Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Psychomotor therapy targeting anger and aggressive behaviour in individuals with mild or borderline intellectual disabilities: A systematic review

Background: Poor anger regulation is considered a risk factor of aggression in individuals with mild or borderline intellectual disabilities. Psychomotor therapy (PMT) targets anger regulation through body- and movement-oriented interventions. This study aims to inform practitioners on efficacy and research-base of PMT in this population.

Method: This systematic review evaluated nine studies which met inclusion criteria in terms of participants, intervention procedures, outcomes and certainty of evidence.

Results: Seven studies revealed a substantial reduction of aggressive behaviour or anger. Certainty of evidence was rated inconclusive in most cases due to absence of experimental control.

Conclusions: We can conclude that body-oriented PMT, involving progressive relaxation and meditation procedure “Soles of the Feet”, is a promising approach. However, the paucity of studies and methodological limitations preclude classifying it as an evidence-based practice. This suggests stronger methodological research and research aimed at PMT’s mechanisms of action (e.g., improved interoceptive awareness) is warranted.     

Maîtrise des risques liés à la production des fluides de dialyse dans une unité de télédialyse

Objective

The “Centre Hospitalier Francois Dunan” is located on an isolated island and ensures patients care in hemodialysis thanks to telemedicine support. Many research studies have demonstrated the importance of hemodialysis fluids composition to reduce morbidity in patients on chronic hemodialysis. The aim of this study was to identify the risks inherent in the production of dialysis fluids in a particular context, in order to set up an improvement action plan to improve risk control on the production of dialysis fluids.

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

The case for a medication first approach to the treatment of opioid use disorder

Background: The opioid addiction and overdose crisis continues to ravage communities across the U.S. Maintenance pharmacotherapy using buprenorphine or methadone is the most effective intervention for Opioid Use Disorder (OUD), yet few have immediate and sustained access to these medications. Objectives: To address lack of medication access for people with OUD, the Missouri Department of Mental Health began implementing a Medication First (Med First) treatment approach in its publicly-funded system of comprehensive substance use disorder treatment programs. Methods: This Perspective describes the four principles of Med First, which are based on evidence-based guidelines. It draws conceptual comparisons between the Housing First approach to chronic homelessness and the Med First approach to pharmacotherapy for OUD, and compares state certification standards for substance use disorder (SUD) treatment (the traditional approach) to Med First guidelines for OUD treatment. Finally, the Perspective details how Med First principles have been practically implemented. Results: Med First principles emphasize timely access to maintenance pharmacotherapy without requiring psychosocial services or discontinuation for any reason other than harm to the client. Early results regarding medication utilization and treatment retention are promising. Feedback from providers has been largely favorable, though clinical- and system-level obstacles to effective OUD treatment remain. Conclusion: Like the Housing First model, Medication First is designed to decrease human suffering and activate the strengths and capacities of people in need. It draws on decades of research and facilitates partnerships between psychosocial and medical treatment providers to offer effective and life-saving care to persons with OUD.     

Outcome of isolated posterior cruciate ligament reconstruction at mean 6.3-year follow up: a consecutive case series

Objectives: There is a paucity of reporting on surgical outcomes of isolated posterior cruciate ligament reconstruction (PCLR). We hypothesize that isolated PCL injuries failing nonoperative treatment achieve good outcomes and are able to return to sport following PCLR.

Methods: A retrospective analysis was performed to identify patients with isolated PCL injuries that underwent reconstruction between 2001 and 2014. Patients with multi-ligamentous injury or another concomitant knee pathology were excluded. Medical records were reviewed for demographic, clinical and operative data. Patients were contacted for administration of a telephone-based questionnaire which included the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form, Lysholm-Tegner scales, Marx activity scale (MAS), return to sport status, and patient satisfaction instruments.

Results: A total of 15 isolated PCL reconstructions in 14 patients with a mean age of 27.5 years (range 17–43) met the study inclusion criteria; mean follow up was 6.3 years (range 1.4–15.2). Pre-operatively, the primary complaint was knee instability in all patients; on physical examination, lack of a firm end point during posterior drawer testing was found in 93% (14/15) of the knees. In total, 12 of 15 knees underwent transtibial, single-bundle PCLR and three of 15 underwent tibial inlay, double bundle PCLR. Graft types included: quadriceps autograft (7/15), Achilles allograft (6/15), and hamstring autograft (2/15). There were no graft failures in our patient cohort. At most recent follow up the mean scores respectively on the IKDC form, Lysholm-Tegner scales and MAS were (standard deviation): 77.3 (16.5), 83.1 (17.9), 6.13 (2.6), and 7.1 (6.0). All fourteen patients were athletes prior to their injury and 79% (11/14) returned to sport and overall patient satisfaction was 9.2/10.

Conclusions: Isolated PCLR provides good outcomes at mean medium-term follow up with restoration of function, high rate of return to sport and overall patient satisfaction.