PIK3/Akt/mTOR pathway alterations in metastatic castration-sensitive prostate cancer.

BACKGROUND: Alterations in the PIK3/Akt/mTOR pathway are commonly seen in metastatic castration-sensitive prostate cancer (mCSPC), however their role in outcomes is unknown. We aim to evaluate the prognostic significance as well as the genetic landscape of PIK3/Akt/mTOR pathway alteration in mCSPC. METHODS: Fourhundred and seventy-two patients with mCSPC were included who underwent next generation sequencing. PIK3/Akt/mTor pathway alterations were defined as mutations in Akt1, mTOR, PIK3CA, PIK3CB, PIK3R1, PTEN, TSC1, and TSC2. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of castration resistant prostate cancer (tdCRPC), and overall survival (OS). Kaplan-Meier analysis was performed and Cox regression hazard ratios (HR) were calculated. RESULTS: One hundred and fifty-two (31.9%) patients harbored a PIK3/Akt/mTOR pathway alteration. Median rPFS and tdCRPC were 23.7 and 21.0 months in PIK3/Akt/mTOR altered compared to 32.8 (p = 0.08) and 32.1 months (p = 0.002) in wildtype tumors. On multivariable analysis PIK3/Akt/mTOR pathway alterations were associated with tdCRPC (HR 1.43, 95% CI, 1.05-1.94, p = 0.02), but not rPFS [Hazard ratio (HR) 1.20, 95% confidence interval (CI), 0.90-1.60, p = 0.21]. PIK3/Akt/mTOR pathway alterations were more likely to be associated with concurrent mutations in TP53 (40% vs. 28%, p = 0.01) and TMPRSS2-ERG (37% vs. 26%, p = 0.02) than tumors without PIK3/Akt/mTOR pathway alterations. Concurrent mutations were typically associated with shorter median times to rPFS and tdCRPC. DAVID analysis showed p53 signaling and angiogenesis pathways were enriched in PIK3/Akt/mTOR pathway altered tumors while beta-catenin binding and altered BRCA pathway were enriched in PIK3/Akt/mTOR pathway wildtype tumors. CONCLUSIONS: PIK3/Akt/mTOR pathway alterations were common in mCSPC and associated with poorer prognosis. The genetic landscape of PIK3/Akt/mTOR pathway altered tumors differed from wildtype tumors. Additional studies are needed to better understand and target the PIK3/Akt/mTOR pathway in mCSPC.

Inference of microbial covariation networks using copula models with mixture margins.

MOTIVATION: Quantification of microbial covariations from 16S rRNA and metagenomic sequencing data is difficult due to their sparse nature. In this article, we propose using copula models with mixed zero-beta margins for the estimation of taxon-taxon covariations using data of normalized microbial relative abundances. Copulas allow for separate modeling of the dependence structure from the margins, marginal covariate adjustment, and uncertainty measurement. RESULTS: Our method shows that a two-stage maximum-likelihood approach provides accurate estimation of model parameters. A corresponding two-stage likelihood ratio test for the dependence parameter is derived and is used for constructing covariation networks. Simulation studies show that the test is valid, robust, and more powerful than tests based upon Pearson's and rank correlations. Furthermore, we demonstrate that our method can be used to build biologically meaningful microbial networks based on a dataset from the American Gut Project. AVAILABILITY AND IMPLEMENTATION: R package for implementation is available at https://github.com/rebeccadeek/CoMiCoN.

Risk Factors for Pediatric Facial Trauma in an Appalachian Region: An Epidemiological Review at a Single Institution.

BACKGROUND: Rural and low-income pediatric populations are at higher risk for trauma. Craniomaxillofacial (CMF) trauma in this population has not been studied. PURPOSE: This study's purpose was to determine if rural populations or low-income populations are at higher risk for pediatric CMF trauma than urban or high-income populations, respectively, and to determine differences in mechanism of injury (MOI). STUDY DESIGN, SETTING, SAMPLE: A retrospective cohort study of CMF trauma patients younger than 17 years-old, living in the region served by one institution in Tennessee, and requiring oral and maxillofacial surgery consultation between January 2011 and December 2022 was performed. Exclusion criteria were incomplete medical records. PREDICTOR VARIABLE: The primary predictor variable was geographic residence of the patient grouped into two categories: rural or urban defined by the state of Tennessee. Secondary variables were postal code (PC) average median household income (MHI) and PC population density. MAIN OUTCOME VARIABLE(S): The main outcome variable was pediatric CMF injury rate per 100,000 people. MOI is a secondary outcome variable. COVARIATE(S): Covariates included sex, age, and race. ANALYSES: Frequencies and percentages, Fisher's exact test, and Poisson regression models were utilized. Statistical significance was assumed at P-value <.05. RESULTS: Rural or urban county designation was not associated with differing trauma rates (incident risk ratio (IRR) = 0.91; 95% confidence interval (CI) 0.78 to 1.05; P = .18) by itself. One standard deviation increase in MHI decreased CMF trauma rates in rural designation counties by 24% (IRR: 0.76, 95% CI: 0.66, 0.88) and 6% in urban designation counties (IRR: 0.94, 95% CI: 0.87, 1.02). Lower rates of CMF trauma were associated with residence in higher income PCs (IRR = 0.91; 95% (CI) 0.86 to 0.97; P = .004), and higher population density (IRR = 0.87; 95% CI 0.79 to 0.94; P < .001). Dog bites and falls were more common in infancy and early childhood. Interpersonal violence was more common in older patients. CONCLUSIONS AND RELEVANCE: Patients in PCs with lower population density or incomes were at highest risk for CMF injuries. MOI differences by age were similar to findings in other studies. Tennessee's urban/rural county designation has complex interactions with MHI and pediatric CMF trauma rates.

The Lung Allograft Microbiome Associates with Pepsin, Inflammation, and Primary Graft Dysfunction.

Rationale: Primary graft dysfunction (PGD) is the principal cause of early morbidity and mortality after lung transplantation. The lung microbiome has been implicated in later transplantation outcomes but has not been investigated in PGD. Objectives: To define the peritransplant bacterial lung microbiome and relationship to host response and PGD. Methods: This was a single-center prospective cohort study. Airway lavage samples from donor lungs before organ procurement and recipient allografts immediately after implantation underwent bacterial 16S ribosomal ribonucleic acid gene sequencing. Recipient allograft samples were analyzed for cytokines by multiplex array and pepsin by ELISA. Measurements and Main Results: We enrolled 139 transplant subjects and obtained donor lung (n = 109) and recipient allograft (n = 136) samples. Severe PGD (persistent grade 3) developed in 15 subjects over the first 72 hours, and 40 remained without PGD (persistent grade 0). The microbiome of donor lungs differed from healthy lungs, and recipient allograft microbiomes differed from donor lungs. Development of severe PGD was associated with enrichment in the immediate postimplantation lung of oropharyngeal anaerobic taxa, particularly Prevotella. Elevated pepsin, a gastric biomarker, and a hyperinflammatory cytokine profile were present in recipient allografts in severe PGD and strongly correlated with microbiome composition. Together, immediate postimplantation allograft Prevotella/Streptococcus ratio, pepsin, and indicator cytokines were associated with development of severe PGD during the 72-hour post-transplantation period (area under the curve = 0.81). Conclusions: Lung allografts that develop PGD have a microbiome enriched in anaerobic oropharyngeal taxa, elevated gastric pepsin, and hyperinflammatory phenotype. These findings suggest a possible role for peritransplant aspiration in PGD, a potentially actionable mechanism that warrants further investigation.

Statistical and computational methods for integrating microbiome, host genomics, and metabolomics data.

Large-scale microbiome studies are progressively utilizing multiomics designs, which include the collection of microbiome samples together with host genomics and metabolomics data. Despite the increasing number of data sources, there remains a bottleneck in understanding the relationships between different data modalities due to the limited number of statistical and computational methods for analyzing such data. Furthermore, little is known about the portability of general methods to the metagenomic setting and few specialized techniques have been developed. In this review, we summarize and implement some of the commonly used methods. We apply these methods to real data sets where shotgun metagenomic sequencing and metabolomics data are available for microbiome multiomics data integration analysis. We compare results across methods, highlight strengths and limitations of each, and discuss areas where statistical and computational innovation is needed.

To what extent do oral and maxillofacial surgery residents suffer from imposter syndrome?

OBJECTIVE: This study aims to evaluate the frequency and severity of imposter syndrome (IS) in oral and maxillofacial surgery (OMS) residents and identify factors associated with higher Clance Imposter Phenomenon Survey (CIPS) scores. STUDY DESIGN: A cross-sectional study was performed with a survey including CIPS, demographic, and training program structure questions distributed to all OMS training programs and residents in the United States. The primary predictor variable was gender, and the main outcome variable was the CIPS score. Statistical analyses were performed using linear regression in R v4.3.1; statistical significance was set to P value < .05. RESULTS: A total of 175 OMS residents responded. The average CIPS score was 59.8 (IQR 52, 70). Statistically significant differences were found between average male and female resident scores (56.5 vs 66.9; P < .001) and male and female single-degree residents (54.3 vs 73.1; P < .001), but not for dual-degree residents (58.8 vs 63.9; P = .35). CONCLUSIONS: The average male resident experiences moderate IS, whereas the average female resident experiences frequent IS. Loss of significance between male and female dual-degree resident scores may be due to the completion of a doctoral degree, an internship, and/or dental board exams upon entering medical school, leading to more favorable accomplishment comparisons among medical school peers.

Gender and the Receipt of the Association of Residents in Radiation Oncology Educator of the Year Award.

Purpose: We hypothesized that there may be a gender disparity in the receipt of the Association of Residents in Radiation Oncology (ARRO) Educator of the Year Award and sought to elucidate factors that contribute to differences in award receipt. Methods and Materials: Using a database provided by the American Society for Radiation Oncology, award recipients were identified from 2010 to 2022. Publicly available websites were accessed to obtain data regarding gender, years since residency graduation, percentage of female faculty, size of residency program, and program director designation. A 1-sample Z-test was used to assess whether the proportion of female ARRO award winners, defined as the proportion of female radiation oncology faculty members in the nominating universities that year, was significantly less than the population average. Secondary analyses used univariable binary logistic regression to identify global associations between gender, year since gradation, or program size. Results: The lowest proportion of female awardees occurred in 2013 (14.3%) and the greatest proportion in 2022 (30.6%). Compared with the proportion of female faculty members in nominating programs for the respective year, there were significantly fewer female awardees in 2010 (18% female awardees vs 32% female faculty members; P = .02) and 2013 (14% female awardees vs 31% female faculty members; P = .01). There was a statistically significant increase in female awardees during the study period (P < .01). On logistic regression analysis, large program size (≥10 residents) (odds ratio [OR], 6.86; 95% CI, 2.71-23.1; P < .001) and medium program size (5-9 residents) (OR, 4.05; 95% CI, 1.60-13.7; P < .001) were associated with a greater proportion of female awardees compared with small program size (1-4 residents). There was no association between awardee gender and years since graduation. Conclusions: A gender disparity was present in the receipt of ARRO Educator Awards. Residency chiefs, program directors, and chairs should work to ensure that a diverse slate of faculty is considered annually for the ARRO Educator Award.

Prostate-Specific Membrane Antigen PET Response Associates with Metastasis-Free Survival After Stereotactic Ablative Radiation in Oligometastatic Prostate Cancer.

Purpose: Emerging data suggest that metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) can detect occult metastatic disease, and PSMA response has been proposed as a biomarker for treatment response. Herein, we identify and validate a PSMA-PET biomarker for metastasis-free survival (MFS) following MDT in omCSPC. Methods and Materials: We performed an international multi-institutional retrospective study of patients with omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation who underwent PSMA-PET/computed tomography (CT) before and after (median, 6.2 months; range, 2.4-10.9 months) treatment. Pre- and post-MDT PSMA-PET/CT maximum standardized uptake value (SUVmax) was measured for all lesions, and PSMA response was defined as the percent change in SUVmax of the least responsive lesion. PSMA response was both evaluated as a continuous variable and dichotomized into PSMA responders, with a complete/partial response (at least a 30% reduction in SUVmax), and PSMA nonresponders, with stable/progressive disease (less than a 30% reduction in SUVmax). PSMA response was correlated with conventional imaging-defined metastasis-free survival (MFS) via Kaplan-Meier and Cox regression analysis. Results: A total of 131 patients with 261 treated metastases were included in the analysis, with a median follow-up of 29 months (IQR, 18.5-41.3 months). After stereotactic ablative radiation, 70.2% of patients were classified as PSMA responders. Multivariable analysis demonstrated that PSMA response as a continuous variable was associated with a significantly worse MFS (hazard ratio = 1.003; 95% CI, 1.001-1.006; P = .016). Patients classified as PSMA responders were found to have a significantly improved median MFS of 39.9 versus 12 months (P = .001) compared with PSMA nonresponders. Our study is limited as it is a retrospective review of a heterogenous population. Conclusions: After stereotactic ablative radiation, PSMA-PET response appears to be a radiographic biomarker that correlates with MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated in a prospective setting.

Antitumor Activity of a Mitochondrial-Targeted HSP90 Inhibitor in Gliomas.

PURPOSE: To investigate the antitumor activity of a mitochondrial-localized HSP90 inhibitor, Gamitrinib, in multiple glioma models, and to elucidate the antitumor mechanisms of Gamitrinib in gliomas. EXPERIMENTAL DESIGN: A broad panel of primary and temozolomide (TMZ)-resistant human glioma cell lines were screened by cell viability assays, flow cytometry, and crystal violet assays to investigate the therapeutic efficacy of Gamitrinib. Seahorse assays were used to measure the mitochondrial respiration of glioma cells. Integrated analyses of RNA sequencing (RNAseq) and reverse phase protein array (RPPA) data were performed to reveal the potential antitumor mechanisms of Gamitrinib. Neurospheres, patient-derived organoids (PDO), cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models were generated to further evaluate the therapeutic efficacy of Gamitrinib. RESULTS: Gamitrinib inhibited cell proliferation and induced cell apoptosis and death in 17 primary glioma cell lines, 6 TMZ-resistant glioma cell lines, 4 neurospheres, and 3 PDOs. Importantly, Gamitrinib significantly delayed the tumor growth and improved survival of mice in both CDX and PDX models in which tumors were either subcutaneously or intracranially implanted. Integrated computational analyses of RNAseq and RPPA data revealed that Gamitrinib exhibited its antitumor activity via (i) suppressing mitochondrial biogenesis, OXPHOS, and cell-cycle progression and (ii) activating the energy-sensing AMP-activated kinase, DNA damage, and stress response. CONCLUSIONS: These preclinical findings established the therapeutic role of Gamitrinib in gliomas and revealed the inhibition of mitochondrial biogenesis and tumor bioenergetics as the primary antitumor mechanisms in gliomas.

Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials.

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.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

A Zero-Inflated Latent Dirichlet Allocation Model for Microbiome Studies.

The human microbiome consists of a community of microbes in varying abundances and is shown to be associated with many diseases. An important first step in many microbiome studies is to identify possible distinct microbial communities in a given data set and to identify the important bacterial taxa that characterize these communities. The data from typical microbiome studies are high dimensional count data with excessive zeros due to both absence of species (structural zeros) and low sequencing depth or dropout. Although methods have been developed for identifying the microbial communities based on mixture models of counts, these methods do not account for excessive zeros observed in the data and do not differentiate structural from sampling zeros. In this paper, we introduce a zero-inflated Latent Dirichlet Allocation model (zinLDA) for sparse count data observed in microbiome studies. zinLDA builds on the flexible Latent Dirichlet Allocation model and allows for zero inflation in observed counts. We develop an efficient Markov chain Monte Carlo (MCMC) sampling procedure to fit the model. Results from our simulations show zinLDA provides better fits to the data and is able to separate structural zeros from sampling zeros. We apply zinLDA to the data set from the American Gut Project and identify microbial communities characterized by different bacterial genera.