Robotic Spleen-Preserving Distal Pancreatectomy: The Warshaw and Kimura Techniques.

Spleen-preserving distal pancreatectomy offers an alternative surgical approach to the traditional distal pancreatectomy combined with splenectomy for removing benign and low-grade malignant lesions in the distal pancreas, avoiding complications associated with splenectomy. This procedure can be accomplished either by resecting and ligating the splenic vessels (Warshaw technique) or by preserving them (Kimura technique). Currently, the widespread use of minimally invasive surgery has established laparoscopic and robotic approaches for spleen-preserving distal pancreatectomy as valid and safe options for treating such conditions. Our protocol aims to describe how the Warshaw and Kimura techniques of spleen-preserving distal pancreatectomy can be performed robotically. The first patient is a 36-year-old female with a neuroendocrine tumor (NET) in the pancreatic body who underwent a spleen-preserving distal pancreatectomy with the ligation of the splenic vessels (WT). The second patient is a 76-year-old male with chronic pancreatitis presenting with a dilated main pancreatic duct in the tail of the pancreas who underwent a spleen-preserving distal pancreatectomy with a vessel-preserving approach (KT).

Comparative immune profiling of pancreatic ductal adenocarcinoma progression among South African patients.

BACKGROUND: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry. METHODS: Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations. RESULTS: Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p < 0.001) cell levels increased as the disease progressed, their subsets: NK CD56dimCD16- (p = 0.024) and NKTs CD56+ (p = 0.008) cell levels reduced significantly. Of note is the negative association of NK CD56dimCD16- (p < 0.001) cell levels with survival time. The gene expression analyses showed no statistically significant correlation when comparing the PDAC groups with the controls. The inflammatory status of PDAC was assessed by ROS levels of serum which were elevated in CP (p = 0.025), (RPC (p = 0.003) and LAPC (p = 0.008)) while no significant change was observed in MPC, compared to the HC group. ROS was shown to be positively correlated with GlycA (R = 0.45, p = 0.0096). Single-cell analyses showed a significant difference in the ratio of NKT cells per total cell counts in LAPC (p < 0.001) and MPC (p < 0.001) groups compared with HC, confirming observations in our sample group. CONCLUSION: The expression of these immune cell markers observed in this pilot study provides insight into their potential roles in tumour progression in the patient group and suggests their potential utility in the development of immunotherapeutic strategies.

Developing the EPI Symptom Questionnaire (EPI-SQ): a qualitative study to understand the symptom experience of patients with exocrine pancreatic insufficiency (EPI).

BACKGROUND: Symptom assessment is the key factor in determining disease status and optimal management of exocrine pancreatic insufficiency (EPI). There is a need for a standardized patient-reported outcome (PRO) questionnaire to assess symptoms in patients diagnosed with EPI. The purpose of this qualitative study was to increase understanding of the EPI symptom experience from the patients' perspective, and to develop and evaluate the content validity of the EPI Symptom Questionnaire (EPI-SQ) in US patients with EPI. METHODS: Concept elicitation interviews (Phase I) were conducted to understand the symptom experience in patients with a clinical diagnosis of EPI (i.e., fecal pancreatic elastase value of ≤ 200 mcg/g based on most recent value) due to chronic pancreatitis or pancreatectomy. The EPI-SQ was developed based on the data extracted from Phase I interviews and feedback from clinical experts. Next, separate cognitive interviews (Phase II) were conducted to evaluate participants' understanding of the instructions, items, response scales, and recall periods of the instrument. RESULTS: During Phase I interviews (n = 21), 19 participants (90%) reported abdominal pain as the most frequent EPI symptom and lifestyle changes were the most frequently endorsed impacts (n = 18; 86%). Phase II results indicated that all participants (n = 7) felt the 12-item EPI-SQ was relevant to their symptom experience and that they understood the items, instructions, and response options as intended. CONCLUSION: The qualitative data from this study support the content validity of the EPI-SQ in measuring EPI symptom severity in US patient populations diagnosed with EPI.

Social disparity is associated with an increased risk of acute and chronic pancreatitis.

AIM: To study social disparity in acute pancreatitis (AP) and chronic pancreatitis (CP).We also aimed at exploring whether an interaction exists between alcohol intake and socioeconomic factors. METHODS: Prospective cohort study based on data from 271 696 men and women participating in the Danish National Health Surveys 2010, and 2013. Information on alcohol and smoking parameters, body mass index (BMI), diet, and education, were self-reported and information on family income was obtained from administrative registers. Outcome variables (acute and chronic pancreatitis) were obtained from national health registers. RESULTS: The incidence rate ratio (IRR) of developing AP and CP increased with decreasing family income. Compared to participants in the highest income quintile, participants in the lowest income quintile had 43 (95% CI: 14-80%), 99 (95% CI: 26-214%), and 56% (95% CI: 26-94%) higher incidence rates of AP, CP, and all pancreatitis, respectively. The associations persisted after adjustment for alcohol intake, smoking, BMI, and diet.Likewise, participants with only primary school education had an IRR for an AP of 1.30 (95% CI: 1.06-1.59) compared to those with higher education after adjustment for baseline year, age, and sex. We found no interactions between alcohol intake and income or between alcohol intake and education in relation to neither AP, CP, nor all pancreatitis. CONCLUSION: This large prospective population study showed a significant social disparity in incidence rates of pancreatitis by family income, with higher rates among those with the lowest income and education independent of risk factors such as alcohol intake, smoking, BMI, and diet.

Vitamin D in blood serum and chronic pancreatitis.

Patients with chronic pancreatitis are at risk of developing malabsorption and malnutrition. Exocrine pancreatic insufficiency is accompanied by decreased serum micronutrient levels and low vitamin D levels are a frequent finding in up to 60-80% of patients. The aim of our prospective study was to investigate vitamin D in the blood serum of subjects with chronic pancreatitis with the possibility of influencing the reduced vitamin D levels with supplementation therapy. MATERIAL AND METHODOLOGY: Fifty patients with chronic pancreatitis and 20 subjects in the control group without gastrointestinal tract diseases, including pancreatic disease, were examined. The vitamin D level in blood serum was determined. The results were evaluated according to the age distribution of subjects with pancreatic disease and according to gender. Patients with low vitamin D levels were treated for 24 weeks with a dose of 1.500.000 IU of vitamin D3 per day, and then blood serum vitamin D levels were determined. RESULTS: In people with chronic pancreatitis, vitamin D levels were statistically significantly reduced compared to the control group. There was no statistically significant relationship of vitamin D with gender and age. Supplementation with vitamin D3 achieved an adjustment of vitamin D level to the level of the control group. CONCLUSION: Blood serum vitamin D levels are significantly reduced in people with chronic pancreatitis. Its correction by oral vitamin D supplementation was effective. Whether this adjustment of levels will be effective also in terms of e.g. beneficial effect on fibrogenesis will require further representative studies, because the limitation of the interpretation of the results of our study is the smaller number of subjects with chronic pancreatitis (Tab. 4, Ref. 29).

Pancreatic enzyme replacement therapy and resource utilization in patients with chronic pancreatitis in a US healthcare system: a retrospective study.

OBJECTIVE: To assess the association between pancreatic enzyme replacement therapy (PERT) and resource utilization among patients with chronic pancreatitis (CP) in a large Midwestern US healthcare system. METHODS: This retrospective cohort study used electronic medical record data. Eligible patients (N = 2445) were aged ≥18 years and diagnosed with non-cystic fibrosis CP between January 2005 and December 2018, with ≥6 months' follow-up; study initiation was first encounter with the healthcare system. Patients in the PERT group were prescribed PERT at ≥1 encounter; patients in the non-PERT group were not prescribed PERT at any encounter. RESULTS: In total, 62,899 encounters were reviewed (PERT, n = 22,935; non-PERT, n = 39,964). More patients in the PERT group were younger, male, White, married/partnered and with private insurance than those in the non-PERT group. They also received longer care and had more overall encounters, fewer outpatient and day surgery/24-hour observation encounters, and more inpatient encounters. Emergency room encounters were similar between groups. Average cost by encounter was similar between groups ($225 and $213, respectively). CONCLUSIONS: Despite similar average costs per encounter, the groups had very different encounter types. More inferential research on PERT use among patients with CP is needed, particularly regarding resource utilization and long-term outcomes.

Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation.

Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSCs), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few research studies have explored the mechanism by which damaged ACs (DACs) contribute to PSCs activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP or limiting the progression of pancreatic fibrosis. In this research, co-culture with intact acinar cells (IACs) suppressed PSC activation, while co-culture with DACs did the opposite. Krüppel-like factor 4 (KLF4) was significantly upregulated in DACs and was established as the key molecule that switches ACs from PSCs-suppressor to PSCs-activator. We revealed the exosomes of IACs contributed to the anti-activated function of IACs-CS on PSCs. MiRNome profiling showed that let-7 family is significantly enriched in IAC-derived exosomes (>30% miRNome), which partially mediates IACs' suppressive impacts on PSCs. Furthermore, it has been observed that the enrichment of let-7 in exosomes was influenced by the expression level of KLF4. Mechanistic studies demonstrated that KLF4 in ACs upregulated Lin28A, thereby decreasing let-7 levels in AC-derived exosomes, and thus promoting PSCs activation. We utilized an adeno-associated virus specifically targeting KLF4 in ACs (shKLF4-pAAV) to suppress PSCs activation in CP, resulting in reduced pancreatic fibrosis. IAC-derived exosomes hold potential as potent weapons against PSCs activation via let-7s, while activated KLF4/Lin28A signaling in DACs diminished such functions. ShKLF4-pAAV holds promise as a novel therapeutic approach for CP.

Heavy metals in cigarette smoke strongly inhibit pancreatic ductal function and promote development of chronic pancreatitis.

BACKGROUND AND AIMS: Smoking is recognised as an independent risk factor in the development of chronic pancreatitis (CP). Cystic fibrosis transmembrane conductance regulator (CFTR) function and ductal fluid and bicarbonate secretion are also known to be impaired in CP, so it is crucial to understand the relationships between smoking, pancreatic ductal function and the development of CP. METHODS: We measured sweat chloride (Cl-) concentrations in patients with and without CP, both smokers and non-smokers, to assess CFTR activity. Serum heavy metal levels and tissue cadmium concentrations were determined by mass spectrometry in smoking and non-smoking patients. Guinea pigs were exposed to cigarette smoke, and cigarette smoke extract (CSE) was prepared to characterise its effects on pancreatic HCO3 - and fluid secretion and CFTR function. We administered cerulein to both the smoking and non-smoking groups of mice to induce pancreatitis. RESULTS: Sweat samples from smokers, both with and without CP, exhibited elevated Cl- concentrations compared to those from non-smokers, indicating a decrease in CFTR activity due to smoking. Pancreatic tissues from smokers, regardless of CP status, displayed lower CFTR expression than those from non-smokers. Serum levels of cadmium and mercury, as well as pancreatic tissue cadmium, were increased in smokers. Smoking, CSE, cadmium, mercury and nicotine all hindered fluid and HCO3 - secretion and CFTR activity in pancreatic ductal cells. These effects were mediated by sustained increases in intracellular calcium ([Ca2+]i), depletion of intracellular ATP (ATPi) and mitochondrial membrane depolarisation. CONCLUSION: Smoking impairs pancreatic ductal function and contributes to the development of CP. Heavy metals, notably cadmium, play a significant role in the harmful effects of smoking. KEY POINTS: Smoking and cigarette smoke extract diminish pancreatic ductal fluid and HCO3 - secretion as well as the expression and function of CFTR Cd and Hg concentrations are significantly higher in the serum samples of smokers Cd accumulates in the pancreatic tissue of smokers.

[Modern endoscopic technologies for chronic calcifying pancreatitis]. / Sovremennye endoskopicheskie tekhnologii pri khronicheskom kal'tsinoznom pankreatite.

OBJECTIVE: To evaluate the effectiveness and safety of electrohydraulic lithotripsy of calculi of the main pancreatic duct using ultrathin SpyGlass DS endoscope. MATERIAL AND METHODS: The study included 29 patients with chronic calcifying pancreatitis and obstructive calculi of the main pancreatic duct. All surgeries were carried out between 2018 and 2023. RESULTS: Complete removal of calculi (≥5 mm) within one procedure was achieved in 25 (86%) patients. CONCLUSION: Pancreatoscopy with electrohydraulic lithotripsy using the digital SpyGlass DS system (BostonScientificCorp, Marlborough, MA) is the most effective method for calculi of the main pancreatic duct.

Longitudinal Quality of Life and Glycemic Outcomes of Total Pancreatectomy With Islet Autotransplantation in Children With Chronic Pancreatitis Followed in a Pediatric Multidisciplinary Pancreas Clinic.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a potentially curative treatment for patients with chronic pancreatitis (CP) refractory to medical and endoscopic therapies. Patients often receive the initial follow-up medical care at the surgery-performing center, but then may follow up closer to where they live. We sought to describe the characteristics and outcomes of pediatric patients who underwent TPIAT at a national surgical referral center and were subsequently followed at our regional subspecialty center, the Children's Hospital Colorado. METHODS: We performed a retrospective analysis of baseline and outcomes data for the 10 pediatric patients who underwent TPIAT from 2007 to 2020 and received follow-up care at our institution. RESULTS: All patients had a diagnosis of CP, and nine of 10 patients had an identified underlying genetic risk factor. Insulin usage was common immediately following TPIAT, but at 1 year of follow-up, five of nine patients (55.6%) were insulin-independent and nine of nine had an HbA1c below 6.5%. For the four patients on insulin 1 year after TPIAT, total daily insulin dose ranged from 0.06 to 0.71 units/kg/day. All patients who underwent mixed meal tolerance testing had a robust peak C-peptide response at 1 year. There were significant improvements in nausea, school/work absences, narcotic dependence, and pancreas-related hospital admissions 1 year after TPIAT. CONCLUSIONS: Patients followed at our center had long-term improvements with low-insulin usage, detectable C-peptide, and improved pancreatitis-related outcomes after TPIAT. Pediatric patients who undergo TPIAT can be successfully co-managed in conjunction with the original surgery-performing center.

Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum.

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.

Endoscopic ultrasound-guided versus surgical pancreatic duct drainage after failed endoscopic retrograde pancreatography: a pilot comparative study.

BACKGROUND: Endoscopic ultrasound-guided pancreatic duct (PD) drainage (EUS-PDD) is being increasingly performed as an alternative method to surgical drainage to achieve PD decompression after failed endoscopic retrograde pancreatography (ERP). However, no directly study has compared EUS-PDD with surgical PD drainage after failed ERP in patients with chronic pancreatitis. METHODS: Consecutive patients who underwent EUS-PDD or longitudinal pancreaticojejunostomy after failed ERP were retrospectively identified from our endoscopy and medical information systems. The primary end point was the Izbicki pain score. The secondary end points were pain relief at the end of follow-up, procedure outcomes, adverse events, readmission, and reintervention. RESULTS: A total of 21 patients (11 EUS-PDD, 10 surgical drainages) were analyzed. There were no significant differences in mean Izbicki pain score (EUS-PDD, 13.6 ± 10.1 vs. surgical drainage 10.7 ± 7.9, p = 0.483) or complete/partial pain relief (60%/30% vs. 70%/30%, p = 0.752) at the end of follow-up of the two groups. The rates of overall adverse events (27.3% vs. 30.0%, p = 0.893) and readmission (63.6% vs. 40.0%, p = 0.290) were similar in the two treatment groups, while patients in EUS-PDD group required more reinterventions (45.5% vs. 0%, p = 0.039) compared with patients in the surgery group. CONCLUSION: EUS-PDD showed comparable pain relief and safety to surgical PD drainage after failed ERP, with a higher rate of reintervention. The selection of EUS-PDD or surgical drainage may be appropriate based on an individualized strategy.

Minimally invasive total pancreatectomy with islet autotransplantation for chronic pancreatitis: the robotic approach.

INTRODUCTION: Total pancreatectomy with islet autotransplantation (TPIAT) treats refractory pain in chronic pancreatitis, prevents episodes of acute exacerbation, and mitigates postoperative brittle diabetes. The minimally invasive (MIS) approach offers a decreased surgical access trauma and enhanced recovery. Having established a laparoscopic TPIAT program, we adopted a robotic approach (R-TPIAT) and studied patient outcomes compared to open TPIAT. METHODS: Between 2013 and 2021, 61 adult patients underwent TPIAT after a comprehensive evaluation (97% chronic pancreatitis). Pancreatic islets were isolated on-site during the procedure. We analyzed and compared intraoperative surgical and islet characteristics, postoperative morbidity and mortality, and 1-year glycemic outcomes. RESULTS: MIS-TPIAT was performed in 41 patients (67%, 15 robotic and 26 laparoscopic), and was associated with a shorter mean length of intensive care unit stay compared to open TPIAT (2.9 vs 4.5 days, p = 0.002). R-TPIAT replaced laparoscopic TPIAT in 2017 as the MIS approach of choice and demonstrated decreased blood loss compared to open TPIAT (324 vs 843 mL, p = 0.004), similar operative time (609 vs 562 min), 30-day readmission rate (7% vs 15%), and 90-day complication rate (13% vs 20%). The glycemic outcomes including C-peptide detection at 1-year (73% vs 88%) and insulin dependence at 1-year (75% vs 92%) did not differ. The mean length of hospital stay after R-TPIAT was 8.6 days, shorter than for laparoscopic (11.5 days, p = 0.031) and open TPIAT (12.6 days, p = 0.017). Both MIS approaches had a 1-year mortality rate of 0%. CONCLUSIONS: R-TPIAT was associated with a 33% reduction in length of hospital stay (4-day benefit) compared to open TPIAT. R-TPIAT was similar to open TPIAT on measures of feasibility, safety, pain control, and 1-year glycemic outcomes. Our data suggest that robotic technology, a new component in the multidisciplinary therapy of TPIAT, is poised to develop into the primary surgical approach for experienced pancreatic surgeons.

Association between chronic pancreatitis and pancreatic cancer at a central hospital in KwaZulu-Natal, South Africa.

BACKGROUND: The frequency of histological chronic pancreatitis (CP) evidence in the resident pancreas of resected periampullary cancers (PACs) has never been studied in Africa. This study aims to describe the spectrum of pathology and outcomes of pancreatic surgeries and address this deficit from a South African central hospital cohort. METHODS: A retrospective audit of patients undergoing pancreatic surgery at Inkosi Albert Luthuli Central Hospital (IALCH) between 2003 and 2023 was conducted. The patient demographics, human immunodeficiency virus (HIV) status, histological subtypes, type and extent of surgery, and 30-day and overall mortality were captured from medical records. The presence of CP in the resident pancreas of patients resected for pancreatic and PAC was obtained from the pathology reports. RESULTS: Of the cohort, 72% were Africans, presenting at an earlier average age than other races. Surgery was performed on 126 (107 for cancer, 19 for CP) patients. Of these, 77 were pancreaticoduodenectomy (PD), of which 34 were for pancreatic ductal adenocarcinoma (PDAC). The prevalence of CP in the resident pancreas was 29.9%, and 55.9% in PDAC. Age was the only factor significantly associated with 30-day mortality, as well as long-term survival amongst patients with pancreatic and PAC. The overall median survival for patients with PAC was seven months; 11 patients are alive. CONCLUSION: In a predominantly African cohort undergoing pancreatic surgery, PDAC presents at a younger age. The high perioperative mortality and low overall survival (OS) in the setting of high CP prevalence in the resident pancreas requires further investigation of its role in the aetiopathogenesis and prognosis in PDAC.

Total pancreatectomy with islet autotransplantation outcomes in patients with pancreatitis of genetic etiology: A single-center experience with a large cohort of patients.

PURPOSE: Total pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment for patients with chronic pancreatitis (CP) when other interventions are unsuccessful. CP has many etiologies including heredity. Metabolic and pain relief outcomes after TPIAT are presented among patients with a genetic CP etiology compared with those with a nongenetic etiology in a large cohort of patients who underwent this procedure at our center. METHODS: A retrospective analysis was performed of 237 patients undergoing TPIAT between 2006 and 2023. We analyzed the differences in patients with genetic (n = 56) vs nongenetic CP etiologies (n = 181) in terms of pre-TPIAT factors including patient characteristics and disease state, results from the isolation process, and outcomes such as long-term glycemic and pain control. RESULTS: Patients with genetic CP underwent TPIAT at a significantly younger age (32.3 vs 41.3 years nongenetic; P < .0001) and endured symptoms for a significantly longer period (10 vs 6 years; P < .01). A significantly lower mass of islets was isolated from patients with genetic CP (P < .01), which increased with body mass index in both groups. Despite lower yields, patients with genetic CP maintained metabolic function similar to patients with nongenetic CP, as indicated by insulin independence and C-peptide, blood glucose, and hemoglobin A1C levels after TPIAT. Post-transplant narcotic usage and pain scores significantly decreased compared with those before TPIAT, and more patients with genetic CP were pain free and narcotic free after TPIAT. CONCLUSION: Our data validate TPIAT as a beneficial procedure for patients enduring CP of genetic etiology. Pain that is inevitably recurrent after minor interventions owing to the nature of the disease and favorable TPIAT outcomes should be considered in the decision to perform early TPIAT in cases of genetic CP.

Novel chymotrypsin C (CTRC) variants from real-world genetic testing of pediatric chronic pancreatitis cases.

BACKGROUND: Chymotrypsin C (CTRC) protects the pancreas against unwanted intrapancreatic trypsin activity through degradation of trypsinogen. Loss-of-function CTRC variants increase the risk for chronic pancreatitis (CP). The aim of the present study was to characterize novel CTRC variants found during genetic testing of CP cases at a pediatric pancreatitis center. METHODS: We used next-generation sequencing to screen patients. We analyzed the functional effects of CTRC variants in HEK 293T cells and using purified enzymes. RESULTS: In 5 separate cases, we detected 5 novel heterozygous CTRC variants: c.407C>T (p.Thr136Ile), c.550G>A (p.Ala184Thr), c.627Cdup (p.Ser210Leufs∗?, where the naming indicates a frame shift with no stop codon), c.628T>C (p.Ser210Pro), and c.779A>G (p.Asp260Gly). Functional studies revealed that with the exception of p.Ser210Leufs∗?, the CTRC variants were secreted normally from transfected cells. Enzyme activity of purified variants p.Thr136Ile, p.Ala184Thr, and p.Asp260Gly was similar to that of wild-type CTRC, whereas variant p.Ser210Pro was inactive. The frame-shift variant p.Ser210Leufs∗? was not secreted but accumulated intracellularly, and induced endoplasmic reticulum stress, as judged by elevated mRNA levels of HSPA5 and DDIT3, and increased mRNA splicing of XBP1. CONCLUSIONS: CTRC variants p.Ser210Pro and p.Ser210Leufs∗? abolish CTRC function and should be classified as pathogenic. Mechanistically, variant p.Ser210Pro directly affects the amino acid at the bottom of the substrate-binding pocket while the frame-shift variant promotes misfolding and thereby blocks enzyme secretion. Importantly, 3 of the 5 novel CTRC variants proved to be benign, indicating that functional analysis is indispensable for reliable determination of pathogenicity and the correct interpretation of genetic test results.

Brusatol alleviates pancreatic carcinogenesis via targeting NLRP3 in transgenic Krastm4Tyj Trp53tm1Brn Tg (Pdx1-cre/Esr1*) #Dam mice.

BACKGROUND: Pancreatic cancer (PanCa), ranked as the 4th leading cause of cancer-related death worldwide, exhibits an dismal 5-year survival rate of less than 5 %. Chronic pancreatitis (CP) is a known major risk factor for PanCa. Brusatol (BRT) possesses a wide range of biological functions, including the inhibition of PanCa proliferation. However, its efficacy in halting the progression from CP to pancreatic carcinogenesis remains unexplored. METHODS: We assess the effects of BRT against pancreatic carcinogenesis from CP using an experimentally induced CP model with cerulein, and further evaluate the therapeutic efficacy of BRT on PanCa by employing Krastm4TyjTrp53tm1BrnTg (Pdx1-cre/Esr1*) #Dam/J (KPC) mouse model. RESULTS: Our finding demonstrated that BRT mitigated the severity of cerulein-induced pancreatitis, reduced pancreatic fibrosis and decreased the expression of α-smooth muscle actin (α-SMA), which is a biomarker for pancreatic fibrosis. In addition, BRT exerted effects against cerulein-induced pancreatitis via inactivation of NLRP3 inflammasome. Moreover, BRT significantly inhibited tumor growth and impeded cancer progression. CONCLUSIONS: The observed effect of BRT on impeding pancreatic carcinogenesis through targeting NLRP3 inflammasome suggests its good potential as a potential agent for treatment of PanCa.

Quality of life instruments in acute and chronic pancreatitis: a consensus-based standards for the selection of health measurement instruments (COSMIN) approach.

BACKGROUND: Pancreatitis is a common surgical emergency, associated with pain and poor quality of life for patients. However, assessment of patient-reported outcome measures in these patients is unclear. This study aimed to identify and evaluate the methodological quality of the health-related quality of life instruments used for patients with acute or chronic pancreatitis. METHODS: Prospective studies that evaluated health-related quality of life in acute or chronic pancreatitis were identified from systematic review of MEDLINE, EMBASE, and Web of Science until 28th June 2023 (PROSPERO: CRD42021274743). Instrument characteristics were extracted, and methodological quality assessed using COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) guidelines and GRADE approach. Narrative synthesis was conducted, with recommendations for use based on COSMIN criteria, evaluated according to World Health Organisation (WHO) quality of life domains. RESULTS: From 3850 records screened, 41 quality of life instruments were identified across 138 studies included. The majority (69.8%, n = 26) were designed to assess general health-related quality of life, whereas the remainder were abdominal-specific (n = 5) or pancreas-specific (n = 10). Only ten instruments (24.3%) demonstrated sufficient content validity, incorporating items in ≥5 WHO quality of life domains. However, only nine instruments (21.9%) incorporated public and patient involvement. Only the Gastrointestinal Quality of Life Index and PAN-PROMISE met the criteria to be recommended for use based on COSMIN methodological assessment. CONCLUSION: There is significant heterogeneity in instruments used to assess quality of life after pancreatitis, with almost all instruments considered insufficient. Robust, validated, and relevant instruments are needed to better understand and determine appropriate interventions to improve quality of life for these patients.

Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression.

Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.

Multivariate analysis and mathematical modeling of the informativeness of patients cases data in chronic pancreatitis associated with concomitant pathology.

OBJECTIVE: Aim: To investigate and analyze homeostatic disorders in patients with a combination of Chronic Pancreatitis(CP) and Arterial Hypertension (AH) and to develop correcting ways of the detected changes. PATIENTS AND METHODS: Materials and Methods: General clinical, laboratory-instrumental examination of 121 patients, who were undergoing inpatient treatment with a diagnosis of Chronic Pancreatitis in combination with Arterial Hypertension of the II stage during 2021-2022. RESULTS: Results: In the majority of cases of patients signs the increasing in IL-1,6 and Cortisol levels were found. A decrease in Ca to the lower limit of the norm was observed (2.18 ± 0.26 mmol/l to the data of control group patients (2.32 ± 0.12 mmol/l, p= 0.01 ), the levels of trace elements Zn and Se were determined within the reference values. The Atherogenic Index was increased 1.8 times and was significantly different from the control group date. During the FE-1 study, a decrease in the level of this indicator was revealed by 151.71±13.91 mg/g of feces, both to the values of reference values and a significant difference to the data of the control group (241.28±29.17 mg/g of feces, p<0 .05). CONCLUSION: Conclusions: Based on the multivariate linear regression analysis of the obtained data, formulas have been developed that can be used to predict the dynamics of the dependent variable (FE-1, IL-1, Selenium level, Glutathione Peroxidase, blood pressure) according to changes in the studied influencing factors.