that these surgical treatments for patients with UR-M PDAC who have had a significant response to chemotherapy may contribute to a prognosis of prolonged survival. We hope that this article summarizing the discussion and agreements at the meeting will serve as the basis for future trials and guidelines.

"Conversion surgery" for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022.

Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called "conversion surgery", at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that "cancer biology is surpassing locoregional anatomical resectability" in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.

Mixed acinar-neuroendocrine carcinoma of the pancreas with positive for microsatellite instability: a case report and review of the literature.

BACKGROUND: Mixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas is a rare tumor. We report a case of successful surgical resection of expansively growing MANEC of the pancreas with microsatellite instability (MSI)-high. CASE PRESENTATION: The patient was an asymptomatic 65-year-old male. A computed tomography (CT) scan for a follow-up after treatment of pneumonia incidentally revealed a hypoenhancing 12-cm expansively growing tumor in the pancreatic body. An endoscopic ultrasound-guided fine-needle aspiration of the tumor suggested the diagnosis of MANEC. We performed distal pancreatectomy with combined resection of the spleen, left adrenal gland, transverse colon, small bowel, and stomach. The intraoperative findings showed that the tumor was capsular and was in contact with the SMA, SMV, and CA; however, obvious infiltration of these vessels was not observed..Pathological findings indicated MANEC with MSI-high. Among mismatch repair (MMR) gene proteins, PMS2 was lost and MLH1, MSH2, and MSH6 were retained. The tumor recurred 5 months after surgery. The patient was treated with gemcitabine plus nab-paclitaxel followed by pembrolizumab, which did not show objective response. DISCUSSION: This is the first report investigating MSI and MMR in MANEC. Standard chemotherapy has not been established for MANEC. Detection of MSI-high is essential since PD-1 monoclonal antibodies for MSI-high cases might be one of the good treatment options. Herein, we discuss the various cytomorphologic and clinical features of MANEC and present a brief review of the literatures. CONCLUSIONS: The accumulation of data from additional cases is necessary to further evaluate this type of carcinoma and provide a standardized optimal therapy for MANEC.

Propensity Score Matching Analysis of the Safety of Completion Total Pancreatectomy for Remnant Pancreatic Tumors Versus that of Initial Total Pancreatectomy for Primary Pancreatic Tumors.

BACKGROUND: The safety and feasibility of completion total pancreatectomy (TP) for remnant pancreatic neoplasms remain controversial and are rarely compared with that of initial TP. Thus, we aimed to compare the safety of these two procedures inducing a pancreatic state. METHODS: Patients who underwent TP for pancreatic neoplasms between 2006 and 2018 at our institution were included in this study. Tumor pathologies were classified into three subgroups according to survival curves. We used 1:1 propensity score matching (PSM) to analyze age, sex, Charlson Comorbidity Index, and tumor stage. Finally, we analyzed the primary outcome Clavien-Dindo classification (CDC) grade, risks of other safety-related outcomes, and the survival rate of patients with invasive cancer. RESULTS: Of 54 patients, 16 underwent completion TP (29.6%) and 38 (70.4%) underwent initial TP. Before PSM analysis, age and Charlson Comorbidity Index were significantly higher, and T category and stage were significantly lower for the completion TP group. Upon PSM analysis, these two groups were equivalent in CDC grade [initial TP vs. completion TP: 71.4% (10/14) vs. 78.6% (11/14); p = 0.678] and other safety-related outcomes. Additionally, while the overall survival and recurrence-free survival of patients with invasive cancer were not significantly different between these two groups, the T category and stage tended to be remarkably severe in the initial TP group. CONCLUSIONS: PSM analysis for prognostic factors showed that completion TP and initial TP have similar safety-related outcomes that can be used as a decision-making reference in the surgery of pancreatic tumors.

Study protocol for a multi-institutional prospective surveillance study among kindreds with familial pancreatic cancer and individuals with hereditary pancreatic cancer syndrome: The Diamond Study.

BACKGROUND: Family history of pancreatic cancer (PC) and some hereditary cancer syndromes are risk factors for PC. Previous studies suggest that conducting surveillance for kindreds at high risk for familial PC may be useful for diagnoses at the stage where resections can still be implemented; however, there is insufficient evidence linking surveillance and increased rates of resectable PC. METHODS: We launched a surveillance study for kindreds with familial PC and individuals with hereditary PC syndrome, titled the "Diamond Study," in June 2020. This Japanese national multi-institutional prospective intervention study has been initiated to conduct evaluations within a prospective clinical trial format. RESULTS: The primary endpoint is the fraction of patients with resectable PC among patients with PC found through surveillance interventions. Endoscopic ultrasound and magnetic resonance imaging combined with magnetic resonance cholangiopancreatography will be performed alternatively every 6 months for up to 15 years, with 400 as the predicted number of registered participants and a predicted registration period of 10 years. CONCLUSION: We intend to scientifically prove the usefulness of surveillance for kindreds with familial PC and individuals with hereditary PC syndrome to improve PC prognoses.

Impact of neoadjuvant intensity-modulated radiation therapy on borderline resectable pancreatic cancer with arterial abutment; a prospective, open-label, phase II study in a single institution.

BACKGROUND: Borderline resectable pancreatic cancer (BRPC) is a category of pancreatic cancer that is anatomically widely spread, and curative resection is uncommon with upfront surgery. Intensity-modulated radiation therapy (IMRT) is a form of radiation therapy that delivers precise radiation to a tumor while minimizing the dose to surrounding normal tissues. Here, we conducted a phase 2 study to estimate the curability and efficacy of neoadjuvant chemoradiotherapy using IMRT (NACIMRT) for patients with BRPC with arterial abutment (BRPC-A). METHODS: A total of 49 BRPC-A patients were enrolled in this study and were treated at our hospital according to the study protocol between June 2013 and March 2021. The primary endpoint was microscopically margin-negative resection (R0) rates and we subsequently analyzed safety, histological effect of the treatment as well as survivals among patients with NACIMRT. RESULTS: Twenty-nine patients (59.2%) received pancreatectomy after NACIMRT. The R0 rate in resection patients was 93.1% and that in the whole cohort was 55.1%. No mortality was encountered. Local therapeutic effects as assessed by Evans classification showed good therapeutic effect (Grade 1, 3.4%; Grade 2a, 31.0%; Grade 2b, 48.3%; Grade 3, 3.4%; Grade 4, 3.4%). Median disease-free survival was 15.5 months. Median overall survival in the whole cohort was 35.1 months. The only independent prognostic pre-NACIMRT factor identified was serum carbohydrate antigen 19-9 (CA19-9) > 400 U/ml before NACIMRT. CONCLUSIONS: NACIMRT showed preferable outcome without significant operative morbidity for BRPC-A patients. NACIMRT contributes to good local tumor control, but a high initial serum CA19-9 implies poor prognosis even after neoadjuvant treatment. TRIAL REGISTRATION: UMIN-CTR Clinical Trial: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000011776 Registration number: UMIN000010113. Date of first registration: 01/03/2013.

International Expert Consensus on Precision Anatomy for minimally invasive distal pancreatectomy: PAM-HBP Surgery Project.

BACKGROUND: Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021). METHODS: Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. RESULTS: Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts. CONCLUSIONS: The expert consensus on precision anatomy for MIDP has been presented as a set of recommendations based on available evidence and expert opinions. These recommendations should guide experts and trainees in performing safe MIDP and foster its appropriate dissemination worldwide.

Preoperative risk stratification of lymph node metastasis for non-functional pancreatic neuroendocrine neoplasm: An international dual-institutional study.

BACKGROUND: /Objectives: Although the presence of lymph node metastasis (LNM) defines malignant potential, preoperative prediction of LNM has not been established for non-functional pancreatic neuroendocrine neoplasm (NF-PNEN). We sought to develop a prediction system using only preoperatively available factors that would stratify the risk of LNM for NF-PNEN. METHODS: We retrospectively reviewed patients who underwent R0/1 resection of NF-PNEN at Kyoto University (2007-2019) and the University of California, San Francisco (2010-2019). Risk stratification of LNM was developed using preoperative factors by the logistic regression analysis. Long-term outcomes were compared across the risk groups. RESULTS: A total of 131 patients were included in this study. Lymph nodes were pathologically examined in 116 patients, 23 (20%) of whom had LNM. Radiological tumor size [1.5-3.5 cm (odds ratio: 13.5, 95% confidence interval: 1.77-398) and >3.5 cm (72.4, 9.06-2257) against ≤1.5 cm], <50% cystic component (8.46 × 10^6, 1.68 × 10^106-), and dilatation of main pancreatic duct ≥5 mm (31.2, 3.94-702) were independently associated with LNM. When patients were classified as the low-risk (43 patients), intermediate-risk (44 patients), and high-risk groups (29 patients), proportions of LNM differed significantly across the groups (0%, 14%, and 59%, respectively). Recurrence-free survival (RFS) of the low- and intermediate-risk groups were significantly better than that of the high-risk group (5-year RFS rates of 92.2%, 85.4%, and 47.1%, respectively). CONCLUSIONS: The prediction system using preoperative radiological factors stratifies the risk of LNM for NF-PNEN. This stratification helps to predict malignant potential and determine the surgical procedure and necessity of regional lymphadenectomy.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

International expert consensus on precision anatomy for minimally invasive pancreatoduodenectomy: PAM-HBP surgery project.

BACKGROUND: The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD. METHODS: Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting. RESULTS: Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection. CONCLUSIONS: MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.

Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of 'cancer stem cells (CSCs)' in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1+ tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1+ and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1+ cells in vivo, revealing the essential roles of Dclk1+ cells in expansion of pancreatic neoplasia in all progressive stages.

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

BACKGROUND: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy. METHODS: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis. RESULTS: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT. CONCLUSION: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.

Left-posterior approach for artery-first en bloc resection in laparoscopic distal pancreatectomy for left-sided pancreatic cancer.

PURPOSE: We describe a "left-posterior approach" in which the important steps in laparoscopic distal pancreatectomy (LDP) for left-sided pancreatic cancer are accomplished in the direction caudal and dorsal to the pancreas. METHODS: The patients who underwent LDP with a left-posterior approach at our hospital from January 2016 to April 2020 were reviewed to evaluate the short-term postoperative outcomes. In LDP, we first dissected retroperitoneal tissues above the left renal vein and superior mesenteric artery, yielding the mobilization of the pancreatic body widely. Then, the splenic artery was divided behind the ventrally lifted pancreas as an artery-first approach. The regional lymphadenectomy was performed in an en bloc manner consecutively in the same operative field. The neck of the pancreas was transected with a linear stapler after mobilization of the spleen. RESULTS: In nine patients (five men and four women) aged 76 years (range: 64-82 years), the operative time was 398 min (276-482 min) with the estimated blood loss of 40 ml (0-80 ml). No patients developed grade B/C pancreatic fistula or delayed gastric emptying. Postoperative complications classified as grade III in the Clavien-Dindo classification occurred in one patient (abdominal abscess). The pathology confirmed R0 resection in all patients who had pancreatic cancer (n = 5), IPMNs (n = 3), and high-grade pancreatic intraepithelial neoplasia (PanIN) (n = 1). The number of retrieved lymph nodes was 35 (11-49). CONCLUSION: The procedure with a left-posterior approach is a rational surgical technique in LDP for left-sided pancreatic cancer.

Postoperative pancreatic fistulas decrease the survival of pancreatic cancer patients treated with surgery after neoadjuvant chemoradiotherapy: A retrospective analysis.

BACKGROUND AND OBJECTIVES: A postoperative pancreatic fistula (POPF) is a critical complication after surgery for pancreatic cancer. Whether a POPF affects the long-term prognosis of pancreatic cancer cases remains controversial. This study aimed to clarify the effect of a POPF on the long-term prognosis of pancreatic cancer patients, especially after neoadjuvant chemoradiotherapy (NACRT). METHODS: Patients who underwent curative pancreatectomy for pancreatic cancer between January 2012 and June 2019 at Kyoto University Hospital were retrospectively investigated. A fistula ≥ Grade B was considered a POPF. RESULTS: During the study period, 148 patients underwent upfront surgery (Upfront group), and 52 patients underwent surgery after NACRT (NACRT group). A POPF developed in 16% of patients in the Upfront group and 13% in the NACRT group (p = 0.824). In the Upfront group, development of a POPF did not have a significant effect on recurrence-free survival (p = 0.766) or overall survival (p = 0.863). However, in the NACRT group, development of a POPF significantly decreased recurrence-free survival (HR 5.856, p = 0.002) and overall survival (HR 7.097, p = 0.020) on multivariate analysis. CONCLUSIONS: The development of a POPF decreases the survival of pancreatic cancer patients treated by surgery after NACRT.

Robotic-assisted pancreaticoduodenectomy with vascular resection. Description of the surgical technique and analysis of early outcomes.

BACKGROUND: Despite the potential benefits, the adoption of the minimally invasive surgery for the treatment of borderline resectable pancreatic cancer is still in the initial phase. We investigated the safety and feasibility of the robotic pancreaticoduodenectomy with venous resection/reconstruction (RPD SMV/PV). METHODS: Since March 2013 to October 2019, a total of 73 RPD and 10 RPD SMV/PV were performed. The two groups were case-matched according to the preoperative characteristics. RESULTS: Mean operative times and estimated blood loss were less in the RPD group in comparison to that in the RPD with SMV-PV group (525 vs 642 min, p = 0.003 and 290 vs 620 ml, p = 0.002, respectively). The mean length of hospital stay was similar in the RPD group in comparison to that in the RPD with SMV-PV group (10 days vs 13 days, p = 0.313). The two groups had similar overall postoperative morbidity rate (57.5% vs 60%, p = 0.686), although the severe complication rate was lower in the RPD group (11% vs 40%, p = 0.004). CONCLUSIONS: RPD with SMV-PV is associated with increased operative time, estimated blood loss, higher major complication rate compared with RPD.

The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation.

BACKGROUND: Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants. METHODS: Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function. RESULTS: Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function. CONCLUSIONS: Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP. METHODS: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP. CONCLUSIONS: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.

Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response.

The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 µg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+ T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. METHODS: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. CONCLUSIONS: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.