Treatment-induced cerebral sinus venous thrombosis in childhood acute lymphoblastic malignancies: New risk factors to consider.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is one of the many side effects encountered during acute lymphoblastic leukemia (ALL) therapy. Due to the rarity of cases, lack of data, and consensus management, no recommendations exist to target the population at risk. METHODS: This is a retrospective chart review of 229 consecutive patients diagnosed with ALL with an age range of 1-21 years, treated at the Children's Cancer Center of Lebanon between October 2007 and February 2018. RESULTS: The incidence of CSVT was 10.5%. Using univariate analysis, increased risk of CSVT was observed with male gender, age >10 years, T-cell immunophenotype, intermediate/high-risk disease, maximum triglyceride (TG) level of >615 mg/dl, presence of mediastinal mass, and larger body surface area (BSA). With multivariate analysis, the only statistically significant risk factors were maximum TG level, BSA, presence of mediastinal mass, and risk stratification (intermediate/high risk). CONCLUSION: Our study was able to unveil TG level of >615 mg/dl, mediastinal mass, and a larger BSA as novel risk factors that have not been previously discussed in the literature.

Height mismatch: An overlooked component of adult heart transplant outcomes.

Heart transplantation guidelines recommend against matching donors with significant weight but not height discrepancies. This study analyzed the impact of donor-recipient height mismatch on mortality among heart transplant recipients. We retrospectively analyzed all adult patients in the United Network for Organ Sharing (UNOS) registry undergoing heart transplantation from 1990 to September 2016. Moderate and severe height mismatch were classified as >10% and >15% difference in donor height from recipient height, respectively. The primary outcome was 1-year mortality. Adjusted Cox hazards regression was performed, and Kaplan-Meier estimates illustrated 10-year survival. Of 44 877 transplants, 4822 (10.7%) were moderately height mismatched. Height-mismatched recipients were more frequently female (41.6% vs 21.8%, P < .001), sex mismatched (53.8% vs 24.9%, P < .001), and weight mismatched (4.9% vs 1.9%, P < .001). After adjustment, recipients of moderately (HR = 1.15 [1.02-1.30]) and severely (HR = 1.38 [1.10-1.74]) taller donor hearts were at increased risk of mortality at 1 year relative to height-matched recipients. Furthermore, of 1042 (21.6%) severe mismatches, recipients with taller (HR = 1.39 [1.11-1.74]) but not shorter (HR = 0.79 [0.44-1.43]) donors faced increased 10-year mortality. The effect was pronounced among re-transplant candidates (HR = 1.96 [1.07-3.59]). In conclusion, matching with moderately or severely taller donors is an independent predictor of mortality among primary and re-transplant candidates.

Donor history of malignancy: A limited risk for heart transplant recipients.

Organ donor contraindications are frequently reassessed for impact on recipient outcomes in attempt to meet demand for transplantation. This study retrospectively analyzed the United Network for Organ Sharing (UNOS) registry for adult heart transplants from 1987 to September 2016 to characterize the impact of donor malignancy history in heart transplantation. Kaplan-Meier estimates illustrated 10-year survival. Propensity score matching was utilized for 1:1 matching of donors with and without history of malignancy, and Cox proportional hazards and logistic regressions were used to analyze the matched population. Of 38 781 heart transplants, 622 (1.6%) had a donor history of malignancy. Cox regressions demonstrated that donor malignancy predicted increased 10-year mortality (HR = 1.16 [1.01-1.33]), but this difference did not persist when conditioned upon 1 year post-transplant survival (log-rank = 0.643). Cox regressions of the propensity score-matched population (455 pairs) found no association between donor malignancy and 10-year mortality (HR = 1.02 [0.84-1.24]). Older age and higher rates of hypertension were observed in donors with a history of malignancy whose recipients died within the first year post-transplant. Therefore, increased recipient mortality is likely due to donor characteristics beyond malignancy, creating the potential for expanded donor selection.

Isolated Central Nervous System Relapse Following Treatment Reduction in Low-risk Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon.

The aim of this trial was to decrease the incidence of life-threatening infections by decreasing the dose and the duration of dexamethasone treatment during maintenance therapy. This was a prospective, nonrandomized trial of low-risk acute lymphoblastic leukemia patients 1 to 18 years of age who were treated at the Children's Cancer Center of Lebanon (CCCL). Patients consecutively diagnosed between 2002 and 2013 were divided into groups 1 and 2 receiving total dexamethasone doses of 1144 and 618 mg/m, respectively. A total of 84 patients were assigned to group 1 and 33 patients to group 2. The 5-year cumulative incidence of isolated central nervous system relapse increased from (n=0% [95% confidence interval: 0%-4.4%]) in group 1 to 9.1% [95% confidence interval: 3%-23%]; P=0.021) in group 2. Decreasing cumulative dose of dexamethasone for low-risk childhood acute lymphoblastic leukemia patients aiming to avoid serious viral infections led to a significant increase in isolated central nervous system relapse.

Impact of Approach and Hospital Volume on Cardiovascular Complications After Pulmonary Lobectomy.

BACKGROUND: Cardiovascular complications contribute significantly to the morbidity and resource utilization after pulmonary resections. Maturation of less-invasive technologies, such as video and robot-assisted thoracoscopic surgery, aims at improving postoperative outcomes by reducing the trauma of surgery. The present work aimed to evaluate changes in cardiovascular complications after open and minimally invasive lobectomies in the United States. METHODS: We performed a retrospective analysis of the Nationwide Inpatient Sample for patients having elective open, video-assisted, and robot-assisted thoracoscopic lobectomy during 2008-2014. Logistic regression was performed to determine predictors of in-hospital mortality, myocardial infarction (MI), cardiac arrest (CA), and postoperative pulmonary embolism (PE). RESULTS: A total of 201,226 patients underwent pulmonary lobectomy over the study period. Open thoracotomy (OPEN) approach has steadily decreased from 75%-52% (P < 0.0001), whereas minimally invasive surgery (MIS) utilization has increased from 25%-48% (P < 0.0001) of all lobectomies. MIS approach was independently associated with decreased odds of mortality (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.50-0.73) and PE (OR 0.67, 95% CI 0.50-0.91). MIS patients at high volume institutions had the lowest odds of all-cause mortality (OR 0.27, 95% CI 0.26-0.53) and MI (OR 0.57, 95% CI 0.38-0.87). Operative approach and institutional lobectomy caseload reduced odds of mortality after MI, CA, or PE. Overall, the incidence of MI, CA, and PE increased. CONCLUSIONS: MIS lobectomies increased without a concurrent reduction in perioperative MI, CA, or PE incidence. High hospital lobectomy volume and MIS approach decrease odds of failure to rescue. Improved perioperative management of cardiovascular risk is warranted to reduce the morbidity, mortality, and resource utilization associated with these complications.

Laparoscopic Adjustable Gastric Band Colonization May Indicate Re-classification of Surgical Wounds.

BACKGROUND: Surgical wounds are classified as either clean, clean-contaminated, contaminated, or dirty wounds. Historically laparoscopic adjustable gastric band (LAGB) removals have been classified as clean wounds since there is thought to be no existing infection and no transection of the gastrointestinal tract. Surgical site infection (SSI) remains a publicly reported source of morbidity after laparoscopic bariatric surgery and is considered a CMS hospital-acquired condition. We present a retrospective chart review to reveal the rate of bacterial colonization of gastric bands. METHODS: This retrospective chart review included 15 patients who underwent removal of LAGB. The entire LAGB and port were removed and then sent for aerobic and anaerobic cultures. Patients were followed up to 1 month, and the incidence of surgical site infection development was recorded. RESULTS: Of the fifteen LAGBs cultured, eight cases (53%) returned positive for bacterial growth. Five of the cultures (33%) were positive for coagulase-negative Staphylococcus. One culture was positive for micrococcus species (6.7%), one culture was positive for Bacteroides fragilis (6.7%) and another was positive for Propionibacterium (6.7%). None of the 15 patients followed in the study developed an SSI by the end of 1 month. CONCLUSIONS: Given the consideration of LAGB removals as clean wounds, the incidence of LAGB colonization is high. Classification of the surgical wounds in LAGB removals should be changed from clean to contaminated. Further studies need to be pursued to determine the correlation between colonized LAGBs and the rate of SSIs. KEY POINTS: • Gastric band removals are a common bariatric procedure. • Surgical site infection remains an outcome of interest to patient, surgeon and payor. • Fifty-three percent of recovered bands were positive for bacterial growth.

Mass spectrometry-detected MGUS is associated with obesity and other novel modifiable risk factors in a high-risk population.

ABSTRACT: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition of multiple myeloma with few known risk factors. The emergence of mass spectrometry (MS) for the detection of MGUS has provided new opportunities to evaluate its risk factors. In total, 2628 individuals at elevated risk for multiple myeloma were enrolled in a screening study and completed an exposure survey (PROMISE trial). Participant samples were screened by MS, and monoclonal proteins (M-proteins) with concentrations of ≥0.2 g/L were categorized as MS-MGUS. Multivariable logistic models evaluated associations between exposures and MS outcomes. Compared with normal weight (body mass index [BMI] of 18.5 to <25 kg/m2), obesity (BMI of ≥30 kg/m2) was associated with MS-MGUS, adjusting for age, sex, Black race, education, and income (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.21-2.47; P = .003). High physical activity (≥73.5 metabolic equivalent of task (MET)-hours per week vs <10.5 MET-hours per week) had a decreased likelihood of MS-MGUS (OR, 0.45, 95% CI, 0.24-0.80; P = .009), whereas heavy smoking and short sleep had increased likelihood of MS-MGUS (>30 pack-years vs never smoker: OR, 2.19; 95% CI, 1.24-3.74; P = .005, and sleep <6 vs ≥6 hours per day: OR, 2.11; 95% CI, 1.26-3.42; P = .003). In the analysis of all MS-detected monoclonal gammopathies, which are inclusive of M-proteins with concentrations of <0.2 g/L, elevated BMI and smoking were associated with all MS-positive cases. Findings suggest MS-detected monoclonal gammopathies are associated with a broader range of modifiable risk factors than what has been previously identified. This trial was registered at www.clinicaltrials.gov as #NCT03689595.

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone.

Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit in previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet studies have been examined in this same population. However, to date, none of these studies examined the impact of depth of response on long-term outcomes of participants treated with lenalidomide-based therapy, and whether the use of the 20/2/20 model or the addition of genomic alterations can further define the population that would benefit the most from early therapeutic intervention. Here, we present the results of the phase II study of the combination of ixazomib, lenalidomide, and dexamethasone in patients with HR-SMM with long-term follow-up and baseline single-cell tumor and immune sequencing that help refine the population to be treated for early intervention studies. Methods: This is a phase II trial of ixazomib, lenalidomide, and dexamethasone (IRD) in HR-SMM. Patients received 9 cycles of induction therapy with ixazomib 4mg on days 1, 8, and 15; lenalidomide 25mg on days 1-21; and dexamethasone 40mg on days 1, 8, 15, and 22. The induction phase was followed by maintenance with ixazomib 4mg on days 1, 8, and 15; and lenalidomide 15mg d1-21 for 15 cycles for 24 months of treatment. The primary endpoint was progression-free survival after 2 years of therapy. Secondary endpoints included depth of response, biochemical progression, and correlative studies included single-cell RNA sequencing and/or whole-genome sequencing of the tumor and single-cell sequencing of immune cells at baseline. Results: Fifty-five patients, with a median age of 64, were enrolled in the study. The overall response rate was 93%, with 31% of patients achieving a complete response and 45% achieving a very good partial response or better. The most common grade 3 or greater treatment-related hematologic toxicities were neutropenia (16 patients; 29%), leukopenia (10 patients; 18%), lymphocytopenia (8 patients; 15%), and thrombocytopenia (4 patients; 7%). Non-hematologic grade 3 or greater toxicities included hypophosphatemia (7 patients; 13%), rash (5 patients; 9%), and hypokalemia (4 patients; 7%). After a median follow-up of 50 months, the median progression-free survival (PFS) was 48.6 months (95% CI: 39.9 - not reached; NR) and median overall survival has not been reached. Patients achieving VGPR or better had a significantly better progression-free survival (p<0.001) compared to those who did not achieve VGPR (median PFS 58.2 months vs. 31.3 months). Biochemical progression preceded or was concurrent with the development of SLiM-CRAB criteria in eight patients during follow-up, indicating that biochemical progression is a meaningful endpoint that correlates with the development of end-organ damage. High-risk 20/2/20 participants had the worst PFS compared to low- and intermediate-risk participants. The use of whole genome or single-cell sequencing of tumor cells identified high-risk aberrations that were not identified by FISH alone and aided in the identification of participants at risk of progression. scRNA-seq analysis revealed a positive correlation between MHC class I expression and response to proteasome inhibition and at the same time a decreased proportion of GZMB+ T cells within the clonally expanded CD8+ T cell population correlated with suboptimal response. Conclusions: Ixazomib, lenalidomide and dexamethasone in HR-SMM demonstrates significant clinical activity with an overall favorable safety profile. Achievement of VGPR or greater led to significant improvement in time to progression, suggesting that achieving deep response is beneficial in HR-SMM. Biochemical progression correlates with end-organ damage. Patients with high-risk FISH and lack of deep response had poor outcomes. ClinicalTrials.gov identifier: (NCT02916771).

Clinical Outcomes and Evolution of Clonal Hematopoiesis in Patients with Newly Diagnosed Multiple Myeloma.

Clonal hematopoiesis (CH) at time of autologous stem cell transplant (ASCT) has been shown to be associated with decreased overall survival (OS) and progression-free survival (PFS) in patients with multiple myeloma not receiving immunomodulatory drugs (IMiD). However, the significance of CH in newly diagnosed patients, including transplant ineligible patients, and its effect on clonal evolution during multiple myeloma therapy in the era of novel agents, has not been well studied. Using our new algorithm to differentiate tumor and germline mutations from CH, we detected CH in approximately 10% of 986 patients with multiple myeloma from the Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) cohort (40/529 transplanted and 59/457 non-transplanted patients). CH was associated with increased age, risk of recurrent bacterial infections and cardiovascular disease. CH at time of multiple myeloma diagnosis was not associated with inferior OS or PFS regardless of undergoing ASCT, and all patients benefited from IMiD-based therapies, irrespective of the presence of CH. Serial sampling of 52 patients revealed the emergence of CH over a median of 3 years of treatment, increasing its prevalence to 25%, mostly with DNMT3A mutations. SIGNIFICANCE: Using our algorithm to differentiate tumor and germline mutations from CH mutations, we detected CH in approximately 10% of patients with newly diagnosed myeloma, including both transplant eligible and ineligible patients. Receiving IMiDs improved outcomes irrespective of CH status, but the prevalence of CH significantly rose throughout myeloma-directed therapy.

Personalised progression prediction in patients with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma (PANGEA): a retrospective, multicohort study.

BACKGROUND: Patients with precursors to multiple myeloma are dichotomised as having monoclonal gammopathy of undetermined significance or smouldering multiple myeloma on the basis of monoclonal protein concentrations or bone marrow plasma cell percentage. Current risk stratifications use laboratory measurements at diagnosis and do not incorporate time-varying biomarkers. Our goal was to develop a monoclonal gammopathy of undetermined significance and smouldering multiple myeloma stratification algorithm that utilised accessible, time-varying biomarkers to model risk of progression to multiple myeloma. METHODS: In this retrospective, multicohort study, we included patients who were 18 years or older with monoclonal gammopathy of undetermined significance or smouldering multiple myeloma. We evaluated several modelling approaches for predicting disease progression to multiple myeloma using a training cohort (with patients at Dana-Farber Cancer Institute, Boston, MA, USA; annotated from Nov, 13, 2019, to April, 13, 2022). We created the PANGEA models, which used data on biomarkers (monoclonal protein concentration, free light chain ratio, age, creatinine concentration, and bone marrow plasma cell percentage) and haemoglobin trajectories from medical records to predict progression from precursor disease to multiple myeloma. The models were validated in two independent validation cohorts from National and Kapodistrian University of Athens (Athens, Greece; from Jan 26, 2020, to Feb 7, 2022; validation cohort 1), University College London (London, UK; from June 9, 2020, to April 10, 2022; validation cohort 1), and Registry of Monoclonal Gammopathies (Czech Republic, Czech Republic; Jan 5, 2004, to March 10, 2022; validation cohort 2). We compared the PANGEA models (with bone marrow [BM] data and without bone marrow [no BM] data) to current criteria (International Myeloma Working Group [IMWG] monoclonal gammopathy of undetermined significance and 20/2/20 smouldering multiple myeloma risk criteria). FINDINGS: We included 6441 patients, 4931 (77%) with monoclonal gammopathy of undetermined significance and 1510 (23%) with smouldering multiple myeloma. 3430 (53%) of 6441 participants were female. The PANGEA model (BM) improved prediction of progression from smouldering multiple myeloma to multiple myeloma compared with the 20/2/20 model, with a C-statistic increase from 0·533 (0·480-0·709) to 0·756 (0·629-0·785) at patient visit 1 to the clinic, 0·613 (0·504-0·704) to 0·720 (0·592-0·775) at visit 2, and 0·637 (0·386-0·841) to 0·756 (0·547-0·830) at visit three in validation cohort 1. The PANGEA model (no BM) improved prediction of smouldering multiple myeloma progression to multiple myeloma compared with the 20/2/20 model with a C-statistic increase from 0·534 (0·501-0·672) to 0·692 (0·614-0·736) at visit 1, 0·573 (0·518-0·647) to 0·693 (0·605-0·734) at visit 2, and 0·560 (0·497-0·645) to 0·692 (0·570-0·708) at visit 3 in validation cohort 1. The PANGEA models improved prediction of monoclonal gammopathy of undetermined significance progression to multiple myeloma compared with the IMWG rolling model at visit 1 in validation cohort 2, with C-statistics increases from 0·640 (0·518-0·718) to 0·729 (0·643-0·941) for the PANGEA model (BM) and 0·670 (0·523-0·729) to 0·879 (0·586-0·938) for the PANGEA model (no BM). INTERPRETATION: Use of the PANGEA models in clinical practice will allow patients with precursor disease to receive more accurate measures of their risk of progression to multiple myeloma, thus prompting for more appropriate treatment strategies. FUNDING: SU2C Dream Team and Cancer Research UK.

Barriers to Receiving Necessary Hearing Care Among US Children.

OBJECTIVE: We aim to clarify the national scope of unmet pediatric hearing care needs and identify specific barriers to hearing care. STUDY DESIGN: Cross-sectional study of a nationally representative data set. SETTING: This study is based on the combined 2016 and 2017 National Survey of Children's Health. This survey covers the physical and emotional health, access to care, and social context of US children and adolescents aged 0 to 17 years. METHODS: Analysis of parent-reported responses of children's hearing status, access to care, and perceived barriers. RESULTS: Overall, 0.3% (n = 206,200) of US children surveyed reported needing hearing care, which was not received. A further 1.3% (n = 934,000) reported deafness or problems with hearing, and of these, 6.4% (n = 60,000) reported not receiving necessary hearing care. Rates of insurance coverage between children with deafness/hearing problems and the general population were similar (91.7% vs 93.9%); however, deaf or hard-of-hearing children with unmet hearing care needs were more likely to be from non-White backgrounds (P = .009) and to lack health insurance coverage (P = .001). Rates of unfulfilled hearing care by reason were as follows: 57.5% without eligibility for the service, 45.4% reporting the service was not available in their area, 53.7% with difficulty obtaining an appointment, and 53.5% reporting issues with cost. CONCLUSION: Over 200,000 children annually do not receive necessary hearing-related care despite high rates of insurance coverage, and nearly 60,000 of these children are deaf or hard of hearing. Cost, eligibility for and distribution of services, and timely appointments are the primary barriers to hearing health care.

First report from the American Society of Metabolic and Bariatric Surgery closed-claims registry: prevalence, causes, and lessons learned from bariatric surgery medical malpractice claims.

BACKGROUND: Bariatric surgery has demonstrated sustained improvements in quality. Malpractice closed claims have been offered as a means of assessing quality. Few studies have investigated malpractice closed claims and opportunities for improvement in bariatric surgery. OBJECTIVES: To examine the prevalence and causes of malpractice claims with examination of prospects for quality improvement. SETTING: University hospital, United States; private practice. METHODS: Four national malpractice insurers participated in the closed-claims registry. Data regarding patients, staff, procedures, and hospital status were gathered from closed-claims files. Following data collection, a clinical summary of each closed claim was collected and later assessed by an expert panel on the basis of the following: contributing diagnosis and treatment events; whether complications were potentially preventable by the surgeon; the role of language, fatigue, distraction, workload, or teaching hospital/trainee supervision; communication concerns; and final care determination. RESULTS: A total of 175 closed claims were collected from index bariatric surgeries within the period from 2006-2014. Of these, 75.9% of surgeons were board certified and 43.3% of the hospitals were accredited for bariatric surgery. Most clinical complications after bariatric surgery that led to malpractice lawsuits were mortality (35.1%) and leaks (17.5%). While they were not the common cause for malpractice suits, bleeding (5.3%), retained foreign body (5.3%), and vascular injury (4.4%) occurred at higher rates than national averages. CONCLUSION: Prevalence of malpractice claims regarding bariatric surgery is low. Failure to diagnose, delay in treatment, postoperative care, and communication domain responses indicate future opportunities for improvement.

Medicine in Unplanned Mass Gatherings: A Qualitative Study of Health-Care Providers' Response and Recommendations to Beirut's Protests.

OBJECTIVE: This study aims at exploring the dynamics of health-care provision during recent unplanned public mass gatherings in Beirut, and how the health-care system adapts to mass movements in protests. METHODS: A qualitative study was conducted using semi-structured interviews with 12 health-care providers who volunteered at medical tents set during protests in Beirut, Lebanon. Responses were transcribed and coded. RESULTS: Three themes were noted: preparedness and logistics, encountered cases, and participants' proposed recommendations. In terms of preparedness and logistics, participants lacked knowledge of field medicine protocols and an organizational structure. They faced difficulties in securing equipment and advertising their services. Most encountered cases were physical injuries rather than mental health problems. The participants proposed both short-term recommendations, including advice on how to boost care provided, and long-term recommendations on structuring the health-care system to be better prepared. CONCLUSIONS: On-site health-care provision during unplanned mass gatherings is a vital need. We recommend forming a task force of health-care workers from various fields led by the Ministry of Public Health in every respective country to plan protocols, train personnel, and secure resources beforehand.

Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia.

Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. We report the prevalence of CH in patients with Waldenström macroglobulinemia (WM) and its association with clinical outcomes. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA) and was detected in 14% of 587 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM) or WM. The presence and size of DTA clones were associated with older age. Patients with CH had an increased risk of progression from MGUS or SWM to WM, but not worse overall survival in this cohort. These findings further illuminate the clinical effects of CH in patients with indolent NHL such as WM.

Single cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis.

Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.

Prevalence of monoclonal gammopathies and clinical outcomes in a high-risk US population screened by mass spectrometry: a multicentre cohort study.

BACKGROUND: Prevalence estimates for monoclonal gammopathy of undetermined significance (MGUS) are based on predominantly White study populations screened by serum protein electrophoresis supplemented with immunofixation electrophoresis. A prevalence of 3% is reported for MGUS in the general population of European ancestry aged 50 years or older. MGUS prevalence is two times higher in individuals of African descent or with a family history of conditions related to multiple myeloma. We aimed to evaluate the prevalence and clinical implications of monoclonal gammopathies in a high-risk US population screened by quantitative mass spectrometry. METHODS: We used quantitative matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and EXENT-iQ software to screen for and quantify monoclonal gammopathies in serum from 7622 individuals who consented to the PROMISE screening study between Feb 26, 2019, and Nov 4, 2021, and the Mass General Brigham Biobank (MGBB) between July 28, 2010, and July 1, 2021. M-protein concentrations at the monoclonal gammopathy of indeterminate potential (MGIP) level were confirmed by liquid chromatography mass spectrometry testing. 6305 (83%; 2211 from PROMISE, 4094 from MGBB) of 7622 participants in the cohorts were at high risk for developing a monoclonal gammopathy on the basis of Black race or a family history of haematological malignancies and fell within the eligible high-risk age range (30 years or older for PROMISE cohort and 18 years or older for MGBB cohort); those over 18 years were also eligible if they had two or more family members with a blood cancer (PROMISE cohort). Participants with a plasma cell malignancy diagnosed before screening were excluded. Longitudinal clinical data were available for MGBB participants with a median follow-up time from serum sample screening of 4·5 years (IQR 2·4-6·7). The PROMISE study is registered with ClinicalTrials.gov, NCT03689595. FINDINGS: The median age at time of screening was 56·0 years (IQR 46·8-64·1). 5013 (66%) of 7622 participants were female, 2570 (34%) male, and 39 (<1%) unknown. 2439 (32%) self-identified as Black, 4986 (65%) as White, 119 (2%) as other, and 78 (1%) unknown. Using serum protein electrophoresis with immunofixation electrophoresis, the MGUS prevalence was 6% (101 of 1714) in high-risk individuals aged 50 years or older. Using mass spectrometry, we observed a total prevalence of monoclonal gammopathies of 43% (1788 of 4207) in this group. We termed monoclonal gammopathies below the clinical immunofixation electrophoresis detection level (<0·2 g/L) MGIPs, to differentiate them from those with higher concentrations, termed mass-spectrometry MGUS, which had a 13% (592 of 4207) prevalence by mass spectrometry in high-risk individuals aged 50 years or older. MGIP was predominantly of immunoglobulin M isotype, and its prevalence increased with age (19% [488 of 2564] for individuals aged <50 years, 29% [1464 of 5058] for those aged ≥50 years, and 37% [347 of 946] for those aged ≥70 years). Mass-spectrometry MGUS prevalence increased with age (5% [127 of 2564] for individuals aged <50 years, 13% [678 of 5058] for those aged ≥50 years, and 18% [173 of 946] for those aged ≥70 years) and was higher in men (314 [12%] of 2570) compared with women (485 [10%] 5013; p=0·0002), whereas MGIP prevalence did not differ significantly by gender. In those aged 50 years or older, the prevalence of mass spectrometry was significantly higher in Black participants (224 [17%] of 1356) compared with the controls (p=0·0012) but not in those with family history (368 [13%] of 2851) compared with the controls (p=0·1008). Screen-detected monoclonal gammopathies correlated with increased all-cause mortality in MGBB participants (hazard ratio 1·55, 95% CI 1·16-2·08; p=0·0035). All monoclonal gammopathies were associated with an increased likelihood of comorbidities, including myocardial infarction (odds ratio 1·60, 95% CI 1·26-2·02; p=0·00016 for MGIP-high and 1·39, 1·07-1·80; p=0·015 for mass-spectrometry MGUS). INTERPRETATION: We detected a high prevalence of monoclonal gammopathies, including age-associated MGIP, and made more precise estimates of mass-spectrometry MGUS compared with conventional gel-based methods. The use of mass spectrometry also highlighted the potential hidden clinical significance of MGIP. Our study suggests the association of monoclonal gammopathies with a variety of clinical phenotypes and decreased overall survival. FUNDING: Stand Up To Cancer Dream Team, the Multiple Myeloma Research Foundation, and National Institutes of Health.

Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.

Preoperative Predictors and Costs of 30-Day Readmission Following Inpatient Pediatric Tonsillectomy in the United States.

OBJECTIVES: To understand national trends in 30-day postoperative readmission following inpatient pediatric tonsillectomy and adenoidectomy. STUDY DESIGN: Retrospective cohort study. SETTING: Nationwide Readmissions Database. METHODS: We used the Nationwide Readmissions Database to identify and analyze 30-day readmissions following inpatient tonsillectomy from 2010 to 2015. Using the International Classification of Disease codes, we identified 66,652 patients and analyzed the incidence, causes, risk factors, and costs of 30-day readmission. RESULTS: Of 66,652 patients who underwent inpatient tonsillectomy, 2660 (4.0%) experienced a readmission. Readmitted patients were more commonly aged <2 years (23.4 vs 10.6%, P = .01) and had a greater burden of comorbidities, including preoperative anemia (3.9 vs 1.3%, P < .001), coagulopathy (3.5 vs 1.4%, P < .001), and neurologic disorders (19.1 vs 6.6%, P < .001). Readmitted patients experienced higher rates of postoperative complications (17.4 vs 9.0%, P < .001) and had a longer length of stay (4.5 vs 2.2 days, P < .001). Index cost of hospitalization was higher among readmitted patients ($14,129 vs $7307, P < .001), and each readmission cost an additional $7576. Postoperative hemorrhage (21.3%) and dehydration (17.7%) were the 2 most common causes for readmission. Independent predictors of readmission included age <3 years, multiple comorbidities, and postoperative neurologic complications. The incidences of tonsillectomies and readmissions declined during the study period, most notably between 2010 and 2012. CONCLUSION: Readmission after inpatient tonsillectomy and adenoidectomy places a substantial financial burden on the health care system. Targeted strategies to improve preoperative assessment and optimize postoperative care may prevent readmission, reduce unnecessary health care expenditures, and improve patient outcomes.

National Analysis of 30-Day Readmission Following Inpatient Sinus Surgery for Chronic Rhinosinusitis.

OBJECTIVES: To characterize the incidence, causes, risk factors, and costs of 30-day readmission after inpatient functional endoscopic sinus surgery (FESS) for patients with chronic rhinosinusitis. STUDY DESIGN: Retrospective cohort study. METHODS: The Nationwide Readmissions Database was used to characterize readmission after inpatient sinus surgery for chronic rhinosinusitis from 2015 to 2017. International Classification of Disease codes were used to identify the patient population, which included 5,644 patients. Incidence, causes, costs, and predictors of readmission were analyzed and determined. RESULTS: Among 6,386 patients who underwent inpatient FESS, 742 (11.6%) were readmitted within 30 days of discharge. On univariate analysis, patients who were readmitted were more commonly older than 70 years (23.3% vs. 16.2%); had a higher burden of comorbidities including chronic kidney disease (15.0% vs. 7.8%), diabetes (25.6% vs. 20.4%), and hypertension (13.5% vs. 8.5%); had a greater rate of postoperative complications (20.7% vs. 12.2%); and had a longer length of stay (12.4 vs. 6.9 days) compared to patients who were not readmitted. Readmissions cost an additional $27,141 per patient. On multivariable analysis, age greater than 70 years, Medicaid insurance, several comorbidities, prolonged length of stay, postoperative neurologic complications, and lower hospital volume were independent predictors of 30-day readmission. The most common cause for readmission was infection (36.3%). CONCLUSION: Readmission following inpatient FESS is not uncommon. Identification and management of preoperative comorbidities, optimized patient selection for inpatient surgery, and thorough postoperative discharge care may improve patient outcomes and decrease healthcare expenditures. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1422-E1428, 2021.

A GRIN3A polymorphism may be associated with glucocorticoid-induced symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

Aim: To evaluate the association between candidate genetic polymorphisms and glucocorticoid-induced osteonecrosis in Arab children treated for acute lymphoblastic leukemia. Methods: A total of 189 children treated for acute lymphoblastic leukemia were genotyped for four SNPs with allele discrimination assays. The incidence and timing of radiologically confirmed symptomatic grade 4 osteonecrosis were classified based on the Ponte di Legno toxicity working group consensus definition. Results: Thirteen children developed grade 4 osteonecrosis (6.8%), of whom 12 received the intermediate/high-risk treatment protocol. GRIN3A variant allele carriers had to stop dexamethasone therapy earlier resulting in significantly shorter duration of dexamethasone treatment (mean [95% CI]: 75.17 [64.28-86.06] vs 85.90 [81.22-90.58] weeks; p = 0.054) and lower cumulative dose (mean [95% CI]: 1118.11 [954.94-1281.29] vs 1341.14 [1264.17-1418.11] mg/m2; p = 0.011). Conclusion: This is the first pharmacogenomics evaluation of the association between GRIN3A variants and glucocorticoid-induced osteonecrosis in Arab children.

Lay abstract This study aimed at uncovering variants in the genetic material of Arab children, that might predispose them to develop a specific treatment-related adverse effect, during their therapy for acute lymphoblastic leukemia (a type of blood cancer). We looked at specific changes in the DNA of our patient cohort that might predispose them to develop treatment-induced osteonecrosis. Osteonecrosis is by definition a loss of blood flow to the bone tissue in one's body, causing the bone to die. Osteonecrosis may be caused by long-term exposure to steroid-based medication, among which dexamethasone. Dexamethasone a main component of the combination of chemotherapeutic agents used to treat acute lymphoblastic leukemia. Our findings suggested that children who had one of the variants detected in a specific location of DNA, the GRIN3A gene, were more likely to develop osteonecrosis earlier and had to stop dexamethasone earlier during therapy.