DEFINITIVE PRIMARY THERAPY IN PATIENTS PRESENTING WITH OLIGOMETASTATIC NON-SMALL CELL LUNG CANCER (NSCLC)

Background: Although palliative chemotherapy is the standard of care for patients diagnosed with stage IV NSCLC, patients with a small metastatic burden, “oligometastatic” disease, may benefit from definitive local therapy. Methods: We identified 186 patients (26% of Stage IV patients) prospectively enrolled in our institutional database from 2002-2012 with oligometastatic disease, which we defined as five or fewer distant metastatic lesions at diagnosis. Univariable and multivariable Cox proportional hazards models were used to identify patient and disease factors associated with improved survival. Using propensity score methods, we investigated the effect of definitive local therapy to the primary site on overall survival. Results: Median age at diagnosis was 61 years, 51% of patients were female, 12% had squamous histology, and 33% had N0-1 disease. On multivariable analysis, ECOG performance status ≥2 (hazard ratio [HR] 2.43), nodal status N2-3 (HR 2.16), squamous pathology, and metastases to multiple organs (HR 2.11) were associated with a greater hazard of death (all p<0.01). Number of metastatic lesions and size of primary were not significantly associated with overall survival. Definitive local therapy to the primary tumor was associated with prolonged survival (HR 0.65, p=0.043). Conclusions: Definitive local therapy to the primary tumor appears to be associated with improved survival in patients with oligometastatic NSCLC. Select patient and tumor characteristics, including good performance status, non-squamous histology, and limited nodal disease, may predict for improved survival in these patients

Distinct clonal identities of B-ALLs arising after lenolidomide therapy for multiple myeloma

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant IgH clonotypes between the tumors were observed in 5 paired MM/B-ALL samples. Across all 17 B-ALL samples, 14 (83%) had a TP53 variant detected. Three MM samples with sufficient sequencing depth (\u3e500×) revealed rare cells (average of 0.6% variant allele frequency, or 1.2% of cells) with the same TP53 variant identified in the subsequent B-ALL sample. A lack of mutational overlap between MM and B-ALL samples shows that B-ALL developed as a second malignancy arising from a founding population of cells that likely represented unrelated clonal hematopoiesis caused by a TP53 mutation. The recurrent variants in TP53 in the B-ALL samples suggest a common path for malignant transformation that may be similar to that of TP53-mutant, treatment-related acute myeloid leukemia. The presence of rare cells containing TP53 variants in bone marrow at the initiation of lenalidomide treatment suggests that cellular populations containing TP53 variants expand in the presence of lenalidomide to increase the likelihood of B-ALL development

Behavioral economic implementation strategies to improve serious illness communication between clinicians and high-risk patients with cancer: protocol for a cluster randomized pragmatic trial

Background Serious illness conversations (SICs) are an evidence-based approach to eliciting patients’ values, goals, and care preferences that improve patient outcomes. However, most patients with cancer die without a documented SIC. Clinician-directed implementation strategies informed by behavioral economics (“nudges”) that identify high-risk patients have shown promise in increasing SIC documentation among clinicians. It is unknown whether patient-directed nudges that normalize and prime patients towards SIC completion—either alone or in combination with clinician nudges that additionally compare performance relative to peers—may improve on this approach. Our objective is to test the effect of clinician- and patient-directed nudges as implementation strategies for increasing SIC completion among patients with cancer. Methods We will conduct a 2 × 2 factorial, cluster randomized pragmatic trial to test the effect of nudges to clinicians, patients, or both, compared to usual care, on SIC completion. Participants will include 166 medical and gynecologic oncology clinicians practicing at ten sites within a large academic health system and their approximately 5500 patients at high risk of predicted 6-month mortality based on a validated machine-learning prognostic algorithm. Data will be obtained via the electronic medical record, clinician survey, and semi-structured interviews with clinicians and patients. The primary outcome will be time to SIC documentation among high-risk patients. Secondary outcomes will include time to SIC documentation among all patients (assessing spillover effects), palliative care referral among high-risk patients, and aggressive end-of-life care utilization (composite of chemotherapy within 14 days before death, hospitalization within 30 days before death, or admission to hospice within 3 days before death) among high-risk decedents. We will assess moderators of the effect of implementation strategies and conduct semi-structured interviews with a subset of clinicians and patients to assess contextual factors that shape the effectiveness of nudges with an eye towards health equity. Discussion This will be the first pragmatic trial to evaluate clinician- and patient-directed nudges to promote SIC completion for patients with cancer. We expect the study to yield insights into the effectiveness of clinician and patient nudges as implementation strategies to improve SIC rates, and to uncover multilevel contextual factors that drive response to these strategies. Trial registration ClinicalTrials.gov , NCT04867850 . Registered on April 30, 2021. Funding National Cancer Institute P50CA24469

Sugar and abscisic acid signaling orthologs are activated at the onset of ripening in grape

The onset of ripening involves changes in sugar metabolism, softening, and color development. Most understanding of this process arises from work in climacteric fruits where the control of ripening is predominately by ethylene. However, many fruits such as grape are nonclimacteric, where the onset of ripening results from the integration of multiple hormone signals including sugars and abscisic acid (ABA). In this study, we identified ten orthologous gene families in Vitis vinifera containing components of sugar and ABA-signaling pathways elucidated in model systems, including PP2C protein phosphatases, and WRKY and homeobox transcription factors. Gene expression was characterized in control- and deficit-irrigated, field-grown Cabernet Sauvignon. Sixty-seven orthologous genes were identified, and 38 of these were expressed in berries. Of the genes expressed in berries, 68% were differentially expressed across development and/or in response to water deficit. Orthologs of several families were induced at the onset of ripening, and induced earlier and to higher levels in response to water deficit; patterns of expression that correlate with sugar and ABA accumulation during ripening. Similar to field-grown berries, ripening phenomena were induced in immature berries when cultured with sucrose and ABA, as evidenced by changes in color, softening, and gene expression. Finally, exogenous sucrose and ABA regulated key orthologs in culture, similar to their regulation in the field. This study identifies novel candidates in the control of nonclimacteric fruit ripening and demonstrates that grape orthologs of key sugar and ABA-signaling components are regulated by sugar and ABA in fleshy fruit

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Paying for artificial intelligence in medicine

Over the past 7 years, regulatory agencies have approved hundreds of artificial intelligence (AI) devices for clinical use. In late 2020, payers began reimbursing clinicians and health systems for each use of select image-based AI devices. The experience with traditional medical devices has shown that per-use reimbursement may result in the overuse use of AI. We review current models of paying for AI in medicine and describe five alternative and complementary reimbursement approaches, including incentivizing outcomes instead of volume, utilizing advance market commitments and time-limited reimbursements for new AI applications, and rewarding interoperability and bias mitigation. As AI rapidly integrates into routine healthcare, careful design of payment for AI is essential for improving patient outcomes while maximizing cost-effectiveness and equity

Unusual presentation in Axenfeld-Rieger syndrome

We report an unusual presentation of a case of Axenfeld-Rieger (A-R) syndrome. A 14-year-old male presented with gradual dimness of vision for 1 year and redness of left eye for 3 days. The patient had megalocornea with Haab's striae in the right eye and posterior embryotoxon in both the eyes. In the left eye, there was a white cord-like structure traversing the anterior chamber with adhesions to iris tissue along its course. On two antiglaucoma medications, his intraocular pressure (IOP) was 22 mm Hg in the right eye and 18 mm Hg in the left eye. Gonioscopy revealed a cord-like structure originating at the level of Schwalbe's line. He underwent right eye trabeculectomy with mitomycin-C. This case highlights a rare presentation of a strange cord-like structure, a rare presentation of A-R syndrome

To Spur Growth in AI, We Need a New Approach to Legal Liability

The existing liability system in the United States and other countries can’t handle the risks relation to AI. That’s a problem because it will slow AI innovation and adoption. The answer is to revamp the system, which involves revising standards of care, changing who compensates parties when inevitable accidents occur via insurance and indemnity; changing default liability options; creating new adjudicators; and revamping regulations to prevent mistakes and exempt certain kinds of liability

Supplemental material - Time of Clinic Appointment and Serious Illness Communication in Oncology

Supplemental material for Supplemental material - Time of Clinic Appointment and Serious Illness Communication in Oncology by Likhitha Kolla, Jinbo Chen and Ravi B. Parikh in Cancer Control Journal</p