Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFß signaling, p53 and ß-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.

Adaptation of Chagas Disease Screening Recommendations for a Community of At-risk HIV in the United States.

Chagas disease (CD), caused by Trypanosoma cruzi, is underdiagnosed in the United States. Improved screening strategies are needed, particularly for people at risk for life-threatening sequelae of CD, including people with human immunodeficiency virus (HIV, PWH). Here we report results of a CD screening strategy applied at a large HIV clinic serving an at-risk population.

Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response.

Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.

The New Era of Long-Acting Antiretroviral Therapy: When and Why to Make the Switch.

PURPOSE OF REVIEW: Despite the availability of safe and effective oral combination antiretroviral therapy, barriers to maintaining viral suppression remain a challenge to ending the HIV epidemic. Long-acting injectable antiretroviral therapy was developed as an alternative to daily oral therapy. This review summarizes the current literature on the efficacy of long-acting cabotegravir plus rilpivirine for the treatment of HIV-1, reasons to switch to injectable therapy, and barriers to switching. RECENT FINDINGS: Long-acting cabotegravir plus rilpivirine is safe and effective in maintaining HIV-1 virologic suppression. Ideal candidates for switching to long-acting cabotegravir plus rilpivirine are virologically suppressed on oral regimens with good adherence and no history of virologic failure or baseline resistance. Indications to switch to injectable therapy include patient preference, the potential for improved adherence, and avoidance of adverse effects. Implementation research is needed to assess and overcome system barriers. Long-acting cabotegravir plus rilpivirine is a novel alternative to oral antiretrovirals, with the potential to improve adherence and quality of life in people with HIV.

Assessing incident depression among older people with and without HIV in U.S.

PURPOSE: Despite substantially higher prevalence of depression among people living with HIV/AIDS (PLWHA), few data exist on the incidence and correlates of depression in this population. This study assessed the effect of HIV infection, age, and cohort period on the risk of developing depression by sex among older U.S. Medicare beneficiaries. METHODS: We constructed a retrospective matched cohort using a 5% nationally representative sample of Medicare beneficiaries (1996-2015). People with newly diagnosed (n = 1309) and previously diagnosed (n = 1057) HIV were individually matched with up to three beneficiaries without HIV (n = 6805). Fine-Gray models adjusted for baseline covariates were used to assess the effect of HIV status on developing depression by sex strata. RESULTS: PLWHA, especially females, had higher risk of developing depression within five years. The relative subdistribution hazards (sHR) for depression among three HIV exposure groups differed between males and females and indicated a marginally significant interaction (p = 0.08). The sHR (95% CI) for newly and previously diagnosed HIV (vs. people without HIV) were 1.6 (1.3, 1.9) and 1.9 (1.5, 2.4) for males, and 1.5 (1.2, 1.8) and 1.2 (0.9, 1.7) for females. The risk of depression increased with age [sHR 1.3 (1.1, 1.5), 80 + vs. 65-69] and cohort period [sHR 1.3 (1.1, 1.5), 2011-2015 vs. 1995-2000]. CONCLUSIONS: HIV infection increased the risk of developing depression within 5 years, especially among people with newly diagnosed HIV and females. This risk increased with older age and in recent HIV epidemic periods, suggesting a need for robust mental health treatment in HIV primary care.

Impact of the COVID-19 Pandemic on Medical Education during Inpatient Internal Medicine Rounds.

OBJECTIVES: Inpatient rounding is a foundational component of medical education in academic hospitals. The coronavirus 2019 (COVID-19) pandemic disrupted traditional inpatient rounding practices. The objectives of this study were to describe how Internal Medicine inpatient team rounding changed because of COVID-19-related precautions and the effect of these changes on education during rounds. METHODS: During February to March 2021, we conducted four virtual focus groups with medical and physician assistant students, interns, upper-level residents, and attending physicians at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas, and designed a codebook to categorize focus group commentary. RESULTS: Focus groups revealed that students believed that certain physical-distancing measures in place early on during the pandemic were ineffective and significantly limited their ability to evaluate patients in person. Residents described increased stress levels related to potential severe acute respiratory-coronavirus 2 exposure and limited time at the bedside, which affected their confidence with clinical assessments. Rounding-team fragmentation precluded the entire team learning from all of the patients on the team's census. Loss of intrateam camaraderie impaired the development of comfortable learning environments. CONCLUSIONS: This study evaluated Internal Medicine team member focus groups to describe how the COVID-19 pandemic affected medical education during rounds. Academic teaching programs can adapt the findings from this study to address and prevent pandemic-related gaps in medical education during rounds now and during future potential disruptions to medical education.

A pilot study of cognition and creativity among persons with HIV disease referred for neuropsychological evaluation.

Creativity can help people to innovate, overcome obstacles, and successfully navigate challenges in daily life. Some aspects of creativity rely on the prefrontostriatal loops and executive functions, which can be compromised in persons with HIV (PWH). This pilot study examined whether neuropsychological functioning plays a role in creativity in PWH. A consecutive series of 41 PWH who were referred to an urban neuropsychology clinic in southeastern Texas were enrolled. Participants completed the Abbreviated Torrance Test for Adults (ATTA) to measure creativity, from which standardized creativity scores of fluency, originality, elaboration, and flexibility were derived. Participants also completed several measures of everyday functioning and a brief clinical neuropsychological battery measuring executive functions, motor skills, memory, and visuoconstruction. Global neuropsychological functioning showed a large, positive association with ATTA creativity performance that did not vary meaningfully by creativity domain and was independent of premorbid IQ. ATTA creativity scores were not associated with any measure of everyday functioning. Findings from this pilot study suggest that higher levels of neuropsychological functioning may support multiple dimensions of creativity in adults with HIV disease. Future studies might examine whether creativity moderates the association between HIV-associated neurocognitive impairment and various health behaviors (e.g., adherence, appointment attendance).

Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2.

Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are important cellular components in the cancer microenvironment and may affect cancer phenotype and patient outcome. The nature of MDSCs and their interaction with CSCs in ovarian carcinoma are unclear. We examined the interaction between MDSCs and CSCs in patients with ovarian carcinoma and showed that MDSCs inhibited T cell activation and enhanced CSC gene expression, sphere formation, and cancer metastasis. MDSCs triggered miRNA101 expression in cancer cells. miRNA101 subsequently repressesed the corepressor gene C-terminal binding protein-2 (CtBP2), and CtBP2 directly targeted stem cell core genes resulting in increased cancer cell stemness and increasing metastatic and tumorigenic potential. Increased MDSC density and tumor microRNA101 expression predict poor survival, as does decreased tumor CtBP2 expression, independent of each other. Collectively, our work identifies an immune-associated cellular, molecular, and clinical network involving MDSCs-microRNA101-CtBP2-stem cell core genes, which extrinsically controls cancer stemness and impacts patient outcome.

The Effect of Initial Patient Experiences and Life Stressors on Predicting Lost to Follow-Up in Patients New to an HIV Clinic.

We conducted a prospective cohort study of 450 patients new to an HIV clinic in Houston, TX, to examine the roles of life stressors and initial care experiences in predicting being lost to follow-up in the first year of care. Patients completed a self-administered survey following their initial provider visit. In logistic regression models, patients who reported better experiences with the HIV provider at the first visit were less likely to be lost to follow-up at 6 months (aOR = 0.866, p = 0.038) and 12 months (aOR = 0.825, p = 0.008). Patients with a higher burden of stressful life events were more likely to be lost to follow-up at 6 months (aOR = 1.232, p = 0.037) and 12 months (aOR = 1.263, p = 0.029). Assessments of patient experience and life stressors at the initial visit have potential to predict patients at risk of dropping out of care.

Acceptability and feasibility of video-based coaching to enhance clinicians' communication skills with patients.

BACKGROUND: Despite a growing call to train clinicians in interpersonal communication skills, communication training is either not offered or is minimally effective, if at all. A critical need exists to develop new ways of teaching communication skills that are effective and mindful of clinician time pressures. We propose a program that includes real-time observation and video-based coaching to teach clinician communication skills. In this study, we assess acceptability and feasibility of the program using clinician interviews and surveys. METHODS: The video-based coaching intervention targets five patient-centered communication behaviors. It uses trained communication coaches and live feed technology to provide coaching that is brief (less than 15 min), timely (same day) and theory-informed. Two coaches were trained to set up webcams and observe live video feeds of clinician visits in rooms nearby. As coaches watched and recorded the visit, they time stamped illustrative clips in real time. Video clips were a critical element of the program. During feedback sessions, coaches used video clips to promote discussion and self-reflection. They also used role play and guided practice techniques to enforce new tips. Clinicians included residents (n = 15), fellows (n = 4), attending physicians (n = 3), and a nurse practitioner (n = 1) at two primary care clinics in Houston, Texas. We administered surveys to clinicians participating in the program. The survey included questions on quality and delivery of feedback, and credibility of the coaches. We also interviewed clinicians following the intervention. We used rapid analysis to identify themes within the interviews. RESULTS: Survey measures showed high feasibility and acceptability ratings from clinicians, with mean item scores ranging from 6.4 to 6.8 out of 7 points. Qualitative analysis revealed that clinicians found that 1) coaches were credible and supportive, 2) feedback was useful, 3) video-clips allowed for self-reflection, 4) getting feedback on the same day was useful, and 5) use of real patients preferred over standardized patients. CONCLUSIONS: Video-based coaching can help clinicians learn new communication skills in a way that is clinician-centered, brief and timely. Our study demonstrates that real-time coaching using live feed and video technology is an acceptable and feasible way of teaching communication skills.

Novel role of ASH1L histone methyltransferase in anaplastic thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies, with an average life expectancy of ∼6 months from the time of diagnosis. The genetic and epigenetic changes that underlie this malignancy are incompletely understood. We found that ASH1-like histone lysine methyltransferase (ASH1L) is overexpressed in ATC relative to the much less aggressive and more common differentiated thyroid cancer. This increased expression was due at least in part to reduced levels of microRNA-200b-3p (miR-200b-3p), which represses ASH1L expression, in ATC. Genetic knockout of ASH1L protein expression in ATC cell lines decreased cell growth both in culture and in mouse xenografts. RNA-Seq analysis of ASH1L knockout versus WT ATC cell lines revealed that ASH1L is involved in the regulation of numerous cancer-related genes and gene sets. The pro-oncogenic long noncoding RNA colon cancer-associated transcript 1 (CCAT1) was one of the most highly (approximately 68-fold) down-regulated transcripts in ASH1L knockout cells. Therefore, we investigated CCAT1 as a potential mediator of the growth-inducing activity of ASH1L. Supporting this hypothesis, CCAT1 knockdown in ATC cells decreased their growth rate, and ChIP-Seq data indicated that CCAT1 is likely a direct target of ASH1L's histone methyltransferase activity. These results indicate that ASH1L contributes to the aggressiveness of ATC and suggest that ASH1L, along with its upstream regulator miR-200b-3p and its downstream mediator CCAT1, represents a potential therapeutic target in ATC.

DeTiN: overcoming tumor-in-normal contamination.

Comparison of sequencing data from a tumor sample with data from a matched germline control is a key step for accurate detection of somatic mutations. Detection sensitivity for somatic variants is greatly reduced when the matched normal sample is contaminated with tumor cells. To overcome this limitation, we developed deTiN, a method that estimates the tumor-in-normal (TiN) contamination level and, in cases affected by contamination, improves sensitivity by reclassifying initially discarded variants as somatic.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Reliability and Validity of a Brief Self-Report Adherence Measure among People with HIV Experiencing Homelessness and Mental Health or Substance Use Disorders.

The study examines the reliability and validity of a 3-item self-report adherence measure among people with HIV (PWH) experiencing homelessness, substance use, and mental health disorders. 336 participants were included from nine sites across the US between September 2013 and February 2017. We assessed the validity of a self-report scale for adherence to antiretroviral therapy by comparing it with viral load (VL) abstracted from medical records at baseline, 6, 12, and 18 months. The items had high internal consistency (Cronbach's alpha coefficients at each time point were > 0.8). The adherence scale scores were higher in the group that achieved VL suppression compared to the group that did not. The c-statistic for the receiver-operating characteristic curves pooled across time points was 0.77 for each adherence sub-item and 0.78 for the overall score. The self-report adherence measure shows good internal consistency and validity that correlated with VL suppression in homeless populations.

Acceptability and preferences for long-acting antiretroviral formulations among people with HIV infection.

The study evaluates the acceptability and preferences for long-acting antiretroviral therapy (LA-ART) among a diverse cohort of people with HIV infection (PWH). It consists of a self-administered survey and chart review of PWH presenting to an HIV clinic in Houston, Texas, between February and June 2018; 374 participants were included; 61% indicated that they were likely or very likely to use LA-ART formulations. When asked about preference, 41% preferred pills, 40% preferred injections, and 18% preferred an implant. The most common benefit reported was eliminating the need to remember taking daily HIV pills (74%); 43% were worried that LA-ART will not be as effective as pills. Participants with a college degree, men who have sex with men, and ART-experienced were more willing to use LA-ART. Participants who reported poor or fair health, or who screened positive for depression or anxiety were significantly less willing to use LA-ART. The likelihood of using LA-ART did not correlate with self-reported adherence and HIV suppression. Patients with difficulty scheduling and attending clinic visits preferred injections and implant over pills. Most participants indicated a willingness to use new LA ART formulations. However, 41% still prefers pills, and those more interested in LA-ART were not less adherent.

The relationship between sex-related alcohol expectancies and hazardous drinking among persons with HIV disease.

Hazardous drinking is a clinically significant problem among persons with HIV (PWH) disease, and is associated with a number of poor outcomes. Hazardous drinking among PWH is associated with risky substance use and sexual behavior, but little work has examined factors that may be associated with greater hazardous drinking and subsequent risky sexual behaviors among PWH. Research among the general population suggests that sex-related alcohol expectancies, defined as drinking to enhance sexual experience, increase sexual risk-taking, and disinhibition of sexual behavior, are associated with greater hazardous alcohol use and risky sexual behavior, but these relations have not been explored among PWH. Therefore, the current study examined the associations of sex-related alcohol expectancies with hazardous alcohol consumption, dependence, and problems among 146 PWH (Mage = 50.99, SD = 9.41) \ enrolled in a clinical trial examining a personalized feedback intervention to reduce hazardous drinking in primary HIV care. Results showed that only sexual disinhibition-related alcohol expectancies were significantly associated with the criterion variables, such that greater drinking alcohol for sexual disinhibition was associated with greater hazardous drinking behaviors. These results sit on the backdrop of a larger literature documenting the links between disinhibition and hazardous alcohol use and provide explanatory specificity to PWH who are hazardous drinkers.

Skin and Soft Tissue Infection in People Living With Human Immunodeficiency Virus in a Large, Urban, Public Healthcare System in Houston, Texas, 2009-2014.

BACKGROUND: Skin and soft tissue infections (SSTIs) disproportionately impact patients with human immunodeficiency virus (HIV). Recent declines in the incidence of SSTIs have been noted in the non-HIV population. We sought to study the epidemiology and microbiology of SSTIs in a population of 8597 patients followed for HIV primary care in a large, urban county system from January 2009 to December 2014. METHODS: SSTIs were identified from the electronic medical record by use of International Classification of Diseases-9 billing codes. Charts were reviewed to confirm each patient's diagnosis of acute SSTI and abstract culture and susceptibility data. We calculated the yearly SSTI incidences using Poisson regression with clustering by patient. RESULTS: There were 2202 SSTIs identified. Of 503 (22.8%) cultured SSTIs, 332 (66.0%) recovered Staphylococcus aureus as a pathogen, of which 287/332 (86.4%) featured S. aureus as the sole isolated organism. Among the S. aureus isolates that exhibited antibiotic susceptibilities, 231/331 (69.8%) were methicillin resistant, and the proportion did not change by year. The observed incidence of SSTI was 78.0 per 1000 person-years (95% confidence interval 72.9-83.4) and declined from 96.0 infections per 1000 person-years in 2009 to 56.5 infections per 1000 person-years in 2014 (P < .001). Other significant predictors of SSTI incidences in both univariate as well as multivariate analyses included a low CD4 count, high viral load, and not being a Spanish-speaking Hispanic. CONCLUSIONS: SSTIs remain a significant problem in the outpatients living with HIV, although rates of SSTIs appear to have declined by approximately 40% between 2009 and 2014.

Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations.

Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of six PDTC in patients ≤21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole-exome sequencing (WES). All tumors had solid, insular, or trabecular growth pattern and high mitotic rate, and five out of six tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (83%) tumors, all of which were "hotspot" mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in five cases which confirmed all hotspot mutations and detected two tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC, and other) were detected. On follow-up, available for five patients, three patients died of disease 8-24 months after diagnosis, whereas two were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.

Targeted RNAseq of Formalin-Fixed Paraffin-Embedded Tissue to Differentiate Among Benign and Malignant Adrenal Cortical Tumors.

Lack of routine fresh or frozen tissue is a barrier to widespread transcriptomic analysis of adrenal cortical tumors and an impediment to translational research in endocrinology and endocrine oncology. Our group has previously pioneered the use of targeted amplicon-based next-generation sequencing for archival formalin-fixed paraffin-embedded (FFPE) adrenal tissue specimens to characterize the spectrum of somatic mutations in various forms of primary aldosteronism. Herein, we developed and validated a novel 194-amplicon targeted next-generation RNA sequencing (RNAseq) assay for transcriptomic analysis of adrenal tumors using clinical-grade FFPE specimens. Targeted RNAseq-derived expression values for 27 adrenal cortical tumors, including aldosterone-producing adenomas (APA; n=8), cortisol-producing adenomas (CPA; n=11), and adrenal cortical carcinomas (ACC; n=8), highlighted known differentially-expressed genes (DEGs; i. e., CYP11B2, IGF2, etc.) and tumor type-specific transcriptional modules (i. e., high cell cycle/proliferation transcript expression in ACC, etc.), and a subset of DEGs was validated orthogonally using quantitative reverse transcription PCR (qRT-PCR). Finally, unsupervised hierarchical clustering using a subset of high-confidence DEGs revealed three discrete clusters representing APA, CPA, and ACC tumors with corresponding unique gene expression signatures, suggesting potential clinical utility for a transcriptomic-based approach to tumor classification. Overall, these data support the use of targeted amplicon-based RNAseq for comprehensive transcriptomic profiling of archival FFPE adrenal tumor material and indicate that this approach may facilitate important translational research opportunities for the study of these tumors.

HIV in Lebanon: Reasons for Testing, Engagement in Care, and Outcomes in Patients with Newly Diagnosed HIV Infections.

Little is known about clinical presentation and cascade of care among patients living with HIV (PLWH) in Beirut, Lebanon. The study aims to examine the reasons for HIV testing and to evaluate the clinical characteristics of, predictors of advanced HIV stage at presentation in, and rates of ART initiation, retention in care, and viral load suppression among PLWH in Lebanon. We conducted a retrospective study of PLWH presenting to a tertiary-care centre-affiliated outpatient clinic from 2008 to 2016 with new HIV infection diagnoses. We identified a total of 423 patients: 89% were men, 55% were 30-50 years old, and 58% self-identified as men who have sex with men. About 35% of the patients had concurrent sexually transmitted diseases at the time of HIV diagnosis. Thirty percent of infection cases were identified by provider-initiated HIV testing, 36% of cases were identified by patient-initiated testing, and 34% of patients underwent testing for screening purposes. The proportion of individuals presenting with advanced HIV disease decreased from 40% in 2008-2009 to 24% in 2014-2015. Age older than 50 years and identification of HIV by a medical provider were independent predictors of advanced HIV infection at presentation. Among patients having indications for treatment (n = 253), 239 (94%) were prescribed antiretroviral therapy, and 147 (58%) had evidence of viral suppression at 1 year. Furthermore, 266 patients (63%) were retained in care. The care continuum for PLWH in Lebanon is comparable with those in high-income countries yet still far behind the Joint United Nations Programme on HIV/AIDS 90-90-90 set target.