Forecasting acute kidney injury and resource utilization in ICU patients using longitudinal, multimodal models.

BACKGROUND: Advances in artificial intelligence (AI) have realized the potential of revolutionizing healthcare, such as predicting disease progression via longitudinal inspection of Electronic Health Records (EHRs) and lab tests from patients admitted to Intensive Care Units (ICU). Although substantial literature exists addressing broad subjects, including the prediction of mortality, length-of-stay, and readmission, studies focusing on forecasting Acute Kidney Injury (AKI), specifically dialysis anticipation like Continuous Renal Replacement Therapy (CRRT) are scarce. The technicality of how to implement AI remains elusive. OBJECTIVE: This study aims to elucidate the important factors and methods that are required to develop effective predictive models of AKI and CRRT for patients admitted to ICU, using EHRs in the Medical Information Mart for Intensive Care (MIMIC) database. METHODS: We conducted a comprehensive comparative analysis of established predictive models, considering both time-series measurements and clinical notes from MIMIC-IV databases. Subsequently, we proposed a novel multi-modal model which integrates embeddings of top-performing unimodal models, including Long Short-Term Memory (LSTM) and BioMedBERT, and leverages both unstructured clinical notes and structured time series measurements derived from EHRs to enable the early prediction of AKI and CRRT. RESULTS: Our multimodal model achieved a lead time of at least 12 h ahead of clinical manifestation, with an Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.888 for AKI and 0.997 for CRRT, as well as an Area Under the Precision Recall Curve (AUPRC) of 0.727 for AKI and 0.840 for CRRT, respectively, which significantly outperformed the baseline models. Additionally, we performed a SHapley Additive exPlanation (SHAP) analysis using the expected gradients algorithm, which highlighted important, previously underappreciated predictive features for AKI and CRRT. CONCLUSION: Our study revealed the importance and the technicality of applying longitudinal, multimodal modeling to improve early prediction of AKI and CRRT, offering insights for timely interventions. The performance and interpretability of our model indicate its potential for further assessment towards clinical applications, to ultimately optimize AKI management and enhance patient outcomes.

Forecasting Acute Kidney Injury and Resource Utilization in ICU patients using longitudinal, multimodal models.

Background: Advances in artificial intelligence (AI) have realized the potential of revolutionizing healthcare, such as predicting disease progression via longitudinal inspection of Electronic Health Records (EHRs) and lab tests from patients admitted to Intensive Care Units (ICU). Although substantial literature exists addressing broad subjects, including the prediction of mortality, length-of-stay, and readmission, studies focusing on forecasting Acute Kidney Injury (AKI), specifically dialysis anticipation like Continuous Renal Replacement Therapy (CRRT) are scarce. The technicality of how to implement AI remains elusive. Objective: This study aims to elucidate the important factors and methods that are required to develop effective predictive models of AKI and CRRT for patients admitted to ICU, using EHRs in the Medical Information Mart for Intensive Care (MIMIC) database. Methods: We conducted a comprehensive comparative analysis of established predictive models, considering both time-series measurements and clinical notes from MIMIC-IV databases. Subsequently, we proposed a novel multi-modal model which integrates embeddings of top-performing unimodal models, including Long Short-Term Memory (LSTM) and BioMedBERT, and leverages both unstructured clinical notes and structured time series measurements derived from EHRs to enable the early prediction of AKI and CRRT. Results: Our multimodal model achieved a lead time of at least 12 hours ahead of clinical manifestation, with an Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.888 for AKI and 0.997 for CRRT, as well as an Area Under the Precision Recall Curve (AUPRC) of 0.727 for AKI and 0.840 for CRRT, respectively, which significantly outperformed the baseline models. Additionally, we performed a SHapley Additive exPlanation (SHAP) analysis using the expected gradients algorithm, which highlighted important, previously underappreciated predictive features for AKI and CRRT. Conclusion: Our study revealed the importance and the technicality of applying longitudinal, multimodal modeling to improve early prediction of AKI and CRRT, offering insights for timely interventions. The performance and interpretability of our model indicate its potential for further assessment towards clinical applications, to ultimately optimize AKI management and enhance patient outcomes.

Vaccination Coverage by Age 24 Months Among Children Born in 2019 and 2020 - National Immunization Survey-Child, United States, 2020-2022.

National Immunization Survey-Child data collected in 2022 were combined with data from previous years to assemble birth cohorts and assess coverage with routine vaccines by age 24 months by birth cohort. Overall, vaccination coverage was similar among children born during 2019-2020 compared with children born during 2017-2018, except that coverage with both the birth dose of hepatitis B vaccine and ≥1 dose of hepatitis A vaccine increased. Coverage was generally higher among non-Hispanic White (White) children (2-21 percentage points higher than coverage for non-Hispanic Black or African American, Hispanic or Latino, and non-Hispanic American Indian/Alaska Native [AI/AN] children), children living at or above poverty (3.5-22 percentage points higher than coverage for children living below the federal poverty level), privately insured children (2.4-38 percentage points higher than coverage for children with Medicaid, other insurance, or no insurance), and children in urban areas (3-16.5 percentage points higher than coverage for children living in rural areas). Coverage with the full series of Haemophilus influenzae type b conjugate vaccine was lower among AI/AN children compared with White children. Trends in vaccination coverage disparities across categories of race and ethnicity, health insurance status, poverty status, and urbanicity were evaluated for the 2016-2020 birth cohorts. Fewer than 5% of 168 trends examined were statistically significant, including six increases (widening of the coverage gap) and one decrease (narrowing of the gap). Analyses revealed a widening of the gap between children living at or above the poverty level (higher coverage) and those living below poverty (lower coverage), for several vaccines. Socioeconomic, demographic, and geographic disparities in vaccination coverage persist; addressing them is important to ensure protection for all children against vaccine-preventable disease.

Integrative Prognostic Machine Learning Models in Mantle Cell Lymphoma.

Patients with mantle cell lymphoma (MCL), an incurable B-cell malignancy, benefit from accurate pretreatment disease stratification. We curated an extensive database of 862 patients diagnosed between 2014 and 2022. A machine learning (ML) gradient-boosted model incorporated baseline features from clinicopathologic, cytogenetic, and genomic data with high predictive power discriminating between patients with indolent or responsive MCL and those with aggressive disease (AUC ROC = 0.83). In addition, we utilized the gradient-boosted framework as a robust feature selection method for multivariate logistic and survival modeling. The best ML models incorporated features from clinical and genomic data types highlighting the need for correlative molecular studies in precision oncology. As proof of concept, we launched our most accurate and practical models using an application interface, which has potential for clinical implementation. We designated the 20-feature ML model-based index the "integrative MIPI" or iMIPI and a similar 10-feature ML index the "integrative simplified MIPI" or iMIPI-s. The top 10 baseline prognostic features represented in the iMIPI-s are: lactase dehydrogenase (LDH), Ki-67%, platelet count, bone marrow involvement percentage, hemoglobin levels, the total number of observed somatic mutations, TP53 mutational status, Eastern Cooperative Oncology Group performance level, beta-2 microglobulin, and morphology. Our findings emphasize that prognostic applications and indices should include molecular features, especially TP53 mutational status. This work demonstrates the clinical utility of complex ML models and provides further evidence for existing prognostic markers in MCL. Significance: Our model is the first to integrate a dynamic algorithm with multiple clinical and molecular features, allowing for accurate predictions of MCL disease outcomes in a large patient cohort.

Disrupted Routine Medical Visits in Children and Adolescents During the COVID-19 Pandemic, January-June 2021.

Introduction: Recent studies have indicated the coronavirus disease 2019 (COVID-19) pandemic has disrupted routine vaccinations. This study describes the prevalence and characteristics of children and adolescents experiencing disrupted routine vaccination and other medical visits in the United States between January and June 2021. Methods: The National Immunization Surveys were the source of data for this cross-sectional analysis (n= 86,893). Parents/guardians of children aged 6 months through 17 years were identified through random digit dialing of cellular phone numbers and interviewed. Disrupted visits were assessed by asking, "In the last two months, was a medical check-up, well child visit, or vaccination appointment for the child delayed, missed, or not scheduled for any reason?" Respondents answering yes were asked "Was it because of COVID-19?" Sociodemographic characteristics of children/adolescents with (1) COVID-19-related missed visits and (2) non-COVID-19-related missed visits were examined. Statistical differences within demographic subgroups were determined using t-tests, with p<0.05 considered statistically significant. Linear regression models were used to examine trends in disrupted visits over time. Results: An estimated 7.9% of children/adolescents had a missed visit attributed to COVID-19; 5.2% had a missed visit that was not COVID-19-related. Among children/adolescents with a COVID-19-related missed visit, a higher percentage were of minority race or ethnicity, lived below the poverty level, had a mother without a college degree, and lived in the western United States. There was a significant decline in COVID-19-related missed visits over time. Conclusion: COVID-19 disrupted routine vaccination or other medical visits inequitably. Catch-up immunizations are essential for achieving adequate vaccination of all children/adolescents.

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations.

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Vaccination Coverage by Age 24 Months Among Children Born During 2018-2019 - National Immunization Survey-Child, United States, 2019-2021.

Millions of young children are vaccinated safely in the United States each year against a variety of potentially dangerous infectious diseases (1). The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination against 14 diseases during the first 24 months of life* (2). This report describes vaccination coverage by age 24 months using data from the National Immunization Survey-Child (NIS-Child).† Compared with coverage among children born during 2016-2017, coverage among children born during 2018-2019 increased for a majority of recommended vaccines. Coverage was >90% for ≥3 doses of poliovirus vaccine (93.4%), ≥3 doses of hepatitis B vaccine (HepB) (92.7%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.6%), and ≥1 dose of varicella vaccine (VAR) (91.1%); coverage was lowest for ≥2 doses of hepatitis A vaccine (HepA) (47.3%). Vaccination coverage overall was similar or higher among children reaching age 24 months during March 2020 or later (during the COVID-19 pandemic) than among those reaching age 24 months before March 2020 (prepandemic); however, coverage with the combined 7-vaccine series§ among children living below the federal poverty level or in rural areas decreased by 4-5 percentage points during the pandemic (3). Among children born during 2018-2019, coverage disparities were observed by race and ethnicity, poverty status, health insurance status, and Metropolitan Statistical Area (MSA) residence. Coverage was typically higher among privately insured children than among children with other insurance or no insurance. Persistent disparities by health insurance status indicate the need to improve access to vaccines through the Vaccines for Children (VFC) program.¶ Providers should review children's histories and recommend needed vaccinations during every clinical encounter and address parental hesitancy to help reduce disparities and ensure that all children are protected from vaccine-preventable diseases.

Associations Between Routine Adolescent Vaccination Status and Parental Intent to Get a COVID-19 Vaccine for Their Adolescent.

This cross-sectional study investigates whether US adolescents' routine vaccination status is associated with their parents' self-reported intent or hesitancy to have them vaccinated for COVID-19.

Vaccination Coverage of Privately Insured Children: Comparing U.S. Survey and Administrative Data.

INTRODUCTION: National Immunization Survey-Child data are used widely to assess childhood vaccination coverage in the U.S. This study compares National Immunization Survey-Child coverage estimates with estimates using other supplementary data sources. METHODS: Retrospective analyses in 2021 assessed vaccination coverage of privately insured children for vaccines recommended by the Advisory Committee on Immunization Practices by age 2 years, using the 2015-2018 MarketScan Commercial Claims and Encounters databases and the 2018-2019 Healthcare Effectiveness Data and Information Set. The coverage estimates were compared statistically with those using the 2016-2018 National Immunization Survey-Child. RESULTS: Estimated coverage ranged from 69.9% (≥2 doses of influenza vaccine) to 95.0% (≥3 doses of diphtheria, tetanus toxoids, and acellular pertussis vaccine) using the MarketScan Commercial Claims and Encounters data and from 68.0% (≥2 doses of influenza vaccine) to 92.2% (≥1 dose of measles, mumps, and rubella vaccine) using the Healthcare Effectiveness Data and Information Set. The difference between the MarketScan Commercial Claims and Encounters and National Immunization Survey-Child estimates ranged from 0.1 to 4.3 percentage points and was statistically significant for 6 of the 13 assessed vaccines/doses and percentage of children receiving no vaccinations. The difference between the Healthcare Effectiveness Data and Information Set and National Immunization Survey-Child estimates ranged from 0.4 to 7.2 percentage points and was statistically significant for 6 of the 10 assessed vaccines/doses. CONCLUSIONS: For certain vaccines and populations of interest, the National Immunization Survey-Child, MarketScan Commercial Claims and Encounters, and Healthcare Effectiveness Data and Information Set data might give comparable coverage of privately insured children.

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma.

PURPOSE: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS: The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

Vaccination Coverage by Age 24 Months Among Children Born in 2017 and 2018 - National Immunization Survey-Child, United States, 2018-2020.

Immunization is a safe and cost-effective means of preventing illness in young children and interrupting disease transmission within the community.* The Advisory Committee on Immunization Practices (ACIP) recommends vaccination of children against 14 diseases during the first 24 months of life (1). CDC uses National Immunization Survey-Child (NIS-Child) data to monitor routine coverage with ACIP-recommended vaccines in the United States at the national, regional, state, territorial, and selected local levels.† CDC assessed vaccination coverage by age 24 months among children born in 2017 and 2018, with comparisons to children born in 2015 and 2016. Nationally, coverage was highest for ≥3 doses of poliovirus vaccine (92.7%); ≥3 doses of hepatitis B vaccine (HepB) (91.9%); ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.6%); and ≥1 dose of varicella vaccine (VAR) (90.9%). Coverage was lowest for ≥2 doses of influenza vaccine (60.6%). Coverage among children born in 2017-2018 was 2.1-4.5 percentage points higher than it was among those born in 2015-2016 for rotavirus vaccine, ≥1 dose of hepatitis A vaccine (HepA), the HepB birth dose, and ≥2 doses of influenza vaccine. Only 1.0% of children had received no vaccinations by age 24 months. Disparities in coverage were seen for race/ethnicity, poverty status, and health insurance status. Coverage with most vaccines was lower among children who were not privately insured. The largest disparities between insurance categories were among uninsured children, especially for ≥2 doses of influenza vaccine, the combined 7-vaccine series, § and rotavirus vaccination. Reported estimates reflect vaccination opportunities that mostly occurred before disruptions resulting from the COVID-19 pandemic. Extra efforts are needed to ensure that children who missed vaccinations, including those attributable to the COVID-19 pandemic, receive them as soon as possible to maintain protection against vaccine-preventable illnesses.

Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

Vaccination Coverage by Age 24 Months Among Children Born in 2016 and 2017 - National Immunization Survey-Child, United States, 2017-2019.

Immunization has been described as a "global health and development success story," and worldwide is estimated to prevent 2-3 million deaths annually.* In the United States, the Advisory Committee on Immunization Practices (ACIP) currently recommends vaccination against 14 potentially serious illnesses by the time a child reaches age 24 months (1). CDC monitors coverage with ACIP-recommended vaccines through the National Immunization Survey-Child (NIS-Child); data from the survey were used to estimate vaccination coverage at the national, regional, state, territorial, and selected local area levels† among children born in 2016 and 2017. National coverage by age 24 months was ≥90% for ≥3 doses of poliovirus vaccine, ≥3 doses of hepatitis B vaccine (HepB), and ≥1 dose of varicella vaccine (VAR); national coverage was ≥90% for ≥1 dose of measles, mumps, and rubella vaccine (MMR), although MMR coverage was <90% in 14 states. Coverage with ≥2 doses of influenza vaccine was higher for children born during 2016-2017 (58.1%) than for those born during 2014-2015 (53.8%) but was the lowest among all vaccines studied. Only 1.2% of children had received no vaccinations by age 24 months. Vaccination coverage among children enrolled in Medicaid or with no health insurance was lower than that among children who were privately insured. The prevalence of being completely unvaccinated was highest among uninsured children (4.1%), lower among those enrolled in Medicaid (1.3%), and lowest among those with private insurance (0.8%). The largest disparities on the basis of health insurance status occurred for ≥2 doses of influenza vaccine and for completion of the rotavirus vaccination series. Considering the disruptions to health care provider operations caused by the coronavirus disease 2019 (COVID-19) pandemic, extra effort will be required to achieve and maintain high levels of coverage with routine childhood vaccinations. Providers, health care entities, and public health authorities can communicate with families about how children can be vaccinated safely during the pandemic, remind parents of vaccinations that are due for their children, and provide all recommended vaccinations to children during clinic visits. This will be especially important for 2020-21 seasonal influenza vaccination to mitigate the effect of two potentially serious respiratory viruses circulating in the community simultaneously.

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis.

Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. We then conducted a meta-analysis using a Bayesian multiregression model to analyze patient-level data in 2127 MCL patients, including prevalence of mutations. In tumor or bone marrow samples taken at diagnosis or baseline, ATM was the most frequently mutated gene (43.5%) followed by TP53 (26.8%), CDKN2A (23.9%), and CCND1 (20.2%). Aberrations were also detected in IGH (38.4%) and MYC (20.8%), primarily through cytogenetic methods. Other common baseline mutations were NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%). Our data also show a change in mutational status from baseline samples to samples at disease progression and present mutations of interest in MCL that should be considered for future analysis. The genes with the highest mutational frequency difference (>5%) are TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1. These findings provide a summary of the mutational landscape of MCL. The genes with the highest change in mutation frequency should be included in targeted next-generation sequencing panels for future studies. These findings also highlight the need for analysis of serial samples in MCL. Patient-level data of prevalent mutations in MCL provide additional evidence emphasizing molecular variability in advancing precision medicine initiatives in MCL.

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.

Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival.

Pneumococcal Conjugate Vaccine Breakthrough Infections: 2001-2016.

BACKGROUND: Most countries use 3-dose pneumococcal conjugate vaccine (PCV) schedules; a 4-dose (3 primary and 1 booster) schedule is licensed for US infants. We evaluated the invasive pneumococcal disease (IPD) breakthrough infection incidence in children receiving 2 vs 3 primary PCV doses with and without booster doses (2 + 1 vs 3 + 1; 2 + 0 vs 3 + 0). METHODS: We used 2001-2016 Active Bacterial Core surveillance data to identify breakthrough infections (vaccine-type IPD in children receiving ≥1 7-valent pneumococcal conjugate vaccine [PCV7] or 13-valent pneumococcal conjugate vaccine [PCV13] dose) among children aged <5 years. We estimated schedule-specific IPD incidence rates (IRs) per 100 000 person-years and compared incidence by schedule (2 + 1 vs 3 + 1; 2 + 0 vs 3 + 0) using rate differences (RDs) and incidence rate ratios. RESULTS: We identified 71 PCV7 and 49 PCV13 breakthrough infections among children receiving a schedule of interest. PCV13 breakthrough infection rates were higher in children aged <1 year receiving the 2 + 0 (IR: 7.8) vs 3 + 0 (IR: 0.6) schedule (incidence rate ratio: 12.9; 95% confidence interval: 4.1-40.4); PCV7 results were similar. Differences in PCV13 breakthrough infection rates by schedule in children aged <1 year were larger in 2010-2011 (2 + 0 IR: 18.6; 3 + 0 IR: 1.4; RD: 16.6) vs 2012-2016 (2 + 0 IR: 3.6; 3 + 0 IR: 0.2; RD: 3.4). No differences between schedules were detected in children aged ≥1 year for PCV13 breakthrough infections. CONCLUSIONS: Fewer PCV breakthrough infections occurred in the first year of life with 3 primary doses. Differences in breakthrough infection rates by schedule decreased as vaccine serotypes decreased in circulation.

Vaccination Coverage by Age 24 Months Among Children Born in 2015 and 2016 - National Immunization Survey-Child, United States, 2016-2018.

The Advisory Committee on Immunization Practices (ACIP) recommends that children be vaccinated against 14 potentially serious illnesses during the first 24 months of life (1). CDC used data from the National Immunization Survey-Child (NIS-Child) to assess vaccination coverage with the recommended number of doses of each vaccine at the national, state, territorial, and selected local levels* among children born in 2015 and 2016. Coverage by age 24 months was at least 90% nationally for ≥3 doses of poliovirus vaccine, ≥1 dose of measles, mumps, and rubella vaccine (MMR), ≥3 doses of hepatitis B vaccine (HepB), and ≥1 dose of varicella vaccine, although MMR coverage was <90% in 20 states. Children were least likely to be up to date by age 24 months with ≥2 doses of influenza vaccine (56.6%). Only 1.3% of children born in 2015 and 2016 had received no vaccinations by the second birthday. Coverage was lower for uninsured children and for children insured by Medicaid than for those with private health insurance. Vaccination coverage can be increased by improving access to vaccine providers and eliminating missed opportunities to vaccinate children during health care visits. Increased use of local vaccination coverage data is needed to identify communities at higher risk for outbreaks of measles and other vaccine-preventable diseases.