Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Liver transplantation for refractory hepatic hydrothorax is associated with a greater survival benefit compared to other complications of cirrhosis.

Hepatic hydrothorax (HH) is a significant complication of cirrhosis associated with increased mortality. Liver transplantation (LT) remains the best treatment modality. We aim to assess predictors of mortality and the survival benefit of LT in patients with HH. A prospectively maintained cohort of adult patients with cirrhosis, being evaluated for LT at our institution, was retrospectively reviewed from 2015 to 2020. The primary outcome was death or LT. Cox proportional hazard regression identified associations between covariates and death. We calculated the years saved due to LT by comparing patients who were on the waiting list with patients who received an LT. This was done by calculating the area under the Kaplan-Meier curve. Censoring occurred at the time of the last follow-up or death. Patients with refractory HH had the lowest median survival of only 0.26 years. Within the HH group, having a refractory HH group was significantly associated with an increased risk of mortality (HR 1.73; 95% CI 1.06-2.81; p -value 0.03). Refractory HH was also significantly associated with mortality when evaluated in the entire cohort and after adjusting for other covariates (HR 1.48, 95% CI 1.03-2.11; p -value 0.03). Patients with refractory HH had the highest 1-year survival benefit with LT (0.48 y), followed by patients with non-refractory HH (0.28 y), then patients with other complications of cirrhosis (0.19 y). In this large study evaluating the prognostic impact of HH on patients with cirrhosis, refractory HH was an independent predictor of mortality. LT provides an additional survival benefit to patients with HH compared with those without HH.

Utility of apical four-chamber longitudinal strain in the assessment of childhood cancer survivors: A multicenter study.

BACKGROUND: A previous multicenter study showed that longitudinal changes in standard cardiac functional parameters were associated with the development of cardiomyopathy in childhood cancer survivors (CCS). Evaluation of the relationship between global longitudinal strain (GLS) changes and cardiomyopathy risk was limited, largely due to lack of quality apical 2- and 3-chamber views in addition to 4-chamber view. We sought to determine whether apical 4-chamber longitudinal strain (A4LS) alone can serve as a suitable surrogate for GLS in this population. METHODS: A4LS and GLS were measured in echocardiograms with acceptable apical 2-, 3-, and 4-chamber views. Correlation was evaluated using Pearson and Spearman coefficients, and agreement was evaluated with Bland-Altman plots. The ability of A4LS to identify normal and abnormal values compared to GLS as the reference was evaluated. RESULTS: Among a total of 632 reviewed echocardiograms, we identified 130 echocardiograms from 56 patients with adequate views (38% female; mean age at cancer diagnosis 8.3 years; mean follow-up 9.4 years). Correlation coefficients between A4LS and GLS were .89 (Pearson) and .85 (Spearman), with Bland-Altman plot of GLS-A4LS showing a mean difference of -.71 ± 1.8. Compared with GLS as the gold standard, A4LS had a sensitivity of 86% (95% CI 79%-93%) and specificity of 82% (69%-95%) when using normal range cutoffs and 90% (82%-97%) and 70% (58%-81%) when using ±2 standard deviations. CONCLUSION: A4LS performs well when compared with GLS in this population. Given the more recent adoption of apical 2- and 3-chamber views in most pediatric echocardiography laboratories, A4LS is a reasonable stand-alone measurement in retrospective analyses of older study cohorts and echocardiogram biorepositories.

Type of donor liver transplant does not affect pregnancy outcomes-a systematic review and meta-analysis.

Liver transplant (LT) has become increasingly common among reproductive-aged women. The effect of the type of liver donor, either a living donor LT (LDLT) or a deceased donor LT, on pregnancy outcomes is unknown. As such, we aim to review the available literature and assess obstetric, pregnancy, or delivery outcomes in LDLT. We conducted a comprehensive literature review of MEDLINE, EMBASE, Cochrane, and Scopus databases. Random-effect meta-regression assessed the association between the percentage of women who underwent LDLT (independent variable) and the proportion of outcomes. Meta-regression results were expressed as a regression coefficient, which transforms the proportion of outcomes of interest associated with a 1% increase in the percentage of LDLT patients. A value of 0 denotes no relationship between the outcomes and LDLT. A total of 6 articles (438 patients) were included, with a total of 806 pregnancies. Eighty-eight (20.09%) patients underwent LDLT. None of the studies segregated the data based on the type of donor LT. The median time from LT to pregnancy was 4.86 (4.62-5.03) years. Twelve (1.5%) stillbirths were reported. LDLT was statistically significantly associated with a higher rate of stillbirths (coefficient 0.002, p < 0.001; I 2 0%). The type of donor LT was not associated with an increased risk of other obstetric, pregnancy, or delivery complications. This is the first meta-analysis to evaluate the effect of the type of donor LT on pregnancy outcomes. This study highlights the lack of robust literature addressing this important topic. The results suggest that pregnancy outcomes after LDLT and deceased donor LT are comparable. Despite LDLT being statistically significantly associated with a higher rate of stillbirths, the association is weak and is unlikely to be clinically significant.

Acute idiopathic pancreatitis is associated with more aggressive disease course in Crohn's disease but not in ulcerative colitis.

PURPOSE: Patients with inflammatory bowel disease (IBD), whether Crohn's disease (CD) or ulcerative colitis (UC), have an increased risk of acute pancreatitis. The prognostic value of diagnosing acute idiopathic pancreatitis in patients with IBD is not well understood. METHODS: A retrospective review of 56 patients with IBD and acute pancreatitis was conducted in a tertiary center from 2011 to 2020. Aggressive disease course was defined as (i)biologic change, (ii)biologic dose escalation, or (iii)IBD-related surgeries occurring within 1 year of acute pancreatitis diagnosis. Logistic regression modelling identified associations between covariates and an aggressive disease course. RESULTS: Baseline characteristics between idiopathic pancreatitis and other causes of acute pancreatitis, in both CD and UC cohorts, were similar. Idiopathic pancreatitis was significantly associated with an aggressive disease course in CD (P = 0.04). No confounding factors were associated with an aggressive disease course in CD. Idiopathic pancreatitis, however, was not associated with an aggressive disease course in UC (P = 0.35). CONCLUSION: The diagnosis of acute idiopathic pancreatitis may provide a prognostic indicator of a more severe disease course in CD. No such association appears to exist with UC. To the best of our knowledge, this is the first study that identifies an association and possible prognostic value between idiopathic pancreatitis and a more severe disease course in CD. More studies with a larger sample size are needed to validate these findings, further define idiopathic pancreatitis as an extraintestinal manifestation of IBD and elucidate a clinical strategy to optimize care in patients with aggressive CD and idiopathic pancreatitis.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Secondary Prophylaxis of Gastric Variceal Bleeding: A Systematic Review and Network Meta-Analysis.

There is no clear consensus regarding the optimal approach for secondary prophylaxis of gastric variceal bleeding (GVB) in patients with cirrhosis. We conducted a systematic review and network meta-analysis (NMA) to compare the efficacy of available treatments. A comprehensive search of several databases from each database's inception to March 23, 2021, was conducted to identify relevant randomized controlled trials (RCTs). Outcomes of interest were rebleeding and mortality. Results were expressed as relative risk (RR) and 95% confidence interval (CI). We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to rate the certainty of evidence. We included 9 RCTs with 647 patients who had histories of GVB and follow-ups >6 weeks. A total of 9 interventions were included in the NMA. Balloon-occluded retrograde transvenous obliteration (BRTO) was associated with a lower risk of rebleeding when compared with ß-blockers (RR, 0.04; 95% CI, 0.01-0.26; low certainty), and endoscopic injection sclerotherapy (EIS)-cyanoacrylate (CYA) (RR, 0.18; 95% CI, 0.04-0.77; low certainty). ß-blockers were associated with a higher risk of rebleeding compared with most interventions and with increased mortality compared with EIS-CYA (RR, 4.12, 95% CI, 1.50-11.36; low certainty), and EIS-CYA + nonselective ß-blockers (RR, 5.61; 95% CI, 1.91-16.43; low certainty). Analysis based on indirect comparisons suggests that BRTO may be the best intervention in preventing rebleeding, whereas ß-blocker monotherapy is likely the worst in preventing rebleeding and mortality. Head-to-head RCTs are needed to validate these results.

Refractory Hepatic Hydrothorax Is an Independent Predictor of Mortality When Compared to Refractory Ascites.

BACKGROUND: Hepatic hydrothorax (HHT) is an uncommon but significant complication of cirrhosis and portal hypertension, associated with a worse prognosis and mortality. Nearly 25% of patients with HHT will have refractory pleural effusion. It is unclear if refractory HHT has a different prognosis compared to refractory ascites. AIMS: We aim to evaluate the prognostic significance of refractory HHT when compared to refractory ascites. METHODS: Forty-seven patients who had refractory HHT in a tertiary care center were identified, and matched, retrospectively, one-to-one by age, gender and MELD-Na with 47 patients with refractory ascites. One-year mortality rate was compared between both groups. Cox proportional hazard regression was used to identify the association between different covariates and primary endpoint. RESULTS: The 1-year mortality was 51.06% in the HHT group compared to 19.15% in the refractory ascites group. The median survival for patients with refractory hepatic hydrothorax was 4.87 months while the median survival for patients with refractory ascites exceeded 1 year. The presence of HHT was statistically significant in predicting the development of 1-year mortality [Hazard Ratio (HR) 4.45, 95% Confidence Interval (CI) 2.25-8.82; P value < 0.001]. Furthermore, refractory HHT remained associated with one-year mortality after adjusting for all other covariates. In a subgroup of patients with MELD-Na ≤ 20, HHT continued to be a significant predictor of one-year mortality (HR 3.30, 95% CI 1.47-7.40; P value 0.004). CONCLUSIONS: Refractory HHT is a significant independent predictor of mortality and offers additional prognostic value.

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

GOALS: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). BACKGROUND: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. MATERIALS AND METHODS: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. RESULTS: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). CONCLUSION: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Cancer survivors exercise at higher intensity in outdoor settings: The GECCOS trial.

PURPOSE: This randomized cross-over group pilot trial assessed feasibility of recruiting survivors from a long-term follow-up clinic to an exercise group and measured whether outdoor or indoor exercise sessions better supported exercise motivation and behaviors in survivors of cancer. METHODS: Sixteen adolescent and young adult survivors of any cancer completed indoor and outdoor exercise sessions in this randomized cross-over pilot trial. Measures of physical activity, motivation, and fatigue were taken 2 weeks before and 2 weeks after indoor sessions and 2 weeks before and 2 weeks after outdoor sessions. Measures of physical activity and fatigue were also taken during each exercise session. RESULTS: Initial recruiting of 19 participants met recruiting goals. Survivors who attended the most sessions lived an average of 8.7 km closer to the clinic. Objectively measured physical activity intensity was 0.63 metabolic equivalents of a task (METs) per minute greater during outdoor exercise sessions as compared to indoor exercise sessions. There were no meaningful differences in long term, habitual physical activity behavior, motivation, or fatigue in the weeks following the outdoor exercise sessions as compared to the indoor exercise sessions. CONCLUSIONS: This study shows the feasibility of recruiting survivors from a long-term follow-up clinic to community-based exercise groups. Although this brief pilot intervention did not show significant effects on habitual physical activity behavior or motivation in adolescent and young adult survivors of cancer, the greater exercise intensity during the outdoor exercise sessions indicate that holding group exercise sessions for survivors outdoors may promote greater intensity during exercise.

Challenges associated with retrospective analysis of left ventricular function using clinical echocardiograms from a multicenter research study.

BACKGROUND: Retrospective multicenter research using echocardiograms obtained for routine clinical care can be hampered by issues of individual center quality. We sought to evaluate imaging and patient characteristics associated with poorer quality of archived echocardiograms from a cohort of childhood cancer survivors. METHODS: A single blinded reviewer at a central core laboratory graded quality of clinical echocardiograms from five centers focusing on images to derive 2D and M-mode fractional shortening (FS), biplane Simpson's ejection fraction (EF), myocardial performance index (MPI), tissue Doppler imaging (TDI)-derived velocities, and global longitudinal strain (GLS). RESULTS: Of 535 studies analyzed in 102 subjects from 2004 to 2017, all measures of cardiac function could be assessed in only 7%. While FS by 2D or M-mode, MPI, and septal E/E' could be measured in >80% studies, mitral E/E' was less consistent (69%), but better than EF (52%) and GLS (10%). 66% of studies had ≥1 issue, with technical issues (eg, lung artifact, poor endocardial definition) being the most common (33%). Lack of 2- and 3-chamber views was associated with the performing center. Patient age <5 years had a higher chance of apex cutoff in 4-chamber views compared with 16-35 years old. Overall, for any quality issue, earlier era of echo and center were the only significant risk factors. CONCLUSION: Assessment of cardiac function using pooled multicenter archived echocardiograms was significantly limited. Efforts to standardize clinical echocardiographic protocols to include apical 2- and 3-chamber views and TDI will improve the ability to quantitate LV function.

Magnetic resonance imaging features in 283 patients with primary biliary cholangitis.

OBJECTIVES: To evaluate magnetic resonance imaging (MRI) features of the liver in primary biliary cholangitis (PBC). METHODS: We conducted a multicenter retrospective review on 283 patients with PBC who underwent an MRI between 2007 and 2018. Patients with overlap syndromes were excluded. MRI studies were independently reviewed by two abdominal radiologists for liver morphology, signal intensity, postcontrast enhancement, and decompensation. Liver and spleen volumes and normalized liver apparent diffusion coefficient (nlADC) were also calculated. MRI features were correlated with fibrosis stage among a subset of patients who had a liver biopsy within 6 months (n = 72). RESULTS: The study population was comprised of 283 patients (89% females) and a mean ± SD age of 59.4 ± 11.8 years. Lymphadenopathy (78.1%), periportal hyperintensity (36.7%), and periportal halo sign (27.6%) were the most common features. A positive correlation was found between fibrosis stage and spleen size (r = 0.457, p < 0.001), spleen volume (r = 0.557, p < 0.001) and portal vein diameter (r = 0.287, p = 0.013), and a negative correlation with nlADC (r = - 0.332, p = 0.011). Fibrosis stage also correlated with the presence of surface nodularity (p < 0.001), periportal halo sign (p = 0.04), collaterals (p = 0.033), and splenomegaly (p = 0.002). No significant differences in nlADC values were found in different fibrosis stages. Spleen size and volume were significantly higher in patients with ascites and collaterals (< 0.001). The periportal halo sign was present only in patients with significant fibrosis. None of the MRI features significantly correlated with inflammation grade. CONCLUSIONS: In PBC, presence of periportal halo sign correlates with significant fibrosis. Heterogeneous T2W intensity, heterogeneous postcontrast enhancement, collaterals, spleen size, and spleen volume correlate with fibrosis stage and may be useful for predicting advanced fibrosis. KEY POINTS: • The presence of periportal halo sign is indicative for significant fibrosis in primary biliary cholangitis. • Liver parenchymal heterogeneous T2 signal intensity, heterogeneous postcontrast enhancement, collaterals, spleen size, and spleen volume correlate with fibrosis stages in PBC and may be useful for predicting advanced fibrosis.

ImageDataExtractor: A Tool To Extract and Quantify Data from Microscopy Images.

The rise of data science is leading to new paradigms in data-driven materials discovery. This carries an essential notion that large data sources containing chemical structure and property information can be mined in a fashion that detects and exploits structure-property relationships, such that chemicals can be predicted to suit a given material application. The success of material predictions is predicated on these large data sources of chemical structure and property information being suited to a target application. Microscopy is commonly used to characterize chemical structure, especially in fields such as nanotechnology where material properties are highly dependent on the size and shape of nanoparticles. Large data sources of nanoparticle information stemming from microscopy images would thus be highly beneficial. Millions of microscopy images exist, but they lie fragmented across the literature, typically presented individually within a paper article and usually in a qualitative fashion therein, even though they harbor a wealth of numeric information. We present the ImageDataExtractor toolkit that autoidentifies and autoextracts microscopy images from scientific documents, whereupon it autonomously analyzes each image to produce quantitative particle size and shape information about its subject material. Each image is quantified by decoding its scale bar information using optical character recognition, with help from super-resolution convolutional neural networks where required. Individual particles are detected and profiled using various thresholding, segmentation, polygon fitting, and edge correction routines. The high-throughput operational capability of ImageDataExtractor means that it can be used to generate large-data sources of particle information for data-driven materials discovery. Evaluation metrics, precision and recall, are greater than 80% for the majority of the image processing steps, and precision is above 80% for all critical steps. The ImageDataExtractor tool is released under the MIT license and is available to download from http://www.imagedataextractor.org.

'Flower of the body': menstrual experiences and needs of young adolescent women with cerebral palsy in Bangladesh, and their mothers providing menstrual support.

BACKGROUND: This study offers voice to young adolescent women with cerebral palsy (CP) in Bangladesh as they describe their menstrual experiences and needs, and their mothers providing menstrual support. METHOD: Semi-structured focus groups with adolescents with CP, and separately their mother. Data was analysed using a material discursive framework and drawing on feminist disability theory. Participants were recruited from the Bangladesh CP Register (BCPR); a population-based surveillance of children and adolescents with CP in rural Bangladesh. RESULTS: Participants were 45 women including 12 female adolescents with CP and 33 female caregivers. Participants reported a wide range of experiences and needs; menarche acted as a gateway to menstrual information although for some a discourse of silence prevailed due to exclusion from peer and familial networks. Menstruation was discursively constructed as a sign of 'female maturation' marked by an expectation of 'independence', required for acceptance into socially valued adult roles, and was positioned alongside increased vulnerability to sexual abuse. Young adolescent women with CP were expected to 'quietly endure' the material aspects of menstruation although unmanaged pain and distress were described. Mothers reported an imperative for meeting their adolescent's menstrual needs however this role was discursively positioned as 'painful', 'irritating' and 'shameful', in part due to an absence of affordable, functional menstrual resources. CONCLUSION: The findings of the present study provide motivation for disability services in Bangladesh to account for the menstrual needs of young adolescent women with CP within service delivery through strategies such as providing menstrual education and by embedding value in constructs such as 'interdependence'. Moreover, interventions focused on alleviating menstrual pain among young adolescent women with CP as well as those targeted to alleviate distress among mothers providing menstrual care are required. Finally, policy responses are required to ensure that 'inclusive development' considers the needs of menstruating women with disability.

Genome-wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma.

Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome-wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome-wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down-regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest-expressing tumors had reduced relapse-free survival. Our functional studies showed that knock-down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

MYCN is recruited to the RASSF1A promoter but is not critical for DNA hypermethylation in neuroblastoma.

Tumor suppressor genes such as RASSF1A are often epigenetically repressed by DNA hypermethylation in neuroblastoma, where the MYCN proto-oncogene is frequently amplified. MYC has been shown to associate with DNA methyltransferases, thereby inducing transcriptional repression of target genes, which suggested that MYCN might play a similar mechanistic role in the hypermethylation of tumor suppressor genes in neuroblastoma. This study tested that hypothesis by using co-immunoprecipitation and ChIP to investigate MYCN-DNA methyltransferase interactions, together with MYCN knock-down and over-expression systems to examine the effect of MYCN expression changes on gene methylation, employing both candidate gene and genome-wide assays. We show that MYCN interacts with DNA methyltransferases and is recruited to the promoter region of RASSF1A. However, using four model systems, we showed that long-term silencing of MYCN induces only a small loss of DNA methylation at the RASSF1A promoter in MYCN amplified neuroblastoma cell lines and over-expression of MYCN does not induce any DNA methylation, suggesting that MYCN is not critical for DNA hypermethylation in neuroblastoma.

A rare case of polyarthritis panniculitis and pancreatitis.

Extra pancreatic manifestations of pancreatitis are rare, with a prevalence of 2-3%. One such rare manifestation is the triad of joint pain (polyarthritis), tender skin lesions (panniculitis), and pancreatic inflammation (pancreatitis), known as PPP. The pathogenesis of this phenomenon is not fully understood but is believed to involve lipolysis by pancreatic enzymes at lipid-rich skin and joint sites. PPP primarily affects middle-aged males with a history of alcohol use disorder. Diagnosis can be challenging due to the absence of typical abdominal symptoms. Delayed diagnosis may significantly worsen outcomes. Supportive therapy is the mainstay, but resolution requires addressing the underlying pancreatic abnormality. We present a case of a patient with a history of alcohol use disorder and recurrent acute pancreatitis who developed joint pain and skin rash. Extensive work-up ruled out other causes, and imaging and biopsy confirmed the diagnosis of PPP. Symptomatic management and treatment of the underlying pancreatic abnormality led to complete resolution of symptoms. Our case serves to raise awareness of this rare but potentially fatal syndrome.

Modified triple pelvic osteotomy for residual acetabular dysplasia through double incisions: Technical note and review of short-term results.

PURPOSE: To assess validity, safety, and efficacy of the modified triple pelvic osteotomy (TPO) approach for correction of residual acetabular dysplasia. METHODS: This is a retrospective case series conducted on 15 hips in 15 patients from 2019 to 2023 with residual acetabular dysplasia treated by modified TPO as described by Tonnis with two modifications. The first modification is using a single medial incision for pubic and ischial cuts (the Vladimirov modification). The second modification is having the ischial cut closer to the acetabulum (Li modification) allowing free movement of the acetabular fragment for better femoral head coverage. The mean age at the time of surgery was 11.85 years, (range 8-23). Cases presenting were 10 males (66.7%) and 5 females (33.3%). The mean follow-up period was 36.533 months (24-60 months). RESULTS: Our study revealed significant clinical and radiological improvement. The CE angle improved from a mean value of 10° (range 2-17) pre-operatively to 32.785° (range 18°-40°) post-operatively. The AI improved from a mean value of 32° pre-operatively to a mean value of 13.89° post-operatively. HHS increased from a preoperative mean value of 74.80° to a post-operative mean value of 90.67°. Also, there was a significant improvement in ROM (abduction and internal rotation). LLD improved from a mean value of 2.60 cm preoperatively to a mean value of 0.37 cm postoperatively. Delayed union was found in 3 cases. No cases of osteonecrosis or neurovascular complication were encountered in our study. CONCLUSION: The modified TPO technique using dual incisions can be considered safe and effective, providing adequate coverage of the femoral head in acetabular dysplasia with less surgical time, satisfactory functional outcomes, and minimal complications. LEVEL OF EVIDENCE: IV.

A pilot randomized controlled trial of an online intervention for Hodgkin lymphoma survivors to increase knowledge about late effects and recommended screening.

BACKGROUND: Hodgkin lymphoma (HL) survivors who received chest radiotherapy are at risk for breast cancer and cardiovascular disease, but screening adherence is low. We assessed the acceptability/feasibility of a web-based educational intervention and its impact on knowledge of health risks and screening. METHODS: HL survivors were randomized to either an interactive online educational intervention or handouts only. Surveys were completed at baseline and 3 months post-intervention. We described the acceptability/feasibility of the intervention and compared knowledge between groups. RESULTS: Fifty-two HL survivors participated; 27 in the intervention group and 25 in the control group. Eighteen (66%) intervention participants completed the intervention and reported high acceptability (89-100%). At baseline, adherence to breast cancer screening was low across all participants. Post-intervention, those in the intervention group more often than controls correctly identified breast cancer and echocardiogram screening guidelines (35% vs. 28%, P = 0.02 and 82% vs. 52%, P = 0.04) and reported knowing how to address potential complications from cancer treatments (87% vs. 64%, P = 0.03). We detected no increase in screening behavior post-intervention. CONCLUSION: Online education modules for high-risk HL survivors are an acceptable method to improve knowledge of health risks and screening guidelines. Future interventions should focus on improving screening uptake in this population. IMPLICATIONS FOR CANCER SURVIVORS: Web-based learning can be useful in increasing cancer survivor knowledge of their unique risks and screening recommendations but does not necessarily change patient behavior. Involvement in a cancer survivorship program can help assess individual barriers and monitor uptake of screening.

Non-Puerperal Chronic Inversion of Uterus Due to Big Fibroid Uterus in a Post-Menopausal Woman.

Uterine inversion occurs in puerperal and non-puerperal conditions; non-puerperal uterine inversion (NPUI) may run acute and chronic clinical course. Most on the NPUI are chronic variety while a few are acute variety. NPUI occurs if there is long standing big sub-mucosal fibroid and it is very rare to present in acute setting. Here we report a case of acutely presented NPUI. A 58-year-old widow of lower socioeconomic status presenting to the emergency center of Chittagong medical college Hospital with complaints of sudden protrusion of a big mass through introitus in an attempt of passing out hard stool during defecation on the day of admission with a history of per vaginal watery discharge for a long time and severe anemia. Anemia was corrected and a broad-spectrum antibiotic was given prior to operative management. Under general anesthesia vaginal myomectomy followed by vaginal hysterectomy was performed in the same sitting. Pathological examination revealed a fibroid uterus. Postoperatively patient recovered without any residual problem. Infection should be suspected and treated with appropriate broad-spectrum antibiotics before planning surgery. Vaginal route restoration of NPUI is very difficult but possible with careful attempt. During a vaginal hysterectomy, care to locate and salvage the bladder and distal urinary collecting system is warranted. So, a high index of suspicion is the key to limit morbidity and approach for proper management of such rare clinical condition.