Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.

Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Hepatocellular carcinoma(HCC)is one of the most common causes of cancerrelated mortality.This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease.This makes the management of patients more challenging,since physicians must take into consideration two different conditions,the chronic liver disease and the tumor.The underlying liver disease has several implications in clinical practice,because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC,obstacles in surveillance,and differences in the efficacy of the treatment against HCC.A shift in the prevalence of liver diseases has been evident over the last few years,with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance.Therefore,in an era of personalized medicine,it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Diagnostic and therapeutic role of endoscopic ultrasound in liver diseases:A systematic review and meta-analysis

BACKGROUND In hepatology,the clinical use of endoscopic ultrasound(EUS)has experienced a notable increase in recent times.These applications range from the diagnosis to the treatment of various liver diseases.Therefore,this systematic review summarizes the evidence for the diagnostic and therapeutic roles of EUS in liver diseases.AIM To examine and summarize the current available evidence of the possible roles of the EUS in making a suitable diagnosis in liver diseases as well as the therapeutic accuracy and efficacy.METHODS PubMed,Medline,Cochrane Library,Web of Science,and Google Scholar databases were extensively searched until October 2023.The methodological quality of the eligible articles was assessed using the Newcastle-Ottawa scale or Cochrane Risk of Bias tool.In addition,statistical analyses were performed using the Comprehensive Meta-Analysis software.RESULTS Overall,45 articles on EUS were included(28 on diagnostic role and 17 on therapeutic role).Pooled analysis demonstrated that EUS diagnostic tests had an accuracy of 92.4%for focal liver lesions(FLL)and 96.6%for parenchymal liver diseases.EUS-guided liver biopsies with either fine needle aspiration or fine needle biopsy had low complication rates when sampling FLL and parenchymal liver diseases(3.1%and 8.7%,respectively).Analysis of data from four studies showed that EUS-guided liver abscess had high clinical(90.7%)and technical success(90.7%)without significant complications.Similarly,EUS-guided interventions for the treatment of gastric varices(GV)have high technical success(98%)and GV obliteration rate(84%)with few complications(15%)and rebleeding events(17%).CONCLUSION EUS in liver diseases is a promising technique with the potential to be considered a first-line therapeutic and diagnostic option in selected cases.

Use of endoscopic ultrasound-guided gallbladder drainage as a rescue approach in cases of unsuccessful biliary drainage

This narrative review provides an overview of the utilization of endoscopic ultrasound-guided gallbladder drainage(EUS-GBD)as a salvage approach in cases of unsuccessful conventional management.EUS-GBD is a minimally invasive and effective technique for drainage in patients with acute cholecystitis with high risk of surgery.The procedure has demonstrated impressive technical and clinical success rates with low rates of adverse events,making it a safe and effective option for appropriate candidates.Furthermore,EUS-GBD can also serve as a rescue option for patients who have failed endoscopic retrograde cholangiopancreatography or EUS biliary drainage for relief of jaundice in malignant biliary stricture.However,patient selection is critical for the success of EUS-GBD,and proper patient selection and risk assessment are important to ensure the safety and efficacy of the procedure.As the field continues to evolve and mature,ongoing research will further refine our understanding of the benefits and limitations of EUS-GBD,ultimately leading to improved outcomes for patients.

Removal of intrahepatic bile duct stone could reduce the risk of cholangiocarcinoma: A single-center retrospective study in South Korea

BACKGROUND Intrahepatic duct(IHD)stones are among the most important risk factors for cholangiocarcinoma(CCC).Approximately 10%of patients with IHD stones develop CCC;however,there are limited studies regarding the effect of IHD stone removal on CCC development.AIM To investigate the association between IHD stone removal and CCC development.METHODS We retrospectively analyzed 397 patients with IHD stones at a tertiary referral center between January 2011 and December 2020.RESULTS CCC occurred in 36 of the 397 enrolled patients.In univariate analysis,chronic hepatitis B infection(11.1%vs 3.0%,P=0.03),carbohydrate antigen 19-9(CA19-9,176.00 vs 11.96 II/mL,P=0.010),stone located in left or both lobes(86.1%vs 70.1%,P=0.042),focal atrophy(52.8%vs 26.9%,P=0.001),duct stricture(47.2%vs 24.9%,P=0.004),and removal status of IHD stone(33.3%vs 63.2%,P<0.001)were significantly different between IHD stone patients with and without CCC.In the multivariate analysis,CA19-9>upper normal limit,carcinoembryonic antigen>upper normal limit,stones located in the left or both lobes,focal atrophy,and complete removal of IHD stones without recurrence were independent factors influencing CCC development.However,the type of removal method was not associated with CCC risk.CONCLUSION Complete removal of IHD stones without recurrence could reduce CCC risk.

Role of fecal microbiota transplant in management of hepatic encephalopathy: Current trends and future directions

Fecal microbiota transplantation(FMT)offers a potential treatment avenue for hepatic encephalopathy(HE)by leveraging beneficial bacterial displacement to restore a balanced gut microbiome.The prevalence of HE varies with liver disease severity and comorbidities.HE pathogenesis involves ammonia toxicity,gut-brain communication disruption,and inflammation.FMT aims to restore gut microbiota balance,addressing these factors.FMT's efficacy has been explored in various conditions,including HE.Studies suggest that FMT can modulate gut microbiota,reduce ammonia levels,and alleviate inflammation.FMT has shown promise in alcohol-associated,hepatitis B and C-associated,and non-alcoholic fatty liver disease.Benefits include improved liver function,cognitive function,and the slowing of disease progression.However,larger,controlled studies are needed to validate its effectiveness in these contexts.Studies have shown cognitive improvements through FMT,with potential benefits in cirrhotic patients.Notably,trials have demonstrated reduced serious adverse events and cognitive enhancements in FMT arms compared to the standard of care.Although evidence is promising,challenges remain:Limited patient numbers,varied dosages,administration routes,and donor profiles.Further large-scale,controlled trials are essential to establish standardized guidelines and ensure FMT's clinical applications and efficacy.While FMT holds potential for HE management,ongoing research is needed to address these challenges,optimize protocols,and expand its availability as a therapeutic option for diverse hepatic conditions.

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26,2023,at the Pakistan Kidney and Liver Institute&Research Centre(PKLI&RC)after initial consultations with the experts.The Pakistan Society for the Study of Liver Diseases(PSSLD)and PKLI&RC jointly organised this meeting.This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma(hCCA).The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients.This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation.The diagnostic and staging workup includes high-quality computed tomography,magnetic resonance imaging,and magnetic resonance cholangiopancreato-graphy.Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis.However,histopathologic confirmation is not always required before resection.Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging.The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification.Selected patients with unresectable hCCA can be considered for liver transplantation.Adjuvant chemotherapy should be offered to patients with a high risk of recurrence.The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions.Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage.Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Bowel function and inflammation: Is motility the other side of the coin?

Digestion and intestinal absorption allow the body to sustain itself and are the emblematic functions of the bowel.On the flip side,functions also arise from its role as an interface with the environment.Indeed,the gut houses microorganisms,collectively known as the gut microbiota,which interact with the host,and is the site of complex immune activities.Its role in human pathology is complex and scientific evidence is progressively elucidating the functions of the gut,especially regarding the pathogenesis of chronic intestinal diseases and inflammatory conditions affecting various organs and systems.This editorial aims to highlight and relate the factors involved in the pathogenesis of intestinal and systemic inflammation.

Validation of prognostic scores for predicting acute liver failure and in-hospital death in patients with dengue-induced severe hepatitis

BACKGROUND Acute liver failure(ALF)in dengue is rare but fatal.Early identification of patients who are at risk of ALF is the key strategy to improve survival.AIM To validate prognostic scores for predicting ALF and in-hospital mortality in dengue-induced severe hepatitis(DISH).METHODS We retrospectively reviewed 2532 dengue patients over a period of 16 years(2007-2022).Patients with DISH,defined as transaminases>10 times the normal reference level and DISH with subsequent ALF,were included.Univariate regre-ssion analysis was used to identify factors associated with outcomes.Youden’s index in conjunction with receiver operating characteristic(ROC)analysis was used to determine optimal cut-off values for prognostic scores in predicting ALF and in-hospital death.Area under the ROC(AUROC)curve values were compared using paired data nonparametric ROC curve estimation.RESULTS Of 193 DISH patients,20 developed ALF(0.79%),with a mortality rate of 60.0%.International normalized ratio,bilirubin,albumin,and creatinine were indepen-dent predictors associated with ALF and death.Prognostic scores showed excel-lent performance:Model for end-stage liver disease(MELD)score≥15 predicted ALF(AUROC 0.917,sensitivity 90.0%,specificity 88.4%)and≥18 predicted death(AUROC 0.823,sensitivity 86.9%,specificity 89.1%);easy albumin-bilirubin(ALBI)score≥-30 predicted ALF and death(ALF:AUROC 0.835,sensitivity80.0%,specificity 72.2%;death:AUROC 0.808,sensitivity 76.9%,specificity 69.3%);ALBI score≥-2 predicted ALF and death(ALF:AUROC 0.806,sensitivity 80.0%,specificity 77.4%;death:AUROC 0.799,sensitivity 76.9%,specificity 74.3%).Platelet-ALBI score also showed good performance in predicting ALF and death(AUROC=0.786 and 0.699,respectively).MELD and EZ-ALBI scores had similar performance in predicting ALF(Z=1.688,P=0.091)and death(Z=0.322,P=0.747).CONCLUSION MELD score is the best predictor of ALF and death in DISH patients.EZ-ALBI score,a simpler yet effective score,shows promise as an alternative prognostic tool in dengue patients.

Advancements in Barrett's esophagus detection:The role of artificial intelligence and its implications

Artificial intelligence(AI)is making significant strides in revolutionizing the detection of Barrett's esophagus(BE),a precursor to esophageal adenocarcinoma.In the research article by Tsai et al,researchers utilized endoscopic images to train an AI model,challenging the traditional distinction between endoscopic and histological BE.This approach yielded remarkable results,with the AI system achieving an accuracy of 94.37%,sensitivity of 94.29%,and specificity of 94.44%.The study's extensive dataset enhances the AI model's practicality,offering valuable support to endoscopists by minimizing unnecessary biopsies.However,questions about the applicability to different endoscopic systems remain.The study underscores the potential of AI in BE detection while highlighting the need for further research to assess its adaptability to diverse clinical settings.

Early detection and intervention in diabetic gastroparesis:Role of body surface gastric mapping

Diabetic gastrointestinal neuropathy is a diabetes-related complication,associated with a complex interplay of hyperglycemic damage,autoimmune responses,oxidative stress,gastrointestinal hormones,and vascular insufficiency.Patients with diabetes should be monitored and therapeutic intervention introduced to prevent neuropathy due to diabetes prior to“the point of no return”.Determining gastric bioelectrical activity by body surface gastric mapping may be a promising option to monitor diabetic gastrointestinal neuropathy.

Digesting gluten with oral endopeptidases to improve the management of celiac disease

In our editorial,we want to comment on the article by Stefanolo et al titled“Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet”.Celiac disease is an immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals.Although avoiding gluten can permit patients to live symptom-free,ongoing voluntary or involuntary exposure to gluten is common and associated with persistent villous atrophy in small bowel mucosa.As villous atrophy predisposes patients to life threatening complications,such as osteoporotic fractures or malignancies,therapeutic adjuncts to gluten-free diet become important to improve patients’quality of life and,if these adjuncts can be shown to improve villous atrophy,avoid complications.Oral administration of enzyme preparations,such as endopeptidases that digest gluten and mitigate its antigenicity to trigger inflam-mation,is one clinical strategy under investigation.The article is about the utility of one endopeptidase isolated from Aspergillus niger.We critique findings of this clinical trial and also summarize endopeptidase-based as well as other strategies and how they can complement gluten-free diet in the management of celiac disease.

Innovative pathways allow safe discharge of mild acute pancreatitis from the emergency room

Acute pancreatitis(AP)is a leading cause of gastrointestinal-related hospitalizations in the United States,resulting in 300000 admissions per year with an estimated cost of over$2.6 billion annually.The severity of AP is determined by the presence of pancreatic complications and end-organ damage.While moderate/severe pancreatitis can be associated with significant morbidity and mortality,the majority of patients have a mild presentation with an uncomplicated course and mortality rate of less than 2%.Despite favorable outcomes,the majority of mild AP patients are admitted,contributing to healthcare cost and burden.In this Editorial we review the performance of an emergency department(ED)pathway for patients with mild AP at a tertiary care center with the goal of reducing hospitalizations,resource utilization,and costs after several years of implementation of the pathway.We discuss the clinical course and outcomes of mild AP patients enrolled in the pathway who were successfully discharged from the ED compared to those who were admitted to the hospital,and identify predictors of successful ED discharge to select patients who can potentially be triaged to the pathway.We conclude that by implementing innovative clinical pathways which are established and reproducible,selected AP patients can be safely discharged from the ED,reducing hospitalizations and healthcare costs,without compromising clinical outcomes.We also identify a subset of patients most likely to succeed in this pathway.

Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

BACKGROUND The GALAD score has improved early hepatocellular carcinoma(HCC)detection rate.The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest.AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis,tumor features,and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers.METHODS This prospective,diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital.Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer(BCLC)categorization.Demographics,HCC etiology,and HCC features were recorded.Biomarkers and the GALAD score were obtained at baseline.The performance of the GALAD score and biomarkers were prospectively assessed.RESULTS Exactly 115 individuals were diagnosed with HCC.The GALAD score increased with disease severity.Between BCLC-0/A and BCLC-B/C/D,the GALAD score predicted HCC staging with an area under the curve(AUC)of 0.868(95%CI:0.80–0.93).For identifying the curative HCC,the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein(AFP)(0.753)and Lens culinaris agglutinin-reactive fraction of AFP-L3(0.706),and as good as that of Protein induced by vitamin K absence-II(PIVKA-II)(0.897).For detecting aggressive features,the GALAD score gave an AUC of 0.839(95%CI:0.75–0.92)and significantly outperformed compared to that of AFP(0.761)and AFP-L3(0.697),with a trend of superiority to that of PIVKA-II(0.772).The performance to predict 1-year mortality of GALAD score(AUC:0.711,95%CI:0.60–0.82)was better than that of AFP(0.541)and as good as that of PIVKA-II(0.736).The optimal cutoff value of GALAD score was≥6.83,with a specificity of 72.63%for exhibiting substantial reduction in the 1-year mortality.CONCLUSION The GALAD model can diagnose HCC at the curative stage,including the characteristic of advanced disease,more than that by AFP and AFP-L3,but not PIVKA-II.The GALAD score can be used to predict the 1-year mortality of HCC.

Genetic risk stratification of inflammatory bowel disease-associated venous thromboembolism:An Asian perspective

The utilisation of polygenic scoring models may enhance the clinician’s ability to risk stratify an inflammatory bowel disease patient’s individual risk for venous thromboembolism(VTE)and guide the appropriate usage of VTE thromboprophylaxis,yet there is a need to validate such models in ethnically diverse populations.

Clinical features of gastroesophageal reflux disease and erosive esophagitis:Insights from patients undergoing esophagogastroduodenoscopy in resource-limited Ethiopia

BACKGROUND Gastroesophageal reflux disease(GERD)is a common disease worldwide with varying clinical presentations and risk factors.Prevalence data for Africa is lacking,but an increasing trend is expected due to demographic and epidemiological transitions.Although endoscopic studies for general gastrointestinal disorders have shown some patients with erosive esophagitis(EE),no studies in Ethiopia have investigated the clinical characteristics,risk factors,and severity of GERD using esophagogastroduodenoscopy(EGD).AIM To assess the clinical features of GERD in Ethiopian patients who underwent EGD and determine the severity and risk factors of EE.METHODS We conducted a multicenter,retrospective cross-sectional study of 221 patients diagnosed with GERD and endoscopic findings of EE at Trauma Associated Severe Hemorrhage and Amniotic Membrane Stem Cell between January 2019 and August 2022.Data were collected from electronic medical records and phone call interviews.We used descriptive statistics and binary logistic regression analysis with SPSS version 26 to identify the association between variables with a statistical significance set at P value<0.05.RESULTS The mean±SD age of the patients was 44.8(±15.9)years,with a male-to-female ratio of 1.6:1.The most commonly reported symptom was epigastric pain(80.5%),followed by heartburn(43%).Los Angeles(LA)-A EE was diagnosed in 71.1%of patients,followed by LA-B(14.9%),LA-C(7.7%),and LA-D(5.9%).Multivariate analysis showed that age 50 or above,presence of bleeding,and endoscopic findings of duodenitis/duodenopathy were significantly associated with severe EE(P<0.05).Stricture and Barrett’s esophagus were observed in 4.5%and 1.36%of patients with EE,respectively.CONCLUSION Most of the patients had milder EE with fewer complications.However,severe EE was more prevalent in older patients and those with duodenitis/duodenopathy.

Identification of breath volatile organic compounds to distinguish pancreatic adenocarcinoma,pancreatic cystic neoplasm,and patients without pancreatic lesions

BACKGROUND Volatile organic compounds(VOCs)are a promising potential biomarker that may be able to identify the presence of cancers.AIM To identify exhaled breath VOCs that distinguish pancreatic ductal adenocar-cinoma(PDAC)from intraductal papillary mucinous neoplasm(IPMN)and healthy volunteers.METHODS We collected exhaled breath from histologically proven PDAC patients,radiological diagnosis IPMN,and healthy volunteers using the ReCIVA®device between 10/2021-11/2022.VOCs were identified by thermal desorption-gas chromatography/field-asymmetric ion mobility spectrometry and compared between groups.RESULTS A total of 156 participants(44%male,mean age 62.6±10.6)were enrolled(54 PDAC,42 IPMN,and 60 controls).Among the nine VOCs identified,two VOCs that showed differences between groups were dimethyl sulfide[0.73 vs 0.74 vs 0.94 arbitrary units(AU),respectively;P=0.008]and acetone dimers(3.95 vs 4.49 vs 5.19 AU,respectively;P<0.001).After adjusting for the imbalance parameters,PDAC showed higher dimethyl sulfide levels than the control and IPMN groups,with adjusted odds ratio(aOR)of 6.98(95%CI:1.15-42.17)and 4.56(1.03-20.20),respectively(P<0.05 both).Acetone dimer levels were also higher in PDAC compared to controls and IPMN(aOR:5.12(1.80-14.57)and aOR:3.35(1.47-7.63),respectively(P<0.05 both).Acetone dimer,but not dimethyl sulfide,performed better than CA19-9 in PDAC diagnosis(AUROC 0.910 vs 0.796).The AUROC of acetone dimer increased to 0.936 when combined with CA19-9,which was better than CA19-9 alone(P<0.05).CONCLUSION Dimethyl sulfide and acetone dimer are VOCs that potentially distinguish PDAC from IPMN and healthy participants.Additional prospective studies are required to validate these findings.

Benefits of endoscopic gallbladder stenting following percutaneous transhepatic gallbladder drainage

BACKGROUND Endoscopic transpapillary gallbladder drainage is challenging because of the complexity of the procedure and high incidence of adverse events(AEs).To overcome these problems,endoscopic gallbladder stenting(EGBS)after percutaneous transhepatic gallbladder drainage(PTGBD)can be effective,as it mitigates inflammation and adhesion.AIM To examine the benefits of EGBS after PTGBD to assess its efficacy and impact on AEs.METHODS We retrospectively analyzed data from 35 patients who underwent EGBS after PTGBD at a single center between January 2016 and December 2023.The primary outcomes were technical success and AEs,and the rate of recurrent cholecystitis was evaluated.In addition,the reasons for the failure of the procedure were identified.RESULTS Among the 35 patients,the technical success rate was 77.1%and the final contrast of the cystic duct was successful in 97.1%of patients.The incidence of early AEs was relatively low(11.4%),with no instances of cystic duct perforation.The rate of recurrent cholecystitis was 3.7%,and no other biliary events were observed.CONCLUSION EGBS after PTGBD may be significantly beneficial,with a substantial success rate and minimal AEs in both short-and long-term follow-ups.

Trends in colorectal cancer incidence according to an increase in the number of colonoscopy cases in Korea

BACKGROUND The incidence of colorectal cancer(CRC)and preinvasive CRC(e.g.,early colon cancer and advanced adenoma)is gradually increasing in several countries.AIM To evaluate the trend in incidence of CRC and preinvasive CRC according to the increase in the number of colonoscopies performed in Korea.METHODS This retrospective cohort study enrolled Korean patients from 2002 to 2020 to evaluate the incidence of CRC and preinvasive CRC,and assess the numbers of diagnostic colonoscopies and colonoscopic polypectomies.Colonoscopy-related complications by age group were also determined.RESULTS The incidence of CRC showed a rapid increase,then decreased after 2012 in the 50-75 year-age group.During the study period,the rate of incidence of preinvasive CRC increased at a similar level in patients under 50 and 50-75 years of age.Since 2009,the increase has been rapid,showing a pattern similar to the increase in colonoscopies.The rate of colonoscopic polypectomy in patients aged under 50 was similar to the rate in patients over 75 years of age after 2007.The rate of complications after colonoscopy and related deaths within 3 mo was high for those over 75 years of age.CONCLUSION The diagnosis of preinvasive CRC increased with the increase in the number of colonoscopies performed.As the risk of colonoscopy-related hospitalization and death is high in the elderly,if early lesions at risk of developing CRC are diagnosed and treated under or at the age of 75,colonoscopy-related complications can be reduced for those aged 76 years or over.

T1 colorectal cancer management in the era of minimally invasive endoscopic resection

T1 colorectal cancer(CRC),defined by tumor invasion confined to the submucosa,has historically been managed by surgery.Improved understanding of recurrence and lymph node metastases risk,coupled with advances in endoscopic resection techniques,have led to an increasing capacity for organ-sparing local excision.Minimally invasive management of T1 CRC begins with optical evaluation of the lesion to diagnose invasive disease and quantify depth of invasion,which informs therapeutic decision making.Modality selection between various available endoscopic resection techniques depends upon lesion characteristics,technique risk-benefit profiles,and location-specific implications.Following endoscopic resection,established histopathology features determine the risk of recurrence and subsequent management including surveillance or adjuvant surgical excision.The management of non-operative candidates deviates from conventional recommendations with emerging treatment strategies in select populations.