Hematology and oncology clinical care during the coronavirus disease 2019 pandemic.

New York City has been at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic that has already infected over a million people and resulted in more than 70,000 deaths as of early May 2020 in the United States alone. This rapid and enormous influx of patients into the health care system has had profound effects on all aspects of health care, including the care of patients with cancer. In this report, the authors highlight the transformation they underwent within the Division of Hematology and Medical Oncology as they prepared for the COVID-19 crisis in New York City. Under stressful and uncertain conditions, some of the many changes they enacted within their division included developing a regular line of communication among division leaders to ensure the development and implementation of a restructuring strategy, completely reconfiguring the inpatient and outpatient units, rapidly developing the ability to perform telemedicine video visits, and creating new COVID-rule-out and COVID-positive clinics for their patients. These changes allowed them to manage the storm while minimizing the disruption of important continuity of care to their patients with cancer. The authors hope that their experiences will be helpful to other oncology practices about to experience their own individual COVID-19 crises.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

Real-world impact of differences in the WHO and ICC classifications of non-Hodgkin lymphoma: a LEO Cohort Study analysis.

Recent introduction of two different lymphoma classifications has raised concerns about consistency in diagnosis, management, and clinical trial enrollment. Data from a large cohort reflecting real-world clinical practice suggest that differences between the classifications will impact <1% of non-Hodgkin lymphomas.

The rise of New Guinea and the fall of Neogene global temperatures.

The ~2,000-km-long Central Range of New Guinea is a hotspot of modern carbon sequestration due to the chemical weathering of igneous rocks with steep topography in the warm wet tropics. These high mountains formed in a collision between the Australian plate and ophiolite-bearing volcanic arc terranes, but poor resolution of the uplift and exhumation history has precluded assessments of the impact on global climate change. Here, we develop a palinspastic reconstruction of the Central Range orogen with existing surface geological constraints and seismic data to generate time-temperature paths and estimate volumes of eroded material. New (U-Th)/He thermochronology data reveal rapid uplift and regional denudation between 10 and 6 Mya. Erosion fluxes from the palinspastic reconstruction, calibrated for time with the thermochronological data, were used as input to a coupled global climate and weathering model. This model estimates 0.6 to 1.2 °C of cooling associated with the Late Miocene rise of New Guinea due to increased silicate weathering alone, and this CO2 sink continues to the present. Our data and modeling experiments support the hypothesis that tropical arc-continent collision and the rise of New Guinea contributed to Neogene cooling due to increased silicate weathering.

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL.

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (OS) was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5%, and 23.5%, respectively, with TET2 mutations significantly associated with CR (P = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266.

Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.

Progressive apraxia of speech (PAOS) is a neurodegenerative motor-speech disorder that most commonly arises from a four-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET and tau uptake on flortaucipir-PET in a large cohort of subjects with PAOS that had been followed for many years. Ninety-one subjects with PAOS (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analysed = 217). Volumes, metabolism and flortaucipir uptake were measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with PAOS subtypes being compared at baseline, 4 years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after 4 years, and faster rates of change in these regions, compared with the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra and thalamus volumes at baseline and after 4 years, as well as faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the supplementary motor area and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in PAOS subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of PAOS.

Actin nucleators safeguard replication forks by limiting nascent strand degradation.

Accurate genome replication is essential for all life and a key mechanism of disease prevention, underpinned by the ability of cells to respond to replicative stress (RS) and protect replication forks. These responses rely on the formation of Replication Protein A (RPA)-single stranded (ss) DNA complexes, yet this process remains largely uncharacterized. Here, we establish that actin nucleation-promoting factors (NPFs) associate with replication forks, promote efficient DNA replication and facilitate association of RPA with ssDNA at sites of RS. Accordingly, their loss leads to deprotection of ssDNA at perturbed forks, impaired ATR activation, global replication defects and fork collapse. Supplying an excess of RPA restores RPA foci formation and fork protection, suggesting a chaperoning role for actin nucleators (ANs) (i.e. Arp2/3, DIAPH1) and NPFs (i.e, WASp, N-WASp) in regulating RPA availability upon RS. We also discover that ß-actin interacts with RPA directly in vitro, and in vivo a hyper-depolymerizing ß-actin mutant displays a heightened association with RPA and the same dysfunctional replication phenotypes as loss of ANs/NPFs, which contrasts with the phenotype of a hyper-polymerizing ß-actin mutant. Thus, we identify components of actin polymerization pathways that are essential for preventing ectopic nucleolytic degradation of perturbed forks by modulating RPA activity.

ESCRT-dependent control of craniofacial morphogenesis with concomitant perturbation of NOTCH signaling.

Craniofacial development is orchestrated by transcription factor-driven regulatory networks, epigenetic modifications, and signaling pathways. Signaling molecules and their receptors rely on endo-lysosomal trafficking to prevent accumulation on the plasma membrane. ESCRT (Endosomal Sorting Complexes Required for Transport) machinery is recruited to endosomal membranes enabling degradation of such endosomal cargoes. Studies in vitro and in invertebrate models established the requirements of the ESCRT machinery in membrane remodeling, endosomal trafficking, and lysosomal degradation of activated membrane receptors. However, investigations during vertebrate development have been scarce. By ENU-induced mutagenesis, we isolated a mouse line, Vps25ENU/ENU, carrying a hypomorphic allele of the ESCRT-II component Vps25, with craniofacial anomalies resembling features of human congenital syndromes. Here, we assessed the spatiotemporal dynamics of Vps25 and additional ESCRT-encoding genes during murine development. We show that these genes are ubiquitously expressed although enriched in discrete domains of the craniofacial complex, heart, and limbs. ESCRT-encoding genes, including Vps25, are expressed in both cranial neural crest-derived mesenchyme and epithelium. Unlike constitutive ESCRT mutants, Vps25ENU/ENU embryos display late lethality. They exhibit hypoplastic lower jaw, stunted snout, dysmorphic ear pinnae, and secondary palate clefting. Thus, we provide the first evidence for critical roles of ESCRT-II in craniofacial morphogenesis and report perturbation of NOTCH signaling in craniofacial domains of Vps25ENU/ENU embryos. Given the known roles of NOTCH signaling in the developing cranium, and notably the lower jaw, we propose that the NOTCH pathway partly mediates the craniofacial defects of Vps25ENU/ENU mouse embryos.

Acalabrutinib alone or in combination with rituximab for follicular lymphoma: An open-label study.

Acalabrutinib is a selective, second-generation Bruton tyrosine kinase inhibitor. In this open-label, parallel-group study, patients with relapsed/refractory (R/R) follicular lymphoma (FL) were randomised to either acalabrutinib monotherapy or acalabrutinib plus rituximab. An additional cohort of patients with treatment-naive (TN) FL received only the acalabrutinib-rituximab combination. Acalabrutinib-rituximab was well tolerated and active in R/R and TN FL; in the TN cohort the overall response rate was 92.3% with most remissions lasting over 4 years. Acalabrutinib monotherapy was also well tolerated and active in R/R FL. These results support further study of acalabrutinib alone and in combination with rituximab in FL.

Machine learning for adverse event prediction in outpatient parenteral antimicrobial therapy: a scoping review.

OBJECTIVE: This study aimed to conduct a scoping review of machine learning (ML) techniques in outpatient parenteral antimicrobial therapy (OPAT) for predicting adverse outcomes and to evaluate their validation, implementation and potential barriers to adoption. MATERIALS AND METHODS: This scoping review included studies applying ML algorithms to adult OPAT patients, covering techniques from logistic regression to neural networks. Outcomes considered were medication intolerance, toxicity, catheter complications, hospital readmission and patient deterioration. A comprehensive search was conducted across databases including Cochrane Central, Cochrane Reviews, Embase, Ovid MEDLINE and Scopus, from 1 January 2000 to 1 January 2024. RESULTS: Thirty-two studies met the inclusion criteria, with the majority being single-centre experiences primarily from North America. Most studies focused on developing new ML models to predict outcomes such as hospital readmissions and medication-related complications. However, there was very little reporting on the performance characteristics of these models, such as specificity, sensitivity and C-statistics. There was a lack of multi-centre or cross-centre validation, limiting generalizability. Few studies advanced beyond traditional logistic regression models, and integration into clinical practice remains limited. DISCUSSION: ML shows promise for enhancing OPAT outcomes by predicting adverse events and enabling pre-emptive interventions. Despite this potential, significant gaps exist in development, validation and practical implementation. Barriers include the need for representative data sets and broadly applicable, validated models. CONCLUSION: Future research should address these barriers to fully leverage ML's potential in optimizing OPAT care and patient safety. Models must deliver timely, accurate and actionable insights to improve adverse event prediction and prevention in OPAT settings.

Rational design of a bacterial import system for new-to-nature molecules.

Integration of novel compounds into biological processes holds significant potential for modifying or expanding existing cellular functions. However, the cellular uptake of these compounds is often hindered by selectively permeable membranes. We present a novel bacterial transport system that has been rationally designed to address this challenge. Our approach utilizes a highly promiscuous sulfonate membrane transporter, which allows the passage of cargo molecules attached as amides to a sulfobutanoate transport vector molecule into the cytoplasm of the cell. These cargoes can then be unloaded from the sulfobutanoyl amides using an engineered variant of the enzyme γ-glutamyl transferase, which hydrolyzes the amide bond and releases the cargo molecule within the cell. Here, we provide evidence for the broad substrate specificity of both components of the system by evaluating a panel of structurally diverse sulfobutanoyl amides. Furthermore, we successfully implement the synthetic uptake system in vivo and showcase its functionality by importing an impermeant non-canonical amino acid.

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

Defining optimal perioperative analgesia in patients undergoing laparotomy for advanced gynecologic malignancy: A randomized controlled trial.

BACKGROUND: Enhanced recovery after surgery (ERAS) pathways utilize multimodal analgesia. In pathways already utilizing incisional injection of liposomal bupivacaine (ILB), we assessed the benefit of adding intrathecal opioid analgesia (ITA). METHODS: In this randomized controlled non-inferiority trial in patients undergoing laparotomy for gynecologic malignancy, we allocated patients 1:1 to ILB alone versus ITA + ILB with 150 µg intrathecal hydromorphone. The primary endpoint was the Overall Benefit of Analgesia Score (OBAS) at 24 h following surgery. Secondary endpoints included pain scores, intravenous opioid use, and cost of care. RESULTS: Demographic and surgical factors were balanced for 105 patients. For the primary endpoint, ILB alone was non-inferior to ITA + ILB (median OBAS at 24 h of 4 vs 4; p = 0.70). We observed a significant reduction in the need for intravenous opioids (26% vs 71%; p < 0.001) and total opioid requirements (median 7.5 vs 39.3 mg morphine equivalents, p < 0.001) in the first 24 h. Clinically relevant improvements in pain scores were identified in the first 16 h after surgery favoring ITA + ILB. Total cost of the index episode, pharmacy costs, and costs at 30 days were not statistically different. CONCLUSIONS: Using OBAS as the primary endpoint, ILB alone was non-inferior to ITA + ILB. However, important cost-neutral benefits for ITA + ILB in the first 24 h post-operatively included lower pain scores and reduced need for intravenous opioids. These early, incremental benefits of adding ITA to ERAS bundles already utilizing ILB should be considered to optimize immediate post-operative pain.

Reduced prosocial motivation and effort in adolescents with conduct problems and callous-unemotional traits.

BACKGROUND: Prosocial behaviours - acts that benefit others - are of crucial importance for many species including humans. However, adolescents with conduct problems (CP), unlike their typically developing (TD) peers, demonstrate markedly reduced engagement in prosocial behaviours. This pattern is particularly pronounced in adolescents with CP and high levels of callous-unemotional traits (CP/HCU) who are at increased risk of developing psychopathy in adulthood. While a substantial amount of research has investigated the cognitive-affective mechanisms thought to underlie antisocial behaviour, much less is known about the mechanisms that could explain reduced prosocial behaviours in adolescents with CP. METHODS: Here we examined the willingness to exert effort to benefit oneself (self) and another person (other, prosocial condition) in children with CP/HCU, CP and lower levels of CU traits (CP/LCU) and their TD peers. The task captured both prosocial choices, and actual effort exerted following prosocial choices, in adolescent boys aged 11-16 (27 CP/HCU; 34 CP/LCU; 33 TD). We used computational modelling to reveal the mechanistic processes involved when choosing prosocial acts. RESULTS: We found that both CP/HCU and CP/LCU groups were more averse to initiating effortful prosocial acts than TD adolescents - both at a cognitive and at a behavioural level. Strikingly, even if they chose to initiate a prosocial act, the CP/HCU group exerted less effort following this prosocial choice than other groups. CONCLUSIONS: Our findings indicate that reduced exertion of effort to benefit others may be an important factor that differentiates adolescents with CP/HCU from their peers with CP/LCU. They offer new insights into what might drive low prosocial behaviour in adolescents with CP, including vulnerabilities that may particularly characterise those with high levels of CU traits.

The impact of the RTS,S malaria vaccine on uncomplicated malaria: evidence from the phase IV study districts, Upper East Region, Ghana, 2020-2022.

BACKGROUND: The RTS,S malaria vaccine has been prequalified for use in endemic settings prioritizing areas with moderate to high disease transmission. The impact of a vaccine at the population level may differ from observations during clinical trial due to programmatic, and individual-related factors, among others. The objective of this study was to assess the impact of the RTS,S malaria vaccine on uncomplicated malaria among children aged 12-59 months in the Phase IV study districts, Upper East Region, Ghana. METHODS: A retrospective study was conducted using routine malaria surveillance data for the period 2020-2022. The burden of uncomplicated malaria was compared between the implementing (Kasena Nankana East and West districts) and comparator areas (Builsa North and South districts). The impact of RTS,S malaria vaccine was assessed by estimating the percentage reduction in uncomplicated malaria and incidence averted in the implementing area, accounting for the effect of confounders. RESULTS: Over 50,000 episodes of uncomplicated malaria among children aged 12-59 months were included in the study. Uncomplicated malaria was reduced by 33% (95%CI 29-36) over the entire study period, but the malaria incidence averted declined from 324/1,000 (95% CI 298-339; p < 0.0001) in 2020 to 287/1000 (95% CI 274-299; p < 0.0001) in 2022. CONCLUSION: The RTS,S malaria vaccine significantly reduced the burden of uncomplicated malaria among children aged 12-59 months in the implementing area. The sequential marginal declines in malaria incidence averted over the study period might be due to waning of protective immunity and acquisition of natural immunity as children age. Strengthening uptake of the currently recommended vaccines and other malaria control interventions is required to improve public health impact.

An assessment of Ghana's pilot of the RTS,S malaria vaccine implementation programme; 2019-2021: a retrospective study.

BACKGROUND: In May 2019, Ghana piloted the introduction of RTS,S malaria vaccine into routine immunization in 42 districts of seven of the 16 regions. The RTS,S malaria vaccine implementation programme (MVIP) post-introduction evaluation (PIE) conducted in Ghana, assessed the immunization system as well as healthcare worker and caregiver experiences during the phase-one rollout but was less expressive on quantitative grading of the respective thematic areas of the vaccine introduction plan. Given the utility of summary statistics in programme evaluation and communication, this follow-up study aimed to provide an overall rating of the country's performance regarding the MVIP . METHODS: A retrospective study was conducted from 10th January to 5th February 2024. It involved review of records to assess key thematic areas of the national MVIP plan, using a study tool adapted from the WHO New Vaccine Introduction (NVI) checklist. A composite score ranging from zero to 100 per cent was generated to assess the country's overall performance regarding introduction of the malaria vaccine, rated on a Likert scale as comprehensive, good, fair, and poor. RESULTS: The overall performance in the MVIP was rated 78.9% (30/38) corresponding to a grading of "good" on the Likert scale. Performance indicators under thematic areas including policy, national coordination mechanisms, waste management, health worker training, and pharmacovigilance were completely achieved. However,  some weaknesses were exhibited in areas such as financial consideration, cold chain, logistics, and vaccine management, and monitoring and evaluation. CONCLUSION: Ghana's MVIP demonstrated remarkable strengths worth leveraging  to improve the national immunization programme. The weaknesses observed in some of the thematic areas present opportunities to engage key immunization partners and stakeholders towards aligning efforts to ensure a more robust expansion phase. The lessons from the MVIP may be relevant to areas introducing malaria vaccine irrespective of the product type-RTS,S or R21.

The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Tackling Challenges in Assessing the Economic Value of Tumor-Agnostic Therapies: A Cost-Effectiveness Analysis of Pembrolizumab as a Case Study.

OBJECTIVES: Assessing the value of tumor-agnostic drugs (TAD) is challenging given the potential variability in treatment effects, trials with small sample sizes, different standards of care (SoC), and lack of comparative data from single-arm basket trials. Our study developed and applied novel methods to assess the value of pembrolizumab compared with SoC to inform coverage decisions. METHODS: We developed a partitioned survival model to evaluate the cost-utility of pembrolizumab for previously treated patients with 8 advanced or metastatic microsatellite instability-high or mismatch repair-deficient cancers from a US commercial payer perspective. Efficacy of pembrolizumab was based on data from trials directly or with adjustment using Bayesian hierarchical models. Eight chemotherapy-based external control arms were constructed from the TriNetX electronic health record databases. Tumor-specific health-state utility values were applied. All costs were adjusted to 2022 US dollars. RESULTS: At a lifetime horizon, pembrolizumab was associated with increased effectiveness compared with chemotherapies in colorectal (quality-adjusted life years [QALYs]: +0.64, life years [LYs]: +0.64), endometrial (QALYs: +3.79, LYs: +5.47), and small intestine cancers (QALYs: +1.73, LYs: +2.48), but not for patients with metastatic gastric, cholangiocarcinoma, pancreatic, ovarian, and brain cancers. Incremental cost-effectiveness ratios varied substantially across tumor types. Pembrolizumab was found to be cost-effective in treating colorectal and endometrial cancers (incremental cost-effectiveness ratios: $121 967 and $139 257, respectively), and not cost-effective for other assessed cancers at a $150 000 willingness-to-pay/QALY threshold, compared with SoC chemotherapies. CONCLUSIONS: The cost-effectiveness of TADs can vary by cancers. Using analytic tools such as external controls and Bayesian hierarchical models can tackle several challenges in assessing the value of TADs and uncertainties from basket trials.

"It gave me a sense of achievement and a sense of purpose"-a qualitative study of patient experiences of a virtually supervised exercise program for adults with advanced cancer and cachexia.

People with advanced cancer and cachexia experience significant body weight loss, adversely impacting physical function and quality of life (QOL). Effective, evidence-based treatments for cancer cachexia are lacking, leaving patients with unmet needs. Exercise holds promise to improve patient QOL. However, information on patients' experiences of exercise, including their ability to cope with structured exercise, is limited. PURPOSE: To explore patient experiences completing a structured, supervised exercise program for people with cachexia due to advanced cancer. METHODS: Semi-structured interviews were conducted with participants enrolled in a phase II feasibility, randomized controlled trial to explore their experiences of an 8-week virtually supervised exercise program delivered via videoconference technology. Interviews were analysed using reflexive thematic analysis. RESULTS: Seventeen participants completed interviews (female n = 9, 53%). Main interview themes included the following: (1) Deciding to exercise involves balancing concerns and expectations, (2) the exercise program is a positive experience, and (3) moving forward after the exercise program. While some participants initially held doubts about their physical capabilities and exercise safety, most wanted to exercise to enhance their wellbeing. Participants described the exercise program as a positive experience, offering diverse benefits. Some would have preferred in-person exercise, but all agreed the virtual format increased convenience. Participants emphasized the need to recommend the program to others in similar circumstances. They underscored the necessity and desire for ongoing support to sustain their new exercise habits. CONCLUSION: Based on patient experiences, virtually supervised exercise programming appears to be feasible and meaningful to people with advanced cancer and cachexia.

Defining the Core Content for Transport Physician Training Programs.

In many parts of the world, emergency medical services (EMS) clinical care is traditionally delivered by different levels or types of EMS clinicians, such as emergency medical technicians and paramedics. In some areas, physicians are also included among the cadre of professionals administering EMS-based care. This is especially true in the interfacility transport (IFT) setting. Though there is significant overlap between the knowledge and skills necessary to safely and effectively provide care in the IFT and prehospital settings, the IFT care environment requires physicians to develop several additional competencies beyond those that are expected of traditional EMS clinicians. NAEMSP first published recommendations regarding what some of these competencies should be in 1983 and subsequently updated those recommendations in 2002. This document is an updated work, given the evolution of the field.