Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction.

BACKGROUND: Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. OBJECTIVE: We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. METHODS: We tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes. RESULTS: The scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10-10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10-8, highest vs lowest quintile of the weighted multifactorial score). CONCLUSION: We found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Genotype-phenotype correlations for pancreatic cancer risk in Dutch melanoma families with pathogenic CDKN2A variants.

BACKGROUND: Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants. METHODS: Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families. RESULTS: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225_243del (p16-Leiden, 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%). CONCLUSIONS: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk.

Mini-laparoscopic cholecystectomy: evolution of a new technique.

BACKGROUND: Since the first laparoscopic cholecystectomy (LC) in 1985, there has been much advancement in laparoscopic surgery in terms of reduction in number and size of ports. We report a new technique of performing mini laparoscopic cholecystectomy using only three ports, 5 mm each. The indications of this procedure include GB polyps, GB dyskinesia, microlithiasis, and idiopathic pancreatitis. CASE PRESENTATION: In this case report, we present a new technique that has been performed safely in a 49-year-old male patient with pancreatitis caused by microlithiasis. This was performed using a novel three port procedure consisting of only 5 mm ports, and he was discharged as a day case without complications. Informed patient consent was obtained. CONCLUSIONS: The fundamentals of this mini-LC technique remain the same as that of a standard laparoscopic cholecystectomy throughout the procedure. It is a feasible option in selected cases, and it has the potential to further augment the inherent benefits of minimal access surgery namely less analgesia, improved cosmesis and faster recovery. Further trials will help ascertain its potential advantages.

Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.

BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. METHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). RESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional ß cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. CONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without ß cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

Percutaneous biliary stent removal for benign biliary stricture post hepaticojejunostomy.

This case report presents the percutaneous extraction of a biliary stent in a patient with a history of liver transplant and Whipple procedure, suffering from benign biliary stricture post hepaticojejunostomy. After failed management with conventional benign biliary protocol, a fully covered WallFlex biliary stent was percutaneously placed and later removed using a balloon catheter technique. The procedure demonstrated anastomosis patency without complications, providing a drain-free option for complex anatomy where endoscopic management was not feasible. This case contributes valuable insights to the limited literature on percutaneous stent removal for benign biliary strictures, emphasising the importance of considering alternative approaches in challenging clinical scenarios.

Isolated pancreatic tuberculosis presenting as mucinous cystic lesion.

A young man in his early 30s presented to our hospital with upper abdominal pain radiating to the back, progressive jaundice with pruritus, low-grade fever, vomiting and significant weight loss over 4 months. The syndrome of extrahepatic biliary obstruction was considered. There was no significant past, personal or family history. Imaging was suggestive of mucinous cystic lesions of the pancreas with significant lymphadenopathy. He was initially planned for surgery. However, endoscopic ultrasound-guided fine-needle aspiration from the lesion tested positive for tuberculosis and he improved dramatically with antituberculosis therapy. When a patient has an atypical presentation, tuberculosis should always be considered, especially if they reside in a tuberculosis-endemic country.

Pancreatic neuroendocrine tumour resection in circumportal pancreas: a rare anatomical anomaly with important surgical implications.

Various congenital anomalies of the pancreas have been reported due to its complex embryological development involving the fusion of two separate buds. Circumportal pancreas is a rare anatomical anomaly where the pancreatic head and uncinate process fuse abnormally with the pancreatic body, encasing the portal vein and/or superior mesenteric vein completely. This anomaly poses several challenges to hepatobiliary surgeons, as the encasement of the portal vein by the abnormal pancreatic tissue makes an additional parenchymal transection necessary. Vascular variants have also been reported with circumportal pancreas, which, if not recognised preoperatively, can be catastrophic. Therefore, careful preoperative evaluation and planning are essential, to ensure safe pancreatic resection and recovery in a patient with circumportal pancreas. We present a case of a successful subtotal pancreatectomy and splenectomy in a patient with circumportal pancreas, for a suspected pancreatic duct adenocarcinoma. The aim of this case report is to contribute valuable insights that can aid hepatobiliary surgeons in enhancing their preoperative planning when encountered with patients with similar anatomical variances.

Total pancreatectomy, splenectomy and remnant gastrectomy for invasive intraductal papillary mucinous neoplasm (IPMN) after prior Roux-en-Y gastric bypass.

A female patient in her 50s presented with abdominal pain, nausea and jaundice. She had a history of prior Roux-en-Y gastric bypass and her body mass index was 52.5 kg/m2 Biochemical testing revealed a total bilirubin level of 14.3 mg/dL (normal<1.2 mg/dL) and carbohydrate antigen 19-9 of 38.3 units/mL (normal<36.0 units/mL). CT demonstrated a 3.2 cm pancreatic head mass, biliary and pancreatic duct dilation and cystic replacement of the pancreas. The findings were consistent with a diagnosis of mixed-type intraductal papillary mucinous neoplasm (IPMN) with invasive malignancy. The patient's Roux-en-Y anatomy precluded endoscopic biopsy, and she underwent upfront resection with diagnostic laparoscopy, open total pancreatectomy, splenectomy and remnant gastrectomy with reconstruction. Pathology confirmed T2N1 pancreatic adenocarcinoma, 1/29 lymph nodes positive and diffuse IPMN. She completed adjuvant chemotherapy. IPMNs have malignant potential and upfront surgical resection should be considered without biopsy in the appropriate clinical setting.

Intrahepatic biloma after intraoperative cholangiography.

A woman in her 30s presented to the emergency department with a month-long history of postprandial epigastric pain radiating to her back. The diagnosis of cholecystolithiasis and suspected choledocholithiasis was made, and the patient underwent cholecystectomy with cholangiography using standard technique. The surgery was complicated by an intrahepatic bile duct injury attributed to high injection pressure during cholangiography. She developed an intrahepatic collection that was drained and confirmed the diagnosis of biloma. In this case report, we discuss a rare complication of intraoperative cholangiography during laparoscopic cholecystectomy and consider a way to prevent it.

Malignancy and mass-forming phenotypes of IgG4-related disease: a challenging diagnosis.

Mass-forming phenotypes of IgG4-related disease (IgG4-RD) mimic malignancy and histological confirmation can be challenging. A woman in her 70s with HIV infection presented with painless obstructive jaundice and weight loss. Magnetic resonance imaging was suggestive of unresectable cholangiocarcinoma. Tumour markers and serum IgG4 were normal. Percutaneous liver biopsy was consistent with IgG4-RD inflammatory pseudotumour, with complete response to glucocorticoid therapy. Two years later, a new episode of obstructive jaundice occurred, with CT showing a solid lesion in the head of the pancreas with double duct sign and encasement of the portal vein. Re-induction therapy was tried without response. Fine-needle biopsy was consistent with pancreatic cancer. Supportive care was offered and the patient died 8 months later, with no signs of disease progression on subsequent imaging. We discuss the challenges of IgG4-RD diagnosis and treatment and the differential diagnosis between mass-forming phenotypes and malignancy, highlighting the difficulties in managing such patients.

Primary pure squamous cell carcinoma of the gallbladder.

SummarySquamous cell carcinoma (SCC) is an uncommon and frequently aggressive subtype of gallbladder cancer known for its poor outcomes compared with other gallbladder tumours. Gallbladder SCC typically presents as higher grade and more advanced than adenocarcinoma, resulting in lower estimated survival. Early recognition of these tumours is ideal, but infrequently achieved. Herein is a case of a male patient in his 80s with new onset abdominal pain who was initially diagnosed with cholecystitis, but diagnostic imaging revealed a gallbladder mass. Surgical resection and pathology revealed pure SCC of the gallbladder without local organ invasion or metastatic disease. Pure SCC histology of the gallbladder is rare, with limited studies on clinical presentation, natural history, and optimal treatment.

Significant elevation of serum CA19-9 and CA242 levels induced by dulaglutide.

The use of dulaglutide, a common medication for managing type 2 diabetes, rarely causes elevated pancreatic tumour markers. Here, we report the case of a woman in her mid-60s with diabetes for over 10 years. The patient presented with markedly elevated serum CA19-9 and CA242 levels revealed during a routine health examination despite being asymptomatic. She had been receiving dulaglutide injections for 16 months. Imaging and interventional assessments did not reveal any hepatobiliary, gastrointestinal or pancreatic neoplasm. After excluding alternate diagnoses, the patient was determined to exhibit an adverse reaction to dulaglutide use. Management involved the discontinuation of dulaglutide, which resulted in normalisation of serum CA19-9 and CA242 levels within 6 weeks. This case underscores the importance of discontinuing dulaglutide and monitoring changes in the biomarker levels in asymptomatic patients receiving dulaglutide, rather than immediately resorting to imaging and endoscopic examinations.

Haemosuccus pancreaticus and seven episodes of recurrent unlocalised upper gastrointestinal bleeding.

Upper gastrointestinal (GI) bleeding is a common medical condition that results in extensive morbidity and mortality, as well as substantial healthcare costs. While there is variation among society and consensus guidelines, the approaches to assessment and evaluation are generally consistent. Our case describes a man in his 40s who presented with seven episodes of recurrent upper GI bleeding over 2 years secondary to haemosuccus pancreaticus. While rare, this case study highlights key principles to the initial diagnostic approach that, in appropriate clinical contexts, should be applied to patients with unlocalised upper GI bleeding. We further perform a complete systematic review of similar cases available in PubMed (36 patients in 24 case reports) to further refine these diagnostic principles.

Spontaneous perforation of the common hepatic duct in a child: an unexpected intraoperative encounter.

Spontaneous or idiopathic bile duct perforation is rare, mostly seen in children from 25 weeks of gestation to 7 years of age, with the confluence of cystic duct and common hepatic duct (CHD) being the most common site. The exact aetiopathogenesis remains elusive and poorly understood, leading to a lack of consensus on its optimal management. The condition is often diagnosed intraoperatively. We present a case of spontaneous perforation of the CHD in a boy in his middle childhood, alongside a review of relevant literature. The patient presented with acute abdomen and pyobiliary peritonitis, for which a hollow viscus perforation was suspected. An emergent laparotomy revealed a 0.5 cm CHD perforation. Surgical intervention involved T-tube insertion and drainage, leading to a successful recovery. This case underscores the challenge of preoperative diagnosis, necessitating prompt exploration after initial resuscitation. There is a need for clinical vigilance and tailored surgical approaches.

Marathon pancreatitis: a case of acute pancreatitis caused by distance running.

Marathon running or other forms of strenuous exercise have been reported as a rare cause of acute pancreatitis. Theories as to the mechanism of acute pancreatitis include microvascular ischaemia due to dehydration or repetitive trauma to the pancreas. We report a case of a healthy woman in her 30s who developed abdominal pain, nausea and vomiting after a 32 km marathon training run. She was found to have elevated lipase and inflammation of the pancreatic tail with associated pericolic and pelvic free fluid on CT scan. Workup including abdominal ultrasound and magnetic resonance cholangiopancreatography (MRCP) did not reveal biliary or pancreatic duct pathology. She improved with conservative management. These findings support the hypothesis of exercise-induced pancreatitis from long-distance running.

Isolated pancreatic tuberculosis masquerading pancreatic malignancy.

Pancreatic tuberculosis is the rarest form of abdominal and extrapulmonary tuberculosis. We present a patient in his 40s who presented with pain abdomen and a fever. On examination, the patient had mild jaundice and right hypochondriac tenderness. Blood investigation was suggestive of obstructive jaundice. Imaging studies were representative of pancreatic head lesion, causing mild intrahepatic biliary radical dilatation. Endoscopic ultrasound-guided fine-needle aspiration done from the pancreatic head lesion was diagnostic of tuberculosis. The patient was started on antitubercular medications and responded well.

Laparoscopic management of combined cholecystogastric and cholecystocolonic fistulae.

Cholecystogastric and cholecystocolonic fistulae are rare sequelae of longstanding cholelithiasis and can complicate surgical management. Our case involves a male patient in his early 40s with a history of chronic cholelithiasis who presented to the emergency department with severe abdominal pain. Findings on imaging were consistent with acute calculous cholecystitis. During laparoscopic cholecystectomy, the presence of both cholecystogastric and cholecystocolonic fistulae was discovered. Fistula resection with cholecystectomy in a one-step approach using indocyanine green (ICG) angiography was performed. The patient improved and was discharged 3 days later. Laparoscopic management complemented by ICG angiography is a viable surgical approach in patients with cholecystogastric and cholecystocolonic fistulae.

Acute pancreatitis presenting as acute scrotum.

Acute pancreatitis can lead to pancreatic and peripancreatic collections that can spread in the retroperitoneum to varying extents based on the severity of the pancreatitis. We present here an unusual case of pancreatitis where the patient presented with an acute scrotum as a result of extension of peripancreatic inflammation to the scrotum.

Pleural empyema secondary to perforated diverticulosis due to biliary neoplasia infiltration.

A long-term female smoker presented to the emergency department with cough, greenish mucus and dyspnoea, without fever. The patient also reported abdominal pain and significant weight loss in recent months. Laboratory tests showed leucocytosis with neutrophilia, lactic acidosis and a faint left lower lobe consolidation on chest X-ray, for which she was admitted to the pneumology department and started on broad-spectrum antibiotherapy. After 3 days of clinical stability, the patient deteriorated rapidly, with worsening of analytical parameters and coma. The patient died a few hours later. Given the rapid and unexplained evolution of the disease, a clinical autopsy was requested, which revealed a left pleural empyema caused by perforated diverticula by neoplastic infiltration of biliary origin.

ERCP with single-use disposable duodenoscopes in four different set-ups.

Endoscopic retrograde cholangiopancreatography (ERCP) has until now always been performed using a reusable non-sterile duodenoscope. The introduction of the new single-use disposable duodenoscope makes it possible to perform perioperative transgastric and rendezvous ERCP in an almost sterile manner. It also eliminates the risk of patient-to-patient transmission of infection in non-sterile settings. We present four patients who underwent different types of ERCP using a sterile single-use duodenoscope. This case report aims to demonstrate the use and the many potential advantages of the new disposable single-use duodenoscope in both sterile and non-sterile settings.