Incidence and survival of pediatric and adult hepatocellular carcinoma, United States, 2001-2020.

BACKGROUND: Hepatocellular carcinoma accounts for approximately 80 % of liver neoplasms. Globally, hepatocellular carcinoma ranks as the third most lethal cancer, with the number of deaths expected to further increase by 2040. In adults, disparities in incidence and survival are well described while pediatric epidemiology is not well characterized. We describe incidence and survival for pediatric (ages 0-19 years) hepatocellular carcinoma cases and compare these measures to adults (ages ≥ 20 years) diagnosed with hepatocellular carcinoma. METHODS: We assessed incidence data from the US Cancer Statistics database during 2003-2020 and 5-year survival from the National Program of Cancer Registries during 2001-2019. Incidence trends were determined by annual percent change (APC) and average APC (AAPC) using joinpoint regression. Five-year survival was evaluated by relative survival, and all-cause survival was estimated using multivariate Cox modeling. Corresponding 95 % confidence intervals (CI) were calculated for all analyses. RESULTS: Incidence rate per 100,000 persons was 0.056 (95 %CI:0.052-0.060) for pediatric cases and 7.793 (7.767-7.819) for adults. Incidence was stable in the pediatric population (0.3 AAPC, - 1.1 to 1.7). In contrast, after periods of increase, incidence declined in adults after 2015 (-1.5 APC). Relative survival increased over time for both pediatric and adult ages and was higher for children and adolescents (46.4 %, 95 %CI:42.4-50.3) than adults (20.7 %, 95 %CI:20.5-20.9). Regression modeling showed that non-Hispanic Black race and ethnicity was associated with higher risk of death in children and adolescents (1.48, 95 %CI:1.07-2.05) and adults (1.11, 95 %CI:1.09-1.12) compared to non-Hispanic white race and ethnicity. CONCLUSIONS: Between 2003 and 2020 in the United States, pediatric incidence was stable while incidence in adults began to decline after 2015. Survival was higher across all stages for children and adolescents compared to adults. Non-Hispanic Black race and ethnicity showed a higher risk of death for both age groups. Further studies could explore the factors that influence these outcome disparities.

Can money buy control of Congress?

Can a political party spend enough across electoral campaigns to garner a majority within the U.S. Congress? Prior research on campaign spending minimizes the importance of campaign heterogeneity and fails to aggregate effects across campaigns, rendering it unable to address this question. Instead, we tackle the question with a system-level analysis of campaign expenditures. First, using a flexible machine learning approach, we show that spending has substantial and nonlinear marginal effects on outcomes at the level of the campaign. Second, by aggregating these effects to the entire U.S. Congress, we show that large seat swings that change congressional control have, in the past, been possible for expenditure levels consonant with those presently observed after having removed the most extreme levels. However, this possibility appears to have faded over the past decade. Our approach also allows us to illustrate the often significant effects that eliminating campaign spending could have.

Antileukemic potential of methylated indolequinone MAC681 through immunogenic necroptosis and PARP1 degradation.

BACKGROUND: Despite advancements in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), resistance and intolerance remain significant challenges. Leukemia stem cells (LSCs) and TKI-resistant cells rely on altered mitochondrial metabolism and oxidative phosphorylation. Targeting rewired energy metabolism and inducing non-apoptotic cell death, along with the release of damage-associated molecular patterns (DAMPs), can enhance therapeutic strategies and immunogenic therapies against CML and prevent the emergence of TKI-resistant cells and LSC persistence. METHODS: Transcriptomic analysis was conducted using datasets of CML patients' stem cells and healthy cells. DNA damage was evaluated by fluorescent microscopy and flow cytometry. Cell death was assessed by trypan blue exclusion test, fluorescent microscopy, flow cytometry, colony formation assay, and in vivo Zebrafish xenografts. Energy metabolism was determined by measuring NAD+ and NADH levels, ATP production rate by Seahorse analyzer, and intracellular ATP content. Mitochondrial fitness was estimated by measurements of mitochondrial membrane potential, ROS, and calcium accumulation by flow cytometry, and morphology was visualized by TEM. Bioinformatic analysis, real-time qPCR, western blotting, chemical reaction prediction, and molecular docking were utilized to identify the drug target. The immunogenic potential was assessed by high mobility group box (HMGB)1 ELISA assay, luciferase-based extracellular ATP assay, ectopic calreticulin expression by flow cytometry, and validated by phagocytosis assay, and in vivo vaccination assay using syngeneic C57BL/6 mice. RESULTS: Transcriptomic analysis identified metabolic alterations and DNA repair deficiency signatures in CML patients. CML patients exhibited enrichment in immune system, DNA repair, and metabolic pathways. The gene signature associated with BRCA mutated tumors was enriched in CML datasets, suggesting a deficiency in double-strand break repair pathways. Additionally, poly(ADP-ribose) polymerase (PARP)1 was significantly upregulated in CML patients' stem cells compared to healthy counterparts. Consistent with the CML patient DNA repair signature, treatment with the methylated indolequinone MAC681 induced DNA damage, mitochondrial dysfunction, calcium homeostasis disruption, metabolic catastrophe, and necroptotic-like cell death. In parallel, MAC681 led to PARP1 degradation that was prevented by 3-aminobenzamide. MAC681-treated myeloid leukemia cells released DAMPs and demonstrated the potential to generate an immunogenic vaccine in C57BL/6 mice. MAC681 and asciminib exhibited synergistic effects in killing both imatinib-sensitive and -resistant CML, opening new therapeutic opportunities. CONCLUSIONS: Overall, increasing the tumor mutational burden by PARP1 degradation and mitochondrial deregulation makes CML suitable for immunotherapy.

Employment Characteristics and Tobacco Product Use, U.S., 2021.

INTRODUCTION: Over 30 million U.S. working adults use tobacco, and tobacco use varies by occupation. Limited information is available on employment characteristics and tobacco use prevalence. The purpose of this study was to describe the prevalence of current tobacco use by employment characteristics and occupation group among U.S. working adults. METHODS: This cross-sectional study used 2021 National Health Interview Survey data for currently working adults (n=16,461) analyzed in 2023. Multivariable logistic regression was used to estimate adjusted odds of tobacco use by employment characteristics and occupation group. RESULTS: In 2021, 20.0% of working adults used tobacco. Any tobacco use was significantly lower among workers who were offered workplace health insurance (AOR=0.86, 95% CI=0.77-0.97), had paid sick leave (AOR=0.81, 95% CI=0.73-0.91), and government versus private employment (AOR=0.61, 95% CI=0.52-0.70). Any tobacco use was significantly higher among workers who usually worked ≥35 hours per week versus did not usually work ≥35 hours per week (AOR=1.21, 95% CI=1.06-1.39), worked a rotating or "some other" shift versus daytime shift (AOR=1.19, 95% CI=1.02-1.38), experienced schedule instability (AOR=1.17, 95% CI=1.03-1.31), and worked while physically ill in the past 3 months (AOR=1.25, 95% CI=1.11-1.41). Tobacco use by employment characteristics also varied by occupation group. CONCLUSIONS: Current tobacco use varied according to employment characteristics and occupation group. Findings from this study could inform workplace tobacco cessation interventions and policies (e.g., access to paid sick leave or insurance coverage) to better support tobacco cessation and overall worker health.

Incidence and survival of pediatric and adult hepatocellular carcinoma, United States, 2001-2020.

Importance: Hepatocellular carcinoma accounts for approximately 80% of liver neoplasms. Globally, hepatocellular carcinoma ranks as the third most lethal cancer, with the number of deaths expected to further increase by 2040. In adults, disparities in incidence and survival are well described while pediatric epidemiology is not well characterized. Objective: To describe incidence and survival for pediatric (ages 0-19 years) hepatocellular carcinoma cases and compare these measures to adults (ages ≥20 years) diagnosed with hepatocellular carcinoma. We evaluated demographic factors and clinical characteristics that influence incidence and outcomes. Design: Population-based cohort study. Setting: Incidence data from the US Cancer Statistics database from 2003 to 2020 and 5-year relative survival from the National Program of Cancer Registries from 2001 to 2019, covering 97% and 83% of the US population, respectively. Participants: 355,349 US Cancer Statistics and 257,406 the National Program of Cancer Registries patients were identified using ICD-O-3 C22.0 and 8170-5 codes. Main Outcomes and Measures: Incidence annual percent change (APC) and average APC (AAPC) using joinpoint regression. Five-year relative survival. All-cause survival estimated using multivariate Cox modeling. Corresponding 95% confidence intervals (CI) were calculated. Results: Incidence rate per 100,000 persons was 0.056 (95%CI:0.052-0.060) for pediatric cases and 7.793 (7.767-7.819) for adults. Incidence was stable in the pediatric population (0.3 AAPC, -1.1-1.7). In contrast, after periods of increase, incidence declined in adults after 2015 (-1.5 APC). Relative survival increased over time for both pediatric and adult ages and was higher for children and adolescents (46.4%, 95%CI:42.4-50.3) than adults (20.7%, 95%CI:20.5-20.9) overall and when stratified by stage. Regression modeling showed that non-Hispanic Black race and ethnicity was associated with higher risk of death in children and adolescents (1.48, 95%CI:1.07-2.05) and adults (1.11, 95%CI:1.09-1.12) compared to non-Hispanic white race and ethnicity. Conclusions and Relevance: Between 2003 and 2020 in the United States, pediatric incidence was stable while incidence in adults began to decline after 2015. Survival was higher across all stages for children and adolescents compared to adults. Non-Hispanic Black race and ethnicity showed a higher risk of death for both age groups. Further studies could explore the factors that influence these outcome disparities.

Outcomes of Patients with Heavily Pretreated Relapsed/Refractory Multiple Myeloma Receiving Salvage Cytotoxic Therapy with Supportive Stem Cell Boost.

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the neoplastic proliferation of plasma cells, which produce monoclonal immunoglobulin that can cause vital organ damage, subsequently leading to significant morbidity and mortality. Autologous hematopoietic stem cell transplant (ASCT) is the standard-of-care management of eligible patients with newly diagnosed MM. Experts recommend collecting enough stem cells upfront to support a possible tandem transplant, salvage ASCT, or a stem cell "boost" to allow for the administration of multiagent cytotoxic chemotherapy in patients with relapsed/refractory disease. OBJECTIVE: There is currently a paucity of data on the response rates and outcomes of patients with relapsed MM who undergo cytotoxic chemotherapy followed by a stem cell boost; this study examines the outcomes of patients treated with this approach. METHODS: We conducted a retrospective chart review from two oncologic treatment centers in the United States of adult patients who underwent a first ASCT between 1999 and 2021 and subsequently received cytotoxic chemotherapy followed by stem cell boost further on in their disease course. Survival analysis was carried out using the Kaplan-Meier method, and the log-rank test was used to compare survival curves. RESULTS: We found that the majority (56.6%) of these patients responded to therapy and that 60.6% of these patients were able to receive at least one subsequent line of therapy post-boost. Furthermore, patients who responded to therapy had significantly longer median overall survival compared to those who did not respond (323 days vs 93 days, p=0.0045), and age did not affect response to therapy. CONCLUSION: This data allow clinicians to appropriately implement and inform patients of the therapeutic uses and clinical outcomes of stem cell boost in patients with multiply relapsed/refractory MM.

Population-Based Data Linkage Describing Patterns of Cancer Clinical Trial Enrollment Among Children and Adolescents.

PURPOSE: Database linkage between cancer registries and clinical trial consortia has the potential to elucidate referral patterns of children and adolescents with newly diagnosed cancer, including enrollment into cancer clinical trials. This study's primary objective was to assess the feasibility of this linkage approach. METHODS: Patients younger than 20 years diagnosed with incident cancer during 2012-2017 in the Kentucky Cancer Registry (KCR) were linked with patients enrolled in a Children's Oncology Group (COG) study. Matched patients between databases were described by sex, age, race and ethnicity, geographical location when diagnosed, and cancer type. Logistic regression modeling identified factors associated with COG study enrollment. Timeliness of patient identification by KCR was reported through the Centers for Disease Control and Prevention's Early Case Capture (ECC) program. RESULTS: Of 1,357 patients reported to KCR, 47% were determined by matching to be enrolled in a COG study. Patients had greater odds of enrollment if they were age 0-4 years (v 15-19 years), reported from a COG-affiliated institution, and had renal cancer, neuroblastoma, or leukemia. Patients had lower odds of enrollment if Hispanic (v non-Hispanic White) or had epithelial (eg, thyroid, melanoma) cancer. Most (59%) patients were reported to KCR within 10 days of pathologic diagnosis. CONCLUSION: Linkage of clinical trial data with cancer registries is a feasible approach for tracking patient referral and clinical trial enrollment patterns. Adolescents had lower enrollment compared with younger age groups, independent of cancer type. Population-based early case capture could guide interventions designed to increase cancer clinical trial enrollment.

Reducing Cancer Risk Through Primary Prevention Activities Among Children: A Demonstration Project.

CONTEXT: Opportunities to reduce the risk of cancer, including cervical, liver, and skin cancer, start early in life. To encourage adoption of primary prevention activities in childhood to reduce cancer risk later in life, Centers for Disease Control and Prevention conducted a demonstration project with 3 National Comprehensive Cancer Control Program (NCCCP) recipients. PROGRAM: Iowa, Northwest Portland Area Indian Health Board (NPAIHB), and Pennsylvania NCCCP recipients implemented evidence-based primary prevention activities for cervical, liver, and skin cancer among children using health care provider education, patient education, and policy development. IMPLEMENTATION: Iowa implemented an announcement approach to improve provider education on human papillomavirus (HPV) vaccination. Pennsylvania focused on patient education for reducing skin cancer risk and both provider and patient education for liver cancer prevention. NPAIHB created a sun safety intervention for tribal organizations, including a policy guide, media materials, and patient education. RESULTS: In Iowa, health care providers taking the announcement approach reported significantly higher mean scores on a posttest compared with a pretest regarding perceptions about HPV vaccination, self-efficacy, and behavioral intentions related to vaccination. Pennsylvania integrated sun safety education and sunscreen dispenser programs as a health and wellness initiative in 8 state parks and the Pennsylvania Department of Conservation and Natural Resources incorporated the program in its Pennsylvania Outdoor Recreation Plan. Pennsylvania also implemented health care provider education on the primary prevention of liver cancer through hepatitis B and hepatitis C screening and hepatitis B vaccination. The NPAIHB skin cancer policy guide was created and distributed for use to all 43 federally recognized tribes of Oregon, Washington, and Idaho served by NPAIHB. DISCUSSION: The identification, dissemination, and implementation of these efforts can serve as best practices for future childhood primary prevention programs. NCCCP recipients and public health professionals can use health care provider education, patient education, and policy development to reduce future risk for cervical, liver, and skin cancer among children.

A comprehensive analysis of neuroblastoma incidence, survival, and racial and ethnic disparities from 2001 to 2019.

BACKGROUND: We characterize the incidence and 5-year survival of children and adolescents with neuroblastoma stratified by demographic and clinical factors based on the comprehensive data from United States Cancer Statistics (USCS) and the National Program of Cancer Registries (NPCR). METHODS: We analyzed the incidence of neuroblastoma from USCS (2003-2019) and survival data from NPCR (2001-2018) for patients less than 20 years old. Incidence trends were calculated by average annual percent change (AAPC) using joinpoint regression. Differences in relative survival were estimated comparing non-overlapping confidence intervals (CI). RESULTS: We identified 11,543 primary neuroblastoma cases in USCS. Age-adjusted incidence was 8.3 per million persons [95% CI: 8.2, 8.5], with an AAPC of 0.4% [95% CI: -0.1, 0.9]. Five-year relative survival from the NPCR dataset (n = 10,676) was 79.7% [95% CI: 78.9, 80.5]. Patients aged less than 1 year had the highest 5-year relative survival (92.5%). Five-year relative survival was higher for non-Hispanic White patients (80.7%) or Hispanic patients (80.8%) compared to non-Hispanic Black patients (72.6%). CONCLUSION: Neuroblastoma incidence was stable during 2003-2019. Differences in relative survival exist by sex, age, race/ethnicity, and stage; patients who were male, older, non-Hispanic Black, or with distant disease had worse survival. Future studies could seek to assess the upstream factors driving disparities in survival, and evaluate interventions to address inequities and improve survival across all groups.

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size.

The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.

Autoinflammatory Diseases/Periodic Fevers.

Children with intermittent fevers present to pediatricians and other primary care child health providers for evaluation. Most patients will have self-limited, benign infectious illnesses. However, the possibility of a periodic fever syndrome should be considered if febrile episodes become recurrent over an extended period and are associated with particular signs and symptoms during each attack. This review discusses the current conceptualization of autoinflammatory diseases with specific focus and detail on familial Mediterranean fever; tumor necrosis factor receptor-associated periodic syndrome; mevalonate kinase deficiency; NLRP3-associated autoinflammatory disease; and periodic fever, aphthous stomatitis, pharyngitis, and adenitis. The genetic mutations associated with these clinical entities are identified, along with the historical nomenclature that predates the current pathogenetic understanding of these diseases. The episodic signs and symptoms seen across these periodic fever syndromes can be overlapping, but there are some distinguishing features that can be useful, and these are described. The disease course and potential complications, particularly amyloidosis, which is a variable risk in these conditions and a potential source of significant morbidity and mortality, are addressed. Treatment strategies are outlined, highlighting the advances in therapy that have resulted from the advent of proinflammatory cytokine-targeting biological agents.

Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial.

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929 .

Counts, incidence rates, and trends of pediatric cancer in the United States, 2003-2019.

BACKGROUND: Cancer is a leading cause of death by disease among children and adolescents in the United States. This study updates cancer incidence rates and trends using the most recent and comprehensive US cancer registry data available. METHODS: We used data from US Cancer Statistics to evaluate counts, age-adjusted incidence rates, and trends among children and adolescents younger than 20 years of age diagnosed with malignant tumors between 2003 and 2019. We calculated the average annual percent change (APC) and APC using joinpoint regression. Rates and trends were stratified by demographic and geographic characteristics and by cancer type. RESULTS: With 248 749 cases reported between 2003 and 2019, the overall cancer incidence rate was 178.3 per 1 million; incidence rates were highest for leukemia (46.6), central nervous system neoplasms (30.8), and lymphoma (27.3). Rates were highest for males, children 0 to 4 years of age, Non-Hispanic White children and adolescents, those in the Northeast census region, the top 25% of counties by economic status, and metropolitan counties with a population of 1 million people or more. Although the overall incidence rate of pediatric cancer increased 0.5% per year on average between 2003 and 2019, the rate increased between 2003 and 2016 (APC = 1.1%), and then decreased between 2016 and 2019 (APC = -2.1%). Between 2003 and 2019, rates of leukemia, lymphoma, hepatic tumors, bone tumors, and thyroid carcinomas increased, while melanoma rates decreased. Rates of central nervous system neoplasms increased until 2017, and then decreased. Rates of other cancer types remained stable. CONCLUSIONS: Incidence of pediatric cancer increased overall, although increases were limited to certain cancer types. These findings may guide future public health and research priorities.

Interaction between age and gender on survival outcomes in extramedullary multiple myeloma over the past two decades.

BACKGROUND: Extramedullary multiple myeloma (MM) (EMM) is a rare and aggressive subentity of MM that can be present at diagnosis or develop anytime during the disease course. There is a paucity of data on the clinical characteristics and overall epidemiology of EMM. Furthermore, there is a scarcity of data on how the interaction of age and gender influences the survival of EMM. AIM: To evaluate the clinical characteristics of patients with EMM over the past 2 decades and to identify epidemiologic characteristics that may impact overall prognosis. METHODS: A total of 858 patients diagnosed with EMM, between 2000 and 2017, were ultimately enrolled in our study by retrieving the Surveillance, Epidemiology, and End Results database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of EMM. Variables with a P value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. RESULTS: From a sample of 858 EMM, the male gender (63.25%), age range 60-79 years (51.05%), and non-Hispanic whites (66.78%) were the most represented. Central Nervous System and the vertebral column was the most affected site (33.10%). Crude analysis revealed higher OM in the age group 80+ [HR = 6.951, 95% confidence interval (95%CI): 3.299-14.647, P = 0], Non-Hispanic Black population (HR = 1.339, 95%CI: 1.02-1.759, P = 0.036), Bones not otherwise specified (NOS) (HR = 1.74, 95%CI: 1.043-2.902, P = 0.034), and widowed individuals (HR = 2.107, 95%CI: 1.511-2.938, P = 0). Skin involvement (HR = 0.241, 95%CI: 0.06-0.974, P = 0.046) and a yearly income of $75000+ (HR = 0.259, 95%CI: 0.125-0.538, P = 0) had the lowest OM in the crude analysis. Crude analysis revealed higher CSM in the age group 80+, Non-Hispanic Black, Bones NOS, and widowed. Multivariate cox proportional hazard regression analyses only revealed higher OM in the age group 80+ (HR = 9.792, 95%CI: 4.403-21.774, P = 0) and widowed individuals (HR = 1.609, 95%CI: 1.101-2.35, P = 0.014). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups. Eyes, mouth, and ENT involvement had the lowest CSM in the multivariate analysis. There was no interaction between age and gender in the adjusted analysis for OM and CSM. CONCLUSION: EMM is a rare entity. To our knowledge, there is a scarcity of data on the clinical characteristics and prognosis factors of patients with extramedullary multiple myeloma. In this retrospective cohort, using a United States-based population, we found that age, marital status, and tumor site were independent prognostic factors. Furthermore, we found that age and gender did not interact to influence the mortality of patients with EMM.

Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study.

CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) vs carfilzomib and dexamethasone (Kd) in adults with relapsed/refectory multiple myeloma (RRMM) with 1 to 3 prior therapies. The CANDOR study met its primary end point of progression-free survival (PFS) in the primary analysis. Here, we report the final analysis of the study, including secondary end points and subgroup analyses thereof. The median follow-up was 50 months. Patients treated with KdD had higher minimal residual disease-negative (MRD-) achievement rates (28% vs 9%; odds ratio [OR], 4.22; 95% confidence interval [95% CI], 2.28-7.83) and MRD- complete response rates (22% vs 8%; OR, 3.55; 95% CI, 1.83-6.88) than those treated with Kd. Median PFS was 28.4 months for KdD vs 15.2 months for Kd (hazard ratio [HR], 0.64; 95% CI, 0.49-0.83). Median overall survival (OS) for KdD was 50.8 months vs 43.6 months for Kd (HR, 0.78 [0.60-1.03]; P = .042). Trends toward improved OS occurred in predefined subgroups, including patients refractory to lenalidomide (KdD, not reached vs Kd, 38.2 months; HR, 0.69 [0.43-1.11]) and refractory to proteasome inhibitor (KdD, 43.2 months vs Kd, 30.0 months; HR, 0.70 [0.45-1.09]), and there was significant improvement in patients with high-risk cytogenetics (KdD, 34.3 months vs Kd: 17.1 months; HR, 0.52 [0.29-0.94]). No new safety signals were identified. In summary, the final analysis of CANDOR confirmed the PFS benefit and showed a trend in OS benefit with KdD vs Kd. These findings reinforce KdD as a standard of care for RRMM, especially in clinically relevant patient subgroups. This trial was registered at www.clinicaltrials.gov as #NCT03158688.

Combining cell-free RNA with cell-free DNA in liquid biopsy for hematologic and solid tumors.

Current use of liquid biopsy is based on cell-free DNA (cfDNA) and the evaluation of mutations or methylation pattern. However, expressed RNA can capture mutations, changes in expression levels due to methylation, and provide information on cell of origin, growth, and proliferation status. We developed an approach to isolate cell-free total nucleic acid (cfDNA) and used targeted next generation sequencing to sequence cell-free RNA (cfRNA) and cfDNA as new approach in liquid biopsy. We demonstrate that cfRNA is overall more sensitive than cfDNA in detecting mutations. We show that cfRNA is reliable in detecting fusion genes and cfDNA is reliable in detecting chromosomal gains and losses. cfRNA levels of various solid tumor biomarkers were significantly higher (P < 0.0001) in samples from solid tumors as compared with normal control. Similarly, cfRNA lymphoid markers and cfRNA myeloid markers were all higher in lymphoid and myeloid neoplasms, respectively as compared with control (P < 0.0001). Using machine learning we demonstrate cfRNA was highly predictive of diagnosis (AUC >0.98) of solid tumors, B-cell lymphoid neoplasms, T-cell lymphoid neoplasms, and myeloid neoplasms. In evaluating the host immune system, cfRNA CD4:CD8B and CD3D:CD19 ratios in normal controls were as expected (median: 5.92 and 6.87, respectively) and were significantly lower in solid tumors (P < 0.0002). This data suggests that liquid biopsy combining analysis of cfRNA with cfDNA is practical and may provide helpful information in predicting genomic abnormalities, diagnosis of neoplasms and evaluating both the tumor biology and the host response.

The Outsized Role of Salps in Carbon Export in the Subarctic Northeast Pacific Ocean.

Periodic blooms of salps (pelagic tunicates) can result in high export of organic matter, leading to an "outsized" role in the ocean's biological carbon pump (BCP). However, due to their episodic and patchy nature, salp blooms often go undetected and are rarely included in measurements or models of the BCP. We quantified salp-mediated export processes in the northeast subarctic Pacific Ocean in summer of 2018 during a bloom of Salpa aspera. Salps migrated from 300 to 750 m during the day into the upper 100 m at night. Salp fecal pellet production comprised up to 82% of the particulate organic carbon (POC) produced as fecal pellets by the entire epipelagic zooplankton community. Rapid sinking velocities of salp pellets (400-1,200 m d-1) and low microbial respiration rates on pellets (<1% of pellet C respired day-1) led to high salp pellet POC export from the euphotic zone-up to 48% of total sinking POC across the 100 m depth horizon. Salp active transport of carbon by diel vertical migration and carbon export from sinking salp carcasses was usually <10% of the total sinking POC flux. Salp-mediated export markedly increased BCP efficiency, increasing by 1.5-fold the proportion of net primary production exported as POC across the base of the euphotic zone and by 2.6-fold the proportion of this POC flux persisting 100 m below the euphotic zone. Salps have unique and important effects on ocean biogeochemistry and, especially in low flux settings, can dramatically increase BCP efficiency and thus carbon sequestration.

Incidence of selected cancers in Non-Hispanic American Indian and Alaska Native adolescent and young adult populations, 1999-2019.

PURPOSE: Studies have highlighted geographic variation in cancer incidence rates among American Indian and Alaska Native (AI/AN) populations. This is the first study to comprehensively evaluate incidence rates and trends among non-Hispanic AI/AN (NH-AI/AN) adolescents and young adults (AYAs) ages 15-39 years. METHODS: Using the United States Cancer Statistics AI/AN Incidence Analytic Database, we identified all malignant cancer cases for NH-AI/AN AYA populations for the years 1999-2019. We calculated age-adjusted incidence rates (per 100,000) for NH-AI/AN populations overall, by region, and by age group. We calculated the total percent change in the incidence of leading AYA cancers between 1999 and 2019, and trends by region and cancer type using Joinpoint analysis. RESULTS: Testicular (13.6) and breast (19.0) cancers had the highest incidence of all AYA cancers in NH-AI/AN males and females, respectively. Overall AYA cancer rates increased by 1.4% in NH-AI/AN males and 1.8% in NH-AI/AN females annually between 1999 and 2019. Increases were observed by age group and geographic region. CONCLUSIONS: This study describes regional differences in incidence rates of AYA cancers among NH-AI/AN populations. This data can help inform resource and cancer control priorities and strategies to reduce cancer risk and enhance access to quality diagnostic and treatment services for this population.

American society of pediatric otolaryngology vascular anomalies task force review of tongue venous malformations: Techniques, pearls, and pitfalls.

Management of tongue venous malformations can be challenging in the pediatric population due to their heterogeneity in presentation, extent of involvement and functional compromise. It is important to recognize the value of various treatment options in order to guide management of each patient in an individualized fashion. Here we describe a series of patients with tongue venous malformations that are managed using diverse modalities to illustrate the relative benefits and risks of each technique. The challenges of venous malformation treatment can be mitigated by tailoring the approach to each individual patient and malformation. This case series also emphasizes the need and importance of working in the setting of a multidisciplinary vascular anomalies team.

Engagement With the Centers for Disease Control and Prevention Coronavirus Self-Checker and Guidance Provided to Users in the United States From March 23, 2020, to April 19, 2021: Thematic and Trend Analysis.

BACKGROUND: In 2020, at the onset of the COVID-19 pandemic, the United States experienced surges in healthcare needs, which challenged capacity throughout the healthcare system. Stay-at-home orders in many jurisdictions, cancellation of elective procedures, and closures of outpatient medical offices disrupted patient access to care. To inform symptomatic persons about when to seek care and potentially help alleviate the burden on the healthcare system, Centers for Disease Control and Prevention (CDC) and partners developed the CDC Coronavirus Self-Checker ("Self-Checker"). This interactive tool assists individuals seeking information about COVID-19 to determine the appropriate level of care by asking demographic, clinical, and nonclinical questions during an online "conversation." OBJECTIVE: This paper describes user characteristics, trends in use, and recommendations delivered by the Self-Checker between March 23, 2020, and April 19, 2021, for pursuing appropriate levels of medical care depending on the severity of user symptoms. METHODS: User characteristics and trends in completed conversations that resulted in a care message were analyzed. Care messages delivered by the Self-Checker were manually classified into three overarching conversation themes: (1) seek care immediately; (2) take no action, or stay home and self-monitor; and (3) conversation redirected. Trends in 7-day averages of conversations and COVID-19 cases were examined with development and marketing milestones that potentially impacted Self-Checker user engagement. RESULTS: Among 16,718,667 completed conversations, the Self-Checker delivered recommendations for 69.27% (n=11,580,738) of all conversations to "take no action, or stay home and self-monitor"; 28.8% (n=4,822,138) of conversations to "seek care immediately"; and 1.89% (n=315,791) of conversations were redirected to other resources without providing any care advice. Among 6.8 million conversations initiated for self-reported sick individuals without life-threatening symptoms, 59.21% resulted in a recommendation to "take no action, or stay home and self-monitor." Nearly all individuals (99.8%) who were not sick were also advised to "take no action, or stay home and self-monitor." CONCLUSIONS: The majority of Self-Checker conversations resulted in advice to take no action, or stay home and self-monitor. This guidance may have reduced patient volume on the medical system; however, future studies evaluating patients' satisfaction, intention to follow the care advice received, course of action, and care modality pursued could clarify the impact of the Self-Checker and similar tools during future public health emergencies.