Effects of a peripherally acting µ-opioid receptor antagonist for the prevention of recurrent acute pancreatitis: study protocol for an investigator-initiated, randomized, placebo-controlled, double-blind clinical trial (PAMORA-RAP trial).

BACKGROUND: Acute and chronic pancreatitis constitute a continuum of inflammatory disease of the pancreas with an increasing incidence in most high-income countries. A subset of patients with a history of pancreatitis suffer from recurrence of acute pancreatitis attacks, which accelerate disease progression towards end-stage chronic pancreatitis with loss of exocrine and endocrine function. There is currently no available prophylactic treatment for recurrent acute pancreatitis apart from removing risk factors, which is not always possible. Pain is the primary symptom of acute pancreatitis, which induces the endogenous release of opioids. This may further be potentiated by opioid administration for pain management. Increased exposure to opioids leads to potentially harmful effects on the gastrointestinal tract, including, e.g. increased sphincter tones and decreased fluid secretion, which may impair pancreatic ductal clearance and elevate the risk for new pancreatitis attacks and accelerate disease progression. Peripherally acting µ-opioid receptor antagonists (PAMORAs) have been developed to counteract the adverse effects of opioids on the gastrointestinal tract. We hypothesize that the PAMORA naldemedine will reduce the risk of new pancreatitis attacks in patients with recurrent acute pancreatitis and hence decelerate disease progression. METHODS: The study is a double-blind, randomized controlled trial with allocation of patients to either 0.2 mg naldemedine daily or matching placebo for 12 months. A total of 120 outpatients will be enrolled from five specialist centres in Denmark and Sweden. The main inclusion criteria is a history of recurrent acute pancreatitis (minimum of two confirmed pancreatitis attacks). The primary endpoint is time to acute pancreatitis recurrence after randomization. Secondary outcomes include changes in quality of life, gastrointestinal symptom scores, new-onset diabetes, exocrine pancreatic insufficiency, disease severity, health care utilization, adherence to treatment, and frequency of adverse events. Exploratory outcomes are included for mechanistic linkage and include the progression of chronic pancreatitis-related findings on magnetic resonance imaging (MRI) and changes in circulating blood markers of inflammation and fibrosis. DISCUSSION: This study investigates if naldemedine can change the natural course of pancreatitis in patients with recurrent acute pancreatitis and improve patient outcomes. TRIAL REGISTRATION: EudraCT no. 2021-000069-34. CLINICALTRIALS: gov NCT04966559. Registered on July 8, 2021.

Incidence of Orofacial Manifestations of Juvenile Idiopathic Arthritis From Diagnosis to Adult Care Transition: A Population-Based Cohort Study.

OBJECTIVE: To estimate the cumulative incidences of orofacial conditions related to temporomandibular joint (TMJ) juvenile idiopathic arthritis (JIA) between diagnosis in childhood to transition into adult care, and to identify features in JIA associated with TMJ involvement. METHODS: A population-based cohort analysis was conducted of patients with JIA involving longitudinal data on orofacial health from 2000 to 2018. Regardless of TMJ status, the patients were referred to the Regional Specialist Craniofacial Clinic of Western Denmark for routine orofacial examinations. Data collection included information about disease-specific background characteristics, TMJ involvement, JIA-induced dentofacial deformity, and orofacial symptoms and dysfunction. RESULTS: A total of 613 patients were followed up with a mean clinical TMJ observation time of 4.0 years. From JIA onset to transition into adult care, the cumulative incidence of patients with JIA involvement of the TMJ was 30.1%. Furthermore, 20.6% of the cohort had developed arthritis-induced dentofacial deformity. A substantial proportion of the cohort experienced several events with orofacial symptoms (23.5%) and dentofacial dysfunction (52%). Young age at diagnosis (<9 years), female gender, and antinuclear antibody positivity were significantly associated with TMJ involvement. CONCLUSION: Orofacial signs and symptoms were frequent findings in children and adolescents with JIA. TMJ involvement was seen in 30.1% of the cohort; and 20.6% of the total cohort developed JIA-related dentofacial deformity before transition into adult care. This is the first population-based study in the era of available biologic treatments to document these frequent orofacial complications in children with JIA.

Cumulative Incidence of Orofacial Manifestations in Early Juvenile Idiopathic Arthritis: A Regional, Three-Year Cohort Study.

OBJECTIVE: To estimate the cumulative incidence of arthritis-induced orofacial symptoms, dysfunction, and dentofacial deformities in growing individuals with juvenile idiopathic arthritis (JIA) in a 36-month regional cohort study and to identify predictors for the development of arthritis-induced dentofacial deformities. METHODS: Data were retrieved from the Aarhus JIA temporomandibular joint (TMJ) cohort register, which contains standardized, longitudinal, observational data regarding orofacial conditions in patients with JIA (n = 1,040). This regional cohort represents the majority of all subjects with JIA from the western part of Denmark between 1990 and 2016, regardless of TMJ arthritis status. Cumulative incidences of orofacial conditions were reported using Kaplan-Meier methods, and predictors for dentofacial deformity were identified using Cox proportional hazards analysis. RESULTS: Follow-up data from 351 subjects for 36 months were included in this study. Median age at first clinical examination was 6.6 years (interquartile range 4.8-9.9 years). Orofacial symptoms and dysfunctions were common findings at 36 months after the first clinical examination and 5 years after JIA onset, with a cumulative incidence of 38% and 53%, respectively. Dentofacial deformities were found in 35% of subjects at the 36-month follow-up and were significantly associated with the presence of orofacial dysfunction. CONCLUSION: Orofacial conditions were frequently observed in individuals with JIA and were represented in all JIA subcategories in this regional study. One-third of subjects had arthritis-induced dentofacial deformities that required orthopedic appliance treatment at the 36-month follow-up.

Unaccounted uncertainty from qPCR efficiency estimates entails uncontrolled false positive rates.

BACKGROUND: Accurate adjustment for the amplification efficiency (AE) is an important part of real-time quantitative polymerase chain reaction (qPCR) experiments. The most commonly used correction strategy is to estimate the AE by dilution experiments and use this as a plug-in when efficiency correcting the Δ Δ C q . Currently, it is recommended to determine the AE with high precision as this plug-in approach does not account for the AE uncertainty, implicitly assuming an infinitely precise AE estimate. Determining the AE with such precision, however, requires tedious laboratory work and vast amounts of biological material. Violation of the assumption leads to overly optimistic standard errors of the Δ Δ C q , confidence intervals, and p-values which ultimately increase the type I error rate beyond the expected significance level. As qPCR is often used for validation it should be a high priority to account for the uncertainty of the AE estimate and thereby properly bounding the type I error rate and achieve the desired significance level. RESULTS: We suggest and benchmark different methods to obtain the standard error of the efficiency adjusted Δ Δ C q using the statistical delta method, Monte Carlo integration, or bootstrapping. Our suggested methods are founded in a linear mixed effects model (LMM) framework, but the problem and ideas apply in all qPCR experiments. The methods and impact of the AE uncertainty are illustrated in three qPCR applications and a simulation study. In addition, we validate findings suggesting that MGST1 is differentially expressed between high and low abundance culture initiating cells in multiple myeloma and that microRNA-127 is differentially expressed between testicular and nodal lymphomas. CONCLUSIONS: We conclude, that the commonly used efficiency corrected quantities disregard the uncertainty of the AE, which can drastically impact the standard error and lead to increased false positive rates. Our suggestions show that it is possible to easily perform statistical inference of Δ Δ C q , whilst properly accounting for the AE uncertainty and better controlling the false positive rate.

Bone Marrow Aspiration: A Randomized Controlled Trial Assessing the Quality of Bone Marrow Specimens Using Slow and Rapid Aspiration Techniques and Evaluating Pain Intensity.

BACKGROUND/AIMS: Bone marrow aspiration (BMA) is an essential procedure in the examination of hematological disorders, but there is limited evidence as to whether the aspiration rate affects specimen quality. We aimed to assess the specimen quality and pain intensity using slow (S-technique) or rapid (R-technique) aspiration. METHODS: This was a single-center, prospective, randomized patient- and assessor-blinded study of 482 patients scheduled for BMA. Specimen quality was evaluated by grading bone marrow (BM) cellularity and counting the number of marrow particles. Pain was assessed using a visual analog scale (VAS). RESULTS: We found a significant difference between the 2 groups with regard to the quality of specimens. For cellularity, the odds ratio (OR) for having a poor quality aspirate using the S-technique versus the R-technique was 3.05 [confidence interval (CI) 1.79-5.31]. For BM particles, the quality of specimens with the S-technique proved to be poor compared with the R-technique (OR 2.52; CI 1.51-4.28). We found a statistically significant difference of 1 VAS point (p < 0.001) of the median pain intensity in favor of the S-technique. CONCLUSION: Even though the pain intensity is significantly higher with the R-technique, the median difference is relatively small. We propose that the R-technique is preferable to the S-technique due to better specimen quality.

Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis.

PURPOSE: Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value. PATIENTS AND METHODS: We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy. RESULTS: Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP-treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell-like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis. CONCLUSION: Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.

A population-based study of prognosis in advanced stage follicular lymphoma managed by watch and wait.

Watch and wait (WAW) is a common approach for asymptomatic, advanced stage follicular lymphoma (FL), but single-agent rituximab is an alternative for these patients. In this nationwide study we describe the outcome of patients selected for WAW. A cohort of 286 out of 849 (34%) stage III-IVA FL patients seen between 2000 and 2011, were managed expectantly and included. The 5-year progression-free survival (PFS) was 35% [95% confidence interval (CI) 29-42]. The 10-year overall survival (OS) was 65% (95%CI 54-78), and the cumulative risk of dying from lymphoma within 10 years of diagnosis was 13% (95%CI 7-20). Elevated lactate dehydrogenase and > four nodal regions involved were associated with a higher risk of lymphoma treatment and death from lymphoma. The WAW patients and a matched background population had similar OS during the first 50 months after diagnosis (P = 0·7), but WAW patients had increased risk of death after 50 months (P < 0·001). The estimated loss of residual life after 10 years was 6·8 months. The 10-year cumulative risk of histological transformation was 22% (95%CI 15-29) and the 3-year OS after transformation was 71% (95%CI 58-87%). In conclusion, advanced stage FL managed by WAW had a favourable outcome and abandoning this strategy could lead to overtreatment in some patients.

Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma.

In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value  = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value  = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis.