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By 2030, 70% of cancers will occur in developing countries. Head and neck cancers are primarily a developing world disease. While anatomical location and the extent of cancers are central to defining prognosis and staging, the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) have incorporated nonanatomic factors that correlate with prognosis into staging (eg, p16 status of oropharyngeal cancers). However, 16 of 17 head and neck surgeons from 13 African countries cannot routinely test for p16 status and hence can no longer apply AJCC/UICC staging to oropharyngeal cancer. While the AJCC/UICC should continue to refine staging that best reflects treatment outcomes and prognosis by incorporating new nonanatomical factors, they should also retain and refine anatomically based staging to serve the needs of clinicians and their patients in resource-constrained settings. Not to do so would diminish their global relevance and in so doing also disadvantage most of the world’s cancer patients.

Snyder's hope theory depicts hope, through the frame of positive psychology, as a cognitive construct with the perceived sense of goal-directed, pathways, and agency thinking (Snyder et al., 1991). Hope levels have been measured in various countries; however, no research to date focused on Haitians. This study, conducted in Petit-Goâve, Haiti, addressed this gap by investigating hope, pathway, and agency levels derived from 135 Haitian-Kreyol adult literacy course participants. This manuscript reports scores of illiterate Haitians' hope levels utilizing Snyder's Adult Hope Dispositional Scale; the scores are explained by Snyder's hope theory taking Haitian cultural and social landscapes into account. Despite the challenging environment and illiterate conditions, Haitian participants reported just below average hope levels, average pathway levels, and low agency levels. These findings suggested this population garnered hope in their everyday lives, despite difficult obstacles.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physicians choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

UNLABELLED: AXIN1 is a major component of the β-catenin destruction complex and is frequently mutated in various cancer types, particularly liver cancers. Truncating AXIN1 mutations are recognized to encode a defective protein that leads to β-catenin stabilization, but the functional consequences of missense mutations are not well characterized. Here, we first identified the GSK3β, β-catenin, and RGS/APC interaction domains of AXIN1 that are the most critical for proper β-catenin regulation. Analysis of 80 tumor-associated variants in these domains identified 18 that significantly affected β-catenin signaling. Coimmunoprecipitation experiments revealed that most of them lost binding to the binding partner corresponding to the mutated domain. A comprehensive protein structure analysis predicted the consequences of these mutations, which largely overlapped with the observed effects on β-catenin signaling in functional experiments. The structure analysis also predicted that loss-of-function mutations within the RGS/APC interaction domain either directly affected the interface for APC binding or were located within the hydrophobic core and destabilized the entire structure. In addition, truncated AXIN1 length inversely correlated with the β-catenin regulatory function, with longer proteins retaining more functionality. These analyses suggest that all AXIN1-truncating mutations at least partially affect β-catenin regulation, whereas this is only the case for a subset of missense mutations. Consistently, most colorectal and liver cancers carrying missense variants acquire mutations in other β-catenin regulatory genes such as APC and CTNNB1. These results will aid the functional annotation of AXIN1 mutations identified in large-scale sequencing efforts or in individual patients. SIGNIFICANCE: Characterization of 80 tumor-associated missense variants of AXIN1 reveals a subset of 18 mutations that disrupt its β-catenin regulatory function, whereas the majority are passenger mutations.

PURPOSE: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS: Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION: Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

UNLABELLED: Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur. We developed a global FEA-computed fracture risk index to increase the prediction accuracy of hip fracture incidence. PURPOSE: Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur to compute the force (fracture load) and energy necessary to break the proximal femur in a particular loading condition. The fracture loads and energies-to-failure are individually associated with incident hip fracture, and provide different structural information about the proximal femur. METHODS: We used principal component analysis (PCA) to develop a global FEA-computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies-to-failure in four loading conditions of 110 hip fracture subjects and 235 age- and sex-matched control subjects from the AGES-Reykjavik study. Using a logistic regression model, we compared the prediction performance for hip fracture based on the stratified resampling. RESULTS: We referred the first principal component (PC1) of the FE parameters as the global FEA-computed fracture risk index, which was the significant predictor of hip fracture (p-value

In monarchE, adjuvant abemaciclib significantly improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS), with sustained benefit beyond the 2-year treatment period. Abemaciclib dose reductions were allowed to proactively manage adverse events. Exploratory analyses to investigate the impact of dose reductions on efficacy were conducted. Across the three patient subgroups as defined by relative dose intensity (≤66%, 66-93%, ≥93%), the estimated 4-year IDFS rates were generally consistent (87.1%, 86.4%, and 83.7%, respectively). In the time-dependent Cox proportional hazard model, the effect of abemaciclib was consistent at the full dose compared to being reduced to a lower dose (IDFS hazard ratio: 0.905; 95% confidence interval: 0.727, 1.125; DRFS hazard ratio: 0.942; 95% confidence interval: 0.742, 1.195). These analyses showed that the efficacy of adjuvant abemaciclib was not compromised by protocol mandated dose reductions for patients with node positive, hormone receptor positive, human epidermal growth factor 2-negative, high-risk early breast cancer.

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. CONCLUSIONS: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.

The fundamental goal of a rare plant translocation is to create self-sustaining populations with the evolutionary resilience to persist in the long term. Yet, most plant translocation syntheses focus on a few factors influencing short-term benchmarks of success (e.g., survival and reproduction). Short-term benchmarks can be misleading when trying to infer future growth and viability because the factors that promote establishment may differ from those required for long-term persistence. We assembled a large (n = 275) and broadly representative data set of well-documented and monitored (7.9 years on average) at-risk plant translocations to identify the most important site attributes, management techniques, and species' traits for six life-cycle benchmarks and population metrics of translocation success. We used the random forest algorithm to quantify the relative importance of 29 predictor variables for each metric of success. Drivers of translocation outcomes varied across time frames and success metrics. Management techniques had the greatest relative influence on the attainment of life-cycle benchmarks and short-term population trends, whereas site attributes and species' traits were more important for population persistence and long-term trends. Specifically, large founder sizes increased the potential for reproduction and recruitment into the next generation, whereas declining habitat quality and the outplanting of species with low seed production led to increased extinction risks and a reduction in potential reproductive output in the long-term, respectively. We also detected novel interactions between some of the most important drivers, such as an increased probability of next-generation recruitment in species with greater seed production rates, but only when coupled with large founder sizes. Because most significant barriers to plant translocation success can be overcome by improving techniques or resolving site-level issues through early intervention and management, we suggest that by combining long-term monitoring with adaptive management, translocation programs can enhance the prospects of achieving long-term success.

Background: Thirdhand smoke (THS) contains toxic residues, including carcinogens, which persist on surfaces and clothes even after cigarette smoke dissipates. The public awareness of THS and its health effects remain low. Objective: This study examined beliefs about THS among Chinese-speaking former smokers and their non-smoking family members, before and after participating in a family-based THS education program. Methods: We implemented a 2-week THS education intervention delivered by lay health workers with 30 Chinese American dyads (N=60) residing in Northern California, consisting of former smokers who quit within the past 2 years and their family members. THS beliefs were assessed using the Beliefs About Thirdhand Smoke (BATHS) questionnaire administered at pre- and postintervention. Focus groups with 8 former smokers and 7 family participants were conducted. We used multivariable regression with Generalized Estimating Equations to account for time points and household correlations to assess changes in BATHS scores (Overall, Persistence and Health subscales). Focus group transcripts underwent independent coding by two researchers and thematic analysis. Results: The study sample included 30 male former smokers (37% with slight to mild craving for smoking), and 30 family members (97% female) who never smoked. A majority (82%) spoke English less than well, 83% were married, 58% lived with children and 27% with current smokers. All multivariable models showed a significant time x role (former smokers vs family) interaction (p < 0.05). Former smokers had lower BATHS scores than their family at preintervention (p < 0.01), but their scores became similar at post-intervention. Former smokers’ BATHS scores increased from pre- to post-intervention (Overall: p=0.02; Persistence: p=0.03; Health: p=0.04) while family had no significant change. Prominent themes from focus groups supported gaining new knowledge for both persistence and health effects of THS. Both former smokers and family members appreciated learning about cleaning methods and both shared increased family discussions and collaboration in household cleaning post intervention. Conclusion: THS education impacts former smokers and their non-smoking family members differently. Family-based interventions are promising to align beliefs and promote collaboration within households in addressing THS. Future randomized controlled trials should investigate broader impacts of the program on enhancing support for motivating quitting for current smokers, maintaining smoking abstinence, and in reducing THS exposure.

Significance: Thirdhand smoke (THS), which includes secondhand smoke contami- nants, can be re-emitted and re-suspended into the air and are embedded into carpets, floors, and clothing. The awareness of THS and the health impacts from exposure to its harmful residues is low in the general population of the United States, especially in immigrant communities where smoking remains prevalent. Our study implemented a THS family-based intervention to promote THS awareness among Chinese American immigrants. Methods: The THS intervention included an education and home cleaning component delivered by lay health workers to 30 Chinese American dyads (N=60). Dyads consisted of former smokers who quit within the last two years and their non-smoking family member living in the same household. Participants completed pre- and post-in- tervention survey interviews and a sub-sample (N=15; 8 former smokers and 7 family members) participated in a post-intervention focus group. Multivariable regression adjusted for dyadic data was conducted to compare pre- and post-intervention changes in the Beliefs About Thirdhand Smoke (BATHS) overall and subscale (Persistence and Health) scores. Transcriptions from focus group interviews, conducted in Cantonese, were transcribed and translated, coded by two independent researchers and themati- cally analyzed using Dedoose. Results: All participants were born outside the US and 59% immigrated at age 30 or older (range: 7 to 63 years old). A majority (82%) spoke English less than “well” and 87% were married. BATHS scores analyses suggested that former smokers increased their THS awareness from pre- to post-intervention: BATHS Overall (M=3.95 [SD=0.50], p=0.021); Persistence (M=3.95 [SD=0.48], p=0.031) and Health (M=3.94 [SD=0.58], p=0.038), and their post-intervention THS scores became similar to the BATH scores of non-smoking family members which did not change at post-intervention. Thematic analyses of focus group interviews revealed emerging themes highlighting impacts on former smokers in increasing THS knowledge and strengthening desires to create dialogue about tobacco use with friends; for example, a former smoker shared “I will share my [THS] knowledge with others. I think it will help [my friends] as well.” Conclusion: A family-based THS education intervention has promising impacts to advance tobacco control in Chinese American immigrant communities by providing new THS knowledge and encouraging former smokers to become agents of change. Future research on empowering former smokers to become effective agents of change to promote tobacco-free communities is warranted.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourettes syndrome, the supplementary motor area in Parkinsons disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

ImportanceCurrent measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact.ObjectiveTo explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI).Evidence reviewA total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022.FindingsOf all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss.Conclusions and relevanceThis eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.