Red cell transfusion thresholds in outpatients with myelodysplastic syndromes: Results of a pilot randomized trial RBC-ENHANCE.

BACKGROUND: The optimal hemoglobin (Hb) threshold for red blood cell transfusions in adult patients with myelodysplastic syndromes (MDS) has not been defined. STUDY DESIGN AND METHODS: We conducted a pilot randomized multi-center study of two transfusion algorithms (liberal, to maintain Hb 110-120 g/L, transfuse 2 units if Hb < 105 g/L and 1 unit if Hb 105-110 g/L vs. restrictive, 85-105 g/L, transfuse 2 units when Hgb < 85 g/L). Primary objectives were 70% compliance in maintaining the q2 week hemoglobin within the targeted range and the achievement of a 15 g/L difference in pre-transfusion Hb. Secondary outcomes included measures of quality of life (QOL), iron studies and safety. RESULTS: Twenty-eight patients were randomized between February 2015-2020, 13 to the restrictive arm and 15 to the liberal arm in three tertiary care centers. The compliance was 66% and 45% and the mean pre-transfusion Hb thresholds were 86 (standard deviation [SD] 8) and 98 g/L (SD 10) in the restrictive and liberal arms, (mean difference 11.8 g/L, p < .0001), respectively. Patients in the liberal arm experienced a mean of 3.4 (SD 2.6) more transfusion visits and received a mean of 5.3 (SD 5.5) more units of blood during the 12-week study. Ferritin increased by 1043 (SD 1516) IU/L and 148 (SD 1319) IU/L in the liberal and restrictive arms, respectively. Selected QOL scores were superior pre-transfusion and more patients achieved clinically important improvements in the liberal arm compared with the restrictive arm for selected symptoms and function domains. CONCLUSION: The results establish that policies for transfusion support can be delivered in practice at multiple hospitals, but further research is required to understand the full clinical effects and safety of liberal transfusion policies in MDS outpatients.

Simple Aspiration versus Drainage for Complete Pneumothorax: A Randomized Noninferiority Trial.

Rationale: Management of first episodes of primary spontaneous pneumothorax remains the subject of debate. Objectives: To determine whether first-line simple aspiration is noninferior to first-line chest tube drainage for lung expansion in patients with complete primary spontaneous pneumothorax. Methods: We conducted a prospective, open-label, randomized noninferiority trial. Adults aged 18-50 years with complete primary spontaneous pneumothorax (total separation of the lung from the chest wall), recruited at 31 French hospitals from 2009 to 2015, received simple aspiration (n = 200) or chest tube drainage (n = 202) as first-line treatment. The primary outcome was pulmonary expansion 24 hours after the procedure. Secondary outcomes were tolerance of treatment, occurrence of adverse events, and recurrence of pneumothorax within 1 year. Substantial discordance in the numerical inputs used for trial planning and the actual trial rates of the primary outcome resulted in a reevaluation of the trial analysis plan. Measurement and Main Results: Treatment failure occurred in 29% in the aspiration group and 18% in the chest tube drainage group (difference in failure rate, 0.113; 95% confidence interval [CI], 0.026-0.200). The aspiration group experienced less pain overall (mean difference, -1.4; 95% CI, -1.89, -0.91), less pain limiting breathing (frequency difference, -0.18; 95% CI, -0.27, -0.09), and less kinking of the device (frequency difference, -0.05; 95% CI, -0.09, -0.01). Recurrence of pneumothorax was 20% in this group versus 27% in the drainage group (frequency difference, -0.07; 95% CI, -0.16, +0.02). Conclusions: First-line management of complete primary spontaneous pneumothorax with simple aspiration had a higher failure rate than chest tube drainage but was better tolerated with fewer adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT01008228).

High transferrin saturation predicts inferior clinical outcomes in patients with myelodysplastic syndromes.

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66 years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

Improvement of downscaled ozone concentrations from the transnational scale to the kilometric scale: Need, interest and new insights.

BACKGROUND: Ground-level ozone is a major public health issue worldwide. An accurate assessment of ozone exposure is necessary. Modeling tools have been developed to tackle this issue in large areas. However, these models could present inaccuracies at the local scale. OBJECTIVES: The objective of this study was i) to assess whether O3 concentrations estimated by transnational modeling at the kilometric scale (9 km2) could be improved, ii) to propose a potential correction of these downscaled ozone concentrations and iii) to evaluate the efficiency and applicability of such a correction. METHOD: The present work was carried out in three phases. First, the performance of a transnational modeling platform (PREV'EST) was assessed at 6 geographic points by comparison with data from 6 air quality monitoring stations. Performance indicators were used for this purpose (MBE (mean bias error), MAE (mean absolute error), RMSE (root mean square error), r (Pearson correlation coefficient), and target plots). Second, several corrections were developed using MARS (multivariate adaptive regression splines) and integrating different sets of variables (mean temperature, relative humidity, rainfall amount, wind speed, elevation, and date). Their performance was evaluated. Third, external validation of the corrections was conducted using the data from six additional air quality monitoring stations. RESULTS: The uncorrected PREV'EST model presented a lack of exactitude and precision. These concentrations did not reproduce the interday variability of the measurements, leading to a lack of temporal contrast in exposure data. For the best performance enhancement, the correction applied improved MBE, MAE, RMSE and r from 14.67, 19.23, 23.18 and 0.67 to 0.00, 8.00, 10.19 and 0.91, respectively. External validation confirmed the efficiency of the corrections at the regional scale. CONCLUSIONS: We propose a validated and efficient methodology integrating local environmental variables. The methodology is adaptable according to the context, needs and data available.

Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study.

The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.

Ustekinumab for Perianal Crohn's Disease: The BioLAP Multicenter Study From the GETAID.

INTRODUCTION: New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort. METHODS: We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method. RESULTS: Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively. DISCUSSION: Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.

High Prevalence of Anal Canal High-Risk Human Papillomavirus Infection in Patients With Crohn's Disease.

BACKGROUND & AIMS: The increasing incidence of anal canal carcinomas requires better knowledge on anal human papillomavirus (HPV) infection. We aimed to assess anal canal HPV infection prevalence and risk factors among patients seen at a gastroenterology department in France. METHODS: We analyzed anal tissue samples collected from 469 consecutive patients (median age 54 years, 52% women), including 112 who received immunosuppressant therapies and 101 with inflammatory bowel disease (70 with Crohn's disease), who underwent colonoscopy examinations from April 1, 2012 to April 30, 2015. HPV was detected and genotyped using the INNO-LiPA assay, and we collected medical and demographic data from all subjects. Risk factors for any HPV, high-risk HPV (HR-HPV) and HPV16 infection were assessed by bivariate and multivariate analysis. The primary outcomes association of HR-HPV or HPV16 with medical and demographic features. RESULTS: We detected HPV DNA in anal tissues from 34% of the subjects and HR-HPV in 18%. HPV16 was the most prevalent genotype (detected in 7%), followed by HPV51, HPV52, and HPV39. HR-HPV was detected in a significantly higher proportion of samples from women (23.1%) than men (12.8%) (P = .0035); HR-HPV and HPV16 were detected in a significantly higher proportion of patients with Crohn's disease (30.0%) than without (18.1%) (P = .005). Female sex, history of sexually transmitted disease, lifetime and past year-number of sexual partners, active smoking, and immunosuppressive therapies were independent risk factors for anal HR-HPV infection in multivariate analysis. CONCLUSION: One third of patients who underwent colonoscopy at a gastroenterology department were found to have anal canal HPV infection. We detected HR-HPV infection in almost 20% of patients and in a significantly higher proportion of patients with Crohn's disease than without. Increasing our knowledge of HPV infection of anal tissues could help physicians identify populations at risk and promote prophylaxis with vaccination and adequate screening.

ATHLETIQUE: interest of an adapted physical activity program in patients with juvenile idiopathic arthritis: a feasibility and preliminary effectiveness study.

Background: Juvenile Idiopathic Arthritis (JIA) is associated with joint inflammation, pain and limited joint mobility, impacting the practice of physical activities. Adapted Physical Activities (APA) are an increasingly used method of rehabilitation, but additional studies are needed to define the nature of the most appropriate physical activity for patients with JIA. The "ATHLETIQUE" project aims to evaluate the impact of a program integrating APA sessions with use of a pedometer watch, on disease activity in patients with JIA. Methods: This study will be a randomized, multicenter, open-label, controlled clinical trial with 2 parallel arms. The patients included in this study will be children and adolescents with JIA, aged 6 to 17 years. The experimental group (30 patients) will participate in an APA program for 3 months and will use a pedometer watch for one year. We will evaluate and compare the change in disease activity measurements (primary objective), fatigue, pain, quality of life, level of physical activity, functional capacities, and muscle strength (secondary objectives) after 14, 26 and 50 weeks. The control group (10 patients) will undergo the same evaluations as the experimental group but will not participate in the APA program and will not wear the pedometer watch. Expected results: The APA program may help to promote an active lifestyle with regular physical activity, preventing comorbidities and motor disability. Promising results on disease activity, functional capacities and quality of life would enable us to envisage a larger research program with a view to optimizing and assessing APA for children with JIA. Discussion: This study will be conducted in the short and medium-term, with one-year follow-up, including 3 months of APA sessions for the experimental group. The sessions proposed during the APA program will mainly be aerobic and bodyweight exercises. Furthermore, in contrast to previous studies on this topic, our study will integrate a novel element, namely the use of a pedometer watch. This watch will help to implement strategies to address motivation. This study aims to improve physical and mental well-being, provide a basis for the design of a larger study, and propose recommendations adapted to children with JIA. Trial registration: Registered with ClinicalTrials.gov under the number NCT05572424.

The burden of red blood cell transfusions in patients with lower-risk myelodysplastic syndromes and ring sideroblasts: an analysis of the prospective MDS-CAN registry.

Many patients with lower-risk myelodysplastic syndromes (LR MDS) require long-term red blood cell (RBC) transfusions to manage anemia. The consequences of RBC transfusions in LR MDS with ring sideroblasts (LR MDS-RS) are not well known. We estimated the association between cumulative RBC dose density and clinical and patient-reported outcomes using data from the MDS-CAN registry for patients enrolled between January 2008 and December 2018. Outcomes included overall survival, hospitalization, and health-related quality of life (HRQoL). A total of 145 enrolled patients with LR MDS and RS ≥5% had a median follow-up time of 27.1 months; 45 had no transfusions during follow-up, 51 had <1 transfusion per month, and 49 had ≥1 transfusion per month. The cumulative density of RBC transfusions was associated with significantly greater mortality, hospitalization, and inferior HRQoL, suggesting that exposure to RBC transfusion may constitute a significant treatment burden in patients with LR MDS-RS.

Impact of Frailty on Health Care Resource Utilization and Costs of Care in Myelodysplastic Syndromes.

PURPOSE: The role of frailty in affecting survival in myelodysplastic syndromes (MDS) is increasingly recognized. Despite this, a paucity of data exists on the association between frailty and other clinically meaningful outcomes including health care resource utilization and costs of care. METHODS: We linked the Ontario subset of the prospective Canadian MDS registry (including baseline patient/disease characteristics) to population-based health system administrative databases. Baseline frailty was calculated from the 15-item MDS-specific frailty scale (FS-15). Primary outcomes were public health care utilization and 30-day standardized costs of care (2019 Canadian dollars) determined for each phase of disease (initial, continuation, and terminal phases). Negative binomial regression was used to assess the association between frailty and health care costs with Poisson regression to explore predictors of hospitalization. RESULTS: Among 461 patients with complete FS-15 scores, 374 (81.1%) had a hospitalization with a mean length of stay of 10.6 days. Controlling for age, comorbidities, Revised International Prognostic Scoring System, and transfusion dependence, the FS-15 was independently associated with hospitalization during the initial (P = .02) and continuation (P = .01) phases but not the terminal disease phase (P = .09). The mean 30-day standardized cost per patient was $8,499 (median, $6,295; interquartile range, $2,798-$11,996), largely driven by cancer clinic visits and hospitalization. On multivariable analysis, the FS-15 was independently associated with costs of care during the initial disease phase (P = .02). CONCLUSION: We demonstrate an association between frailty and clinically meaningful outcomes including hospitalization and costs of care in patients with MDS. Our results suggest that baseline frailty may help to inform patients and physicians of expected outcomes.

Human amniotic membrane application in oral surgery-An ex vivo pilot study.

Objectives: The purpose of this pilot porcine study was to explore and illustrate the surgical application of human amniotic membrane (hAM) in an ex vivo model of medication-related osteonecrosis of the jaw (MRONJ). Material and methods: Five oral and maxillofacial surgeons participated to this study. MRONJ was simulated on porcine mandible specimens. hAM was applied using four different techniques: implantation with complete coverage, implantation with partial coverage, apposition and covering graft material. At the same time, the surgeons evaluated how well the hAM handled and its physical properties during the surgery. Results: Surgeons found that hAM had suitable mechanical properties, as it was easy to detach from the support, handle, bind to the defect and bury. hAM was also found to be strong and stable. The "implantation with complete coverage" and "implantation with partial coverage" techniques were the preferred choices for the MRONJ indication. Conclusion: This study shows that hAM is a graft material with suitable properties for oral surgery. It is preferable to use it buried under the gingiva with sutures above it, which increases its stability. This technical note aims to educate surgeons and provide them with details about the handling of hAM in oral surgery. Clinical relevance: Two surgical techniques for hAM application in MRONJ were identified and illustrated. hAM handling and physical properties during surgery were reported.

Clinical effectiveness of hypertonic sodium lactate infusion for intraoperative brain relaxation in patients undergoing scheduled craniotomy for supratentorial brain tumor resection: A study protocol of a single center double-blind randomized controlled phase II pilot trial.

INTRODUCTION: Hyperosmolar solutions are prescribed in neurosurgery patients to provide satisfactory intraoperative brain relaxation and to lower cerebral injuries related to surgical retractors. Mannitol is traditionally considered as the first-choice solution for brain relaxation in neurosurgery patients. Hypertonic sodium lactate infusion was reported to provide a higher and longer osmotic effect compared to mannitol in severely brain-injured patients and to prevent impaired cerebral energetics related to brain injuries. To date, the clinical effectiveness of hypertonic sodium lactate infusion has never been studied in neurosurgery patients. The hypothesis of the study is that hyperosmolar sodium lactate infusion may provide satisfactory intraoperative brain relaxation in patients undergoing scheduled craniotomy for supratentorial brain tumor resection. METHODS AND ANALYSIS: We designed a phase II randomized, controlled, double-blind, single-center pilot trial, and aim to include 50 adult patients scheduled for craniotomy for supratentorial brain tumor resection under general anesthesia. Patients will be randomized to receive either mannitol (conventional group) or hypertonic sodium lactate (intervention group) infusion at the time of skin incision. Brain relaxation (primary outcome) will be assessed immediately after opening the dura by the neurosurgeon blinded to the treatment allocated using a validated 4-point scale. The primary outcome is the proportion of satisfactory brain relaxation, defined as brain relaxation score of 3 or 4. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee (Comité de Protection des Personnes Est III) and authorized by the French Health Authority (Agence Nationale de Sécurité des Médicaments, Saint-Denis, France). The University Hospital of Besancon is the trial sponsor and the holder of all data and publication rights. Results of the study will be submitted for publication in a peer-review international medical journal and for presentation in abstract (oral or poster) in international peer-reviewed congresses. REGISTRATION: The trial is registered with ClinicalTrials.gov (Identifier: NCT04488874, principal investigator: Prof Guillaume Besch, date of registration: July 28, 2020).

Perioperative blood glucose variability and autonomic nervous system activity in on-pump cardiac surgery patients: Study protocol of a single-center observational study.

INTRODUCTION: On-pump coronary artery bypass graft (CABG) and surgical valve replacement (SVR) are high-risk procedures. Several studies reported that perioperative blood glucose (BG) variability was independently associated with impaired postoperative outcome. However, the underlying mechanisms contributing to increased perioperative BG variability and to its deleterious impact remain unknown. The hypothesis of the study is that perioperative BG variability could be related to perioperative alteration of the autonomic nervous system (ANS) activity and to preoperative BG variability. METHODS AND ANALYSIS: We designed a prospective observational single-center study. Four groups of 30 patients will be studied: group 1, including insulin-requiring type 2 diabetic patients undergoing on-pump CABG; group 2, including non-insulin-requiring type 2 diabetic patients undergoing on-pump CABG; group 3, including non-diabetic patients undergoing aortic SVR; and group 4, including non-diabetic patient undergoing on-pump CABG. Preoperative (baseline) and postoperative BG variability will be quantified using the Abbott's Freestyle Libre Pro sensor allowing for continuous subcutaneous BG monitoring. Preoperative (baseline) and postoperative ANS activity will be measured using noninvasive continuous heart rate monitoring (Mooky HR memory®). Blood level and urinary concentration of inflammatory and endothelial dysfunction biomarkers will be measured from blood and urinary samples at the end of the surgery and on postoperative day 1 and 2. The primary objective is to describe the relationship between baseline BG variability and postoperative BG variability. The secondary objectives are to describe the relationship: between baseline and postoperative BG variability according to the diabetes phenotype and to the type of surgery; between the ANS activity and the BG variability; and between postoperative BG variability and, urinary and blood biomarkers.

A machine learning model of response to hypomethylating agents in myelodysplastic syndromes.

Hypomethylating agents (HMA) prolong survival and improve cytopenias in individuals with higher-risk myelodysplastic syndrome (MDS). Only 30-40% of patients, however, respond to HMAs, and responses may not occur for more than 6 months after HMA initiation. We developed a model to more rapidly assess HMA response by analyzing early changes in patients' blood counts. Three institutions' data were used to develop a model that assessed patients' response to therapy 90 days after the initiation using serial blood counts. The model was developed with a training cohort of 424 patients from 2 institutions and validated on an independent cohort of 90 patients. The final model achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 in the train/test group and 0.84 in the validation group. The model provides cohort-wide and individual-level explanations for model predictions, and model certainty can be interrogated to gauge the reliability of a given prediction.

Reporting Criteria for Clinical Trials on Medication-Related Osteonecrosis of the Jaw (MRONJ): A Review and Recommendations.

Medication-related osteonecrosis of the jaw (MRONJ) is a complication caused by anti-resorptive agents and anti-angiogenesis drugs. Since we wanted to write a protocol for a randomized clinical trial (RCT), we reviewed the literature for the essential information needed to estimate the size of the active patient population and measure the effects of therapeutics. At the same time, we designed a questionnaire intended for clinicians to collect detailed information about their practices. Twelve essential criteria and seven additional items were identified and compiled from 43 selected articles. Some of these criteria were incorporated in the questionnaire coupled with data on clinical practices. Our review found extensive missing data and a lack of consensus. For example, the success rate often combined MRONJ stages, diseases, and drug treatments. The occurrence date and evaluation methods were not harmonized or quantitative enough. The primary and secondary endpoints, failure definition, and date coupled to bone measurements were not well established. This information is critical for writing a RCT protocol. With this review article, we aim to encourage authors to contribute all their findings in the field to bridge the current knowledge gap and provide a stronger database for the coming years.

Tips and Tricks and Clinical Outcome of Cryopreserved Human Amniotic Membrane Application for the Management of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Pilot Study.

Medication-related osteonecrosis of the jaw (MRONJ) is a complication of certain pharmacological treatments such as bisphosphonates, denosumab, and angiogenesis inhibitors. There are currently no guidelines on its management, particularly in advanced stages. The human amniotic membrane (hAM) has low immunogenicity and exerts anti-inflammatory, antifibrotic, antimicrobial, antiviral, and analgesic effects. It is a source of stem cells and growth factors promoting tissue regeneration. hAM acts as an anatomical barrier with suitable mechanical properties (permeability, stability, elasticity, flexibility, and resorbability) to prevent the proliferation of fibrous tissue and promote early neovascularization at the surgical site. In oral surgery, hAM stimulates healing and facilitates the proliferation and differentiation of epithelial cells in the oral mucosa and therefore its regeneration. We proposed using cryopreserved hAM to eight patients suffering from cancer (11 lesions) with stage 2-3 MRONJ on a compassionate use basis. A collagen sponge was added in some cases to facilitate hAM grafting. One or three hAMs were applied and one patient had a reapplication. Three patients had complete closure of the surgical site with proper epithelialization at 2 weeks, and two of them maintained it until the last follow-up. At 1 week after surgery, three patients had partial wound dehiscence with partial healing 3 months later and two patients had complete wound dehiscence. hAM reapplication led to complete healing. All patients remained asymptomatic with excellent immediate significant pain relief, no infections, and a truly positive impact on the patients' quality of life. No adverse events occurred. At 6 months of follow-up, 80% of lesions had complete or partial wound healing (30 and 50%, respectively), while 62.5% of patients were in stage 3. Radiological evaluations found that 85.7% of patients had stable bone lesions (n = 5) or new bone formation (n = 1). One patient had a worsening MRONJ but remained asymptomatic. One patient did not attend his follow-up radiological examination. For the first time, this prospective pilot study extensively illustrates both the handling and surgical application of hAM in MRONJ, its possible association with a collagen sponge scaffold, its outcome at the site, the application of multiple hAM patches at the same time, and its reapplication.

A natural history of lower-risk myelodysplastic syndromes with ring sideroblasts: an analysis of the MDS-CAN registry.

Patients with lower-risk (LR) myelodysplastic syndromes (MDS) with ring sideroblasts (RS) have better prognosis than those without RS, but how they fare over time is not fully understood. This study's objective was to assess the natural history of LR MDS with RS ≥5% using MDS-CAN registry individual data. Kaplan-Meier estimates and generalized linear mixed models were used to describe time-to-event outcomes and continuous outcomes, respectively. One hundred and thirty-eight patients were enrolled; median times from diagnosis to enrollment and follow-up were 6.6 and 39.6 months, respectively. Within 5 years of enrollment, 65% of patients had ≥1 red blood cell transfusion dependence episode. Within 5 years of diagnosis, 59% developed iron overload, 38% received iron chelation therapy, 14% progressed to acute myeloid leukemia, and 42% died. Patients exhibited inferior health-related quality of life trends. These first real-world data in LR MDS-RS in Canada indicate a high level of morbidity and mortality over a 5-year period. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.

Studying Clinical, Biologic and Echocardiography Criteria to Predict a Resistant Kawasaki Disease in Children.

BACKGROUND: Resistant Kawasaki disease (KD) represents 10%-15% of KD patients and increases risk of coronary artery abnormalities (CAAs). Different scores exist to predict resistant KD but only in Japanese population, although a French team has recently proposed a new scoring system. The principal objective of this study is to establish criteria to predict resistant KD in our representative French population. The second objective is an attempt to develop a predictive score of resistant KD. METHODS: We conducted a retrospective multicenter study including 2 universities and five secondary hospitals in Eastern France. Patients were included over a period from January 1, 2010 through December 31, 2019. Diagnosis of KD was recorded to the European Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative criteria. RESULTS: Two hundred two eligible patients had KD and 194 patients were analyzed: 160 sensitive KD and 34 (17.5%) resistant KD. In univariate model, serum sodium <133 mmol/L (odds ratio [OR] 2.97 [1.40-6.45]), hemoglobin level <110 g/L (OR 3.17 [1.46-7.34]), neutrophils >80% (OR 2.36 [1.03-5.25]), C reactive protein level >150 mg/L (OR 4.47 [2.07-10.19]), CAA (OR 3.85 [1.67-8.79]) or myocarditis (OR 6.98 [1.47-36.95]) at the diagnosis were statistically significant, but only serum sodium was an independent factor of resistant KD. CONCLUSION: This study shows an association between resistant KD and biologic and echocardiography criteria, but only serum sodium is an independent predictive factor. A score to predict resistant KD could not yet be established.