Targeting the EGFR pathway in chemotherapy-resistant triple-negative breast cancer - a phase II study.

PURPOSE: Epidermal growth factor receptor (EGFR) pathway activation causes chemotherapy resistance and inhibition of the EGFR pathway sensitizes TNBC to chemotherapy in preclinical models. Given the high prevalence of EGFR overexpression in TNBC, we conducted a single-arm phase II study of panitumumab (anti-EGFR monoclonal antibody), carboplatin, and paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02593175). PATIENTS AND METHODS: Patients with early-stage, AC-resistant TNBC, defined as disease progression or ≤80% reduction in tumor volume after 4 cycles of AC. were eligible for this study and received panitumumab (2.5 mg/kg IV, Q1 week x 13), paclitaxel (80mg/m2 IV Q1 week x 12), and carboplatin (AUC=4 IV, Q3 weeks x 4) as the second phase of NAT. A two-stage Gehan-type design was employed to detect an improvement in the pCR/residual cancer burden class I (RCB-I) rate from 5% to 20%. Whole exome sequencing was performed on diagnostic tumor biospecimens, where available. RESULTS: From 11/3/2016 through 8/3/2021, 43 patients with AC-resistant TNBC were enrolled. The combined pCR/RCB-I rate was 30.2%. The most common treatment-related adverse events were neutropenia (72%) and anemia (61%), with 7 (16%), 16 (37%), and 8 (19%) patients experiencing grade 4 neutropenia, grade 3 neutropenia, and grade 3 anemia, respectively. No new safety signals were observed. CONCLUSIONS: This study met its primary endpoint (pCR/RCB-I=30.2% vs. 5% in historical controls), suggesting that panitumumab should be evaluated as a component of neoadjuvant therapy in patients with chemotherapy-resistant TNBC in a larger, randomized clinical trial.

BST2 facilitates activation of hematopoietic stem cells through ERK signaling.

The proinflammatory cytokine interferon gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell-surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, because it is induced upon IFN stimulation and required for IFN-dependent HSC activation. To identify the mechanism by which BST2 promotes IFN-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knockout (KO) of BST2 in a murine model does not disrupt immune cell responses to IFN-inducing mycobacterial infection. Furthermore, intravital imaging studies indicate that BST2 KO does not disrupt localization of HSCs relative to endothelial or osteoblastic niches in the bone marrow. However, using imaging-based flow cytometry, we found that IFNγ treatment shifts the lipid raft polarity of wild-type (WT) but not Bst2-/- hematopoietic stem and progenitor cells (HSPCs). Furthermore, RNAseq analysis, reverse-phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNγ-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of IFN-dependent HSPC activation. These findings inform future approaches in the treatment of cancer and bone marrow failure.

Decline in Vaccination Coverage by Age 24 Months and Vaccination Inequities Among Children Born in 2020 and 2021 - National Immunization Survey-Child, United States, 2021-2023.

Data from the National Immunization Survey-Child (NIS-Child) were analyzed to estimate coverage with childhood vaccines recommended by the Advisory Committee on Immunization Practices among U.S. children by age 24 months. Coverage with nearly all vaccines was lower among children born in 2020 and 2021 than it was among those born in 2018 and 2019, with declines ranging from 1.3 to 7.8 percentage points. Analyses of NIS-Child data for earlier birth cohorts have not revealed such widespread declines in routine childhood vaccination coverage. Coverage among children born during 2020-2021 varied by race and ethnicity, health insurance status, poverty status, urbanicity, and jurisdiction. Compared with non-Hispanic White children, coverage with four of the 17 vaccine measures was lower among non-Hispanic Black or African American children as well as Hispanic or Latino (Hispanic) and non-Hispanic American Indian or Alaska Native children. Coverage was also generally lower among those covered by Medicaid or other nonprivate insurance, uninsured children, children living below the federal poverty level, and children living in rural areas. Coverage varied widely by jurisdiction, especially coverage with ≥2 doses of influenza vaccine. Children born during 2020-2021 were born during or after the period of major disruption of primary care from the COVID-19 pandemic. Providers should review children's histories and recommend needed vaccinations during every clinical encounter. Addressing financial barriers, access issues, vaccine hesitancy, and vaccine-related misinformation can also help to increase coverage, reduce disparities, and protect all children from vaccine-preventable diseases. Strategies that have been found effective include implementation of standing orders and reminder and recall systems, strong physician recommendations to vaccinate, and use of immunization information systems to identify areas of lower coverage that could benefit from targeted interventions to increase immunization rates.

Vital Signs: Trends and Disparities in Childhood Vaccination Coverage by Vaccines for Children Program Eligibility - National Immunization Survey-Child, United States, 2012-2022.

Introduction: The Vaccines for Children (VFC) program was established in 1994 to provide recommended vaccines at no cost to eligible children and help ensure that all U.S. children are protected from life-threatening vaccine-preventable diseases. Methods: CDC analyzed data from the 2012-2022 National Immunization Survey-Child (NIS-Child) to assess trends in vaccination coverage with ≥1 dose of measles, mumps, and rubella vaccine (MMR), 2-3 doses of rotavirus vaccine, and a combined 7-vaccine series, by VFC program eligibility status, and to examine differences in coverage among VFC-eligible children by sociodemographic characteristics. VFC eligibility was defined as meeting at least one of the following criteria: 1) American Indian or Alaska Native; 2) insured by Medicaid, Indian Health Service (IHS), or uninsured; or 3) ever received at least one vaccination at an IHS-operated center, Tribal health center, or urban Indian health care facility. Results: Overall, approximately 52.2% of U.S. children were VFC eligible. Among VFC-eligible children born during 2011-2020, coverage by age 24 months was stable for ≥1 MMR dose (88.0%-89.9%) and the combined 7-vaccine series (61.4%-65.3%). Rotavirus vaccination coverage by age 8 months was 64.8%-71.1%, increasing by an average of 0.7 percentage points annually. Among all children born in 2020, coverage was 3.8 (≥1 MMR dose), 11.5 (2-3 doses of rotavirus vaccine), and 13.8 (combined 7-vaccine series) percentage points lower among VFC-eligible than among non-VFC-eligible children. Conclusions and implications for public health practice: Although the VFC program has played a vital role in increasing and maintaining high levels of childhood vaccination coverage for 30 years, gaps remain. Enhanced efforts must ensure that parents and guardians of VFC-eligible children are aware of, have confidence in, and are able to obtain all recommended vaccines for their children.

Enhancing the understanding of coinfection outcomes: Impact of natural atypical porcine pestivirus infection on porcine reproductive and respiratory syndrome in pigs.

Atypical porcine pestivirus (APPV) is a novel member of the Pestivirus genus detected in association with congenital tremor (CT) type A-II outbreaks and from apparently healthy pigs, both as singular infection and as part of multi-pathogen infections. 'Classical' pestiviruses are known to cause immunosuppression of their host, which can increase susceptibility to secondary infections, severely impacting health, welfare, and production. To investigate APPV's effect on the host's immune system and characterise disease outcomes, 12 piglets from a natural APPV CT type A-II outbreak were experimentally infected with porcine reproductive and respiratory syndrome virus (PRRSV), a significant porcine pathogen. Rectal temperatures indicating febrile responses, viremia and viral-specific humoral and cellular responses were assessed throughout the study. Pathological assessment of the lungs and APPV-PRRSV co-localisation within the lungs was performed at necropsy. Viral co-localisation and pathological assessment of the lungs (Immunohistochemistry, BaseScope in situ hybridisation) were performed post-mortem. APPV status did not impact virological or immunological differences in PRRSV-infected groups. However, significantly higher rectal temperatures were observed in the APPV+ve/PRRSV+ve group over four days, indicating APPV increased the febrile response. Significant differences in the lung consolidation of the apical and intermediate lobes were also present, suggesting that APPV co-infection may augment lung pathology.

Changes in vaccine hesitancy among parents of children aged 6 months - 17 Years, National Immunization Surveys, 2019-2022.

BACKGROUND: Vaccine hesitancy (VH) has been a major contributor to large outbreaks of vaccine-preventable diseases globally, including in the United States. METHODS: Data from the 2019-2022 National Immunization Surveys were analyzed to assess parental hesitancy toward routine vaccination of their children aged 6 months -17 years. Joinpoint regression was employed to investigate trends in VH from 2019 to 2022 nationally overall and among socio-demographic subgroups. Using logistic regression, the difference between the prevalence of VH before and after the authorization of the COVID-19 vaccine for children aged 6 months-4 years, 5-11 years, and 12-17 years was computed. Both unadjusted and adjusted estimates were reported. VH was also compared within each socio-demographic subgroup with a reference level, at two-time points- before and after the authorization of the COVID-19 vaccine for each age group. RESULTS: Overall, VH remained around 19.0 % from Q2 2019 to Q3 2022. Parents of non-Hispanic Black children had the largest average quarterly decrease in VH (ß = -0.55; p < 0.05 by test for trend). After the authorization of the COVID-19 vaccine for children aged 6 months to 4 years, the adjusted percentage of children having parents that reported VH decreased by 2.2 (95 % CI: -3.9, -0.6) percentage points (pp) from 21.6 % to 19.4 %. Conversely, for children aged 5-11 years, VH increased by 1.2 (95 % CI: 0.2, 2.3) pp, from 19.8 % to 21.0 %. VH among parents of non-Hispanic Black children decreased after the authorization of the COVID-19 vaccine for adolescents aged 12-17 years but remained significantly higher compared to parents of non-Hispanic White children before and after authorization of the COVID-19 vaccine for all age groups. DISCUSSION: About 1 in 5 children had parents reporting VH from 2019 to 2022. Parental VH increased after the authorization of the COVID-19 vaccine for children aged 5-11 years and declined for children aged 6 months-4 years.

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.