Current considerations on intraductal papillary neoplasms of the bile duct and pancreatic duct

Pancreatobiliary intraductal papillary neoplasms(IPNs)represent precursors of pancreatic cancer or bile duct cholangiocarcinoma that can be detected and treated.Despite advances in diagnostic methods,identifying these premalignant lesions is still challenging for treatment providers.Modern imaging,biomarkers and molecular tests for genomic alterations can be used for diagnosis and follow-up.Surgical intervention in combination with new chemotherapeutic agents is considered the optimal treatment for malignant cases.The balance between the risk of malignancy and any risk of resection guides management policy;therefore,treatment should be individualized based on a meticulous preoperative assessment of high-risk stigmata.IPN of the bile duct is more aggressive;thus,early diagnosis and surgery are crucial.The conservative management of low-risk pancreatic branch-duct lesions is safe and effective.

Multi-institutional retrospective analysis of FOLFIRI in patients with advanced biliary tract cancers

BACKGROUND Gemcitabine plus platinum is the standard of care first-line treatment for advanced biliary tract cancers(BTC).There is no established second-line therapy,and retrospective reviews report median progression-free survival(PFS)less than 3 mo on second-line therapy.5-Fluorouracil plus irinotecan(FOLFIRI)is a commonly used regimen in patients with BTC who have progressed on gemcitabine plus platinum,though there is a paucity of data regarding its efficacy in this population.AIM To assess the efficacy of FOLFIRI in patients with biliary tract cancers.METHODS We retrospectively identified patients with advanced BTC who were treated with FOLFIRI at MD Anderson,University of Michigan and Mayo Clinic in Jacksonville.Data were collected on patient demographics,BTC subtype,response per RECIST v1.1,progression and survival.RESULTS Ninety-eight patients were included of which 74(75%)had metastatic and 24(25%)had locally advanced disease at the time of treatment with FOLFIRI.The median age was 60(range,22-86)years.The number of patients with extrahepatic cholangiocarcinoma,gall bladder cancer and intrahepatic cholangiocarcinoma were 10,17 and 71,respectively.FOLFIRI was used as 1st,2nd,3rd or 4th–Nth lines in 8,50,36 and 4 patients,respectively.Median duration on FOLFIRI in the entire cohort was 2.2(range,0.5-8.4)mo.The median PFS and overall survival were 2.4(95%confidence interval(CI):1.7-3.1)and 6.6(95%CI:4.7-8.4)mo,respectively.Median PFS for patients treated with FOLFIRI in 1st,2nd,3rd or 4th–Nth lines were 3.1,2.5,2.3 and 1.5 mo,respectively.Eighteen patients received concurrent bevacizumab(n=13)or EGFR-targeted therapy(n=5)with FOLFIRI,with a median PFS of 2.7 mo(95%CI:1.7-5.1).CONCLUSION In this largest multi-institution retrospective review of 98 patients with BTC treated with FOLFIRI,efficacy appears to be modest with outcomes similar to other cytotoxic chemotherapy regimens.

New trends in diagnosis and management of gallbladder carcinoma

Gallbladder(GB)carcinoma,although relatively rare,is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis.It is closely associated with cholelithiasis and long-standing large(>3 cm)gallstones in up to 90%of cases.The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes,GB wall calcification(porcelain)or mainly mucosal microcalcifications,and GB polyps≥1 cm in size.Diagnosis is made by ultrasound,computed tomography(CT),and,more precisely,magnetic resonance imaging(MRI).Preoperative staging is of great importance in decisionmaking regarding therapeutic management.Preoperative staging is based on MRI findings,the leading technique for liver metastasis imaging,enhanced three-phase CT angiography,or magnetic resonance angiography for major vessel assessment.It is also necessary to use positron emission tomography(PET)-CT or ^(18)F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake.Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6%of cases.Multimodality treatment is needed,including surgical resection,targeted therapy by biological agents according to molecular testing gene mapping,chemotherapy,radiation therapy,and immunotherapy.It is of great importance to understand the updated guidelines and current treatment options.The extent of surgical intervention depends on the disease stage,ranging from simple cholecystectomy(T1a)to extended resections and including extended cholecystectomy(T1b),with wide lymph node resection in every case or IV-V segmentectomy(T2),hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y,and adjacent organ resection if necessary(T3).Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery,but much attention must be paid to avoiding injuries.In addition to surgery,novel targeted treatment along with immunotherapy and recent improvements in radiotherapy and chemotherapy(neoadjuvant-adjuvant capecitabine,cisplatin,gemcitabine)have yielded promising results even in inoperable cases calling for palliation(T4).Thus,individualized treatment must be applied.

Endoscopic management of occluded metal biliary stents:Metal versus 10F plastic stents

AIM:To compare the efficacy of self-expandable metal stents(SEMSs) with 10F plastic stents(PSs) in the endoscopic management of occluded SEMSs.METHODS:We retrospectively reviewed the medical records of 56 patients who underwent SEMS insertion for palliation of unresectable malignant biliary obstruction between 2000 and 2007 and subsequent endoscopic retrograde biliary drainage(ERBD) with SEMS or PS for initial SEMS occlusion between 2000 and 2008.RESULTS:Subsequent ERBD with SEMS was performed in 29 patients and with PS in 27.The median time to stent occlusion after subsequent ERBD was 186 d in the SEMS group and 101 d in the PS group(P= 0.118).Overall median stent patency was 79 d for the SEMS group and 66 d for the PS group(P = 0.379).The mean number of additional biliary drainage procedures after subsequent ERBD in patients that died(n = 50) during the study period was 2.54 ± 4.12 for the SEMS group and 1.85 ± 1.95 for the PS group(P = 0.457).The mean total cost of additional biliary drainage procedures after the occlusion of subsequent SEMS or PS was $410.04 ± 692.60 for the SEMS group and $630.16 ± 671.63 for the PS group(P = 0.260).Tumor ingrowth as the cause of initial SEMS occlusion was the only factor associated with a shorter time to subsequent stent occlusion(101 d for patients with tumor ingrowth vs 268 d for patients without tumor ingrowth,P = 0.008).CONCLUSION:Subsequent ERBD with PSs offered similar patency and number of additional biliary drainage procedures compared to SEMSs in the management of occluded SEMS.

Associations between serum uric acid and hepatobiliary-pancreatic cancer:A cohort study

BACKGROUND Uric acid is the end product of purine metabolism.Previous studies have found that serum uric acid(SUA)levels are associated with the total cancer risk.However,due to the dual effect of uric acid on cancer,the relationship between the SUA levels and most specific-site cancer remains unclear.AIM To investigate the associations between the SUA levels and incidence of hepatobiliary-pancreatic cancer.METHODS In this prospective cohort study,444462 participants free of cancer from the UK Biobank were included.The SUA levels were measured at baseline,and the incidence of hepatobiliary-pancreatic cancer was determined by contacting the cancer registry.The hazard ratios(HRs)and 95%confidence intervals(CIs)between the SUA levels and hepatobiliary-pancreatic cancer were investigated using multiple adjusted Cox regression models adjusted for potential confounders.RESULTS In total,920 participants developed liver,gallbladder,biliary tract or pancreatic cancer during a median of 6.6 yrs of follow-up.We found that the HR of pancreatic cancer in the highest SUA group was 1.77(95%CI:1.29-2.42)compared with that in the lowest group.After stratifying by gender,we further found that SUA was associated with an increased risk of pancreatic cancer only among the females(highest quartile vs lowest quartile HR 2.04,95%CI:1.35-3.08).Among the males,the SUA levels were positively associated with the gallbladder cancer risk(highest quartile vs lowest quartile HR 3.09,95%CI:1.28-7.46),but a U-shaped association with the liver cancer risk was observed(P-nonlinear=0.03).CONCLUSION SUA is likely to have gender-specific effects on hepatobiliary-pancreatic cancer.High SUA levels are a risk factor for pancreatic cancer in females and gallbladder cancer in males.A U-shaped association with the liver cancer risk was identified.

Management of occluded self-expanding biliary metal stents in malignant biliary disease

Background: Occlusion of self-expanding metal stents(SEMS) in malignant biliary obstruction occurs in up to 40% of patients. This study aimed to compare the different techniques to resolve stent occlusion in our collective of patients.Methods: Patients with malignant biliary obstruction and occlusion of biliary metal stent at a tertiary referral endoscopic center were retrospectively identified between April 1, 1994 and May 31, 2014. The clinical records were further analyzed regarding the characteristics of patients, malignant strictures, SEMS,management strategies, stent patency, subsequent interventions, survival time and case charges.Results: A total of 108 patients with biliary metal stent occlusion were identified. Seventy-nine of these patients were eligible for further analysis. Favored management was plastic stent insertion in 73.4% patients. Second SEMS were inserted in 12.7% patients. Percutaneous transhepatic biliary drainage and mechanical cleansing were conducted in a minority of patients. Further analysis showed no statistically significant difference in median overall secondary stent patency(88 vs. 143 days, P = 0.069), median survival time(95 vs. 192 days, P = 0.116), median subsequent intervention rate(53.4% vs. 40.0%, P = 0.501)and median case charge(€5145 vs. €3473, P = 0.803) for the treatment with a second metal stent insertion compared to plastic stent insertion. In patients with survival time of more than three months,significantly more patients treated with plastic stents needed re-interventions than patients treated with second SEMS(93.3% vs. 57.1%, P = 0.037).Conclusions: In malignant biliary strictures, both plastic and metal stent insertions are feasible strategies for the treatment of occluded SEMS. Our data suggest that in palliative biliary stenting, patients especially those with longer expected survival might benefit from second SEMS insertion. Careful patient selection is important to ensure a proper decision for either management strategy.

Endoscopic retrograde cholangiopancreatography drainage for palliation of malignant hilar biliary obstruction——stent-in-stent or side-by-side?A systematic review and meta-analysis

BACKGROUND Biliary drainage,either by the stent-in-stent(SIS)or side-by-side(SBS)technique,is often required when treating a malignant hilar biliary obstruction(MHBO).Both methods differ from each other and have distinct advantages.AIM To compare both techniques regarding their efficacy and safety in achieving drainage of MHBO.METHODS A comprehensive search of multiple electronic databases(MEDLINE,Embase,LILACS,BIREME,Cochrane)was conducted and grey literature from their inception until December 2020 with no restrictions regarding the year of publication or language,since there was at least an abstract in English.The included studies compared SIS and SBS techniques through endoscopic retrograde cholangiopancreatography.Outcomes analyzed included technical and clinical success,early and late adverse events(AEs),stent patency,reintervention,and procedure-related mortality.RESULTS Four cohort studies and one randomized controlled trial evaluating a total of 250 patients(127 in the SIS group and 123 in the SBS group)were included in this study.There were no statistically significant differences between the two groups concerning the evaluated outcomes,except for stent patency,which was higher in the SIS compared with the SBS technique[mean difference(d)=33.31;95%confidence interval:9.73 to 56.90,I2=45%,P=0.006].CONCLUSION The SIS method showed superior stent patency when compared to SBS for achieving bilateral drainage in MHBO.Both techniques are equivalent in terms of technical success,clinical success,rates of both early and late AEs,reintervention,and procedure-related mortality.

Biliary drainage in inoperable malignant biliary distal obstruction: A systematic review and meta-analysis

BACKGROUND Endoscopic drainage remains the treatment of choice for unresectable or inoperable malignant distal biliary obstruction(MDBO).AIM To compare the safety and efficacy of plastic stent(PS)vs self-expanding metal stent(SEMS)placement for treatment of MDBO.METHODS This meta-analysis was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.A comprehensive search was performed in MEDLINE,Cochrane,Embase,Latin American and Caribbean Health Sciences Literature,and grey literature to identify randomized clinical trials(RCTs)comparing clinical success,adverse events,stent dysfunction rate,reintervention rate,duration of stent patency,and mean survival.Risk difference(RD)and mean difference(MD)were calculated and heterogeneity was assessed with I2 statistic.Subgroup analyses were performed by SEMS type.RESULTS Twelve RCTs were included in this study,totaling 1005 patients.There was no difference in clinical success(RD=-0.03,95%confidence interval[CI]:-0.01,0.07;I 2=0%),rate of adverse events(RD=-0.03,95%CI:-0.10,0.03;I2=57%),and mean patient survival(MD=-0.63,95%CI:-18.07,19.33;I2=54%)between SEMS vs PS placement.However,SEMS placement was associated with a lower rate of reintervention(RD=-0.34,95%CI:-0.46,-0.22;I2=57%)and longer duration of stent patency(MD=125.77 d,95%CI:77.5,174.01).Subgroup analyses revealed both covered and uncovered SEMS improved stent patency compared to PS(RD=152.25,95%CI:37.42,267.07;I2=98%and RD=101.5,95%CI:38.91,164.09;I2=98%;respectively).Stent dysfunction was higher in the covered SEMS group(RD=-0.21,95%CI:-0.32,-0.1;I²=205%),with no difference in the uncovered SEMS group(RD=-0.08,95%CI:-0.56,0.39;I²=87%).CONCLUSION While both stent types possessed a similar clinical success rate,complication rate,and patient-associated mean survival for treatment of MDBO,SEMS were associated with a longer duration of stent patency compared to PS.

Spontaneous rupture of a mucinous cystic neoplasm of the liver resulting in a huge biloma in a pregnant woman:A case report

BACKGROUND Mucinous cystic neoplasm of the liver(MCN-L)and intraductal papillary neoplasm of the bile duct(IPN-B)are two different types of mucin-producing bile duct tumour that may complicate the course of pregnancy.To the best of our knowledge,we describe herein the first case of MCN-L with spontaneous rupture during pregnancy necessitating complex surgical treatment.CASE SUMMARY A 24-year-old woman was initially admitted to another hospital in October 2018 with signs of jaundice(serum bilirubin level 12 mg/dL)and upper abdominal pain radiating to the left shoulder.Initial magnetic resonance imaging(MRI)of the abdominal cavity revealed a multilocular cystic tumour of the liver hilum(37 mm×40 mm in diameter)located between segments 3 and 4 of the left liver lobe.Six weeks later(December 2018),the patient was found to be 12 wk pregnant and was referred to our institution for further diagnostics and treatment.At admission,a soft,palpable,and tender mass in the left upper abdomen was found.It was determined via MRI(with no intravenous contrast in view of the first-trimester pregnancy)to be a large collection of fluid(19 cm×17 cm×10 cm)located close to the liver hilum and below the left liver lobe.The patient did not undergo any diagnostic or therapeutic procedures nor did they have any abdominal trauma in the preceding weeks.The fluid collection proved to be of biliary origin following percutaneous drainage.Therefore,we concluded this was a spontaneous rupture of an MCN-L with the formation of a biloma.The MRI study also revealed the previously found cystic tumour of the liver hilum communicating with the left hepatic duct,which,together with left hepatic duct dilatation,suggested the diagnosis of IPN-B.The follow-up MRI with intravenous gadolinium contrast performed in the second trimester of pregnancy(week 14)showed,in turn,some features of MCN-L,including enhancement of the internal septations within the cystic liver mass.A precise preoperative differential diagnosis between IPN-B and MCN-L was therefore not possible.The patient was submitted to surgery in the second trimester of pregnancy(week 18).Surgery included a cholecystectomy,left hepatectomy,and concomitant resection of the extrahepatic bile ducts followed by anastomosis of the right hepatic duct with the Roux limb of the jejunum.The post-operative period was uneventful and the patient was discharged 8 days after surgery.The histopathological examination of the resected specimen revealed a final diagnosis of MCN-L with low-grade dysplasia and epithelium surrounded by ovarian-type stromal tissue.The patient delivered a healthy baby girl and both remain well at present,after 2 years of follow-up since surgery.CONCLUSION The differential diagnosis and management of MCN-L and IPN-B may be very challenging,particularly in the setting of pregnancy.When indications for surgery are obvious,the final diagnosis is based on histopathological examination,with ovarian-type stroma being pathognomonic for MCN-L.We believe that the growth of this subepithelial stroma secondary to the high levels of sex hormones produced during pregnancy might have been the main causative factor leading to the tumour rupture with the formation of a biloma in our patient.

Imaging features and appropriate treatment strategy of a rare biliary tract neoplasm

Mucin-producing bile duct tumors （MPBTs） are characterized by intraductal papillary tumorsproducing large amounts of mucin. The tumor comprises macroscopically prominent intraductal papillary neoplastic epithelia and produces a large amount of viscid mucin, resulting in dilatation of the bile ducts.1 These tumors of the peripheral bile duct, which include benign and malignant lesions, have also been referred to as intraductal growth- type peripheral cholangiocarcinomas,2 mucin-producing cholangiocellular carcinomas,3 intraductal papillary neoplasms （IPNs） of the biliary tract,4 IPNs of the liver,5 or IPNs of the bile duct.6 MPBTs have been the subject of recent attention due to its peculiar histopathology, biological and clinical behavior, varied radiological manifestations, and good prognosis of the patients] Due to the rarity of this disease entity and the non-specific clinical presentation, MPBTs are not well characterized. The purpose of this study was to define the precise diagnosis and correct management of MPBTs with the help of nine clinical cases observed in the last 10 years. The preoperative differential diagnosis, surgical procedure, and postoperative course of these nine cases were retrospectively reviewed.

Successful endoscopic procedures for intraductal papillary neoplasm of the bile duct:A case report

Attention has recently been focused on biliary papillary tumors as the novel disease entity intraductal papillary neoplasm of the bile duct(IPNB),which consists of papillary proliferation of dysplastic biliary epithelium.As even benign papillary tumors are considered as premalignant,some investigators recommend aggressive surgical therapy for IPNB,although no guidelines are available to manage this disease.Few reports have described long-term follow-up of patients with benign IPNB without radical resection.If patients with IPNB who are treated only with endoscopic procedures are noted,clinical profiles and alternative therapies other than resection may be recommended.We report the case of a patient who experienced repetitive cholangitis for 10 years and was finally diagnosed with IPNB.Radical resection could not be recommended because of the age of the patient,therefore,endoscopic sphincterotomy was performed.Although an endoscopic retrograde biliary drainage catheter was placed several times for repetitive cholangitis,the patient has done well during follow-up.Our case may offer insights into the natural course and management decisions for the novel disease entity of IPNB.