Assessment of ubiquitin specific Peptidase-18 gene in peripheral blood of chronic hepatitis C patients treated with direct-acting antiviral drugs.

Hepatitis C virus (HCV) infection remains one of the leading causes of liver complications globally. Ubiquitin Specific Peptidase-18 (USP18) is a ubiquitin-specific protease that cleaves interferon-stimulated gene 15 (ISG15) from ISGylated protein complexes and is involved in regulating interferon responsiveness. To study the effect of direct-acting antivirals (DAAs) on the USP18 gene using qPCR, 132 participants were recruited and classified into different groups based on treatment duration. USP18 expression was raised compared to rapid virologic response (RVR) and early virologic response (EVR) groups with P = 0.0026 and P = 0.0016, respectively. USP18 was found to be 7.36 folds higher in naïve patients than those with RVR and sustained viral response (SVR). In RVR and SVR groups where patients had cleared HCV RNA after treatment with direct-acting antiviral agents (DAA) therapy, the expression of USP18 was found to be low, with a fold change of 1.3 and 1.4 folds, respectively. Expression of USP18 was significantly higher in the non-RVR group than in the RVR group. In the No EVR group, gene expression was significantly higher than in the EVR group. It is concluded that targeting HCV proteins using DAAs can cause USP18 expression to be normalized more effectively. Moreover, USP18 is a vital marker indicating treatment resistance and distinguishing responders from non-responders during DAA therapy.

LncRNA MALAT1 Expression Regulates Breast Cancer Progression via PI3K/AKT/mTOR Pathway Modulation.

Breast cancer is a significant health challenge for women globally, including the Pakistani population. Numerous pathways and small molecules like noncoding ribonucleotides are implicated in breast cancer development and progression. Among these, lncRNAs, have garnered considerable attention due to their role in breast cancer tumorigenesis and metastasis. In the current study involving 52 mammary tumor samples from the Pakistani population, the expression of lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) was studied via RT-PCR (Real-Time polymerase chain reaction). In addition, PI3K/AKT/mTOR pathway expression was also assessed through RT-PCR and immunohistochemistry in breast cancer patient samples. The study also investigated the cross-talk of lncRNA MALAT1 and PI3K pathway genes by inhibiting it with PI3K inhibitor (LY294002) in MDA-MB-231 cell line. Furthermore, lncRNA MALAT1 was silenced in MDA-MB-231 cells using siRNA to determine its impact on breast cancer proliferation and metastasis. The results revealed an upregulated expression of MALAT1 and PI3K/AKT/mTOR pathway genes in grade II and III breast tissue samples before chemotherapy. The proliferation, growth, and invasion of breast cancer cells were significantly reduced upon MALAT1 silencing in MDA-MB-231. Further, its downregulation substantially reduced the PI3K pathway expression levels at mRNA and protein levels. In conclusion, the current study suggests that MALAT1 could serve as a therapeutic target for breast cancer, underscoring its role in breast cancer proliferation and metastasis. Moreover, the study proposes a mechanism of action of MALAT1, demonstrating that its inhibition can reduce the expression of the PI3K/AKT/mTOR axis. These findings emphasize the potential significance of targeting MALAT1 as a therapeutic strategy for breast cancer, and further exploration of this interaction is warranted to gain deeper insight into the molecular mechanism of this lncRNA.

ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction

This clinical guideline from the American Society for Gastrointestinal Endoscopy (ASGE) provides an evidence-based approach for the management of patients with malignant hilar obstruction (MHO). This document was developed using the Grading of Recommendations Assessment, Development and Evaluation framework and addresses primary drainage modality (percutaneous transhepatic biliary drainage [PTBD] vs endoscopic biliary drainage [EBD]), drainage strategy (unilateral vs bilateral), and stent selection (plastic stent [PS] vs self-expandable metal stent [SEMS]). Regarding drainage modality, in patients with MHO undergoing drainage before potential resection or transplantation, the panel suggests against routine use of PTBD as first-line therapy compared with EBD. In patients with unresectable MHO undergoing palliative drainage, the panel suggests PTBD or EBD. The final decision should be based on patient preferences, disease characteristics, and local expertise. Regarding drainage strategy, in patients with unresectable MHO undergoing palliative stent placement, the panel suggests placement of bilateral stents compared with a unilateral stent in the absence of liver atrophy. Finally, regarding type of stent, in patients with unresectable MHO undergoing palliative stent placement, the panel suggests placing SEMSs or PSs. However, in patients who have a short life expectancy and who place high value on avoiding repeated interventions, the panel suggests using SEMSs compared with PSs. If optimal drainage strategy has not been established, the panel suggests placing PSs. This document clearly outlines the process, analyses, and decision processes used to reach the final recommendations and represents the official ASGE recommendations on the above topics.

ASGE guideline on the management of cholangitis

Cholangitis is a GI emergency requiring prompt recognition and treatment. The purpose of this document from the American Society for Gastrointestinal Endoscopy's (ASGE) Standards of Practice Committee is to provide an evidence-based approach for management of cholangitis. This document addresses the modality of drainage (endoscopic vs percutaneous), timing of intervention (<48 hours vs >48 hours), and extent of initial intervention (comprehensive therapy vs decompression alone). Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to formulate recommendations on these topics. The ASGE suggests endoscopic rather than percutaneous drainage and biliary decompression within 48 hours. Additionally, the panel suggests that sphincterotomy and stone removal be combined with drainage rather than decompression alone, unless patients are too unstable to tolerate more extensive endoscopic treatment.

ASGE guideline on the management of cholangitis.

Cholangitis is a GI emergency requiring prompt recognition and treatment. The purpose of this document from the American Society for Gastrointestinal Endoscopy's (ASGE) Standards of Practice Committee is to provide an evidence-based approach for management of cholangitis. This document addresses the modality of drainage (endoscopic vs percutaneous), timing of intervention (<48 hours vs >48 hours), and extent of initial intervention (comprehensive therapy vs decompression alone). Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to formulate recommendations on these topics. The ASGE suggests endoscopic rather than percutaneous drainage and biliary decompression within 48 hours. Additionally, the panel suggests that sphincterotomy and stone removal be combined with drainage rather than decompression alone, unless patients are too unstable to tolerate more extensive endoscopic treatment.

ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction.

This clinical guideline from the American Society for Gastrointestinal Endoscopy (ASGE) provides an evidence-based approach for the management of patients with malignant hilar obstruction (MHO). This document was developed using the Grading of Recommendations Assessment, Development and Evaluation framework and addresses primary drainage modality (percutaneous transhepatic biliary drainage [PTBD] vs endoscopic biliary drainage [EBD]), drainage strategy (unilateral vs bilateral), and stent selection (plastic stent [PS] vs self-expandable metal stent [SEMS]). Regarding drainage modality, in patients with MHO undergoing drainage before potential resection or transplantation, the panel suggests against routine use of PTBD as first-line therapy compared with EBD. In patients with unresectable MHO undergoing palliative drainage, the panel suggests PTBD or EBD. The final decision should be based on patient preferences, disease characteristics, and local expertise. Regarding drainage strategy, in patients with unresectable MHO undergoing palliative stent placement, the panel suggests placement of bilateral stents compared with a unilateral stent in the absence of liver atrophy. Finally, regarding type of stent, in patients with unresectable MHO undergoing palliative stent placement, the panel suggests placing SEMSs or PSs. However, in patients who have a short life expectancy and who place high value on avoiding repeated interventions, the panel suggests using SEMSs compared with PSs. If optimal drainage strategy has not been established, the panel suggests placing PSs. This document clearly outlines the process, analyses, and decision processes used to reach the final recommendations and represents the official ASGE recommendations on the above topics.

International, multicenter retrospective trial comparing the efficacy and safety of bi-flanged versus lumen-apposing metal stents for endoscopic drainage of walled-off pancreatic necrosis.

BACKGROUND: To compare fully covered bi-flanged metal stents (BFMS) and lumen-apposing metal stents (LAMS) for endoscopic ultrasound (EUS)-guided drainage/debridement of pancreatic walled-off necrosis (WON). METHODS: Patients with WON managed by EUS-guided therapy were divided into those who underwent: 1) drainage using BFMS; and 2) drainage using LAMS and scheduled direct endoscopic necrosectomy (DEN). Clinical success (resolution of the WON), technical success (successful stent placement), and adverse events (AEs) were evaluated. RESULTS: 387 patients underwent WON endoscopic drainage, 205 using BFMS and 182 using LAMS. The clinical success in the BFMS or LAMS groups were similar (197 [96.1%] vs. 174 [95.6%]; P=0.81). Median number of procedures required for WON resolution was significantly lower in BFMS compared to LAMS (2 vs. 3, P<0.001). Technical success for stent placement was similar in BFMS and LAMS groups (203 [99%] vs. 180 [99%], P=0.90). Procedure-related AEs were similar in the BFMS and LAMS groups (19 [9.3%] vs. 20 [10.9%], P=0.61). Stent dysfunction with occluding debris was higher in the BFMS group compared to LAMS group (21 [10.2 %] vs. 11 [5.9%], P=0.04). The migration rate was higher in the BFMS group than in the LAMS group (15 [7.3%] vs. 3 [1.6%]; P<0.001). DEN was required in 23 [11.2%] patients in the BFMS group after lack of WON resolution by conservative means. CONCLUSION: BFMS with a "step-up approach" and LAMS with scheduled DEN are both safe and effective for EUS-guided drainage/debridement of WON.

ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction.

This American Society for Gastrointestinal Endoscopy guideline provides evidence-based recommendations for the endoscopic management of gastric outlet obstruction (GOO). We applied the Grading of Recommendations, Assessment, Development and Evaluation methodology to address key clinical questions. These include the comparison of (1) surgical gastrojejunostomy to the placement of self-expandable metallic stents (SEMS) for malignant GOO, (2) covered versus uncovered SEMS for malignant GOO, and (3) endoscopic and surgical interventions for the management of benign GOO. Recommendations provided in this document were founded on the certainty of the evidence, balance of benefits and harms, considerations of patient and caregiver preferences, resource utilization, and cost-effectiveness.

American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in familial adenomatous polyposis syndromes.

Familial adenomatous polyposis (FAP) syndrome is a complex entity, which includes FAP, attenuated FAP, and MUTYH-associated polyposis. These patients are at significant risk for colorectal cancer and carry additional risks for extracolonic malignancies. In this guideline, we reviewed the most recent literature to formulate recommendations on the role of endoscopy in this patient population. Relevant clinical questions were how to identify high-risk individuals warranting genetic testing, when to start screening examinations, what are appropriate surveillance intervals, how to identify endoscopically high-risk features, and what is the role of chemoprevention. A systematic literature search from 2005 to 2018 was performed, in addition to the inclusion of seminal historical studies. Most studies were from worldwide registries, which have compiled years of data regarding the natural history and cancer risks in this cohort. Given that most studies were retrospective, recommendations were based on epidemiologic data and expert opinion. Management of colorectal polyps in FAP has not changed much in recent years, as colectomy in FAP is the standard of care. What is new, however, is the developing body of literature on the role of endoscopy in managing upper GI and small-bowel polyposis, as patients are living longer and improved endoscopic technologies have emerged.

ASGE guideline on minimum staffing requirements for the performance of GI endoscopy.

Efforts to increase patient safety and satisfaction, a critical concern for health providers, require periodic evaluation of all factors involved in the provision of GI endoscopy services. We aimed to develop guidelines on minimum staffing requirements and scope of practice of available staff for the safe and efficient performance of GI endoscopy. The recommendations in this guideline were based on a systematic review of published literature, results from a nationwide survey of endoscopy directors, along with the expert guidance of the American Society for Gastrointestinal Endoscopy (ASGE) Standards of Practice Committee members, ASGE Practice Operation Committee members, and the ASGE Governing Board.

American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in the management of acute colonic pseudo-obstruction and colonic volvulus.

Colonic volvulus and acute colonic pseudo-obstruction (ACPO) are 2 causes of benign large-bowel obstruction. Colonic volvulus occurs most commonly in the sigmoid colon as a result of bowel twisting along its mesenteric axis. In contrast, the exact pathophysiology of ACPO is poorly understood, with the prevailing hypothesis being altered regulation of colonic function by the autonomic nervous system resulting in colonic distention in the absence of mechanical blockage. Prompt diagnosis and intervention leads to improved outcomes for both diagnoses. Endoscopy may play a role in the evaluation and management of both entities. The purpose of this document from the American Society for Gastrointestinal Endoscopy's Standards of Practice Committee is to provide an update on the evaluation and endoscopic management of sigmoid volvulus and ACPO.

Expression of TRIM22 mRNA in chronic hepatitis C patients treated with direct-acting antiviral drugs.

Hepatitis C is a global public health problem, and Pakistan is the second largest country in the globe with highest prevalence rate of hepatitis C virus (HCV). Until 2014, pegylated interferon (PEG-IFN) plus ribavirin (RBV) has been the standard therapy for HCV, however, owing to its adverse side effects and very low sustained virologic response (SVR) rates therapeutics trend is shifted toward direct-acting antivirals. Tripartite motif containing 22 (TRIM22) is a dynamic antiviral protein that can inhibit multiple viruses in vivo. Expression of TRIM22 mRNA has been linked to outcome of PEG-IFN and ribavirin therapy, where its higher expression leads to rapid virus clearance. However, in terms of therapy with direct-acting antiviral (DAA) or double DAA, impact of TRIM22 expression is largely unknown. These new drugs show more than 90% of SVR rates and lesser side effects and have proven to be better than IFN therapy. Endogenous IFN system suppresses various pathogens through the induction of antiviral effectors termed as interferon-stimulating genes (ISGs). We have studied the expression levels of one of these antiviral effectors, TRIM22 in response to sofosbuvir (SOF) and daclatasvir (DAC) in combination with RBV, using quantitative PCR in the peripheral blood mononuclear cells (PBMCs) of HCV-infected patients. We have observed sustained virus clearance in more than 90% of patients treated with DAA and double DAA and have seen the expression of TRIM22 to be higher in patients who attained SVR as compared to the untreated patients. We have also observed downregulation of TRIM22 in patients who failed to attain rapid virus clearance, and upregulation in those who achieved rapid clearance of virus. Genetic factors that determine the lower TRIM22 expression in these patients are needed to be explored that may also play a role in lower response to anti-HCV therapy. Endogenous IFN system and effects of antiviral proteins in response to DAA therapy is needed to be studied in order to better understand the host response toward these drugs to make them more effective.

ASGE guideline on the management of achalasia.

Achalasia is a primary esophageal motor disorder of unknown etiology characterized by degeneration of the myenteric plexus, which results in impaired relaxation of the esophagogastric junction (EGJ), along with the loss of organized peristalsis in the esophageal body. The criterion standard for diagnosing achalasia is high-resolution esophageal manometry showing incomplete relaxation of the EGJ coupled with the absence of organized peristalsis. Three achalasia subtypes have been defined based on high-resolution manometry findings in the esophageal body. Treatment of patients with achalasia has evolved in recent years with the introduction of peroral endoscopic myotomy. Other treatment options include botulinum toxin injection, pneumatic dilation, and Heller myotomy. This American Society for Gastrointestinal Endoscopy Standards of Practice Guideline provides evidence-based recommendations for the treatment of achalasia, based on an updated assessment of the individual and comparative effectiveness, adverse effects, and cost of the 4 aforementioned achalasia therapies.

ASGE review of adverse events in colonoscopy.

Colonoscopy is the most commonly performed endoscopic procedure and overall is considered a low-risk procedure. However, adverse events (AEs) related to this routinely performed procedure for screening, diagnostic, or therapeutic purposes are an important clinical consideration. The purpose of this document from the American Society for Gastrointestinal Endoscopy's Standards of Practice Committee is to provide an update on estimates of AEs related to colonoscopy in an evidence-based fashion. A systematic review and meta-analysis of population-based studies was conducted for the 3 most common and important serious AEs (bleeding, perforation, and mortality). In addition, this document includes an updated systematic review and meta-analysis of serious AEs (bleeding and perforation) related to EMR and endoscopic submucosal dissection for large colon polyps. Finally, a narrative review of other colonoscopy-related serious AEs and those related to specific colonic interventions is included.

ASGE guideline on the role of endoscopy for bleeding from chronic radiation proctopathy.

Chronic radiation proctopathy is a common sequela of radiation therapy for malignancies in the pelvic region. A variety of medical and endoscopic therapies have been used for the management of bleeding from chronic radiation proctopathy. In this guideline, we reviewed the results of a systematic search of the literature from 1946 to 2017 to formulate clinical questions and recommendations on the role of endoscopy for bleeding from chronic radiation proctopathy. The following endoscopic modalities are discussed in our document: argon plasma coagulation, bipolar electrocoagulation, heater probe, radiofrequency ablation, and cryoablation. Most studies were small observational studies, and the evidence for effectiveness of endoscopic therapy for chronic radiation proctopathy was limited because of a lack of controlled trials and comparative studies. Despite this limitation, our systematic review found that argon plasma coagulation, bipolar electrocoagulation, heater probe, and radiofrequency ablation were effective in the treatment of rectal bleeding from chronic radiation proctopathy.

ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis

Each year choledocholithiasis results in biliary obstruction, cholangitis, and pancreatitis in a significant number of patients. The primary treatment, ERCP, is minimally invasive but associated with adverse events in 6% to 15%. This American Society for Gastrointestinal Endoscopy (ASGE) Standard of Practice (SOP) Guideline provides evidence-based recommendations for the endoscopic evaluation and treatment of choledocholithiasis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to rigorously review and synthesize the contemporary literature regarding the following topics: EUS versus MRCP for diagnosis, the role of early ERCP in gallstone pancreatitis, endoscopic papillary dilation after sphincterotomy versus sphincterotomy alone for large bile duct stones, and impact of ERCP-guided intraductal therapy for large and difficult choledocholithiasis. Comprehensive systematic reviews were also performed to assess the following: same-admission cholecystectomy for gallstone pancreatitis, clinical predictors of choledocholithiasis, optimal timing of ERCP vis-à-vis cholecystectomy, management of Mirizzi syndrome and hepatolithiasis, and biliary stent therapy for choledocholithiasis. Core clinical questions were derived using an iterative process by the ASGE SOP Committee. This body developed all recommendations founded on the certainty of the evidence, balance of risks and harms, consideration of stakeholder preferences, resource utilization, and cost-effectiveness.

ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis.

Each year choledocholithiasis results in biliary obstruction, cholangitis, and pancreatitis in a significant number of patients. The primary treatment, ERCP, is minimally invasive but associated with adverse events in 6% to 15%. This American Society for Gastrointestinal Endoscopy (ASGE) Standard of Practice (SOP) Guideline provides evidence-based recommendations for the endoscopic evaluation and treatment of choledocholithiasis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to rigorously review and synthesize the contemporary literature regarding the following topics: EUS versus MRCP for diagnosis, the role of early ERCP in gallstone pancreatitis, endoscopic papillary dilation after sphincterotomy versus sphincterotomy alone for large bile duct stones, and impact of ERCP-guided intraductal therapy for large and difficult choledocholithiasis. Comprehensive systematic reviews were also performed to assess the following: same-admission cholecystectomy for gallstone pancreatitis, clinical predictors of choledocholithiasis, optimal timing of ERCP vis-à-vis cholecystectomy, management of Mirizzi syndrome and hepatolithiasis, and biliary stent therapy for choledocholithiasis. Core clinical questions were derived using an iterative process by the ASGE SOP Committee. This body developed all recommendations founded on the certainty of the evidence, balance of risks and harms, consideration of stakeholder preferences, resource utilization, and cost-effectiveness.