Management of intrahepatic and perihilar cholangiocarcinomas: Guidelines of the French Association for the Study of the Liver (AFEF).

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.

Impact of annual case volume on colorectal endoscopic submucosal dissection outcomes in a large prospective cohort study.

OBJECTIVES: The adoption of colorectal endoscopic submucosal dissection (ESD) is still limited in the West. A recent randomized trial showed ESD is more effective and only slightly riskier than piecemeal endoscopic mucosal resection (EMR); reproducibility outside expert centers was questioned. We evaluated the results according to the annual case volume in a multicentric prospective cohort. METHODS: Between 09/2019 and 09/2022, colorectal ESD was consecutively performed at 13 participating centers classified as low-volume (LV), middle-volume (MV), and high-volume (HV). The main procedural outcomes were assessed. Multivariate and propensity score matching (PSM) analyses were performed. RESULTS: 3770 ESDs were included. HV centers treated larger and more often colonic lesions than MV and LV centers. En bloc, R0 and curative resection rates were 95.2%, 87.4%, and 83.2%, respectively, and were higher at HV than at MV and LV centers. HV centers achieved also a faster dissection speed. Delayed bleeding and surgery for complications rates were 5.4% and 0.8%, respectively, without significant differences. The perforation rate (overall: 9%) was higher at MV than at LV and HV centers. Lesion characteristics, but not volume center, were independently associated with both R1 resection and perforation. However, after PSM, R0 rates were significantly higher at HV than at LV centers, and perforation rates were significantly higher at MV than at HV centers. CONCLUSIONS: Colorectal ESD can be successfully implemented in the West, even in nonexpert centers. However, difficult lesions must still be referred to experts.

EUS vs. ERCP-guided primary drainage of inoperable distal malignant biliary obstruction: systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Several randomized controlled trials (RCTs) compared endoscopic ultrasound-guided biliary drainage (EUS-BD) to endoscopic retrograde cholangiopancreatography (ERCP) as first-line interventions in distal malignant biliary obstruction (DMBO). We assessed the efficacy and safety of these two approaches. METHODS: A PubMed/Medline, Embase and Cochrane databases bibliographic search until 01/12/2023 was performed to identify RCTs comparing EUS-BD to ERCP for primary biliary drainage in inoperable patients with DMBO. Primary outcome was technical success. Secondary outcomes were clinical success, adverse events (AEs), mean procedure time, 1-year stent patency, and overall survival. Relative risk (RR) with 95% confidence interval (CI) were calculated using random-effect model. RESULTS: Five studies (519 patients) were included. The RR for pooled technical success in EUS-BD was 1.06 ([0.96-1.17]; P=0.27) and 1.02 [0.97-1.08]; P=0.45) for clinical success. 1-year stent patency was similar among the two groups (RR 1.15; [0.94-1.42], P=0.17), with lower reintervention in the EUS-BD group (RR 0.58; [0.37-0.9]; P=0.01). The RR of AEs rate was 0.85 [0.49-1.46]; P=0.55) and severe AEs of 0.97 [0.10-0.17]; P=0.98). On subgroup analysis, EUS-lumen apposing metal stents (LAMS) outperformed ERCP in term of technical success (RR 1.17; [1.01-1.35]; P=0.03). Procedure time was lower in EUS-BD (standardized mean difference -2.36 minutes; [-2.68 to -2.05]; P<0.001). CONCLUSIONS: EUS-BD showed a statistically significant lower re-intervention rate compared to ERCP, but with similar technical success rate, stent patency, clinical success rate and safety profile, while in the subgroup of EUS-LAMS, the technical success was better than ERCP Keywords: distal; biliary obstruction; efficacy; safety.

School nurses and menstrual communication: Destigmatizing the stigma among adolescents.

OBJECTIVE: The purpose of this study is to understand how school nurses, often the first line of defense for menstruating adolescents, use communication to assist adolescents in destigmatizing menstruation. DESIGN: I conducted semi-structured narrative interviews with nine nurses employed in a large school district in Northeast Indiana. METHODS: Interviews were coded, categorized, and used a phronetic iterative approach. RESULTS: Analysis determines that nurses assist menstruating students using steps toward accepting menstruation and suggesting ways to avoid menstrual stigmatization. CONCLUSION: This study suggests that school nurses use positive language to assist students in handling their menstruation problems, develop allyships with parents and other teachers, and stress menstrual education. This study highlights the need for more funding for menstrual products and additional school nurses.

Coming to Terms with Our Racecar Brains: Academic Mothers Experiencing Adult Diagnosis of ADHD.

This collaborative autoethnography explores the experiences of women academics and mothers who received late diagnoses of Attention Deficit Hyperactivity Disorder (ADHD). Due to the historical underdiagnosis of women, little research has focused on this specific demographic. We shed light on how ADHD presents in women, interweaving our stories with extant literature and emphasizing the need to understand this demographic's experiences better. This piece discusses our process of seeking diagnosis and treatment, the communicative disenfranchisement we faced, and the stigma associated with ADHD. Our narratives highlight the generational impact of ADHD, with family members often sharing our diagnosis. Through divulging our experiences, we hope to contribute to the destigmatization of ADHD, particularly for women and academics.

Endoscopic En Bloc Versus Piecemeal Resection of Large Nonpedunculated Colonic Adenomas : A Randomized Comparative Trial.

BACKGROUND: Endoscopic resection of adenomas prevents colorectal cancer, but the optimal technique for larger lesions is controversial. Piecemeal endoscopic mucosal resection (EMR) has a low adverse event (AE) rate but a variable recurrence rate necessitating early follow-up. Endoscopic submucosal dissection (ESD) can reduce recurrence but may increase AEs. OBJECTIVE: To compare ESD and EMR for large colonic adenomas. DESIGN: Participant-masked, parallel-group, superiority, randomized controlled trial. (ClinicalTrials.gov: NCT03962868). SETTING: Multicenter study involving 6 French referral centers from November 2019 to February 2021. PARTICIPANTS: Patients with large (≥25 mm) benign colonic lesions referred for resection. INTERVENTION: The patients were randomly assigned by computer 1:1 (stratification by lesion location and center) to ESD or EMR. MEASUREMENTS: The primary end point was 6-month local recurrence (neoplastic tissue on endoscopic assessment and scar biopsy). The secondary end points were technical failure, en bloc R0 resection, and cumulative AEs. RESULTS: In total, 360 patients were randomly assigned to ESD (n = 178) or EMR (n = 182). In the primary analysis set (n = 318 lesions in 318 patients), recurrence occurred after 1 of 161 ESDs (0.6%) and 8 of 157 EMRs (5.1%) (relative risk, 0.12 [95% CI, 0.01 to 0.96]). No recurrence occurred in R0-resected cases (90%) after ESD. The AEs occurred more often after ESD than EMR (35.6% vs. 24.5%, respectively; relative risk, 1.4 [CI, 1.0 to 2.0]). LIMITATION: Procedures were performed under general anesthesia during hospitalization in accordance with the French health system. CONCLUSION: Compared with EMR, ESD reduces the 6-month recurrence rate, obviating the need for systematic early follow-up colonoscopy at the cost of more AEs. PRIMARY FUNDING SOURCE: French Ministry of Health.

Systematic Resection of the Visible Scar After Incomplete Endoscopic Resection of Rectal Neuroendocrine Tumors.

INTRODUCTION: When initial resection of rectal neuroendocrine tumors (r-NETs) is not R0, persistence of local residue could lead to disease recurrence. This study aimed to evaluate the interest of systematic resection of non-R0 r-NET scars. METHODS: Retrospective analysis of all the consecutive endoscopic revisions and resections of the scar after non-R0 resections of r-NETs. RESULTS: A total of 100 patients were included. Salvage endoscopic procedure using endoscopic submucosal dissection or endoscopic full-thickness resection showed an R0 rate of near 100%. Residual r-NET was found in 43% of cases. DISCUSSION: In case of non-R0 resected r-NET, systematic scar resection by endoscopic full-thickness resection or endoscopic submucosal dissection seems necessary.

A 3D-printed pedal fixator for connecting different pedal-operated tools reduces the number of mistakes during endoscopic submucosal dissection.

Background and study aims What distinguishes endoscopic submucosal dissection (ESD) from endoscopic mucosal resection is the need for three foot pedals to activate the electrosurgical unit, flushing and knife injection. The lack of connection between the various pedals of different shapes and brands leads to numerous pedals displacements and potential mistakes. The aim of this study was to evaluate an Innovative PEdal FIXator (IPEFIX) to reduce pedal mistakes during ESD. Methods This was a prospective, multicenter, randomized study. Consecutive ESD procedures were randomly assigned to two groups: a control group with the three pedals free and the IPEFIX group in which the three pedals were linked by IPEFIX. The main outcome evaluated was the number of foot mistakes (wrong pedal, foot push beside the pedal). Results A total of 107 ESDs were performed by eight experts in five centers. The median number of mistakes per hour of ESD procedure was 0/h in the IPEFIX group and 1.9/h in the control group ( P <0.001). The mean number of times to look down to control the position of the pedals was 2.2/h the IPEFIX group and 7.7/h in the control group ( P <0.001). Mean replacements of the pedals were 0./h in the IPEFIX group and 1.7/h in the control group ( P <0.001). Similar results were obtained in trainees in simulated ESD on animal models. Conclusions IPEFIX is a simple device to connect different pedals during endoscopic procedures. It helps to reduce the numbers of foot mistakes during ESD and improves operator comfort.

Use of endoscopic submucosal dissection or full-thickness resection device to treat residual colorectal neoplasia after endoscopic resection: a multicenter historical cohort study.

INTRODUCTION : Residual colorectal neoplasia (RCN) after previous endoscopic mucosal resection is a frequent challenge. Different management techniques are feasible including endoscopic full-thickness resection using the full-thickness resection device (FTRD) system and endoscopic submucosal dissection (ESD). We aimed to compare the efficacy and safety of these two techniques for the treatment of such lesions. METHODS : All consecutive patients with RCN treated either using the FTRD or by ESD were retrospectively included in this multicenter study. The primary outcome was the R0 resection rate, defined as an en bloc resection with histologically tumor-free lateral and deep margins. RESULTS : 275 patients (median age 70 years; 160 men) who underwent 177 ESD and 98 FTRD procedures for RCN were included. R0 resection was achieved in 83.3 % and 77.6 % for ESD and FTRD, respectively (P = 0.25). Lesions treated by ESD were however larger than those treated by FTRD (P < 0.001). The R0 rates for lesions of 20-30 mm were 83.9 % and 57.1 % in the ESD and FTRD groups, respectively, and for lesions of 30-40 mm were 93.6 % and 33.3 %, respectively. On multivariable analysis, ESD procedures were associated with statistically higher en bloc and R0 resection rates after adjustment for lesion size (P = 0.02 and P < 0.001, respectively). The adverse event rate was higher in the ESD group (16.3 % vs. 5.1 %), mostly owing to intraoperative perforations. CONCLUSION: ESD is effective in achieving R0 resection for RCN whatever the size and location of the lesions. When residual lesions are smaller than 20 mm, the FTRD is an effective alternative.

Endoscopic submucosal dissection of appendicular lesions is feasible and safe: a retrospective multicenter study (with video).

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) is challenging for appendicular lesions. We report the outcomes of ESD in this context. METHODS: We collected data of ESD procedures for appendiceal neoplasia in a multicenter prospective registry. Main study endpoints were R0, en-bloc, and curative resection rates and adverse event rate. RESULTS: One hundred twelve patients were included, 47 (42%) with previous appendectomy. Fifty-six (50%) were Toyonaga type 3 lesions (15 [13.4%] postappendectomy). En-bloc and R0 resection rates were 86.6% and 80.4%, respectively, with no significant difference associated with different grades of appendiceal invasion (P = .9 and P = .4, respectively) or previous appendectomy (P = .3 for both). The curative resection rate was 78.6%. Additional surgery was performed in 16 cases (14.3%), including 10 (62.5%) Toyonaga type 3 lesions (P = .04). This included the treatment of 5 cases (4.5%) of delayed perforation and 1 acute appendicitis. CONCLUSIONS: ESD for appendicular lesions is a potentially safer and effective alternative to surgery for a significant proportion of patients.

Mechanisms of esophageal stricture after extensive endoscopic resection: a transcriptomic analysis.

Background and study aims Esophageal stricture is the most frequent adverse event after endoscopic resection for early esophageal neoplasia. Currently available treatments for the prevention of esophageal stricture are poorly effective and associated with major adverse events. Our aim was to identify transcripts specifically overexpressed or repressed in patients who have developed a post-endoscopic esophageal stricture, as potential targets for stricture prevention. Patients and methods We conducted a prospective single-center study in a tertiary endoscopy center. Patients scheduled for an endoscopic resection and considered at risk of esophageal stricture were offered inclusion in the study. The healthy mucosa and resection bed were biopsied on Days 0, 14, and 90. A transcriptomic analysis by microarray was performed, and the differences in transcriptomic profile compared between patients with and without esophageal strictures. Results Eight patients, four with esophageal stricture and four without, were analyzed. The mean ± SD circumferential extension of the mucosal defect was 85 ±â€Š11 %. The transcriptomic analysis in the resection bed at day 14 found an activation of the interleukin (IL)-1 group (Z score = 2.159, P  = 0.0137), while interferon-gamma (INFγ) and NUPR1 were inhibited (Z score = -2.375, P  = 0.0022 and Z score = -2.333, P  = 0.00131) in the stricture group. None of the activated or inhibited transcripts were still significantly so in any of the groups on Day 90. Conclusions Our data suggest that IL-1 inhibition or INFγ supplementation could constitute promising targets for post-endoscopic esophageal stricture prevention.

Multicenter randomized trial comparing diagnostic sensitivity and cellular abundance with aggressive versus standard biliary brushing for bile duct stenosis without mass syndrome.

BACKGROUND : The diagnosis of cholangiocarcinoma in patients with a biliary stricture without mass syndrome can be obtained by biliary brushing with a sensitivity of ~50 %. We performed a multicenter randomized crossover trial comparing the aggressive Infinity brush with the standard RX Cytology Brush. The aims were to compare sensitivity for cholangiocarcinoma diagnosis and cellularity obtained. METHODS : Biliary brushing was performed consecutively with each brush, in a randomized order. Cytological material was studied with blinding to the brush type used and order. The primary end point was sensitivity for cholangiocarcinoma diagnosis; the secondary end point was the abundance of cellularity obtained with each brush, with cellularity quantified in order to determine if one brush strongly outperformed the other. RESULTS : 51 patients were included. Final diagnoses were cholangiocarcinoma (n = 43; 84 %), benign (n = 7; 14 %), and indeterminate (n = 1; 2 %). Sensitivity for cholangiocarcinoma was 79 % (34 /43) for the Infinity brush versus 67 % (29/43) for the RX Cytology Brush (P = 0.10). Cellularity was rich in 31/51 cases (61 %) with the Infinity brush and in 10/51 cases (20 %) with the RX Cytology Brush (P < 0.001). In terms of quantification of cellularity, the Infinity brush strongly outperformed the RX Cytology Brush in 28/51 cases (55 %), while the RX Cytology Brush strongly outperformed the Infinity brush in 4/51 cases (8 %; P < 0.001). CONCLUSIONS : This randomized crossover trial showed that the Infinity brush is not significantly more effective than the RX Cytology Brush for biliary stenosis without mass syndrome in terms of sensitivity for cholangiocarcinoma diagnosis, but does offer a significantly higher abundance of cellularity.

Diagnostic endoscopic submucosal dissection for colorectal lesions with suspected deep invasion.

BACKGROUND: Endoscopic submucosal dissection (ESD) is potentially a curative treatment for T1 colorectal cancer under certain conditions. The aim of this study was to evaluate the feasibility and effectiveness of ESD for lesions with a suspicion of focal deep invasion. METHODS: In this retrospective multicenter study, consecutive patients with colorectal neoplasia displaying a focal (< 15 mm) deep invasive pattern (FDIP) that were treated by ESD were included. We excluded ulcerated lesions (Paris III), lesions with distant metastasis, and clearly advanced tumors (tumoral strictures). RESULTS: 124 patients benefited from 126 diagnostic dissection attempts for FDIP lesions. Dissection was feasible in 120/126 attempts (95.2 %) and, where possible, the en bloc and R0 resection rates were 95.8 % (115/120) and 76.7 % (92/120), respectively. Thirty-three resections (26.2 %) were for very low risk tumors, so considered curative, and 38 (30.2 %) were for low risk lesions. Noncurative R0 resections were for lesions with lymphatic or vascular invasion (LVI; n = 8), or significant budding (n = 9), and LVI + budding combination (n = 4). CONCLUSION: ESD is feasible and safe for colorectal lesions with an FDIP ≤ 15 mm. It was curative in 26.6 % of patients and could be a valid option for a further 30.6 % of patients with low risk T1 cancers, especially for frail patients with co-morbidities.

Efficacy of EUS-guided hepaticogastrostomy in prolonging survival of patients with perihilar cholangiocarcinoma.

Background and Objectives: The background of this study was to evaluate the outcomes of perihilar cholangiocarcinoma (pCCA) patients treated with EUS-guided hepaticogastrostomy (EUS-HGS). Methods: All patients with pCCA who underwent EUS-HGS from 2010 to 2020 were analyzed. The primary outcome was clinical success; the secondary outcomes were technical success, adverse events (AEs), stent patency, and oncological outcomes. Cox proportional-hazards regression and Kaplan-Meier curves were analyzed to identify variables related to survival. Results: Thirty-four patients (50% females, 76 years old) were included; 24 (70.6%) presented with distant metastasis. Indications for EUS-HGS were ERCP failure (64.7%), duodenal stricture (23.5%), postsurgical anatomy (5.9%), and dilation limited to the left intrahepatic duct (5.9%). The technical success rate was 97.1%. The clinical success rate was 64.7%. Nine (26.5%) presented AEs, 2 fatal (bleeding and leakage). The overall survival was 91 (31-263) days. On multivariate analysis, EUS-HGS clinical success (Exp[b]: 0.23 [0.09-0.60]; P = 0.003) and chemotherapy (Exp[b]: 0.06 [0.02-0.23]; P < 0.001) were significantly associated with survival. The survival was longer in patients who achieved EUS-HGS clinical success (178[61-393] vs. 15[73-24] days; hazard ratio: 6.3; P < 0.001) and in those starting chemotherapy (324[178-439] vs. 31 [9-48]; hazard ratio: 1.2; P < 0.001). Conclusions: EUS-HGS is effective in pCCA patients despite a not negligible AE rate. Clinical success, potentially leading to jaundice resolution and chemotherapy start, significantly improves survival.

Accuracy and agreement of a large panel of endosonographers for endomicroscopy-guided virtual biopsy of pancreatic cystic lesions.

BACKGROUND: Although emerging data evidences that EUS-guided needle-based confocal laser endomicroscopy (nCLE) accurately diagnoses pancreatic cystic lesions (PCLs), there are a lack of interobserver agreement (IOA) studies utilizing reference histopathological diagnosis and for specific PCL subtypes. Hence, we sought to assess the IOA, intra-observer reliability (IOR), and diagnostic performance of EUS-nCLE using a large cohort of patients with histopathological diagnosis amongst a broad panel of international observers. METHODS: EUS-nCLE videos (n = 76) of subjects with PCLs [intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystadenoma (SCA), pseudocyst, and cystic-neuroendocrine tumors/solid pseudopapillary neoplasm (cystic-NET/SPN)], simulating clinical prevalence rates were obtained from 3 prospective studies. An international panel of 13 endosonographers with nCLE experience, blinded to all PCL data, evaluated the video library twice with a two-week washout for PCL differentiation (mucinous vs. non-mucinous) and subtype diagnosis. RESULTS: The IOA (κ = 0.82, 95% CI 0.77-0.87) and IOR (κ = 0.82, 95% CI 0.78-0.85) were "almost perfect" to differentiate mucinous vs. non-mucinous PCLs. For PCL subtype, IOA was highest for SCA (almost perfect; κ = 0.85), followed by IPMN (substantial, κ = 0.72), and cystic-NET/SPN (substantial, κ = 0.73). The IOA was moderate for MCN (κ = 0.47), and pseudocyst (κ = 0.57). Compared to histopathology, observers differentiated mucinous vs. non-mucinous PCLs with high accuracy (94.8%, 95% CI 93.3-96.1). For detecting specific PCLs subtypes, EUS-nCLE was highly accurate in diagnosing non-mucinous cysts (SCA: 98%; cystic-NET/SPN: 96%; pseudocyst: 96%) and slightly less accurate for mucinous lesions (IPMN: 86%; MCN: 84%). CONCLUSION: Diagnosis of PCLs by EUS-nCLE guided virtual biopsy is very accurate and reliable for the most prevalent pancreatic cysts in clinical practice.

Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.

Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer's disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.