Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.

BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause. RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).

Pathway to independence: perspectives on the future.

In this Perspective, our 2024 Pathway to Independence Fellows provide their thoughts on the future of their field. Covering topics as diverse as plant development, tissue engineering and adaptation to climate change, and using a wide range of experimental organisms, these talented postdocs showcase some of the major open questions and key challenges across the spectrum of developmental biology research.

Measurement of adhesion and traction of cells at high yield reveals an energetic ratchet operating during nephron condensation.

Developmental biology-inspired strategies for tissue-building have extraordinary promise for regenerative medicine, spurring interest in the relationship between cell biophysical properties and morphological transitions. However, mapping gene or protein expression data to cell biophysical properties to physical morphogenesis remains challenging with current techniques. Here, we present multiplexed adhesion and traction of cells at high yield (MATCHY). MATCHY advances the multiplexing and throughput capabilities of existing traction force and cell-cell adhesion assays using microfabrication and a semiautomated computation scheme with machine learning-driven cell segmentation. Both biophysical assays are coupled with serial downstream immunofluorescence to extract cell type/signaling state information. MATCHY is especially suited to complex primary tissue-, organoid-, or biopsy-derived cell mixtures since it does not rely on a priori knowledge of cell surface markers, cell sorting, or use of lineage-specific reporter animals. We first validate MATCHY on canine kidney epithelial cells engineered for rearranged during transfection (RET) tyrosine kinase expression and quantify a relationship between downstream signaling and cell traction. We then use MATCHY to create a biophysical atlas of mouse embryonic kidney primary cells and identify distinct biophysical states along the nephron differentiation trajectory. Our data complement expression-level knowledge of adhesion molecule changes that accompany nephron differentiation with quantitative biophysical information. These data reveal an "energetic ratchet" that accounts for spatial trends in nephron progenitor cell condensation as they differentiate into early nephron structures, which we validate through agent-based computational simulation. MATCHY offers semiautomated cell biophysical characterization at >10,000-cell throughput, an advance benefiting fundamental studies and new synthetic tissue strategies for regenerative medicine.

Marine sponge microbe provides insights into evolution and virulence of the tubercle bacillus.

Reconstructing the evolutionary origins of Mycobacterium tuberculosis, the causative agent of human tuberculosis, has helped identify bacterial factors that have led to the tubercle bacillus becoming such a formidable human pathogen. Here we report the discovery and detailed characterization of an exceedingly slow growing mycobacterium that is closely related to M. tuberculosis for which we have proposed the species name Mycobacterium spongiae sp. nov., (strain ID: FSD4b-SM). The bacterium was isolated from a marine sponge, taken from the waters of the Great Barrier Reef in Queensland, Australia. Comparative genomics revealed that, after the opportunistic human pathogen Mycobacterium decipiens, M. spongiae is the most closely related species to the M. tuberculosis complex reported to date, with 80% shared average nucleotide identity and extensive conservation of key M. tuberculosis virulence factors, including intact ESX secretion systems and associated effectors. Proteomic and lipidomic analyses showed that these conserved systems are functional in FSD4b-SM, but that it also produces cell wall lipids not previously reported in mycobacteria. We investigated the virulence potential of FSD4b-SM in mice and found that, while the bacteria persist in lungs for 56 days after intranasal infection, no overt pathology was detected. The similarities with M. tuberculosis, together with its lack of virulence, motivated us to investigate the potential of FSD4b-SM as a vaccine strain and as a genetic donor of the ESX-1 genetic locus to improve BCG immunogenicity. However, neither of these approaches resulted in superior protection against M. tuberculosis challenge compared to BCG vaccination alone. The discovery of M. spongiae adds to our understanding of the emergence of the M. tuberculosis complex and it will be another useful resource to refine our understanding of the factors that shaped the evolution and pathogenesis of M. tuberculosis.

Jamming of nephron-forming niches in the developing mouse kidney creates cyclical mechanical stresses.

Urinary collecting tubules form during kidney embryogenesis through the branching of the ureteric bud epithelium. A travelling mesenchyme niche of nephron progenitor cells caps each branching ureteric bud tip. These 'tip domain' niches pack more closely over developmental time and their number relates to nephron endowment at birth. Yet, how the crowded tissue environment impacts niche number and cell decision-making remains unclear. Here, through experiments and mathematical modelling, we show that niche packing conforms to physical limitations imposed by kidney curvature. We relate packing geometries to rigidity theory to predict a stiffening transition starting at embryonic day 15 in the mouse, validated by micromechanical analysis. Using a method to estimate tip domain 'ages' relative to their most recent branch events, we find that new niches overcome mechanical resistance as they branch and displace neighbours. This creates rhythmic mechanical stress in the niche. These findings expand our understanding of kidney development and inform engineering strategies for synthetic regenerative tissues.

Large variation in availability of Maya food plant sources during ancient droughts.

Paleoclimatic evidence indicating a series of droughts in the Yucatan Peninsula during the Terminal Classic period suggests that climate change may have contributed to the disruption or collapse of Classic Maya polities. Although climate change cannot fully account for the multifaceted, political turmoil of the period, it is clear that droughts of strong magnitude could have limited food availability, potentially causing famine, migration, and societal decline. Maize was undoubtedly an important staple food of the ancient Maya, but a complete analysis of other food resources that would have been available during drought remains unresolved. Here, we assess drought resistance of all 497 indigenous food plant species documented in ethnographic, ethnobotanical, and botanical studies as having been used by the lowland Maya and classify the availability of these plant species and their edible components under various drought scenarios. Our analysis indicates availability of 83% of food plant species in short-term drought, but this percentage drops to 22% of food plant species available in moderate drought up to 1 y. During extreme drought, lasting several years, our analysis indicates availability of 11% of food plant species. Our results demonstrate a greater diversity of food sources beyond maize that would have been available to the Maya during climate disruption of the Terminal Classic period than has been previously acknowledged. While drought would have necessitated shifts in dietary patterns, the range of physiological drought responses for the available food plants would have allowed a continuing food supply under all but the most dire conditions.

Dual-Signal Chemical Exchange Saturation Transfer (Dusi-CEST): An Efficient Strategy for Visualizing Drug Delivery Monitoring in Living Cells.

We report a dual-signal chemical exchange saturation transfer (Dusi-CEST) strategy for drug delivery and detection in living cells. The two signals can be detected by operators in complex environments. This strategy is demonstrated on a cucurbit[6]uril (CB[6]) nanoparticle probe, as an example. The CB[6] probe is equipped with two kinds of hydrophobic cavities: one is found inside CB[6] itself, whereas the other exists inside the nanoparticle. When the probe is dispersed in aqueous solution as part of a hyperpolarized 129Xe NMR experiment, two signals appear at two different chemical shifts (100 and 200 ppm). These two resonances correspond to the NMR signals of 129Xe in the two different cavities. Upon loading with hydrophobic drugs, such as paclitaxel, for intracellular drug delivery, the two resonances undergo significant changes upon drug loading and cargo release, giving rise to a metric enabling the assessment of drug delivery success. The simultaneous change of Dusi-CEST likes a mobile phone that can receive both LTE and Wi-Fi signals, which can help reduce the occurrence of false positives and false negatives in complex biological environments and help improve the accuracy and sensitivity of single-shot detection.

An overview of Parafrankia (Nod+/Fix+) and Pseudofrankia (Nod+/Fix-) interactions through genome mining and experimental modeling in co-culture and co-inoculation of Elaeagnus angustifolia.

In many frankia, the ability to nodulate host plants (Nod+) and fix nitrogen (Fix+) is a common strategy. However, some frankia within the Pseudofrankia genus lack one or two of these traits. This phenomenon has been consistently observed across various actinorhizal nodule isolates, displaying Nod- and/or Fix- phenotypes. Yet, the mechanisms supporting the colonization and persistence of these inefficient frankia within nodules, both with and without symbiotic strains (Nod+/Fix+), remain unclear. It is also uncertain whether these associations burden or benefit host plants. This study delves into the ecological interactions between Parafrankia EUN1f and Pseudofrankia inefficax EuI1c, isolated from Elaeagnus umbellata nodules. EUN1f (Nod+/Fix+) and EuI1c (Nod+/Fix-) display contrasting symbiotic traits. While the prediction suggests a competitive scenario, the absence of direct interaction evidence implies that the competitive advantage of EUN1f and EuI1c is likely contingent on contextual factors such as substrate availability and the specific nature of stressors in their respective habitats. In co-culture, EUN1f outperforms EuI1c, especially under specific conditions, driven by its nitrogenase activity. Iron-depleted conditions favor EUN1f, emphasizing iron's role in microbial competition. Both strains benefit from host root exudates in pure culture, but EUN1f dominates in co-culture, enhancing its competitive traits. Nodulation experiments show that host plant preferences align with inoculum strain abundance under nitrogen-depleted conditions, while consistently favoring EUN1f in nitrogen-supplied media. This study unveils competitive dynamics and niche exclusion between EUN1f and EuI1c, suggesting that host plant may penalize less effective strains and even all strains. These findings highlight the complex interplay between strain competition and host selective pressure, warranting further research into the underlying mechanisms shaping plant-microbe-microbe interactions in diverse ecosystems. IMPORTANCE: While Pseudofrankia strains typically lack the common traits of ability to nodulate the host plant (Nod-) and/or fix nitrogen (Fix-), they are still recovered from actinorhizal nodules. The enigmatic question of how and why these unconventional strains establish themselves within nodule tissue, thriving either alongside symbiotic strains (Nod+/Fix+) or independently, while considering potential metabolic costs to the host plant, remains a perplexing puzzle. This study endeavors to unravel the competitive dynamics between Pseudofrankia inefficax strain EuI1c (Nod+/Fix-) and Parafrankia strain EU1Nf (Nod+/Fix+) through a comprehensive exploration of genomic data and empirical modeling, conducted both in controlled laboratory settings and within the host plant environment.

Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Drought stress influences foraging preference of a solitary bee on two wildflowers.

BACKGROUND AND AIMS: Pollinators provide critical ecosystem services, maintaining biodiversity and benefiting global food production. However, plants, pollinators, and their mutualistic interactions may be affected by drought, which has increased in severity and frequency under climate change. Using two annual, insect-pollinated wildflowers (Phacelia campanularia and Nemophila menziesii), we asked how drought impacts floral traits and foraging preferences of a solitary bee (Osmia lignaria) and explore potential implications for plant reproduction. METHODS: In greenhouses, we experimentally subjected plants to drought to induce water stress, as verified by leaf water potential. To assess the impact of drought on floral traits, we measured flower size, floral display size, nectar volume, and nectar sugar concentration. To explore how drought-induced effects on floral traits affected bee foraging preferences, we performed choice trials. Individual female bees were placed into foraging arenas with two conspecific plants, one droughted and one non-droughted, and were allowed to forage freely. KEY RESULTS: We determined that P. campanularia is more drought-tolerant than N. menziesii based on measures of turgor loss point, and confirmed that droughted plants were more drought-stressed than non-droughted plants. For droughted plants of both species, floral display size was reduced, and flowers were smaller and produced less, more-concentrated nectar. We found that bees preferred non-droughted flowers of N. menziesii. However, bee preference for non-droughted P. campanularia flowers depended on the time of day and was detected only in the afternoon. CONCLUSIONS: Our findings indicate that bees prefer visiting non-droughted flowers, likely reducing pollination success for drought-stressed plants. Lack of preference for non-droughted P. campanularia flowers in the morning may reflect the higher drought tolerance of this species. This work highlights the potentially intersecting, short-term physiological and pollinator behavioral responses to drought and suggests that such responses may reshape plant-pollinator interactions, ultimately reducing reproductive output for less drought-tolerant wildflowers.

Keratinocyte carcinomas in survivors of childhood cancer: A report from the childhood cancer survivor study.

BACKGROUND: Childhood cancer survivors (CCS) are at increased risk for keratinocyte carcinomas (KC) however, the long-term incidence of single and multiple KC is not well established. OBJECTIVE: Identify risk factors and quantify KC cumulative incidence and multiple-incidence burden in CCS. METHODS: KC were identified among Childhood Cancer Survivor Study participants, a cohort of 5-year cancer survivors diagnosed <21 years of age between 1970 and 1999 in North America. Cumulative incidence was estimated and multivariable models assessed relative rates of KC associated with survivor and treatment characteristics. RESULTS: Among 25,658 participants, 1446 developed 5363 KC (93.5% basal cell carcinoma, 6.7% squamous cell carcinoma; mean age 37.0 years (range 7.3-67.4), mean latency 25.7 years; 95.3% White and 88.4% with radiotherapy). Mean lesion count was 3.7 with 26.1% experiencing ≥4. Radiotherapy imparted a 4.5-fold increase in the rate of any KC and 9.4-fold increase in the rate of ≥4 KC. Allogeneic and autologous hematopoietic cell transplant were associated with a 3.4- and 2.3-fold increased rate of KC, respectively. LIMITATIONS: Participant self-reporting of some data including race without skin phototype and past medical history may have impacted analysis. CONCLUSIONS: The burden of KC in CCS remains high, but predictable risk factors should guide screening.

Nuclear induction line shape: Non-Markovian diffusion with boundaries.

The dynamics of viscoelastic fluids are governed by a memory function, essential yet challenging to compute, especially when diffusion faces boundary restrictions. We propose a computational method that captures memory effects by analyzing the time-correlation function of the pressure tensor, a viscosity indicator, through the Stokes-Einstein equation's analytic continuation into the Laplace domain. We integrate this equation with molecular dynamics simulations to derive necessary parameters. Our approach computes nuclear magnetic resonance (NMR) line shapes using a generalized diffusion coefficient, accounting for temperature and confinement geometry. This method directly links the memory function with thermal transport parameters, facilitating accurate NMR signal computation for non-Markovian fluids in confined geometries.

Newly Acquired Burnout During the Coronavirus Disease 2019 (COVID-19) Pandemic: A Retrospective Cohort Study on the Experiences of New York State Primary Care Clinicians.

The well-being of primary care clinicians represents an area of increasing interest amid concerns that the COVID-19 pandemic may have exacerbated already high prevalence rates of clinician burnout. This retrospective cohort study was designed to identify demographic, clinical, and work-specific factors that may have contributed to newly acquired burnout after the onset of the COVID-19 pandemic. An anonymous web-based questionnaire distributed in August 2020 to New York State (NYS) primary care clinicians, via email outreach and newsletters, produced 1,499 NYS primary care clinician survey respondents. Burnout assessment was measured pre-pandemic and early in the pandemic using a validated single-item question with a 5-point scale ranging from (1) enjoy work to (5) completely burned out. Demographic and work factors were assessed via the self-reporting questionnaire. Thirty percent of 1,499 survey respondents reported newly acquired burnout during the early pandemic period. This was more often reported by clinicians who were women, were younger than 56 years old, had adult dependents, practiced in New York City, had dual roles (patient care and administration), and were employees. Lack of control in the workplace prior to the pandemic was predictive of burnout early in the pandemic, while work control changes experienced following the pandemic were associated with newly acquired burnout. Low response rate and potential recall bias represent limitations. These findings demonstrate that reporting of burnout increased among primary care clinicians during the pandemic, partially due to varied and numerous work environment and systemic factors.

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.

Impact of Volumetric Dosimetry on the Projected Cost of Radiation-Related Late Effects Screening After Childhood Cancer: A Real-World Cohort Analysis.

BACKGROUND: Screening guidelines for childhood cancer survivors treated with radiation currently rely on broad anatomic irradiated regions (IR) to determine risk for late effects. However, contemporary radiotherapy techniques use volumetric dosimetry (VD) to define organ-specific exposure, which supports more specific screening recommendations that could be less costly. PATIENTS AND METHODS: This was a cross-sectional study of 132 patients treated with irradiation at Children's Hospital Los Angeles from 2000 to 2016. For 5 key organs (cochlea, breast, heart, lung, and colon), radiation exposure was determined retrospectively using both IR and VD methods. Under each method, Children's Oncology Group Long-Term Follow-Up Guidelines were used to identify organs flagged for screening and recommended screening tests. Projected screening costs incurred under each method were computed through age 65 using insurance claims data. RESULTS: Median age at the end of treatment was 10.6 years (range, 1.4-20.4). Brain tumor was the most common diagnosis (45%) and head/brain the most common irradiated region (61%). For all 5 organs, use of VD rather than IR resulted in fewer recommended screening tests. This led to average cumulative estimated savings of $3769 (P = .099), with significant savings in patients with CNS tumors (P = .012). Among patients with savings, average savings were $9620 per patient (P = .016) and significantly more likely for females than males (P = .027). CONCLUSION: Use of VD to enhance precision of guideline-based screening for radiation-related late effects permits fewer recommended screening tests and generates cost-savings.

Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Irrigated urban trees exhibit greater functional trait plasticity compared to natural stands.

Urbanization creates novel ecosystems comprised of species assemblages and environments with no natural analogue. Moreover, irrigation can alter plant function compared to non-irrigated systems. However, the capacity of irrigation to alter functional trait patterns across multiple species is unknown but may be important for the dynamics of urban ecosystems. We evaluated the hypothesis that urban irrigation influences plasticity in functional traits by measuring carbon-gain and water-use traits of 30 tree species planted in Southern California, USA spanning a coastal-to-desert gradient. Tree species respond to irrigation through increasing the carbon-gain trait relationship of leaf nitrogen per specific leaf area compared to their native habitat. Moreover, most species shift to a water-use strategy of greater water loss through stomata when planted in irrigated desert-like environments compared to coastal environments, implying that irrigated species capitalize on increased water availability to cool their leaves in extreme heat and high evaporative demand conditions. Therefore, irrigated urban environments increase the plasticity of trait responses compared to native ecosystems, allowing for novel response to climatic variation. Our results indicate that trees grown in water-resource-rich urban ecosystems can alter their functional traits plasticity beyond those measured in native ecosystems, which can lead to plant trait dynamics with no natural analogue.

Approaches to the Assessment of Clinical Benefit of Treatments for Conditions That Have Heterogeneous Symptoms and Impacts: Potential Applications in Rare Disease.

OBJECTIVES: Evaluating the clinical benefit of interventions for conditions with heterogeneous symptom and impact presentations is challenging. The same condition can present differently across and within individuals over time. This occurs frequently in rare diseases. The purpose of this review was to identify (1) assessment approaches used in clinical trials to address heterogeneous manifestations that could be relevant in rare disease research and (2) US Food and Drug Administration (FDA)-approved labeling claims that used these approaches. METHODS: A targeted literature review was conducted examining peer-reviewed publications and FDA-approved labeling claims from January 2002 to July 2020, focusing on claims incorporating clinical outcome assessments. Approaches were then assessed for their potential application in rare diseases. RESULTS: A total of 6 assessment approaches were identified: composite or other multicomponent endpoints, multidomain responder index, most bothersome symptom (MBS), goal attainment scaling, sliding dichotomy, and adequate relief. A total of 59 FDA-approved labeling claims associated with these approaches were identified: composite or other multicomponent endpoints (n=49), MBS (n=9), and adequate relief (n=1). A total of 10 FDA-approved labeling claims, all using multicomponent endpoints, were identified for rare diseases. CONCLUSIONS: Multicomponent, MBS, and adequate relief have been included in FDA-approved labeling claims. Multicomponent endpoints, including composite endpoints, were the most frequent way to address heterogeneous manifestations of both common and rare diseases. MBS may be acceptable to regulators, whereas multidomain responder index is unlikely to be. The goal attainment scaling and adequate relief approaches may have potential utility in rare disease trials, assuming the theoretical and statistical challenges inherent in each approach are managed.

A comprehensive review of 30 years of pediatric clinical trial radiotherapy dose constraints.

BACKGROUND: Radiation therapy normal tissue dose constraints are critical when treating pediatric patients. However, there is limited evidence supporting proposed constraints, which has led to variations in constraints over the years. In this study, we identify these variations in dose constraints within pediatric trials both in the United States and in Europe used in the past 30 years. PROCEDURE: All pediatric trials from the Children's Oncology Group website were queried from inception until January 2022 and a sampling of European studies was included. Dose constraints were identified and built into an organ-based interactive web application with filters to display data by organs at risk (OAR), protocol, start date, dose, volume, and fractionation scheme. Dose constraints were evaluated for consistency over time and compared between pediatric US and European trials RESULTS: One hundred five closed trials were included-93 US trials and 12 European trials. Thirty-eight separate OAR were found with high-dose constraint variability. Across all trials, nine organs had greater than 10 different constraints (median 16, range 11-26), including serial organs. When comparing US versus European dose tolerances, the United States constraints were higher for seven OAR, lower for one, and identical for five. No OAR had constraints change systematically over the last 30 years. CONCLUSION: Review of pediatric dose-volume constraints in clinical trials showed substantial variability for all OAR. Continued efforts focused on standardization of OAR dose constraints and risk profiles are essential to increase consistency of protocol outcomes and ultimately to reduce radiation toxicities in the pediatric population.

Patient preferences and health state utilities associated with the treatment process of antiretroviral therapy for people living with HIV.

PURPOSE: People living with HIV (PLHIV) have reported challenges associated with daily oral antiretroviral therapy (ART), including missed doses, negative psychological impact, and difficulty remaining discreet while at home or traveling. Recently approved long-acting injectable (LAI) ART may help eliminate these concerns. The purpose of this study was to examine patient preferences and estimate health state utilities associated with oral and LAI treatment for ART. METHODS: Four health state vignettes were developed based on published literature, clinician interviews, and a pilot study. All vignettes included the same description of HIV, but differed in treatment regimens: (A) single daily oral tablet, (B) two daily oral tablets, (C) injections once monthly, and (D) injections every two months. PLHIV in the UK reported their preferences and valued the health states in time trade-off utility interviews. RESULTS: The sample included 201 PLHIV (83.1% male; mean age = 44.9y). The health states frequently selected as most preferable were D (n = 119; 59.2%) and A (n = 75; 37.3%). Utility differences among health states were relatively small, which is typical for treatment process utilities (mean utilities: A, 0.908; B, 0.905; C, 0.900; D, 0.910). Statistically significant differences in utility were found for one vs. two tablets and injections every month vs. every two months (p < 0.001). Participants' quotations highlight the wide range of reasons for treatment process preferences. CONCLUSIONS: Current results indicate that many PLHIV would prefer LAI ART. The reported utilities may be useful in economic modeling comparing oral vs. LAI ART.