Diagnosis and treatment of bacterial peritonitis in patients with gastrointestinal cancer: an observational multicenter study.

Background: Bacterial peritonitis (BP) in patients with gastrointestinal (GI) cancer has been poorly described, and its prevalence is unknown. Objectives: This study aimed to evaluate in patients with both GI cancer and ascites the prevalence of BP, associated features, mechanisms, prognosis, and the diagnostic performance of neutrophil count in ascites. Design: A retrospective, multicenter, observational study. Methods: All patients with GI cancer and ascites who underwent at least one paracentesis sample analyzed for bacteriology over a 1-year period were included. BP was defined by a positive ascites culture combined with clinical and/or biological signs compatible with infection. Secondary BP was defined as BP related to a direct intra-abdominal infectious source. Results: Five hundred fifty-seven ascites from 208 patients included were analyzed. Twenty-eight patients had at least one episode of BP and the annual prevalence rate of BP was 14%. Among the 28 patients with BP, 19 (65%) patients had proven secondary BP and 17 (59%) patients had multi-microbial BP, mainly due to Enterobacterales. A neutrophil count greater than 110/mm3 in ascites had negative and positive predictive values of 96% and 39%, respectively, for the diagnosis of BP. The median survival of patients with BP was 10 days (interquartile range 6-40) after the diagnosis. Conclusion: BP is not rare in patients with GI cancer and is associated with a poor short-term prognosis. When a patient with GI cancer is diagnosed with BP, a secondary cause should be sought. Further studies are needed to better define the best management of these patients.

Reappraising imaging features of pancreatic acinar cystic transformation: be aware of differential diagnoses.

OBJECTIVES: Imaging features of pancreatic acinar cystic transformation (ACT) have been published. We aimed to describe the clinical and radiological characteristics of patients with a presumed pancreatic ACT diagnosis, reappraising the value of these published imaging criteria. MATERIALS AND METHODS: Single-center retrospective study (2003-2021) of consecutive patients with a presumed diagnosis of ACT as suggested by the local expert multidisciplinary case review board. Patients without available imaging (CT or MRI) for review were excluded. Patients were classified into "certain" ACT (if ≥ 2 imaging criteria and no differential diagnosis) or "uncertain" ACT (if ≥ 1 imaging criteria and suggested differential diagnoses). RESULTS: Sixty-four patients (35 males, [55%]) were included. ACT was considered "certain" for 34 patients (53%) and "uncertain" for 30 patients (47%). The number of ACT criteria did not differ between groups, with 91.2% of patients with ≥ 3 ACT imaging criteria in the "certain" group vs 93.3% in the "uncertain" group (p = 0.88). In the "uncertain" group, the main suggested differentials were branch-duct intraductal papillary mucinous neoplasm (18/30 patients, 60%), calcifying chronic pancreatitis (8/30 patients, 27%), both (three patients, 10%) and serous cystadenoma (one patient, 3%). Calcifications were significantly more frequent in the "uncertain" group (89% vs 63% in the "certain" group, p = 0.02). CONCLUSION: Published ACT imaging criteria are frequently associated with features suggesting differential diagnoses. They appear insufficient to reach a final diagnosis in a subset of patients. CLINICAL RELEVANCE STATEMENT: ACT displays a heterogeneous morphological imaging presentation challenging the non-invasive diagnostic work-up. Physicians' and radiologists' awareness of this entity is important to better understand its natural history and improve non-invasive diagnostic criteria. KEY POINTS: The criteria to help diagnose ACT are frequently associated with features suggestive of differentials. The main alternatives suggested when ACT diagnosis was "uncertain" were branch-duct intraductal papillary mucinous neoplasm and calcifying chronic pancreatitis. Published ACT diagnostic imaging criteria can be insufficient for a definite non-invasive diagnosis.

Diagnostic yield of repeat genetic testing in idiopathic chronic pancreatitis.

Genetic testing is performed for unexplained pancreatitis. The aim of this study was to evaluate the diagnostic value of repeating genetic testing in idiopathic pancreatitis when new predisposing genes are identified. We investigated 330 patients who were initially screened for PRSS1, SPINK1 and CFTR genes. A new analysis was performed by Next-Generation Sequencing (NGS) for PRSS1, SPINK1, CFTR, CTRC, CASR, CPA1, TRPV6 genes and the CEL-HYB1 allele in clinical practice, and patients were included in our cohort study. Additional rare variants were identified in 7.3 % of the patients. Screening for new pancreatitis genes is recommended when initial screening is limited. Routine use of NGS is a useful diagnostic tool in these cases.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

Outcome and survival were similar with laparoscopic and open pancreatectomy in 102 solid pseudopapillary neoplasms.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors predominantly in young women. We report the largest single-center cohort study comparing resection of SPNP by laparoscopic approach (LA) and the open approach (OA). METHOD: Between 2001 and 2021, 102 patients (84% women, median age: 30) underwent pancreatectomy for SPNP and were retrospectively studied. Demographic, perioperative, pathological, early and the long-term results were evaluated between patients operated by LA and those by OA. RESULTS: Population included 40 LA and 62 OA. There were no significant differences in demographics data between the groups. A preoperative biopsy by endoscopic ultrasound was performed in 45 patients (44%) with no difference between the groups. Pancreatoduodenectomy (PD) was less frequently performed by LA (25 vs 53%, p = 0.004) and distal pancreatectomy (DP) was more frequently performed by LA (40 vs 16%, p = 0.003). In the subgroup analysis by surgical procedure, LA-PD was associated with one mortality, less median blood loss (180 vs 200 ml, p = 0.034) and fewer harvested lymph nodes (11 vs 15, p = 0.02). LA-DP was associated with smaller median tumor size on imaging (40 vs 80mm, p = 0.048), shorter surgery (135 vs 190 min, p = 0.028), and fewer complications according to the median comprehensive complication index score (0 vs 8.7, p = 0.048). LA-Central pancreatectomy was associated with shorter surgery (160 vs 240, p = 0.037), less median blood loss (60 vs 200, p = 0.043), and less harvested lymph nodes (5 vs 2, p = 0.025). After a median follow-up of 60 months, two recurrences (2%) were observed and were unrelated to the approach. CONCLUSIONS: The LA for SPNP appears to be safe, should be applied cautiously in case of PD for large lesion, and was not associated with recurrence.

Epidemiology, treatment and outcomes of infected pancreatic necrosis in France: a bicenter study.

INTRODUCTION: Acute necrotizing pancreatitis (ANP) mortality increases when pancreatic necrosis is infected (IPN). Current treatment of IPN relies on prolonged antibiotic therapies associated with a step-up strategy of drainage. The objective of this study was to analyze IPN treatment outcomes in two referral centers in France. METHODS: Data of consecutive patients with documented IPN hospitalized in two expert centers in France between 2014 and 2019 were retrospectively reviewed. The composite primary outcome was the proportion of unsuccessful management outcome, defined as new emergency drainage to treat sepsis with organ failure, an unplanned new antibiotic course, an unplanned prolongation of antibiotic course and/or death by septic shock, within three months following the diagnosis of ANP. RESULTS: All in all, 187 patients (138 males; 74.0%), with documented IPN were included. The most frequently identified microorganism was Escherichia coli (26.2%). Ninety-eight patients (52.4%) were admitted to an intensive care unit or resuscitation ward within the first two days of ANP care. Overall, 126 patients (67.4%) endured an unsuccessful outcome: new emergency drainage to treat acute sepsis (62.0%), unplanned new antibiotic course (47.1%), unplanned prolongation of antibiotic course (44.9%) and/or death by septic shock complicating IPN (8.0%). CONCLUSION: The unfavorable evolution in two thirds of patients shows that determination of optimal drainage timing and choice of antibiotic therapy remain major challenges in 2024.

Long-term quality of life is better after laparoscopic compared to open pancreatoduodenectomy.

BACKGROUND: Three randomized controlled trials have reported improved functional recovery after Laparoscopic pancreatoduodenectomy (LPD), as compared to open pancreatoduodenectomy (OPD). Long-term results regarding quality of life (QoL) are lacking. The aim of this study was to compare long-term QoL of LPD versus OPD. METHODS AND PATIENTS: A monocentric retrospective cross-sectional study was performed among patients < 75 years old who underwent LPD or OPD for a benign or premalignant pathology in a high-volume center (2011-2021). An electronic three-part questionnaire was sent to eligible patients, including two diseases specific QoL questionnaires (the European Organization for Research and Treatment in Cancer Quality of Life Questionnaire for cancer (QLQ-C30) and a pancreatic cancer module (PAN26) and a body image questionnaire. Patient demographics and postoperative data were collected and compared between LPD and OPD. RESULTS: Among 948 patients who underwent PD (137 LPD, 811 OPD), 170 were eligible and 111 responded (58 LPD and 53 OPD). LPD versus OPD showed no difference in mean age (51 vs. 55 years, p = 0.199) and female gender (40% vs. 45%, p = 0.631), but LPD showed lower BMI (24 vs 26; p = 0.028) and higher preoperative pancreatitis (29% vs 13%; p = 0.041). The postoperative outcome showed similar Clavien-Dindo ≥ III morbidity (19% vs. 23%; p = 0.343) and length of stay (24 vs. 21 days, p = 0.963). After a similar median follow-up (3 vs. 3 years; p = 0.122), LPD vs OPD patients reported higher QoL (QLQ-C30: 49.6 vs 56.3; p = 0.07), better pancreas specific health status score (PAN20: 50.5 vs 55.5; p = 0.002), physical functioning (p = 0.002), and activities limitations (p = 0.02). Scar scores were better after LPD regarding esthetics (p = 0.001), satisfaction (p = 0.04), chronic pain at rest (p = 0.036), moving (p = 0.011) or in daily activities (p = 0.02). There was no difference in digestive symptoms (p = 0.995). CONCLUSION: This monocentric study found improved long-term QoL in patients undergoing LPD, as compared to OPD, for benign and premalignant diseases. These results could be considered when choosing the surgical approach in these patients.

Prediction of Adjuvant Gemcitabine Sensitivity in Resectable Pancreatic Adenocarcinoma Using the GemPred RNA Signature: An Ancillary Study of the PRODIGE-24/CCTG PA6 Clinical Trial.

PURPOSE: GemPred, a transcriptomic signature predictive of the efficacy of adjuvant gemcitabine (GEM), was developed from cell lines and organoids and validated retrospectively. The phase III PRODIGE-24/CCTG PA6 trial has demonstrated the superiority of modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) over GEM as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma at the expense of higher toxicity. We evaluated the potential predictive value of GemPred in this population. PATIENTS AND METHODS: Routine formalin-fixed paraffin-embedded surgical specimens of 350 patients were retrieved for RNA sequencing and GemPred prediction (167 in the GEM arm and 183 in the mFOLFIRINOX [mFFX] arm). Survival analyses were stratified by resection margins, lymph node status, and cancer antigen 19-9 level. RESULTS: Eighty-nine patients' tumors (25.5%) were GemPred+ and were thus predicted to be gemcitabine-sensitive. In the GEM arm, GemPred+ patients (n = 50, 30%) had a significantly longer disease-free survival (DFS) than GemPred- patients (n = 117, 70%; median 27.3 v 10.2 months, hazard ratio [HR], 0.43 [95% CI, 0.29 to 0.65]; P < .001) and cancer-specific survival (CSS; median 68.4 v 28.6 months, HR, 0.42 [95% CI, 0.27 to 0.66]; P < .001). GemPred had no prognostic value in the mFFX arm. DFS and CSS were similar in GemPred+ patients who received adjuvant GEM and mFFX (median 27.3 v 24.0 months, and 68.4 v 51.4 months, respectively). The statistical interaction between GEM and GemPred+ status was significant for DFS (P = .008) and CSS (P = .004). GemPred+ patients had significantly more adverse events of grade ≥3 in the mFFX arm (76%) compared with those in the GEM arm (40%; P = .001). CONCLUSION: This ancillary study of a phase III randomized trial demonstrates that among the quarter of patients with a GemPred-positive transcriptomic signature, survival was comparable with that of mFOLFIRINOX, whereas those receiving adjuvant gemcitabine had fewer adverse events.

[Hereditary and familial forms of pancreatic adenocarcinoma: Genetic determinism, patients eligible for systematic screening, screening methods and results]. / Les formes héréditaires et familiales des adénocarcinomes pancréatiques : déterminisme génétique, population éligible à un dépistage systématique, modalités et résultats du dépistage.

Systematic screening for pancreatic cancer in high risk individuals is justified by the poor prognosis of the majority of cases diagnosed at a symptomatic stage that are mostly advanced and unresectable Individual risk assessment is based on both genetic data and family history. The screening of a panel of susceptibiility genes should be offered to any affected individual when a genetic predisposition is suspected. An international consortium has proposed a definition of the at risk population, candidate for screening, and there is a consensus on the target lesions of this screening: early adenocarcinoma and benign lesions with a high potential for malignant transformation: Intraductal Papillary Mucinous Neopasm (IPMN) and Pancreatic Intraepithelial Neoplasia (PanIN) with high-grade dysplasia. Its modalities currently consist of an annual pancreatic MRI and/or endoscopic ultrasound (EUS), associated with screening for diabetes mellitus. The main limitation of screening, the effectiveness of which has not yet been demonstrated, is its lack of sensitivity, which results in a non-negligible rate of interval cancers and sometimes advanced diagnoses. Insufficient specificity is also imperfect, in particular with regard to benign lesions with a low potential for degeneration, and can lead to the proposal of unjustified surgeries. This situation makes the future integration of new imaging techniques and promising new biological approaches that are being explored highly desirable.

Childhood and adulthood passive and active smoking, and the ABO group as risk factors for pancreatic cancer in women.

OBJECTIVES: Active smoking and the A blood group are associated with pancreatic adenocarcinoma (PC) risk. However, potential interactions between those risk factors and the role of passive smoking have been little investigated. We aimed to explore specific and joint associations of passive and active smoking, and effect modification by the ABO blood group in French women. METHODS: The study included 96,594 women from the E3N prospective cohort, mean age: 49 years (SD 6.7). Information on active and passive smoking was reported at inclusion and throughout follow-up. Cases were classified according to the International Classification of Diseases 10. Associations with passive and active smoking and effect modification by the ABO blood group were investigated with multivariable Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During a 24-year median follow-up, 346 incident PC cases were identified. Current smoking compared with never and former smoking (HR 1.51 [95% CI 1.08-2.10]), and passive smoking in childhood compared with no childhood exposure (HR 1.47 [95% CI 1.08-2.00]) were associated with increased PC risk, but not passive exposure in adulthood (HR 1.16 [95% CI 0.91-1.47]). Exposure to both passive smoking in childhood and current smoking was associated with a stronger risk (HR 2.80 [95% CI 1.42-5.52]) than exposure to both current smoking and passive smoking only in adulthood (HR 1.68 [95% CI 1.10-2.57]) compared with neither passive nor active smoking. Associations between active smoking and PC risk were strongest in the O or B groups, while associations with passive smoking were strongest in the A or AB blood groups, but the interaction terms were not statistically significant. CONCLUSIONS: Both current smoking and passive smoking in childhood were associated with PC risk, with a maximal risk of current smokers exposed to passive smoking during childhood. Possible interactions between blood groups and active or passive smoking must be investigated in a larger series.

Genetic and functional analysis of chymotrypsin-like protease (CTRL) in chronic pancreatitis.

BACKGROUND: Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor. METHODS: We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress. RESULTS: We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress. CONCLUSION: We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP.

Pancreatic Acinar Cystic Transformation: Familial Forms Do Exist.

ABSTRACT: Pancreatic acinar cystic transformation (ACT) is a recently described entity of the pancreatic cysts' spectrum. It is a nonneoplastic pancreatic lesion, mostly asymptomatic, and is considered a rare disease, with less than 100 reported cases. Its benign nature and the absence of reported cases of malignant transformation or invasive lesions were a plea for a conservative approach. As a consequence, little is known about the pathogenesis of this lesion. No familial history of ACT has been previously described. Here, we report a familial case of 2 siblings with typical ACT imaging lesions giving evidence for familial aggregation. No obvious environmental exposure was identified as a potential risk factor for ACT development. No physiological data exist to suggest a congenital nature of these lesions, but for the first patient, the calcifications seem to have appeared with time. Further research, with high throughput sequencing technologies, may elucidate genetic polymorphisms explaining potential ACT familial phenotype. In practice, careful family history collection must be performed to identify a possible familial form of ACT when this diagnosis is proposed.

A protocol for an international, multicenter, prospective, non-interventional observational registry for patients with hypertriglyceridemia.

BACKGROUND: In the study on triglyceride-induced pancreatitis (TG-IAP), a core clinical dataset using the Jandhyala method was developed to collect the minimum amount of information for each patient presenting with TG-IAP globally. This approach offered a unified framework for observing multiple populations of TG-IAP patients using the same set of indicators, resulting in a considerably larger and uniform real-world population. It was understood that when this core dataset is implemented in a patient registry it could address the issue of missing data in observational studies and produce higher-quality research. In this paper, the protocol used to design and implement a patient registry for this core dataset to generate real-world evidence from multiple sites is described. METHOD: The study is designed as an international, multicenter, non-interventional, observational registry that will enroll adult patients with hypertriglyceridemia to collect natural history data on the treatment, progression, and long-term outcomes of hypertriglyceridemia-induced acute pancreatitis. Patients with both hypertriglyceridemia and pancreatitis will be invited to participate in the registry at participating hospitals and centers worldwide. DISCUSSION: Data from this registry, and others like it, is intended for healthcare providers to optimize clinical decision-making through an enhanced understanding of the variability, progression, and natural history of hypertriglyceridemia as well as the burden of disease. CONCLUSION: Global epidemiological data on hypertriglyceridemia and its role in acute pancreatitis is limited. Using real-world evidence, this registry, along with others like it, may help healthcare providers understand the variability, progression, natural history, and burden of the disease, and improve the diagnosis and management of HTG and TG-IAP.

In a 2022 study, information was collected from literature, patients, and doctors who care for patients to create a record with the most important information needed to understand patients with a disease called triglyceride-induced acute pancreatitis (TG-IAP). This type of record may help people find patients with the disease and the type of care or treatment they require. The study was started and completed because the doctors used methods to guide and help them understand what needed to be done. This paper describes the method used for this study, including information on: Data collection: how the relevant information about TG-IAP patients was collected;Permissions: how permission was gained to do the study;Patient information: how the information collected about TG-IAP patients will be used; andPatient protection: how the patients who takes part in the study will be protected.

Classification of PRSS1 variants responsible for chronic pancreatitis: An expert perspective from the Franco-Chinese GREPAN study group.

BACKGROUND: PRSS1 was the first reported chronic pancreatitis (CP) gene. The existence of both gain-of-function (GoF) and gain-of-proteotoxicity (GoP) pathological PRSS1 variants, together with the fact that PRSS1 variants have been identified in CP subtypes spanning the range from monogenic to multifactorial, has made the classification of PRSS1 variants very challenging. METHODS: All currently reported PRSS1 variants (derived primarily from two databases) were manually reviewed with respect to their clinical genetics, functional analysis and population allele frequency. They were classified by variant type and pathological mechanism within the framework of our recently proposed ACMG/AMP guidelines-based seven-category system. RESULTS: The total number of distinct germline PRSS1 variants included for analysis was 100, comprising 3 copy number variants (CNVs), 12 5' and 3' variants, 19 intronic variants, 5 nonsense variants, 1 frameshift deletion variant, 6 synonymous variants, 1 in-frame duplication, 3 gene conversions and 50 missense variants. Based upon a combination of clinical genetic and functional analysis, population data and in silico analysis, we classified 26 variants (all 3 CNVs, the in-frame duplication, all 3 gene conversions and 19 missense) as "pathogenic", 3 variants (missense) as "likely pathogenic", 5 variants (four missense and one promoter) as "predisposing", 13 variants (all missense) as "unknown significance", 2 variants (missense) as "likely benign", and all remaining 51 variants as "benign". CONCLUSIONS: We describe an expert classification of the 100 PRSS1 variants reported to date. The results have immediate implications for reclassifying many ClinVar-registered PRSS1 variants as well as providing optimal guidelines/standards for reporting PRSS1 variants.

Observed consensus on research priorities for the hypertriglyceridemia patient registry.

BACKGROUND: Priority setting in health research has been described as essential due to disparities within and between countries and populations. Commercial benefits to the pharmaceutical industry may increase the generation and use of regulatory Real-World Evidence which has recently been reported in the literature. Research must be steered by valuable priorities. This study's objective is to identify key gaps in the knowledge of triglyceride-induced acute pancreatitis by generating a list of potential research priorities for a Hypertriglyceridemia Patient Registry. METHOD: The Jandhyala Method was used to observe the consensus of expert opinion from ten specialist clinicians in the treatment of triglyceride-induced acute pancreatitis across the US and EU. RESULTS: Ten participants completed the consensus round of the Jandhyala method and generated 38 unique items which they all agreed with. The items were included in the generation of research priorities for a hypertriglyceridemia patient registry and presented a novel application of the Jandhyala method for the development of research questions, in aid of the validation of a core dataset. CONCLUSION: The TG-IAP core dataset and research priorities combined can develop a globally harmonized framework where TG-IAP patients can be observed simultaneously using the same set of indicators. This will increase knowledge of the disease and facilitate higher-quality research by addressing issues related to incomplete data sets in observational studies. Furthermore, validation of new tools will be enabled, and diagnosis and monitoring will be improved as well as the detection of changes in disease severity and subsequent disease progression, improving the management of patients with TG-IAP overall. This will inform personalized patient management plans and improve patient outcomes along with their quality of life.

The differences in healthcare between countries and groups of people will likely affect the type of research needed. This is why people that have experience with specific diseases need to be spoken to, to understand what their concerns are. These types of people could be doctors or patients. When this information is gathered, this could help inform organizations interested in a specific disease on how to help patients in real life situations.For this study, the researchers worked with ten expert doctors who treat a disease called triglyceride-induced acute pancreatitis (TG-IAP). These doctors were from the United States and the European Union, and they were asked to share their opinions on what the most important research areas are using the Jandhyala method. The doctors generated and agreed on 38 items, all related to the most important research areas for TG-IAP.The research areas identified can be used with important data collected about patients with TG-IAP to create a study where these patients are monitored in different locations using the same measurements. This study will help people learn more about the disease and improve the quality of research by making sure the most important data is collected. As a result, patients with TG-IAP can have their healthcare improved.

Identification of protease-sensitive but not misfolding PNLIP variants in familial and hereditary pancreatitis.

Mutations in the PNLIP gene have recently been implicated in chronic pancreatitis. Several PNLIP missense variants have been reported to cause protein misfolding and endoplasmic reticulum stress although genetic evidence supporting their association with chronic pancreatitis is currently lacking. Protease-sensitive PNLIP missense variants have also been associated with early-onset chronic pancreatitis although the underlying pathological mechanism remains enigmatic. Herein, we provide new evidence to support the association of protease-sensitive PNLIP variants (but not misfolding PNLIP variants) with pancreatitis. Specifically, we identified protease-sensitive PNLIP variants in 5 of 373 probands (1.3%) with a positive family history of pancreatitis. The protease-sensitive variants, p.F300L and p.I265R, were found to segregate with the disease in three families, including one exhibiting a classical autosomal dominant inheritance pattern. Consistent with previous findings, protease-sensitive variant-positive patients were often characterized by early-onset disease and invariably experienced recurrent acute pancreatitis, although none has so far developed chronic pancreatitis.

Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma.

Two tumor (Classical/Basal) and stroma (Inactive/active) subtypes of Pancreatic adenocarcinoma (PDAC) with prognostic and theragnostic implications have been described. These molecular subtypes were defined by RNAseq, a costly technique sensitive to sample quality and cellularity, not used in routine practice. To allow rapid PDAC molecular subtyping and study PDAC heterogeneity, we develop PACpAInt, a multi-step deep learning model. PACpAInt is trained on a multicentric cohort (n = 202) and validated on 4 independent cohorts including biopsies (surgical cohorts n = 148; 97; 126 / biopsy cohort n = 25), all with transcriptomic data (n = 598) to predict tumor tissue, tumor cells from stroma, and their transcriptomic molecular subtypes, either at the whole slide or tile level (112 µm squares). PACpAInt correctly predicts tumor subtypes at the whole slide level on surgical and biopsies specimens and independently predicts survival. PACpAInt highlights the presence of a minor aggressive Basal contingent that negatively impacts survival in 39% of RNA-defined classical cases. Tile-level analysis ( > 6 millions) redefines PDAC microheterogeneity showing codependencies in the distribution of tumor and stroma subtypes, and demonstrates that, in addition to the Classical and Basal tumors, there are Hybrid tumors that combine the latter subtypes, and Intermediate tumors that may represent a transition state during PDAC evolution.

Quantitative imaging predicts pancreatic fatty infiltration on routine CT examination.

PURPOSE: The purpose of this study was to assess the performance of quantitative computed tomography (CT) imaging for detecting pancreatic fatty infiltration, using the results of histopathological analysis as reference. MATERIALS AND METHODS: Sixty patients who underwent pancreatic surgery for a pancreatic tumor between 2016 and 2019 were retrospectively included. There were 33 women and 27 men with a mean age of 56 ± 12 (SD) years (age range: 18-79 years). Patients with dilatation of the main pancreatic duct, chronic pancreatitis, or preoperative treatment were excluded to prevent any bias in the radiological-pathological correlation. Pancreatic fatty infiltration was recorded at pathology. Pancreatic surface lobularity, pancreatic attenuation, visceral fat area, and subcutaneous fat area were derived from preoperative CT images. The performance for the prediction of fatty infiltration was assessed using area under receiver operating characteristic curve (AUC) and backward binary logistic regression analysis. Results were validated in a separate cohort of 34 patients (17 women; mean age, 50 ± 14 [SD] years; age range: 18-73). RESULTS: A total of 28/60 (47%) and 17/34 (50%) patients had pancreatic fatty infiltration in the derivation and validation cohorts, respectively. In the derivation cohort, patients with pancreatic fatty infiltration had a significantly higher PSL (P < 0.001) and a lower pancreatic attenuation on both precontrast and portal venous phase images (P = 0.011 and 0.003, respectively), and higher subcutaneous fat area and visceral fat area (P = 0.010 and 0.007, respectively). Multivariable analysis identified pancreatic surface lobularity > 7.6 and pancreatic attenuation on portal venous phase images < 83.5 Hounsfield units as independently associated with fatty infiltration. The combination of these variables resulted in an AUC of 0.85 (95% CI: 0.74-0.95) and 0.83 (95% CI: 0.67-0.99) in the derivation and validation cohorts, respectively. CONCLUSION: CT-based quantitative imaging accurately predicts pancreatic fatty infiltration.

Efficacy and tolerance of LV5FU2-carboplatin chemotherapy in patients with advanced pancreatic ductal adenocarcinoma after failure of standard regimens.

Background: Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. Objectives: We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. Design: We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2-carboplatin between 2009 and 2021 in an expert center. Methods: We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. Results: In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2-carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0-6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4-3.0). At multivariable analysis, no extrahepatic metastases (p = 0.083), no ascites or opioid-requiring pain (p = 0.023), <2 prior treatment lines (p < 0.001), full dose of carboplatin (p = 0.004), and treatment initiation >18 months after initial diagnosis (p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48-4.92) and was influenced by the presence of extrahepatic metastases (p = 0.058), opioid-requiring pain or ascites (p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3-4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Conclusion: Although the efficacy of LV5FU2-carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients.

Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.