SPINK1 Mutations Research Articles

Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

Heterozygous Spink1 Deficiency Promotes Trypsin-dependent Chronic Pancreatitis in Mice

Heterozygous SPINK1 mutations are strong risk factors for chronic pancreatitis in humans, yet heterozygous disruption of mouse Spink1 yielded no pancreatic phenotype. To resolve this contradiction, we usedCRISPR/Cas9-mediated genome editing to generate heterozygous Spink1-deleted mice (Spink1-KOhet) in the C57BL/6N strain and studied the effect of this allele in trypsin-independent and trypsin-dependent pancreatitis models. We investigated severity of acute pancreatitis and progression to chronic pancreatitis in Spink1-KOhet mice after transient (10 injections) and prolonged (2× 8 injections) cerulein hyperstimulation. We crossed Spink1-KOhet mice with T7D23A and T7D22N,K24R mice that carry strongly autoactivating trypsinogen mutants and exhibit spontaneous chronic pancreatitis. Prolonged but not transient cerulein stimulation resulted in increased intrapancreatic trypsin activity and more severe acute pancreatitis in Spink1-KOhet mice relative to the C57BL/6N control strain. After the acute episode, Spink1-KOhet mice developed progressive disease with chronic pancreatitis-like features, whereas C57BL/6N mice recovered rapidly. Trypsinogen mutant mice carrying the Spink1-KOhet allele exhibited strikingly more severe chronic pancreatitis than the respective parent strains. Heterozygous Spink1 deficiency caused more severe acute pancreatitis after prolonged cerulein stimulation and promoted chronic pancreatitis after the cerulein-induced acute episode, and in two strains of trypsinogen mutant mice with spontaneous disease. In contrast, acute pancreatitis induced with limited cerulein hyperstimulation was unaffected by heterozygous Spink1 deletion, in agreement with recent observations that trypsin activity does not mediate pathologic responses in this model. Taken together, the findings strongly support the notion that loss-of-function SPINK1 mutations inhumans increase chronic pancreatitis risk in a trypsin-dependent manner.

Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.

The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children. The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents. There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant. The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.

Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach.

Chronic pancreatitis is one of the main risk factors for pancreatic cancer, but it is a rare event. Inflammation and oncogenes work hand in hand as key promoters of this disease. Tobacco is another co-factor. During alcoholic chronic pancreatitis, the cumulative risk of cancer is estimated at 4% after 15 to 20 years. This cumulative risk is higher in hereditary pancreatitis: 19 and 12% in the case of PRSS1 and SPINK1 mutations, respectively, at an age of 60 years. The diagnosis is difficult due to: (i) clinical symptoms of cancer shared with those of chronic pancreatitis; (ii) the parenchymal and ductal remodeling of chronic pancreatitis rendering imaging analysis difficult; and (iii) differential diagnoses, such as pseudo-tumorous chronic pancreatitis and paraduodenal pancreatitis. Nevertheless, the occurrence of cancer during chronic pancreatitis must be suspected in the case of back pain, weight loss, unbalanced diabetes, and jaundice, despite alcohol withdrawal. Imaging must be systematically reviewed. Endoscopic ultrasound-guided fine-needle biopsy can contribute by targeting suspicious tissue areas with the help of molecular biology (search for KRAS, TP53, CDKN2A, DPC4 mutations). Short-term follow-up of patients is necessary at the clinical and paraclinical levels to try to diagnose cancer at a surgically curable stage. Pancreatic surgery is sometimes necessary if there is any doubt.

Pancreatic Secretory Trypsin Inhibitor (SPINK1) Gene Mutation in Patients with Acute Alcohol Pancreatitis (AAP) Compared to Healthy Controls and Heavy Alcohol Users without Pancreatitis

Only 3-5% of heavy alcohol users develop acute alcohol pancreatitis (AAP). This suggests that additional triggers are required to initiate the inflammatory process. Genetic susceptibility contributes to the development of AAP, and SPINK1 mutation is a documented risk factor. We investigated the prevalence of the SPINK1(N34S) mutation in patients with AAP compared to heavy alcohol users who had never suffered an episode of pancreatitis. Blood samples for the mutational analysis from patients with first episode (n = 60) and recurrent AAP (n = 43) and from heavy alcohol users without a history of AAP (n = 98) as well as from a control population (n = 1914) were obtained. SPINK1 mutation was found in 8.7% of the patients with AAP. The prevalence was significantly lower in healthy controls (3.4%, OR 2.72; 1.32-5.64) and very low in alcoholics without pancreatitis (1.0%, OR 9.29; 1.15-74.74). In a comparison adjusted for potential cofounders between AAP patients and alcoholics, SPINK1 was found to be an independent marker for AAP. The prevalence of the SPINK1 mutation is overrepresented in AAP patients and very low in alcoholics without pancreatitis. This finding may play a role in understanding the variable susceptibility to AAP found in heavy alcohol users.

ODP232 Postoperative Glycemic Management of Children Undergoing Pancreatectomy with Islet Autotransplantation

Abstract Background Children with severe pancreatitis may require pancreatectomy, resulting in insulin-dependent diabetes. Our center has provided pediatric pancreatectomy with islet autotransplantation (PIAT) since 2003 to preserve pancreatic endocrine function and potentially prevent diabetes. We describe our experience with postoperative glycemic management after pediatric PIAT to provide guidance for future management. Method: We reviewed inpatient records for children who underwent PIAT. Data collected included age, indication for pancreatectomy, islet mass infused and details on insulin and nutritional support requirements. Descriptive analysis was performed. Results Twelve pediatric patients have undergone PIAT at our centre, with mean age 12.4 years (range 2.5-18.9) and mean duration of post-operative hospitalization 25 days (range 9-60). Indications for pancreatectomy included ten patients with chronic pancreatitis due to mutations in PRSS1, SPINK1, or CFTR, 1 patient due to trauma, and 1 patient due to tumor. Ten patients underwent total pancreatectomy, and 2 had partial pancreatectomies. Mean islet mass infused per body weight was 5867 IEQ/kg (range 1630-10276). Two patients did not receive insulin during hospitalization. The remaining ten required insulin, with mean maximum total daily dose of 0.9 u/kg/day (range 0.14-1.88). Total daily doses were higher while on parenteral nutrition (mean 0.75 versus 0.27 u/kg/day on days without parenteral nutrition). Duration of insulin therapy was also longer in patients who received parenteral nutrition (mean 25 versus 4 days). Six of the insulin-treated patients were able to discontinue insulin prior to discharge, with mean duration of insulin therapy 13 days (range 1-40). Four remained on insulin at discharge, with a mean total daily dose of 0.46 u/kg/day (range 0.12-0.82). Patients who were on insulin at discharge all had total pancreatectomies, were older (mean 17 versus 9 years), and had smaller islet mass per kilogram infused (mean 2718 versus 8116 IEQ/kg) compared to those not on insulin. Discussion We report our center's experience with PIAT. Seven of twelve patients were insulin-independent at discharge, and the remainder needed modest doses. Previous publications on islet autotransplantation have also demonstrated favourable outcomes in children, with insulin independence rates up to 82%1. Younger age and larger islet mass infused per kilogram predicted insulin independence in our cohort, similar to the findings of Chinnakotla et al2. In addition, our study suggests that feeding difficulties requiring parenteral nutrition increase daily insulin requirements and prolong the need for insulin therapy.

PSUN236 Previously Undiagnosed Hereditary Pancreatitis Presenting as New Onset Type 3c Diabetes Mellitus

Abstract Background Type 3c Diabetes Mellitus (DM3c) or Pancreatogenic Diabetes is defined as diabetes secondary to pancreatic disease. The most common cause of Type 3c Diabetes is chronic pancreatitis, accounting for 80% of cases.1 Hereditary pancreatitis, with mutations such as SPINK1, CFTR, CTRC, is an underdiagnosed cause of chronic pancreatitis leading to Type 3c Diabetes Mellitus.1 The typical disease course for hereditary pancreatitis is recurrent episodes of acute pancreatitis that leads to chronic pancreatitis.1 The average time between hereditary pancreatitis diagnosis and development of DM3c has been shown to be 80 +/- 24 months.1 We present a case of previously undiagnosed hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus. Clinical Case A 33-year-old male presents with a two month history of diarrhea, epigastric pain, and weight loss. Vital signs on presentation were blood pressure 105/74, heart rate 59, BMI 13. Physical exam revealed a cachectic appearing male with epigastric tenderness. Lab-work showed blood glucose 819 mg/dL, SOsm 313 mOsm/kg, lipase 21 U/L, bicarbonate 33 mmol/L. A computed tomography (CT) of the abdomen revealed punctate pancreatic parenchymal calcifications, suggestive of chronic pancreatitis. He was admitted to general medicine for management of HHS, where he was treated with IV hydration and insulin therapy. Workup for new onset diabetes revealed a negative anti-GAD Ab &amp;lt;5.0 U/mL, and C peptide level 0.5 ng/mL which suggested β cell dysfunction and decreased endogenous insulin secretion. With these lab values, along with radiographic findings consistent with chronic pancreatitis, the likely driving factor for his diabetes was pancreatic disease and he was diagnosed with DM3c. Severe pancreatic disease was further shown by a reduced fecal elastase level of &amp;lt;50, suggesting exocrine pancreatic insufficiency. Investigating the etiology of his chronic pancreatitis, history revealed no prior episodes of acute pancreatitis or abdominal pain, and no family history of pancreatitis. Workup for common causes of pancreatitis, including alcohol use, hypertriglyceridemia, and gallstones was negative, and genetic workup was pursued. The patient was found to be heterozygous for a SPINK1 mutation, which is a known mutation in hereditary pancreatitis.1 Therefore, hereditary pancreatitis was determined to be the likely cause of his chronic pancreatitis which led to Type 3c Diabetes Mellitus. He was started on daily insulin therapy and pancreatic enzymes for his endocrine and exocrine pancreatic dysfunction respectively, with improvement in symptoms. Conclusion This is a unique case of hereditary pancreatitis presenting as new onset Type 3c Diabetes Mellitus with no prior episodes of acute pancreatitis or established diagnosis of chronic pancreatitis. References Ramalho, G. X., &amp; Dytz, M. G. (2020). Diabetes of the exocrine pancreas related to hereditary pancreatitis, an update. Current Diabetes Reports, 20(6). Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Combined SPINK1 mutations induce early-onset severe chronic pancreatitis in a child with severe obesity.

SummaryThe most frequent causes of pancreatitis classically have been known to be gallstones or alcohol. However, genetics can also play a key role in predisposing patients to both chronic and acute pancreatitis. The serine protease inhibitor Kazal type 1 (SPINK 1) gene is known to be strongly associated with pancreatitis. Patients with these underlying genetic mutations can have severe diseases with a high morbidity rate and frequent hospitalization. We report an Arab girl who presented with acute pancreatitis at the age of 7 years progressing to recurrent chronic pancreatitis over a few years. She had severe obesity from the age of 4 years and developed type 2 diabetes at the age of 12. She had a normal biliary system anatomy. Genetic analysis showed that she had combined heterozygous mutations in the SPINK1 gene (SPINK1, c.101A>G p.(Asn34Ser) and SPINK1, c.56-37T>C). Her parents were first-degree cousins, but neither had obesity. Mother was detected to have the same mutations. She had type 2 diabetes but never presented with pancreatitis. This case is the first to be reported from the Arab region with these combined mutations leading to recurrent chronic pancreatitis. It illustrates the importance of diagnosing the underlying genetic mutation in the absence of other known causes of pancreatitis. Considering the absence of pancreatitis history in the mother who did not have obesity but harboured the same mutations, we point out that severe obesity might be a triggering factor of pancreatitis in the presence of the mutations in SPINK1 gene in this child. While this is not an assumption from a single patient, we show that not all carriers of this mutation develop the disease even within the same family. Triggering factors like severe obesity might have a role in developing the disease.Learning pointsAcute recurrent pancreatitis and chronic pancreatitis are uncommon in children but might be underdiagnosed.Biliary tract anomalies and dyslipidaemias are known causative factors for pancreatitis, but pancreatitis can be seen in children with intact biliary system.Genetic diagnosis should be sought in children with pancreatitis in the absence of known underlying predisposing factors.SPINK1 mutations can predispose to an early-onset severe recurrent pancreatitis and acute pancreatitis.

The clinical and genetic features of hereditary pancreatitis in South Australia

ObjectiveTo characterise the clinical phenotypes and genetic variants of hereditary pancreatitis in people diagnosed in South Australia.Design, setting, participantsCross‐sectional study of people who received molecular diagnoses of hereditary pancreatitis from one of four major diagnostic services in South Australia, 1 January 2006 – 30 June 2021.Main outcome measuresGenotypic and clinical features of people with hereditary pancreatitis, including age at onset, attack frequency, pain indices, use of opioid medications, and physical and mental health impact of hereditary pancreatitis.ResultsWe identified 44 people from ten families who received molecular diagnoses of hereditary pancreatitis during 2006–21 (including 25 Indigenous people [57%] and 27 women [61%]): 36 with PRSS1, five with SPINK1, and three with PRSS1 and SPINK1 mutations (determined by whole exome sequencing). Symptom onset before the age of ten years was reported by 37 people (84%). Pancreatitis‐related pain during the preceding four weeks was described as moderate or high by 35 people (79%); 38 people regularly used opioids (86%). Fifteen patients had diabetes mellitus (34%), and eight had undergone pancreatic surgery (18%). The estimated prevalence of hereditary pancreatitis was 1.1 (95% CI, 0.72–1.4) cases per 100 000 population for non‐Indigenous and 71 (95% CI, 66–77) cases per 100 000 population for Indigenous South Australians. Among people with adult‐onset chronic pancreatitis admitted to South Australian public hospitals during 2001–2019, the proportions of Indigenous people (12%) and women (38%) were smaller than we report for hereditary pancreatitis.ConclusionThe estimated prevalence of hereditary pancreatitis in South Australia is higher than in Europe. PRSS1 gene mutations are important causes, particularly among Indigenous young people.

Hereditary pancreatitis: An updated review in pediatrics.

Hereditary Pancreatitis (HP) has emerged as a significant cause of acute, acute recurrent and chronic pancreatitis in the pediatric population. Given that it presents similarly to other causes of pancreatitis, a positive family history and/or isolation of a gene mutation are vital in its designation. Inheritance patterns remain complex, but mutations involving the PRSS1, SPINK1, CFTR and CTRC genes are commonly implicated. Since being first described in 1952, dozens of genetic alterations that modify the action of pancreatic enzymes have been identified. Among children, these variants have been isolated in more than 50% of patients with chronic pancreatitis. Recent research has noted that such mutations in PRSS1, SPINK1 and CFTR genes are also associated with a faster progression from acute pancreatitis to chronic pancreatitis. Patients with HP are at increased risk of developing diabetes mellitus, exocrine pancreatic insufficiency, and pancreatic adenocarcinoma. Management follows a multi-disciplinary approach with avoidance of triggers, surveillance of associated conditions, treatment of pancreatic insufficiency and use of endoscopic and surgical interventions for complications. With significant sequela, morbidity and a progressive nature, a thorough understanding of the etiology, pathophysiologic mechanisms, diagnostic evaluation, current management strategies and future research considerations for this evolving disease entity in pediatrics is warranted.

SPINK1 mutations and risk of pancreatic cancer in a Chinese cohort

ObjectiveThe relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). MethodsThis is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients’ demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. ResultsPC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. In this cohort, SPINK1 c.194+2T > C was the most common variant with a proportion of 39.1%. And the risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14–1.04), P = 0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04–0.80), P = 0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. ConclusionsCP patients harboring SPINK1 mutations do not have an elevated risk of PC development compared to mutation-negative CP patients. On the contrary, SPINK1 mutations may be a protective factor in non-smoking patients with CP.

Factors associated with prior acute pancreatitis episodes among patients with chronic pancreatitis

BackgroundThe relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP. AimsThe aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP. MethodsThis was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model. ResultsBefore diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P < 0.001), harboring the SPINK1 mutation(P < 0.001), diabetes(P < 0.001) and steatorrhea(P < 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P < 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors. ConclusionsSPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations.

Deep Targeted Sequencing and Its Potential Implication for Cancer Therapy in Chinese Patients with Gastric Adenocarcinoma.

IntroductionGastric cancer (GC) has a high incidence and mortality rate, especially in East Asians, and about 90% of GCs are adenocarcinomas. Histological and etiological heterogeneity and ethnic diversity make molecular subtyping of GC complicated, thus making it difficult to determine molecular division systems and standard treatment modalities. Limited cohorts from South Korea, Singapore, Australia, and Japan have been studied; however, the mutational landscape of gastric adenocarcinomas in Chinese patients is still unknown.MethodsWe performed a targeted sequencing panel focusing on cancer‐related genes and tumor‐associated microorganisms of 529 gastric adenocarcinoma samples with matched blood controls. We identified 449 clinically relevant gene mutations.ResultsApproximately 47.1% of Chinese patients with GC harbored at least one actionable mutation. The top somatic mutations were TP53, ARID1A, LRP1B, PIK3CA, ERBB2, CDH1, KRAS, FAT4, CCNE1, and KMT2D. Truncation mutations of ARID1A, KMT2D, RNF43, TGFBR2, and CIC occurred in patients with high tumor mutational burden. Gene amplifications of ERBB2, CCNE1, CDK12, and CCND1 were detected in patients with low tumor mutational burden. Pathway analysis revealed common gene alterations in the Wnt and PI3K/Akt signaling pathways. The ratio of patients with high microsatellite instability was significantly lower than other cohorts, and high microsatellite instability and Epstein‐Barr virus (EBV)–positive features seemed mutually inclusive in Chinese patients with GC. In 44 (8.3%) patients, 45 germline mutations were identified, among which SPINK1 mutations, all SPINK1 c.194 + 2T > C, were present in 15.9% (7/44) of patients. Microorganisms found in Chinese patients with GC included Helicobacter pylori, EBV, hepatitis B virus, and human papillomavirus types 16 and 18.ConclusionIdentification of varied molecular features by targeted next‐generation sequencing provides more insight into patient stratification and offers more possibilities for both targeted therapies and immunotherapies of Chinese patients with GC.Implications for PracticeThis study investigated the genomic alteration profile of 529 Chinese patients with gastric adenocarcinoma by deep targeting sequencing, which might be the largest Chinese cohort on the genomic research of gastric adenocarcinoma up to now.

&lt;i&gt;SPINK1&lt;/i&gt; Mutations and Risk of Pancreatic Cancer in Patients with Chronic Pancreatitis: Data from a Prospective Cohort Study

Objective: The relationship between SPINK1 and pancreatic cancer (PC) remains controversial. The current study aimed to determine the effect of SPINK1 mutations on PC development among patients with chronic pancreatitis (CP). Methods: This is a prospective observational study including a large cohort of 965 CP patients with 11-year follow-up. Patients’ demographic characteristics and clinical CP outcomes were documented in detail. Genetic testing was performed, and rare pathogenic variants of SPINK1 were included in the study. The effect of SPINK1 mutations on the clinical development of PC was explored using Cox proportional hazards regression. Subgroup analyses conducted included the consideration of gender, onset age of CP (early- and late-onset), etiologies of CP, smoking, and alcoholic drinking status. Results: PC was diagnosed in 2.5% (24/965) of patients, and the cumulative incidence rates were 0.2%, 0.8%, and 1.5% at 3, 5, and 10 years since the onset of CP, respectively. SPINK1 c.194+2T>C was the most common variant with a proportion of 39.1%. The risk of PC development varied marginally between patients with and without SPINK1 mutations (Cox HR 0.39(0.14-1.04), P=0.059). In the subgroup analyses, patients carrying SPINK1 mutations had a significantly lower risk of PC (Cox HR 0.18(0.04-0.80), P=0.025) in the non-smoking group. SPINK1 mutations showed no significant effect in the other subgroups considered. Conclusions: CP patients harboring SPINK1 mutations do not have an elevated risk of PC development. On the contrary, SPINK1 mutation appears to be a protective factor in non-smoking patients with CP. The exact relationship between SPINK1 mutations and PC warrants further investigation. Funding Statement: Financial support for this study came from the National Natural Science Foundation of China (Grant Nos. 82070661 [W.B.Z.], 81970560[Z.L.], 81873588[Z.S.L.]); Scientific Innovation Program of Shanghai Municipal Education Committee (No. 201901070007E00052); the fund for “Clinical Technology Innovation Project Task (Contract)” of Shanghai Shenkang Hospital Development Center (to ZL, No. SHDC2020CR2032B). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of Changhai Hospital.

Unusual type of diabetes: fibrocalculous pancreatic diabetes.

A 34-year-old Thai man complained about recurrent upper abdominal pain, polyuria, and a 5-kg weight loss in 6 months. He had no history of steatorrhea, jaundice, gallstones, alcohol intake, or cassava consumption. Physical examination was unremarkable except for his body mass index of 17.6 kg/m². The plasma glucose level was 672 mg/dL with normal serum amylase and lipase. Laboratory investigation showed serum osmolality of 287 mOsm/kg, bicarbonate 22 mEq/L and negative for serum ketone. Fibrocalculous pancreatic diabetes (FCPD) was diagnosed from a plain abdominal X-ray study showing multiple large calcifications over a pancreatic area (A). Computerized tomography of the abdomen revealed a large tubular calcification in dilated pancreatic duct during entering the duodenum (B). Scattered calcifications along the pancreatic duct were also noted (C). A genetic study revealed a SPINK1 N34S heterozygous mutation. His hyperglycemia responded well to insulin therapy. FCPD, a late stage of tropical chronic pancreatitis (TCP), is classified as a secondary cause of diabetes resulting from pancreatic dysfunction. The clinical picture consists of a triad of pancreatic calcification, abdominal pain, and diabetes. Its distinctive features are young age at onset, lean or underweight, ketosis-resistant diabetes, presence of large intraductal pancreatic calculi, and reported mainly in tropical developing countries. An etiology was previously thought to relate to malnutrition; however, a strong association with SPINK1 mutation is noted. The major morbidities are recurrent abdominal pain, steatorrhea, and malnutrition, while the majority of death is associated with diabetic nephropathy and pancreatic cancer. Treatment includes pancreatic enzyme supplementation, insulin therapy, and surgical drainage.

Chronic Pancreatitis in Thai Patients: A Comprehensive Review of 236 Patients from One Institution

Background: Reports of chronic pancreatitis (CP) in Thailand are rare. Clinical information is lacking. Objective: To study the etiology, genetics, presentations, clinical courses, complications, treatments, and outcomes of CP in Siriraj Hospital. Materials and Methods: Retrospective study of all CP patients during 2005 to 2018 was done. CP was diagnosed by abdominal radiography, ultrasonography, computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasonography (EUS). Etiology, genetics, presentations, clinical courses, complications, treatments and outcomes were analyzed. Results: There were 236 CP patients. The median follow-up was 37 months. There were 160 patients (68%) with alcoholic CP (ACP), 35 (15%) with early-onset idiopathic CP (E-ICP), 36 (15%) with late-onset idiopathic CP (L-ICP), 1 (0.4%) with tropical CP, 3 (1%) with hereditary pancreatitis (HP) and 1 (0.4%) with obstructive CP. Mean ages of onset were 47, 28 and 60 years in ACP, E-ICP and L-ICP, respectively (p&lt;0.001). Male was predominant in all types of CP (98%, 40% and 56%; p&lt;0.001). Initial presentations were abdominal pain (59%), recurrent acute pancreatitis (RAP, 22%), diabetes (DM, 8%) and steatorrhea (8%). Clinical manifestations during the course were abdominal pain in 89%, 89% and 83% (p = 0.832), RAP in 41%, 48% and 11% (p = 0.001), steatorrhea in 31%, 25% and 25% (p = 0.661), weight loss in 38%, 31% and 44% (p = 0.526), DM in 29%, 37% and 25% (p = 0.502), respectively. Median time to pain relief were 33, 74, and 16 months (p = 0.002). Common complications were pseudocyst (16%) and biliary obstruction (15%). SPINK1 mutation was detected in 83% of E-ICP, 45% of L-ICP and 21% of ACP (p&lt;0.001). PRSS1 mutation was found in all HP. Medical therapy included analgesics (62%), pancreatic enzymes (76%) and antioxidants (9%). Endoscopic therapy was done in 48 patients (20%). Surgery was performed in 31 patients (13%). Conclusion: ACP, E-ICP and L-ICP are common etiologies of CP. Presentations were RAP, abdominal pain, DM and steatorrhea. Painless L-ICP was uncommon. Spontaneous pain relief occurred quickly. SPINK1 mutation was common in ICP. Endoscopic and surgical therapy were required in one-fifth. Keywords: Chronic pancreatitis, Etiology, Genetics, Management, Manifestation, Natural course, Review &nbsp;

The analysis of SPINK1 mutations in population of Swieokrzyskie voivodeship, Poland

The analysis of SPINK1 mutations in population of Swieokrzyskie voivodeship, Poland

Pancreaticopleural fistula in children with chronic pancreatitis: a case report and literature review

BackgroundPancreaticopleural fistula (PPF) is a very rare and critical complication of pancreatitis in children. The majority of publications relevant to PPF are case reports. No pooled analyses of PPF cases are available. Little is known about the pathogenesis and optimal therapeutic schedule. The purpose of this study was to identify the pathogenesis and optimal therapeutic schedule of PPF in children.Case presentationThe patient was a 13-year-old girl who suffered from intermittent chest tightness and dyspnea for more than 3 months; she was found to have chronic pancreatitis complicated by PPF. The genetic screening revealed SPINK1 mutation. She was treated with endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic retrograde pancreatic drainage (ERPD); her symptoms improved dramatically after the procedures.ConclusionsPPF is a rare pancreatic complication in children and causes significant pulmonary symptoms that can be misdiagnosed frequently. PPF in children is mainly associated with chronic pancreatitis (CP); therefore, we highlight the importance of genetic testing. Endoscopic treatment is recommended when conservative treatment is ineffective.

Disordered Gut Microbiota in Children Who Have Chronic Pancreatitis and Different Functional Gene Mutations.

OBJECTIVES:Chronic pancreatitis (CP) is a serious condition whose pathogenic mechanism is unclear. Interactions of host genetic factors with gut microbiota have a role, but little is known, especially in children with CP (CCP), in which the external factors are less important. Our objective was to identify the main gut microbiota genera in CCP and to characterize the functional mutations of these patients.METHODS:We used 16S rRNA sequencing to compare the gut microbiota of healthy controls with patients who had CCP and different functional gene mutations.RESULTS:CCP is characterized by gut microbiota with remarkably reduced alpha diversity. Receiver operating characteristic curve analyses indicated that the abundances of 6 genera—Faecalibacterium, Subdoligranulum, Phascolarctobacterium, Bifidobacterium, Eubacerium, and Collinsella—were significantly decreased in CCP, with an area under curve (AUC) of 0.92 when considering all 6 genera together. Functional analysis of gut microbiota in CCP indicated reduced ribosomal activity, porphyrin and chlorophyll metabolism, starch and sucrose metabolism, and aminoacyl-tRNA biosynthesis, but an enrichment of phosphotransferase system pathways. The abundance of Butyricicoccus was significantly decreased in CCP in the presence of CFTR mutations when combined with mutations in CASR, CTSB, SPINK1, and/or PRSS1. The abundance of Ruminococcaceae was significantly increased in CCP when there were mutations in CASR, CTSB, SPINK1, and/or PRSS1. Patients with CCP but no gene mutations had greater abundances of Veillonella and reduced abundances of Phascolarctobacterium.DISCUSSION:CCP is associated with a depletion of probiotic gut microbiota, and CCP patients with different functional gene mutations have different gut microbiota.