The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression.

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

Prediction of 30-day unplanned hospital readmission through survival analysis.

Background and Objective: Unplanned hospital readmissions are a severe and recurrent problem that affects all health systems. Estimating the risk of being readmitted the following days after discharge is difficult since many heterogeneous factors can influence this. The extensive work concerning this problem proposes solutions mostly based on classification machine-learning models. Survival analysis methods could make a better match with the assessment of readmission risk and are yet to become well-established in this field. Methods: We compare different statistical and machine learning survival analysis models trained with right-censored all-cause hospital admission data with covariates available at the moment of discharge. The main focus is on tree-ensemble regression methods based on the assumption of proportional hazards. These models are more thoroughly evaluated at a 30-day time period after discharge, although the actual prediction could be set to any time up to 90 days. Results: The mean performance obtained by each of the proposed survival models ranges from 0.707 to 0.716 C-Index and 0.709 to 0.72 ROC-AUC at a 30-day time period after discharge. The model with the lower performance on both metrics was Cox Proportional Hazards, while the model marking the upper end on both ranges is an XGBoost Regression model with a Cox objective function. Conclusions: Our findings indicate that survival models perform well addressing the hospital readmission problem, machine-learning models getting the edge over statistical methods. There seems to be an improvement over classification models when attempting to predict at a 30-day period since discharge, perhaps due to a better handling of cases nearing the 30-day boundary. Some preprocessing steps, such as limiting the observation period to 90 days after discharge, are also highlighted since they resulted in a performance boost.

[Evolution and quality of life at three months after hospitalization for COVID pneumonia]. / Evolución y calidad de vida a los tres meses tras hospitalización por neumonía COVID.

OBJECTIVE: Assess clinical evolution and health-related quality of life at three months after discharge in patients who were admitted and diagnosed with COVID-19 pneumonia, evaluated by the Rehabilitation Service and received physiotherapy in Fuenlabrada Hospital. METHODS: Data were collected from 59 patients, separating those who were assessed in ICU (41 patients) from those assessed in the hospital ward (18). Data were obtained from their Electronic Medical Record, and a telephone interview was performed three months after their discharge. Data about their clinical progress during their hospitalization, after discharge, over the next months and their condition at the time of the interview is analyzed. Patients were asked to assess the quality of the physiotherapy received and to answer the SF-36 health-related quality of life questionnaire. RESULTS: These patients had the worst progress of the COVID pneumonia among all patients hospitalized in our hospital, but they had a good functional recovery with the inpatient physiotherapy received, which was positively rated. After three months, 84% have persistent symptoms, with the most common being dyspnoea, fatigue and anxiety/depression, and score worse in the SF-36 questionnaire than the reference population. CONCLUSIONS: Most patients who require rehabilitation during their COVID pneumonia admission have persistent symptoms and perceive a deterioration in their health-related quality of life after three months of discharge.

Chronic rhinosinusitis is associated with prolonged SARS-CoV-2 RNA shedding in upper respiratory tract samples: A case-control study.

BACKGROUND: SARS-CoV-2, the COVID-19 causative agent, has infected millions of people and killed over 1.6 million worldwide. A small percentage of cases persist with prolonged positive RT-PCR on nasopharyngeal swabs. The aim of this study was to determine risk factors for prolonged viral shedding amongst patient's basal clinical conditions. METHODS: We have evaluated all 513 patients attended in our hospital between 1 March and 1 July. We have selected all 18 patients with prolonged viral shedding and compared them with 36 sex-matched randomly selected controls. Demographic, treatment and clinical data were systematically collected. RESULTS: Global median duration of viral clearance was 25.5 days (n = 54; IQR, 22-39.3 days), 48.5 days in cases (IQR 38.7-54.9 days) and 23 days in controls (IQR 20.2-25.7), respectively. There were not observed differences in demographic, symptoms or treatment data between groups. Chronic rhinosinusitis and atopy were more common in patients with prolonged viral shedding (67%) compared with controls (11% and 25% respectively) (P < 0.001 and P = 0.003). The use of inhaled corticosteroids was also more frequent in case group (P = 0.007). Multivariate analysis indicated that CRS (odds ratio [OR], 18.78; 95% confidence interval [95%CI], 3.89-90.59; P < 0.001) was independently associated with prolonged SARS-CoV-2 RNA shedding in URT samples, after adjusting for initial PCR Ct values. CONCLUSION: We found that chronic rhinosinusitis and atopy might be associated with increased risk of prolonged viral shedding. If confirmed in prospective trials, this finding might have clinical implications for quarantine duration due to increased risk of pandemic spread.

Results of a self-management program added to standard physical therapy in chronic neck pain.

OBJECTIVE: To evaluate the effectiveness of a self-management treatment added to a physical therapy program compared to a physical therapy program in patients with chronic neck pain. METHODS: Fifty-three patients with chronic neck pain were randomly allocated to a physical therapy intervention (control group) or an individualized self-management combined with physical therapy intervention (experimental group). Both interventions were developed over a four-week period. Outcome measures included were Disability, Fear-Avoidance Beliefs, Health-Related Quality of Life, Pain, and Anxiety and Depression. All outcomes were measured before and after the treatment and at three-month follow-up. RESULTS: There were not significant differences between groups at baseline. After the intervention both groups obtained better results in the Neck Disability Index but there were not significant differences between them (p > 0.05). At follow-up, the self-management group obtained significant better results compared to the control group (95 % CI: -5.20(-6.8 to -1.5), p = 0.032). CONCLUSIONS: An individualized self-management program added to a physical therapy program led to a greater improvement in disability at 3 months follow up compared to a physical therapy program alone. Catastrophizing, pain, and health-related quality of life improved significantly after the intervention and at follow-up compared to the standard care alone. PRACTICAL IMPLICATIONS: This study indicates that physical therapy for patients with chronic neck pain preferably should include self-management education.

Massive spontaneous haemoperitoneum in a post-partum patient with neurofibromatosis type 1. / Hemoperitoneo espontáneo masivo en paciente puérpera afecta de neurofibromatosis tipo 1.

Neurofibromatosis type 1 (NF-1) or von Recklinghausen's disease is a genetic, progressive, multi-system disease that predominantly affects the skin and nervous system. Vascular involvement is rare, but can have catastrophic results. Pregnant patients with this disease need careful, multidisciplinary follow up in order to control possible vascular alterations, which usually affect the kidneys. We present the case of a patient diagnosed with NF-1 who debuted with massive spontaneous hemoperitoneum in the late postoperative period of an elective Cesarean section. Spontaneous bleeding from large vessels is a rare but potentially lethal complication that can occur in patients with NF-1, and may require urgent surgical treatment.

Efficacy of bortezomib to intensify the conditioning regimen and the graft-versus-host disease prophylaxis for high-risk myeloma patients undergoing transplantation.

This multicenter phase I trial was designed to evaluate the safety and efficacy of bortezomib (Bz) as part of both the conditioning regimen and the graft-versus-host disease (GvHD) prophylaxis. Patients received fludarabine, melphalan and Bz (days -9 and -2). GVHD prophylaxis consisted of Bz (days +1, +4, and +7), sirolimus (Siro) from day -5 and tacrolimus (Tk) from -3 (except the first five patients that did not receive Tk). Twenty-five patients with poor prognostic multiple myeloma were included. Eleven out of the 19 patients had high-risk features. Out of the 21 patients evaluable at day +100, 14 were in CR (67%) and 7 (33%) in PR. Cumulative incidence (CI) of nonrelapse mortality at 1 year was 24%. CI of grades 2-4 and 3-4 acute GvHD was 35% and 10%, respectively; CI of chronic GvHD was 35% and 55% at 1 and 2 years, respectively. Overall and event free survival at 2 years were 64% and 31%, respectively. Bz as part of the conditioning regimen and in the combination with Siro/tacrolimus for GvHD prophylaxis is safe and effective allowing an optimal disease control early after transplant and reducing the risk of GvHD.

Drug Challenge Tests With General Anesthetics: Predictive Value of Skin Tests.

BACKGROUND: The study of perioperative drug reactions remains a major challenge for both diagnosis and therapy. The lack of a standard assessment of allergy to general anesthetics and of data establishing the true value of skin tests for most drugs used in induction and maintenance of anesthesia, as well as the lack of commercially available reagents for in vitro tests, renders the study of these reactions problematic. The aims of this study were to provide a diagnostic protocol for drug challenge testing with general anesthetics, to establish an etiological diagnosis that is as specific as possible, and to determine the predictive value of skin tests. METHODS: Twenty-nine patients with perioperative drug reactions were included in the study from November 2008 to December 2018. RESULTS: We confirmed the high negative predictive value of the tests (96%-100%) in the case of propofol, rocuronium, and fentanyl. To our knowledge, this is the first study to describe drug challenge testing with general anesthetics and, therefore, to establish the true negative predictive value of skin tests, which leads to a definitive diagnosis and safer surgery. CONCLUSIONS: After assessing risks and benefits and considering the importance of this group of drugs, we conclude that drug challenge testing with general anesthetics is necessary. We propose a protocol for perioperative drug reactions that enables us to make a highly accurate etiological diagnosis with minimum risk for the patient.

Three-dimensional photographic analysis of the face in European adults from southern Spain with normal occlusion: reference anthropometric measurements.

BACKGROUND: Recent non-invasive 3D photography method has been applied to facial analysis, offering numerous advantages in orthodontic. The purpose of this study was to analyze the faces of a sample of healthy European adults from southern Spain with normal occlusion in order to establish reference facial soft tissue anthropometric parameters in this specific geographic-ethnic population, as well as to analyze sexual dimorphism. METHODS: A sample of 100 healthy adult volunteers consisting of 50 women (mean age, 22.92 ± 1.56 years) and 50 men (mean age, 22.37 ± 2.12 years) were enrolled in this study. All participants had normal occlusion, skeletal Class I, mesofacial pattern, and healthy body mass index. Three-dimensional photographs of the faces were captured non-invasively using Planmeca ProMax 3D ProFace®. Thirty landmarks related to the face, eyes, nose, and orolabial and chin areas were identified. RESULTS: Male displayed higher values in all vertical and transversal dimensions, with the exception of the lower lip height. Larger differences between sexes were observed in face, mandible, and nose. Male also had higher values in the angular measurements which referred to the nose. No sex differences were found in transverse upper lip prominence or transverse mandibular prominence. No differences were found in the ratio measurements, with the exception of intercantal width/nasal width, which was higher in women than in men. CONCLUSIONS: Reference anthropometric measurements of facial soft tissues have been established in European adults from southern Spain with normal occlusion. Significant sexual dimorphism was found, with remarkable differences in size between sexes.

Risk factors for symptomatic venous thromboembolism during therapy for childhood acute lymphoblastic leukemia.

BACKGROUND: Symptomatic venous thromboembolism (VTE) is an unpredictable and life-threatening toxicity, which occurs early in childhood acute lymphoblastic leukemia (ALL) therapy. Approximately 5% of children will experience VTE which is treated with anticoagulation. Asparaginase and corticosteroids are etiologic factors for VTE, however other clinical factors may modify this risk. PROCEDURE: We sought to i) assess published pre-treatment VTE risk factors ii) identify early clinical factors that were associated with VTE and iii) determine whether single nucleotide polymorphisms (SNPs) associated with VTE in non-cancer patients contributed to VTE in children with ALL. We performed a detailed, retrospective analysis of 1021 ALL patients treated between 1998 and 2013. Individual patient records were reviewed to ascertain VTE incidence and document treatment-related clinical variables. RESULTS: The incidence of VTE was 5.1%. Extremes of weight at diagnosis (<5th or >95th centile) was an independent risk factor in multivariable analysis, when added to published risk factors of age ≥10 years and mediastinal mass. When factors during induction/consolidation were considered separately: bacteremia, elevated serum gamma-glutamyl transferase and bilirubin were associated with VTE occurrence. None of the SNPs associated with VTE in non-cancer populations were significantly associated with VTE in our cohort. CONCLUSION: We found two known risk factors (age ≥ 10 years and mediastinal mass) in a large cohort of children treated for ALL and identified other factors associated with VTE such as weight extremes at diagnosis, bacteremia, and abnormal liver function which warrant further study. These VTE risk factors may form the basis of future thromboprophylaxis trials.

Correction: Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond.

Following the publication of this article the authors noted that the MRD data under the Table 1 column "Remark" of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.

Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC).

Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p ≤ 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.

Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Respiratory syncytial virus burden among adults during flu season: an underestimated pathology.

BACKGROUND: Information on the role of respiratory syncytial virus (RSV) in adult patients with influenza-like syndrome is scarce. AIM: To assess the clinical characteristics of RSV in adult patients with respiratory manifestations during a regular influenza season. METHODS: Prospective study in a tertiary Spanish hospital from December 2015 to February 2016. The study population included only adult patients with either community-acquired or hospital/healthcare-associated influenza-like illness, according to the European Centre for Disease Prevention and Control criteria. Samples were analysed using a rapid molecular assay (Xpert® Flu/RSV). RSV-positive patients were compared with a randomly negative control group and with an influenza-positive control group. FINDINGS: Twelve hundred patients with influenza-like respiratory infection were included. Overall, 114 of the samples (9%) were positive for influenza and 95 (8%) were positive for RSV. When RSV-positive and influenza-positive patients were compared, RSV-positive patients were older (57.7 vs 48.9 years; P = 0.03), and their disease was more frequently healthcare-related (26/95, 27.3% vs 5/114, 1.7%; P < 0.001). They also had significantly more antibiotics prescribed (77/95, 81.0% vs 70/114, 61.4%; P < 0.001) and more frequently needed hospital admission (93/95, 97.8% vs 69/114, 60.5%; P < 0.001). Mortality was also significantly higher in RSV-positive patients (14/95, 14.7% vs 7/114, 6.1%; P = 0.04). CONCLUSION: RSV is a major cause of moderate-to-severe respiratory infection during the influenza season; acquisition is frequently nosocomial or healthcare-related; and mortality is significantly higher than with influenza virus infection. The use of a rapid molecular test as a first-step diagnostic technique is necessary to ensure that isolation measures are implemented and that spread is prevented.

Health-related quality of life of survivors of childhood acute lymphoblastic leukemia: a systematic review.

PURPOSE: Acute lymphoblastic leukemia (ALL) survivors are the largest group of childhood cancer survivors; however, their risk for late effects is high. Cancer-related late effects have the potential to compromise health-related quality of life (HRQL) long into survivorship. None of the reviews so far have focused on ALL solely, but described HRQL for all childhood cancers. We aimed to identify ALL survivors at risk for poor HRQL and identify possible risk factors. METHOD: Following PRISMA guidelines, we performed a systematic review, searching published literature in Pubmed, PsycInfo, Embase, and the Cochrane database including all publications up to December 16, 2016. Two independent reviewers (JV and ER) screened eligible articles and assessed article quality. RESULTS: We found 31 studies representing 4356 survivors and 901 proxies. Thirteen studies found worse, eight found no difference, and three better, overall HRQL scores compared with healthy controls or norms. ALL survivors typically had better overall HRQL scores than survivors of other childhood cancers. Clinical variables (e.g., treatment received) were not consistently associated with HRQL; however, experiencing worse late effects was associated with lower HRQL. Survivor and parent socio-demographic factors and psychological factors such as resilience and depression were also associated with HRQL. CONCLUSION: ALL survivors appeared to have worse or equivalent HRQL compared with controls, but better HRQL than survivors of other cancer types. However, studies reported a wide variability in HRQL and potential risk factors for poor HRQL. Measuring ALL survivors' HRQL longitudinally and comprehensively assessing potential risk factors might identify future avenues to intervene early.