Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Association of Ultra-Widefield Fluorescein Angiography-Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time.

Importance: Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. Objective: To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. Results: After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening. Conclusions and Relevance: This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema.

BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).

Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.

A randomized controlled trial of manual versus powered tooth brushing during haematopoietic stem cell transplantation.

AIM: To compare manual and powered tooth brushing (MT and PT) with respect to patient compliance to brushing frequency advice, plaque removal and severity of oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT) after high-dose chemotherapy. MATERIALS & METHODS: A randomized controlled trial was conducted. Forty-six patients scheduled to receive myeloablative conditioning regimen before autologous HSCT were included and randomly assigned to control (MT, n = 23) or test (PT, n = 23) groups. Starting at day 1 (day of hospital admission for HSCT), brushing frequency (patient recorded diary), plaque scores (Plaque Control Index) and oral mucositis (Oral Mucositis Nursing Index) were recorded daily. Data for days 1 to 17 were analysed using regression analysis and general linear models. RESULTS: Few patients maintained 4 times per day brushing, but most brushed at least 2 times per day throughout the study. In PT, overall plaque scores were lower by 6.98% (p = .006) as compared to MT. No differences were seen in OM scores between the groups (p = .968). A small but significant positive correlation was found between plaque scores and OM severity: R2 =0.15 (p < .01). CONCLUSIONS: Powered tooth brushing resulted in lower plaque scores, but was not associated with reduced OM severity. Individual plaque scores were positively related to OM severity.

Drug withdrawal in patients with autoimmune hepatitis in long-term histological remission: A prospective observational study.

BACKGROUND: Recommendations for drug withdrawal in patients with autoimmune hepatitis (AIH) in longstanding remission are conflicting and rely on retrospective data. We prospectively investigated the predictive value of histological normalisation for successful treatment withdrawal in AIH patients. METHODS: Non-cirrhotic patients with established AIH and complete biochemical remission (normalisation of serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and immunoglobulin G [IgG]) of at least 2 years were biopsied. Immunosuppressive therapy was only withdrawn in patients with histological normalisation (histological activity index [HAI] ≤3) with a minimum follow-up of 12 months. RESULTS: A total of 17 patients in biochemical remission for at least 2 years were included. Persistent histological inflammatory activity (HAI >3) precluded drug withdrawal in five patients. These had higher values of ALT (25 vs. 16 U/L; p = 0.01) and AST (26 vs. 22 U/L; p = 0.01) compared with patients in histological remission. Immunosuppressive medication was withdrawn in 12 patients; eight (67%, C.I. 40-93% p = 0.4) remained in remission during a median follow-up of 62 months (range: 13-75 months); and four (33%, C.I. 7-60% p = 0.4) required reinstitution of therapy after 1, 6, 11, and 40 months, all without clinical signs of disease progression or hepatic decompensation. No predictors of relapse were identified. CONCLUSION: Two-thirds of the patients who prove to have histological normalisation after at least 2 years of biochemical remission achieve treatment-free remission. Although patient numbers were small and results should be interpreted with caution, these findings support a liver biopsy prior to drug withdrawal.

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.

Antibiotic Treatment in the First Week of Life Impacts the Growth Trajectory in the First Year of Life in Term Infants.

OBJECTIVE: Antibiotic treatment in early life appears to increase the risk for childhood overweight and obesity. So far, the association between antibiotics administrated specifically during the first week of life and growth has not been studied. Therefore, we studied the association between growth and antibiotics, given in the first week of life and antibiotic courses later in the first year of life. METHOD: A prospective observational birth cohort of 436 term infants with 151 receiving broad-spectrum antibiotics for suspected neonatal infection (AB+), and 285 healthy controls (AB-) was followed during their first year. Weight, height, and additional antibiotic courses were collected monthly. A generalized-additive-mixed-effects model was used to fit the growth data. Growth curve estimation was controlled for differences in sex, gestational age, delivery mode, exclusive breast-feeding, tobacco exposure, presence of siblings, and additional antibiotic courses. RESULTS: Weight-for-age and length-for-age increase was lower in AB+ compared with AB- (P < 0.0001), resulting in a lower weight and length increase 6.26 kg (standard error [SE] 0.07 kg) and 25.4 cm (SE 0.27 cm) versus 6.47 kg (SE 0.06 kg) and 26.4 cm (SE 0.21 cm) (P < 0.05 and P < 0.005, respectively) in the first year of life. Approximately 30% of the children in both groups received additional antibiotic course(s) in their first year, whereafter additional weight gain of 76 g per course was observed (P = 0.0285). CONCLUSIONS: Decreased growth was observed after antibiotics in the first week of life, whereas increased growth was observed after later antibiotic course(s) in term born infants in the first year of life. Therefore, timing of antibiotics may determine the association with growth.

Salivary Changes before and after Hematopoietic Stem Cell Transplantation: A Systematic Review.

Severe oral problems, including oral mucositis (OM) and xerostomia, often occur after conditioning therapy for hematopoietic stem cell transplantation (HSCT). Saliva plays a major role in protecting the oral mucosa and teeth. Alterations in salivary flow rate or salivary components resulting in decreased salivary defence mechanisms may affect oral/mucosal health and may influence the severity of OM. A systematic review was conducted to assess the current scientific knowledge on changes in salivary function and composition before and after HSCT. All English or Dutch articles examining salivary flow rate or salivary components before and after HSCT were included after title/abstract selection by 2 independent reviewers (weighted κ = .91). After quality assessment and exclusion of all research groups with both children age <14 years and adults, 33 articles were included for data analysis. Overall, the salivary flow rate was decreased at several days and months after HSCT. Although several salivary components were studied, most components were examined in only 1 or 2 studies with different patient populations or at different time points after HSCT. At 7 days after HSCT, albumin and proinflammatory cytokines were increased, whereas secretory IgA and components of the salivary antioxidant system were decreased. Secretory IgA levels were still reduced at 1 month after HSCT but returned to pre-HSCT values at 6 months after HSCT. Lactoferrin, secretory leukocyte protease inhibitor, and ß2-microglobulin levels were increased at 6 months after HSCT. Our findings show that changes in saliva reflect an inflammatory response occurring immediately after HSCT, followed by evidence of increased salivary antimicrobial defense mechanisms by 6 months after HSCT.

Efficacy of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review.

We conducted a systematic review to evaluate the efficacy and adverse effects of newer drugs used to treat lower urinary tract symptoms (LUTS). The drugs were either Food and Drug Administration (FDA) approved for benign prostatic hyperplasia (BPH) or not FDA approved for BPH but have been evaluated for treatment of BPH since 2008. We searched bibliographic databases through September 2017. We included randomized controlled trials (RCTs) lasting one month or longer published in English. Outcomes of interest were LUTS assessed by validated measures. Efficacy was interpreted using established thresholds indicating clinical significance that identified the minimal detectable difference. Twenty-three unique, generally short-term, RCTs evaluating over 9000 participants were identified. Alpha-blocker silodosin and phosphodiesterase type 5 inhibitor tadalafil were more effective than placebo in improving LUTS (moderate strength evidence) but these drugs had more adverse effects, including abnormal ejaculation (silodosin). Anticholinergics were only effective versus placebo when combined with an alpha-blocker. Evidence was generally low strength or insufficient for other drugs. Evidence was insufficient to assess long-term efficacy, prevention of symptom progression, need for surgical intervention, or long-term adverse effects. Longer trials are needed to assess the effect of these therapies on response rates using established minimal detectable difference thresholds, disease progression, and harms.

Physical exercise prior to hematopoietic stem cell transplantation: A feasibility study.

PURPOSE: This study explores the feasibility and preliminary effectiveness of an exercise program in people scheduled for hematopoietic stem cell transplantation (HSCT). METHODS: In this controlled clinical trial, we compare pre-transplantation exercise to no exercise in the waiting period for an allogeneic of autologous HSCT. The supervised individually tailored exercise program (4-6 weeks) consisted of aerobic endurance, muscle strength, and relaxation exercises, administered twice a week in the period prior to HSCT. Feasibility was determined based on inclusion rate, attrition rate, adherence to intervention, safety, and satisfaction (0-10). Preliminary effectiveness was determined primarily by self-perceived physical functioning, quality of life (QOL), and fatigue. Secondary outcomes were global perceived effect (GPE), blood counts, hospital stay, and physical fitness. RESULTS: Forty-six patients were eligible, of whom 29 (69%) participated: 14 in the intervention group and 15 in the control group. The adherence rate to training was 69%. No adverse events or injuries occurred. Satisfaction of training conditions was high (mean 9.2 ± 1.3). Positive (follow-up) trends in favor of the intervention group were found for self-perceived physical functioning, QOL, fatigue, GPE, blood counts, and hospital stay. CONCLUSION: Exercise prior to HSCT is safe and feasible, and positive trends suggest favorable preliminary effectiveness. Adherence to the exercise program needs to be optimized in a future trial.

Smoking is associated with severity of liver fibrosis but not with histological severity in nonalcoholic fatty liver disease. Results from a cross-sectional study.

OBJECTIVES: To assess the influence of smoking on histological disease severity and fibrosis in real-world NAFLD patients. MATERIAL AND METHODS: Consecutive NAFLD patients were identified with liver biopsies performed between 2008 and 2015. Characteristics such as smoking status and total number of pack years were collected. Biopsies were revised and BRUNT fibrosis and NAFLD activity score (NAS) determined. Patients with a high NAS (≥5) were compared to patients with a low NAS (<5) and with advanced fibrosis (stage 3-4) to patients with no-early fibrosis (stage 0-2). Patients with a history of smoking (current or past smoker) were defined ever smokers. RESULTS: Fifty-six patients were included (mean age 49 ± 14.3, 68.9% males and 39.3% history of smoking). Ever smokers had a higher fibrosis score than never smokers; two (IQR 0-3) versus one (IQR 1-1.5) (p = .040). Patients with advanced fibrosis smoked significantly more pack years than patients with no-early fibrosis; 10.6 (IQR 0-25.8) versus 0 (IQR 0-7) (p = .011). There is a weak to moderate correlation between fibrosis stage and number of pack years (Spearman's Rho = 0.341, p = .012). There was no difference in NAS between never and ever smokers; 2.8 ± 1.5 versus 3.3 ± 1.4 (p = .205). Patients with NAS <5 had a median number of pack years of 0 (IQR 0-9) versus a median of 10.3 pack years (IQR 0-24) in patients with NAS ≥5 (p = .127). CONCLUSION: Smoking is associated with severity of NAFLD-related liver fibrosis but not with histological disease severity. This supports the recommendation to cease smoking for NAFLD patients.

Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy.

BACKGROUND: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination. METHODS: An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist. RESULTS: Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670). CONCLUSIONS: The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.

Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.

Comparative Effectiveness of Newer Medications for Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: A Systematic Review and Meta-analysis.

CONTEXT: Alpha-blockers (ABs) and 5-alpha reductase inhibitors have an established role in treating male lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia (BPH). Recently, newer drugs have shown promise for this indication. OBJECTIVE: To assess the comparative effectiveness and adverse effects (AEs) of newer drugs to treat LUTS attributed to BPH through a systematic review and meta-analysis. EVIDENCE ACQUISITION: Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Ovid Embase bibliographic databases (through June 2016) were hand searches for references of relevant studies. Eligible studies included randomized controlled trials published in English of newer ABs, antimuscarinics, a beta-3 adrenoceptor agonist, phosphodiesterase type-5 inhibitors, or combination therapy with one of these medications as an active comparator. Observational studies of the same agents with a duration ≥1 yr that reported AEs were also included. EVIDENCE SYNTHESIS: We synthesized evidence from 43 randomized controlled trials as well as five observational studies. Based on improvement of mean International Prostate Symptom Score and quality of life scores, the effectiveness of the newer ABs was not different from the older ABs (moderate strength of evidence [SOE]), but had more AEs (low SOE). Antimuscarinics/AB combination therapy had similar outcomes as AB monotherapy (all moderate SOE), but often had more AEs. Phosphodiesterase type-5 inhibitors alone or in combination with ABs had similar or inferior outcomes than ABs alone. Evidence was insufficient for the beta-3 adrenoceptor agonist. For all newer agents, the evidence was generally insufficient to assess long-term efficacy, prevention of symptom progression, or AEs. CONCLUSIONS: None of the drugs or drug combinations newly used to treat LUTS attributed to BPH showed outcomes superior to traditional AB treatment. Given the lack of superior outcomes, the studies' short time-horizon, and less assurance of their safety, their current value in treating LUTS attributable to BPH appears low. PATIENT SUMMARY: In this paper, we reviewed the evidence of newer drugs to treat men with urinary problems attributable to an enlarged prostate. We found none of the new drugs to be better but there was more concern about side effects.

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study.

BACKGROUND: Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. METHODS: We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. RESULTS: In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45-2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. CONCLUSIONS: Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease.

BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. METHODS: A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. RESULTS: One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. CONCLUSIONS: The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers: results from a large cohort in the Netherlands.

OBJECTIVES: Hepatocellular carcinoma (HCC) usually occurs in patients with cirrhosis, but can also develop in noncirrhotic livers. In the present study we explored associated risk factors for HCC without cirrhosis and compared patient and tumor characteristics and outcomes in HCC patients with and without underlying cirrhosis. METHODS: Patients with HCC diagnosed in the period 2005-2012 in five Dutch academic centers were evaluated. Patients were categorized according to the presence of cirrhosis on the basis of histology or combined radiological and laboratory features. RESULTS: In total, 19% of the 1221 HCC patients had no underlying cirrhosis. Noncirrhotic HCC patients were more likely to be female and to have nonalcoholic fatty liver disease or no risk factors for underlying liver disease, and less likely to have hepatitis C virus or alcohol-related liver disease than did cirrhotic HCC patients. HCCs in noncirrhotic livers were more often unifocal (67 vs. 48%), but tumor size was significantly larger (8 vs. 4 cm). Despite the larger tumors, more patients underwent resection (50 vs. 10%) and overall survival was significantly better than in cirrhotics. In multivariate analyses, absence of cirrhosis [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.38-0.63] and presence of hepatitis B (HR 0.68, 95% CI 0.51-0.91) were independent predictors for lower mortality, whereas hepatitis C virus was associated with higher mortality (HR 1.32, 95% CI 1.01-1.65). CONCLUSION: HCC without cirrhosis was strongly associated with female sex and presence of nonalcoholic fatty liver disease or no risk factors for underlying liver disease. In absence of cirrhosis, resections were more often performed, with better survival despite larger tumor size.

Risk factors for primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease of unknown cause, but strongly associated with inflammatory bowel disease (IBD). Potential risk factors triggering PSC have never been studied on a population level. The aim of this study was to evaluate smoking, appendectomy, family history and geographical distribution in a population-based cohort of PSC patients, as compared to IBD control patients and healthy controls (HC). METHODS: For this case-control study 343 PSC patients, 370 IBD controls and 232 HC's living in a geographically defined area in the Netherlands filled-out a questionnaire concerning smoking, appendectomy and family history of IBD and autoimmune liver diseases. RESULTS: Smoking was associated with a lower risk of developing PSC in PSC-ulcerative colitis (UC) patients (adjusted OR 0.21; 95% CI 0.12-0.34; P < 0.001). Comparable results were found for PSC-Crohn's disease (CD) patients (16% former smokers) compared to CD patients (55% former smokers) (adjusted OR 0.17; 95% CI 0.08-0.39; P < 0.001). Frequency of appendectomy did not differ between PSC and HC, but PSC-UC patients had undergone appendectomy more often than UC patients (13% vs. 6%) (adjusted OR 2.51; 95%CI 1.04-6.07; P = 0.041). We found no association between family history of IBD or autoimmune liver disease and risk of PSC. Degree of urbanization was not associated with PSC incidence. CONCLUSION: In this large population-based case-control study we confirm that smoking is associated with a lower risk of developing PSC, independent of its protective effect for developing UC. Appendectomy is not associated with the risk of developing PSC.

Assessment of the histopathological key features in autoimmune hepatitis.

AIMS: In this study, we aimed to evaluate the use of typical histological features of both the revised original (1999) and simplified (2008) criteria in the diagnosis of autoimmune hepatitis (AIH) in clinical practice. METHODS AND RESULTS: We performed a detailed histopathological evaluation of the pretreatment biopsies of 63 AIH patients, and used biopsies of 62 untreated chronic viral hepatitis patients [hepatitis B (n = 21) or hepatitis C (n = 41)] as a reference cohort. Biopsies were systematically reviewed for inflammation, fibrosis and the presence of interface hepatitis, plasma cells, rosettes and emperipolesis with a well-defined assessment method. AIH biopsies showed more interface hepatitis (87% versus 63%, P = 0.002), more plasma cell-rich infiltrates (48% versus 27%, P = 0.02), more rosettes (49% versus 23%, P = 0.004) and more emperipolesis (78% versus 50%, P = 0.001) than chronic viral hepatitis biopsies. Emperipolesis (P = 0.01) and rosettes (P < 0.01) were superior to plasma cells and interface hepatitis as independent predictors for AIH. Moderate to severe lymphocytic cholangitis was found in 28% of AIH patients. CONCLUSIONS: Emperipolesis and rosette formation are superior histological predictors of AIH than the classic hallmark features of interface hepatitis and plasma cells. In addition, moderate to severe lymphocytic cholangitis does not preclude the diagnosis of AIH.