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PURPOSE: To validate the prognostic usefulness of gene expression profile (GEP) testing in patients with uveal melanoma. To determine whether combining tumor size with the GEP classification provides additional prognostic value. DESIGN: Retrospective analysis. PARTICIPANTS: Patients with a diagnosis of choroidal melanoma examined at Yale New Haven Hospital; University of California, San Diego; and Memorial Sloan Kettering Cancer Center. METHODS: Patients demographic and clinical data and tumor characteristics were collected. Univariate and multivariate Cox hazard regression analysis were used to assess the association between tumor characteristics and GEP classification with metastasis as an outcome. MAIN OUTCOME MEASURES: Metastasis-free survival (MFS). RESULTS: Of the 337 individuals included in the study, 87 demonstrated metastases. The mean follow-up time was 37.2 (standard deviation [SD], 40.2) months for patients with metastases and 55.0 (SD, 49.3) months for those without metastases. Tumors of larger thickness and GEP class 2 (vs. class 1) were associated significantly with increased risk of metastasis. Tumor thickness showed better prognostic usefulness than GEP classification (Wald statistic, 40.7 and 24.2, respectively). Class 2 tumors with a thickness of 7.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 7.0 mm (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.61-6.51), whereas class 1 tumors with a thickness of 9.0 mm or more were associated with increased risk of metastasis than tumors with a thickness of < 9.0 mm (HR, 2.07; 95% CI, 0.86-4.99). No difference in MFS was found between patients with class 1A tumors compared with those with class 1B tumors (P = 0.8). Patients with class 2 tumors showed an observed 5-year MFS of 47.5% (95% CI, 36.0%-62.8%). CONCLUSIONS: Tumor size was the most significant predictor of metastasis and provided additional prognostic value independent of GEP classification. In addition, rates of metastasis for class 2 tumors were lower than estimates reported by Castle Bioscience, and no difference in rates of metastasis were found between class 1A and 1B tumors. This indicates that tumor size should be accounted for when relying on GEP for prognostication and that patients with GEP class 1A or 1B tumors may benefit from the same metastatic surveillance protocols. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Natural disasters are becoming more frequent and destructive due to climate change and have been shown to be associated with a variety of adverse mental health outcomes in children and adolescents. This study utilizes data from three cohort studies of Hurricane Katrina survivors--including low-income mothers from New Orleans; displaced and highly impacted families from Louisiana and Mississippi; and Vietnamese immigrants in New Orleans--to examine the relationship between cumulative natural disaster exposure and adolescent psychological distress approximately 13 years after Katrina. Among 648 respondents with children ages 10-17, 112 (17.2%) reported that their child had exhibited one or more symptoms of psychological distress in the past month. Overall, respondents had experienced an average of 0.6 (SD 1.0) natural disasters following Hurricane Katrina. Each additional natural disaster experienced by the respondent was associated with 1.41 (95% CI 1.05, 1.88) greater odds of his or child experiencing psychological distress in the past month. This relationship was not significantly moderated by any measures of family resilience or vulnerability, nor by race/ethnicity or socioeconomic status, although family functioning, parental coping, and caregiver mental health were independently associated with adolescent psychological distress. The results of this analysis suggest that natural disasters have cumulative, detrimental impacts on adolescent mental health. Key Take Away Points: (1) 648 participants from three longitudinal cohorts impacted by Hurricane Katrina were surveyed in 2018 on their co-resident adolescents' psychological distress in the past month; (2) 17.2% of respondents reported that their child had symptoms of psychological distress; (3) Respondents experienced 0.6 (SD 1.0) natural disasters, on average, in addition to Hurricane Katrina; (4) Each additional natural disaster experienced by the respondent was associated with 1.40 (95% CI 1.05, 1.88) greater odds of his or child experiencing psychological distress in the past month; and (5) Family functioning, parental coping, and caregiver mental health were independently associated with adolescent psychological distress.

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

The Gulf of Mexico (GoM) region is prone to disasters, including recurrent oil spills, hurricanes, floods, industrial accidents, harmful algal blooms, and the current COVID-19 pandemic. The GoM and other regions of the U.S. lack sufficient baseline health information to identify, attribute, mitigate, and facilitate prevention of major health effects of disasters. Developing capacity to assess adverse human health consequences of future disasters requires establishment of a comprehensive, sustained community health observing system, similar to the extensive and well-established environmental observing systems. We propose a system that combines six levels of health data domains, beginning with three existing, national surveys and studies plus three new nested, longitudinal cohort studies. The latter are the unique and most important parts of the system and are focused on the coastal regions of the five GoM States. A statistically representative sample of participants is proposed for the new cohort studies, stratified to ensure proportional inclusion of urban and rural populations and with additional recruitment as necessary to enroll participants from particularly vulnerable or under-represented groups. Secondary data sources such as syndromic surveillance systems, electronic health records, national community surveys, environmental exposure databases, social media, and remote sensing will inform and augment the collection of primary data. Primary data sources will include participant-provided information via questionnaires, clinical measures of mental and physical health, acquisition of biological specimens, and wearable health monitoring devices. A suite of biomarkers may be derived from biological specimens for use in health assessments, including calculation of allostatic load, a measure of cumulative stress. The framework also addresses data management and sharing, participant retention, and system governance. The observing system is designed to continue indefinitely to ensure that essential pre-, during-, and post-disaster health data are collected and maintained. It could also provide a model/vehicle for effective health observation related to infectious disease pandemics such as COVID-19. To our knowledge, there is no comprehensive, disaster-focused health observing system such as the one proposed here currently in existence or planned elsewhere. Significant strengths of the GoM Community Health Observing System (CHOS) are its longitudinal cohorts and ability to adapt rapidly as needs arise and new technologies develop.

Intraarterial chemotherapy (Ophthalmic Artery Chemosurgery/OAC) for retinoblastoma has transformed management of retinoblastoma worldwide since Pierre Gobin MD and I introduced it in 2006. Case reports, institutional series, meta-analyses, and randomized trials have validated its effectiveness and safety. It allows more eyes to be saved (at Memorial Sloan Kettering Cancer Center (MSKCC) as a result, we have gone from removing 96% of retinoblastoma eyes that presented with leukocoria (comparable to modern day International Classification “D” and “E” eyes) to saving 95% of these eyes with primary OAC management allows the majority of advanced intraocular eyes to be salvaged (both “D” and “E” eyes) prior to the chemoreduction era to saving 95% of these eyes with primary OAC management. OAC attains cures faster than intravenous protocols, has fewer systemic side effects, and is overall cheaper than intravenous approaches (because of the absence of side effects which are the main driver of cost in pediatric oncology). Unlike systemic chemotherapy no ports are needed (and no removal of ports for life threatening infections), it does not alter the immune system (so children can be immunized), it does not affect patient growth (and children who had received systemic chemotherapy catch up in growth during OAC), it does not affect hearing (which systemic Carboplatin does-especially in children <6 months of age), it eliminates the second cancers caused by radiation and systemic chemotherapy and does not compromise survival with all series showing patient survival >98%. [ABSTRACT FROM AUTHOR]

Background: The frequency and destructiveness of hurricanes and related extreme weather events (e.g., cyclones, severe storms) have been increasing due to climate change. A growing body of evidence suggests that victims of hurricanes have increased incidence of cardiovascular disease (CVD), likely due to increased stressors around time of the hurricane and in their aftermath. Objectives: The objective was to systematically examine the evidence of the association between hurricanes (and related extreme weather events) and adverse CVD outcomes with the goal of understanding the gaps in the literature. Methods: A comprehensive literature search of population-level and cohort studies focused on CVD outcomes (i.e., myocardial infarction, stroke, and heart failure) related to hurricanes, cyclones, and severe storms was performed in the following databases from inception to December 2021: Ovid MEDLINE, Ovid EMBASE, Web of Science, and The Cochrane Library. Studies retrieved were then screened for eligibility against predefined inclusion/exclusion criteria. Studies were then qualitatively synthesized based on the time frame of the CVD outcomes studied and special populations that were studied. Gaps in the literature were identified based on this synthesis. Results: Of the 1,103 citations identified, 48 met our overall inclusion criteria. We identified articles describing the relationship between CVD and extreme weather, primarily hurricanes, based on data from the United States (42), Taiwan (3), Japan (2), and France (1). Outcomes included CVD and myocardial infarction-related hospitalizations (30 studies) and CVVD-related mortality (7 studies). Most studies used a retrospective study design, including one case-control study, 39 cohort studies, and 4 time-series studies. Discussion: Although we identified a number of papers that reported evaluations of extreme weather events and short- term adverse CVD outcomes, there were important gaps in the literature. These gaps included a) a lack of rigorous long-term evaluation of hurricane exposure, b) lack of investigation of hurricane exposure on vulnerable populations regarding issues related to environmental justice, c) absence of research on the exposure of multiple hurricanes on populations, and d) absence of an exploration of mechanisms leading to worsened CVD outcomes. Future research should attempt to fill these gaps, thus providing an important evidence base for future disaster- related policy. https://doi.org/10.1289/EHP 11252, Introduction Hurricanes and related extreme weather events (e.g., cyclones and severe storms) are destructive events and are likely to increase in both number and destructiveness driven by climate change. In [...]

Background Retinoblastoma (Rb) is the most common primary ocular malignancy of childhood. Left untreated, it is 100% fatal and carries a substantial risk of impaired vision and removal of one or both eyes. Intra-arterial chemotherapy (IAC) has become a pillar in the treatment paradigm for Rb that allows for better eye salvage and vision preservation without compromising survival. We describe the evolution of our technique over 15 years. Methods A retrospective chart review was conducted of 571 patients (697 eyes) and 2391 successful IAC sessions over 15 years. This cohort was separated into three 5-year periods (P1, P2, P3) to assess trends in IAC catheterization technique, complications, and drug delivery. Results From a total of 2402 attempted IAC sessions, there were 2391 successful IAC deliveries, consistent with a 99.5% success rate. The rate of successful super-selective catheterizations over the three periods ranged from 80% in P1 to 84.9% in P2 and 89.2% in P3. Catheterization-related complication rates were 0.7% in P1, 1.1% in P2, and 0.6% in P3. Chemotherapeutics used included combinations of melphalan, topotecan and carboplatin. The rate of patients receiving triple therapy among all groups was 128 (21%) in P1, 487 (41.9%) in P2, and 413 (66.7%) in P3. Conclusions The overall rate of successful catheterization and IAC started high and has improved over 15 years, and catheterization-related complications are rare. There has been a significant trend towards triple chemotherapy over time. [ABSTRACT FROM AUTHOR]

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis. Inhibition of CSF-1R with recurrent activating alterations and other actionable targets identified by genomic sequencing elicits clinical activity in patients with histiocytosis., Author(s): Benjamin H. Durham [sup.1] [sup.2] , Estibaliz Lopez Rodrigo [sup.3] [sup.4] , Jennifer Picarsic [sup.5] [sup.6] , David Abramson [sup.7] , Veronica Rotemberg [sup.8] , Steven De Munck [sup.9] [...]

Recently we have seen an increase in the calls for universities and the education community to re-think undergraduate education and create opportunities that prepare students as effective global professionals. The key motivator is the need to build a research and industrial workforce that works collaboratively across cultures and disciplines to address major global challenges. At the same time, computing, information, and communication technology facilitates a comprehensive "cyberinfrastructure" on which new types of scientific and engineering knowledge environments and organizations can be constructed. We describe our four-year pilot experience with the Pacific Rim Experiences for Undergraduates (PRIME) project. The goals of PRIME are to: develop an integrated and sustainable undergraduate international research program that serves as a model for 21st Century undergraduate education; prepare students to become effective global professionals and citizens; and give students a head-start on careers in science, engineering and technology research. We discuss the design and motivation for the scheme, salient implementation details, outcomes to date and discuss challenges of scalability and sustainability.