Synergistic effects of social determinants of health and race-ethnicity on 30-day all-cause readmission disparities: a retrospective cohort study.

OBJECTIVE: The objective of this study is to assess the effects of social determinants of health (SDOH) and race-ethnicity on readmission and to investigate the potential for geospatial clustering of patients with a greater burden of SDOH that could lead to a higher risk of readmission. DESIGN: A retrospective study of inpatients at five hospitals within Henry Ford Health (HFH) in Detroit, Michigan from November 2015 to December 2018 was conducted. SETTING: This study used an adult inpatient registry created based on HFH electronic health record data as the data source. A subset of the data elements in the registry was collected for data analyses that included readmission index, race-ethnicity, six SDOH variables and demographics and clinical-related variables. PARTICIPANTS: The cohort was composed of 248 810 admission patient encounters with 156 353 unique adult patients between the study time period. Encounters were excluded if they did not qualify as an index admission for all payors based on the Centers for Medicare and Medicaid Service definition. MAIN OUTCOME MEASURE: The primary outcome was 30-day all-cause readmission. This binary index was identified based on HFH internal data supplemented by external validated readmission data from the Michigan Health Information Network. RESULTS: Race-ethnicity and all SDOH were significantly associated with readmission. The effect of depression on readmission was dependent on race-ethnicity, with Hispanic patients having the strongest effect in comparison to either African Americans or non-Hispanic whites. Spatial analysis identified ZIP codes in the City of Detroit, Michigan, as over-represented for individuals with multiple SDOH. CONCLUSIONS: There is a complex relationship between SDOH and race-ethnicity that must be taken into consideration when providing healthcare services. Insights from this study, which pinpoint the most vulnerable patients, could be leveraged to further improve existing models to predict risk of 30-day readmission for individuals in future work.

Prostaglandin E2 affects mitochondrial function in adult mouse cardiomyocytes and hearts.

Prostaglandin E2 (PGE2) signals differently through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic/pathologic effects. We previously reported that PGE2 via its EP3 receptor reduces cardiac contractility and male mice with cardiomyocyte-specific deletion of the EP4 receptor (EP4 KO) develop dilated cardiomyopathy. The aim of this study was to identify pathways responsible for this phenotype. We performed ingenuity pathway analysis (IPA) and found that genes differentiating WT mice and EP4 KO mice were significantly overrepresented in mitochondrial (adj. p value = 6.28 × 10-26) and oxidative phosphorylation (adj. p value = 1.58 × 10-27) pathways. Electron microscopy from the EP4 KO hearts show substantial mitochondrial disarray and disordered cristae. Not surprisingly, isolated adult mouse cardiomyocytes (AVM) from these mice have reduced ATP levels compared to their WT littermates and reduced expression of key genes involved in the electron transport chain (ETC) in older mice. Moreover, treatment of AVM from C57Bl/6 mice with PGE2 or the EP3 agonist sulprostone resulted in changes of various genes involved in the ETC, measured by the Mitochondrial Energy Metabolism RT2-profiler assay. Lastly, the EP4 KO mice have reduced expression of superoxide dismuatse-2 (SOD2), whereas treatment of AVM with PGE2 or sulprostone increase superoxide production, suggesting increased oxidative stress levels in these EP4 KO mice. Altogether the current study supports the premise that PGE2 acting via its EP4 receptor is protective, while signaling through its other receptors, likely EP3, is deleterious.

The Impact of Environmental Benzene, Toluene, Ethylbenzene, and Xylene Exposure on Blood-Based DNA Methylation Profiles in Pregnant African American Women from Detroit.

African American women in the United States have a high risk of adverse pregnancy outcomes. DNA methylation is a potential mechanism by which exposure to BTEX (benzene, toluene, ethylbenzene, and xylenes) may cause adverse pregnancy outcomes. Data are from the Maternal Stress Study, which recruited African American women in the second trimester of pregnancy from February 2009 to June 2010. DNA methylation was measured in archived DNA from venous blood collected in the second trimester. Trimester-specific exposure to airshed BTEX was estimated using maternal self-reported addresses and geospatial models of ambient air pollution developed as part of the Geospatial Determinants of Health Outcomes Consortium. Among the 64 women with exposure and outcome data available, 46 differentially methylated regions (DMRs) were associated with BTEX exposure (FDR adjusted p-value < 0.05) using a DMR-based epigenome-wide association study approach. Overall, 89% of DMRs consistently exhibited hypomethylation with increasing BTEX exposure. Biological pathway analysis identified 11 enriched pathways, with the top 3 involving gamma-aminobutyric acid receptor signaling, oxytocin in brain signaling, and the gustation pathway. These findings highlight the potential impact of BTEX on DNA methylation in pregnant women.

Psychotherapy Disruption Before and After the Transition to Virtual Mental Health Care Induced by the COVID-19 Pandemic.

OBJECTIVE: This study aimed to examine population-level disruption in psychotherapy before and after the rapid shift to virtual mental health care induced by the onset of the COVID-19 pandemic in the United States. METHODS: This retrospective study used electronic health record and insurance claims data from three U.S. health systems. The sample included 110,089 patients with mental health conditions who were members of the health systems' affiliated health plans and attended at least two psychotherapy visits from June 14, 2019, through December 15, 2020. Data were subdivided into two 9-month periods (before vs. after COVID-19 onset, defined in this study as March 14, 2020). Psychotherapy visits were measured via health records and categorized as in person or virtual. Disruption was defined as a gap of >45 days between visits. RESULTS: Visits in the preonset period were almost exclusively in person (97%), whereas over half of visits in the postonset period were virtual (52%). Approximately 35% of psychotherapy visits were followed by a disruption in the preonset period, compared with 18% in the postonset period. Disruption continued to be less common (adjusted OR=0.45) during the postonset period after adjustment for visit, mental health, and sociodemographic factors. The magnitude of the difference in disruption between periods was homogeneous across sociodemographic characteristics but heterogeneous across psychiatric diagnoses. CONCLUSIONS: This study found fewer population-level disruptions in psychotherapy receipt after rapid transition to virtual mental health care following COVID-19 onset. These data support the continued availability of virtual psychotherapy.

Precocious infant fecal microbiome promotes enterocyte barrier dysfuction, altered neuroendocrine signaling and associates with increased childhood obesity risk.

Early life gut microbiome composition has been correlated with childhood obesity, though microbial functional contributions to disease origins remain unclear. Here, using an infant birth cohort (n = 349) we identify a distinct fecal microbiota composition in 1-month-old infants with the lowest rate of exclusive breastfeeding, that relates with higher relative risk for obesity and overweight phenotypes at two years. Higher-risk infant fecal microbiomes exhibited accelerated taxonomic and functional maturation and broad-ranging metabolic reprogramming, including reduced concentrations of neuro-endocrine signals. In vitro, exposure of enterocytes to fecal extracts from higher-risk infants led to upregulation of genes associated with obesity and with expansion of nutrient sensing enteroendocrine progenitor cells. Fecal extracts from higher-risk infants also promoted enterocyte barrier dysfunction. These data implicate dysregulation of infant microbiome functional development, and more specifically promotion of enteroendocrine signaling and epithelial barrier impairment in the early-life developmental origins of childhood obesity.

Trends in Prostate Cancer Screening in the Pre- and Peri-COVID-19 Pandemic Period.

INTRODUCTION: This study sought to examine PSA testing rates before, early in, and later in the COVID-19 pandemic. METHODS: Our cohort included test results from men >45 years who received PSA testing at least once at our institution from November 2018 to September 2021 and were alive at the end of that period. Monthly trends were evaluated for 3 periods: pre-COVID (November 2018-February 2020), early-COVID (March-May 2020), and late-COVID (June 2020-September 2021). Univariable and multivariable analysis tested the impact of these periods on PSA testing rate, after accounting for available confounders. All analyses were stratified by prostate cancer diagnosis status. RESULTS: A total of 141,777 PSA tests met inclusion criteria. The monthly number of tests in men without prostate cancer declined from 3,669 pre-COVID to 1,760 early-COVID (52% decrease; P = .0086) before increasing to 4,171 (14% increase from pre-COVID; P < .0001) late-COVID. The monthly average of first-time tests declined from 805 pre-COVID to 315 early-COVID (61% decrease; P = .008) before rebounding to 795 (1% decrease from pre-COVID; P = .7) late-COVID. The monthly number of tests in prostate cancer patients declined from 343 pre-COVID to 195 early-COVID (43% decrease; P = .008) before partially rebounding to 313 (9% decrease; P = .03) late-COVID. These differences remained within multivariable models. CONCLUSIONS: A number of men have forgone first-time PSA testing opportunities following the COVID-19 outbreak; thus, early cancer diagnoses in some individuals might have been missed. Likewise, many prostate cancer patients have forgone follow-up in the late-COVID period, which might compromise their oncologic outcomes.

Progression of C-reactive protein from birth through preadolescence varies by mode of delivery.

Introduction: Delivery via caesarean section (C-section) has been associated with an increased risk of childhood chronic diseases such as obesity and asthma, which may be due to underlying systemic inflammation. However, the impact of specific C-section types may be differential, as emergency C-sections typically involve partial labor and/or membrane rupture. Our objectives were to determine if mode of delivery associates with longitudinal profiles of high sensitivity CRP (hs-CRP) -a marker of systemic inflammation-from birth through preadolescence, and to examine if CRP mediates the association between mode of delivery and preadolescent body mass index (BMI). Methods: Data from the WHEALS birth cohort (N = 1,258) were analyzed; 564 of the 1,258 children in the cohort had data available for analysis. Longitudinal plasma samples (birth through 10-years of age) from 564 children from were assayed for hs-CRP levels. Maternal medical records were abstracted to obtain mode of delivery. Growth mixture models (GMMs) were used to determine classes of hs-CRP trajectories. Poisson regression with robust error variance was used to calculate risk ratios (RRs). Results: Two hs-CRP trajectory classes were identified: class 1 (76% of children) was characterized by low hs-CRP, while class 2 (24% of children) was characterized by high and steadily increasing hs-CRP. In multivariable models, children delivered via planned C-section had 1.15 times higher risk of being in hs-CRP class 2, compared to vaginal deliveries (p = 0.028), while no association was found for unplanned C-section deliveries [RR (95% CI) = 0.96 (0.84, 1.09); p = 0.49]. Further, the effect of planned C-section on BMI z-score at age 10 was significantly mediated by hs-CRP class (percent mediated = 43.4%). Conclusions: These findings suggest potentially beneficial effects of experiencing partial or full labor, leading to a lower trajectory of systemic inflammation throughout childhood and decreased BMI during preadolescence. These findings may have implications for chronic disease development later in life.

Multiple Correspondence Analysis and HLA-Associations of Organ Involvement in a Large Cohort of African-American and European-American Patients with Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with predominant pulmonary involvement and vast heterogeneity of clinical manifestations and disease outcomes. African American (AA) patients suffer greater morbidity and mortality. Using Multiple Correspondence Analysis, we identified seven clusters of organ involvement in European American (EA; n = 385) patients which were similar to those previously described in a Pan-European (GenPhenReSa) and a Spanish cohort (SARCOGEAS). In contrast, AA (n = 987) had six, less well-defined and overlapping clusters with little similarity to the cluster identified in the EA cohort evaluated at the same U.S. institutions. Association of cluster membership with two-digit HLA-DRB1 alleles demonstrated ancestry-specific patterns of association and replicated known HLA effects.These results further support the notion that genetically influenced immune risk profiles, which differ based on ancestry, play a role in phenotypic heterogeneity. Dissecting such risk profiles will move us closer to personalized medicine for this complex disease.

Cross-phenotype relationship between opioid use disorder and suicide attempts: new evidence from polygenic association and Mendelian randomization analyses.

Clinical epidemiological studies have found high co-occurrence between suicide attempts (SA) and opioid use disorder (OUD). However, the patterns of correlation and causation between them are still not clear due to psychiatric confounding. To investigate their cross-phenotype relationship, we utilized raw phenotypes and genotypes from >150,000 UK Biobank samples, and genome-wide association summary statistics from >600,000 individuals with European ancestry. Pairwise association and a potential bidirectional relationship between OUD and SA were evaluated with and without controlling for major psychiatric disease status (e.g., schizophrenia, major depressive disorder, and alcohol use disorder). Multiple statistical and genetics tools were used to perform epidemiological association, genetic correlation, polygenic risk score prediction, and Mendelian randomizations (MR) analyses. Strong associations between OUD and SA were observed at both the phenotypic level (overall samples [OR = 2.94, P = 1.59 ×10-14]; non-psychiatric subgroup [OR = 2.15, P = 1.07 ×10-3]) and the genetic level (genetic correlation rg = 0.38 and 0.5 with or without conditioning on psychiatric traits, respectively). Consistently, increasing polygenic susceptibility to SA is associated with increasing risk of OUD (OR = 1.08, false discovery rate [FDR] =1.71 ×10-3), and similarly, increasing polygenic susceptibility to OUD is associated with increasing risk of SA (OR = 1.09, FDR = 1.73 ×10-6). However, these polygenic associations were much attenuated after controlling for comorbid psychiatric diseases. A combination of MR analyses suggested a possible causal association from genetic liability for SA to OUD risk (2-sample univariable MR: OR = 1.14, P = 0.001; multivariable MR: OR = 1.08, P = 0.001). This study provided new genetic evidence to explain the observed OUD-SA comorbidity. Future prevention strategies for each phenotype needs to take into consideration of screening for the other one.

Artificial Intelligence in Facial Plastic Surgery: A Review of Current Applications, Future Applications, and Ethical Considerations.

From virtual chat assistants to self-driving cars, artificial intelligence (AI) is often heralded as the technology that has and will continue to transform this generation. Among widely adopted applications in other industries, its potential use in medicine is being increasingly explored, where the vast amounts of data present in electronic health records and need for continuous improvements in patient care and workflow efficiency present many opportunities for AI implementation. Indeed, AI has already demonstrated capabilities for assisting in tasks such as documentation, image classification, and surgical outcome prediction. More specifically, this technology can be harnessed in facial plastic surgery, where the unique characteristics of the field lends itself well to specific applications. AI is not without its limitations, however, and the further adoption of AI in medicine and facial plastic surgery must necessarily be accompanied by discussion on the ethical implications and proper usage of AI in healthcare. In this article, we review current and potential uses of AI in facial plastic surgery, as well as its ethical ramifications.

Translational Research Techniques for the Facial Plastic Surgeon: An Overview.

The field of facial plastic and reconstructive surgery (FPRS) is an incredibly diverse, multispecialty field that seeks innovative and novel solutions for the management of physical defects on the head and neck. To aid in the advancement of medical and surgical treatments for these defects, there has been a recent emphasis on the importance of translational research. With recent technological advancements, there are now a myriad of research techniques that are widely accessible for physician and scientist use in translational research. Such techniques include integrated multiomics, advanced cell culture and microfluidic tissue models, established animal models, and emerging computer models generated using bioinformatics. This study discusses these various research techniques and how they have and can be used for research in the context of various important diseases within the field of FPRS.

Identification of Environmental Exposures Associated with Risk of Sarcoidosis in African Americans.

Rationale: Sarcoidosis is a racially disparate granulomatous disease likely caused by environmental exposures, genes, and their interactions. Despite increased risk in African Americans, few environmental risk factor studies in this susceptible population exist. Objectives: To identify environmental exposures associated with the risk of sarcoidosis in African Americans and those that differ in effect by self-identified race and genetic ancestry. Methods: The study sample comprised 2,096 African Americans (1,205 with and 891 without sarcoidosis) compiled from three component studies. Unsupervised clustering and multiple correspondence analyses were used to identify underlying clusters of environmental exposures. Mixed-effects logistic regression was used to evaluate the association of these exposure clusters and the 51 single-component exposures with risk of sarcoidosis. A comparison case-control sample of 762 European Americans (388 with and 374 without sarcoidosis) was used to assess heterogeneity in exposure risk by race. Results: Seven exposure clusters were identified, five of which were associated with risk. The exposure cluster with the strongest risk association was composed of metals (P < 0.001), and within this cluster, exposure to aluminum had the highest risk (odds ratio, 3.30; 95% confidence interval [95% CI], 2.23-4.09; P < 0.001). This effect also differed by race (P < 0.001), with European Americans having no significant association with exposure (odds ratio, 0.86; 95% CI, 0.56-1.33). Within African Americans, the increased risk was dependent on genetic African ancestry (P = 0.047). Conclusions: Our findings support African Americans having sarcoidosis environmental exposure risk profiles that differ from those of European Americans. These differences may underlie racially disparate incidence rates that are partially explained by genetic variation differing by African ancestry.

Convolutional Neural Network Quantification of Gleason Pattern 4 and Association With Biochemical Recurrence in Intermediate-Grade Prostate Tumors.

Differential classification of prostate cancer grade group (GG) 2 and 3 tumors remains challenging, likely because of the subjective quantification of the percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-predicted %GP4 is associated with biochemical recurrence (BCR) risk in intermediate-risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999-2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate 4 tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) tumors for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the 4 tissue types. Furthermore, CNN-predicted %GP4 was significantly higher in GG 3 than in GG 2 tumors (P = 7.2 × 10-11). %GP4 was associated with an increased risk of BCR (adjusted hazard ratio, 1.09 per 10% increase in %GP4; P = .010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted hazard ratio, 1.12; P = .006). Our findings demonstrate the feasibility of CNN-predicted %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathologic assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.

The impact of prenatal dog keeping on infant gut microbiota development.

INTRODUCTION: Prenatal and early-life dog exposure has been linked to reduced childhood allergy and asthma. A potential mechanism includes altered early immune development in response to changes in the gut microbiome among dog-exposed infants. We thus sought to determine whether infants born into homes with indoor dog(s) exhibit altered gut microbiome development. METHODS: Pregnant women living in homes with dogs or in pet-free homes were recruited in southeast Michigan. Infant stool samples were collected at intervals between 1 week and 18 months after birth and microbiome was assessed using 16S ribosomal sequencing. Perinatal maternal vaginal/rectal swabs and stool samples were sequenced from a limited number of mothers. Mixed effect adjusted models were used to assess stool microbial community trajectories comparing infants from dog-keeping versus pet-free homes with adjustment for relevant covariates. RESULTS: Infant gut microbial composition among vaginally born babies became less similar to the maternal vaginal/rectal microbiota and more similar to the maternal gut microbiota with age-related accumulation of bacterial species with advancing age. Stool samples from dog-exposed infants were microbially more diverse (p = .041) through age 18 months with enhanced diversity most apparent between 3 and 6 months of age. Statistically significant effects of dog exposure on ß-diversity metrics were restricted to formula-fed children. Across the sample collection period, dog exposure was associated with Fusobacterium genera enrichment, as well as enrichment of Collinsella, Ruminococcus, Clostridaceae and Lachnospiraceae OTUs. CONCLUSION: Prenatal/early-life dog exposure is associated with an altered gut microbiome during infancy and supports a potential mechanism explaining lessened atopy and asthma risk. Further research directly linking specific dog-attributable changes in the infant gut microbiome to the risk of allergic disorders is needed.

Urine Cell Transcriptomes Implicate Specific Renal Inflammatory Pathways Associated With Difficult-to-Control Hypertension.

Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group (P<0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.

Early-life gut microbiota and attention deficit hyperactivity disorder in preadolescents.

BACKGROUND: Gut microbiota maturation coincides with nervous system development. Cross-sectional data suggest gut microbiota of individuals with and without attention deficit hyperactivity disorder (ADHD) differs. We hypothesized that infant gut microbiota composition is associated with later ADHD development in our on-going birth cohort study, WHEALS. METHODS: Gut microbiota was profiled using 16S ribosomal RNA and the internal transcribed spacer region 2 (ITS2) sequencing in stool samples from 1 month and 6 months of age. ADHD was defined by parent-reported or medical record doctor diagnosis at age 10. RESULTS: A total of 314 children had gut microbiota and ADHD data; 59 (18.8%) had ADHD. After covariate adjustment, bacterial phylogenetic diversity (p = 0.017) and bacterial composition (unweighted UniFrac p = 0.006, R2 = 0.9%) at age 6 months were associated with development of ADHD. At 1 month of age, 18 bacterial and 3 fungal OTUs were associated with ADHD development. At 6 months of age, 51 bacterial OTUs were associated with ADHD; 14 of the order Lactobacillales. Three fungal OTUs at 6 months of age were associated with ADHD development. CONCLUSIONS: Infant gut microbiota is associated with ADHD development in pre-adolescents. Further studies replicating these findings and evaluating potential mechanisms of the association are needed. IMPACT: Cross-sectional studies suggest that the gut microbiota of individuals with and without ADHD differs. We found evidence that the bacterial gut microbiota of infants at 1 month and 6 months of age is associated with ADHD at age 10 years. We also found novel evidence that the fungal gut microbiota in infancy (ages 1 month and 6 months) is associated with ADHD at age 10 years. This study addresses a gap in the literature in providing longitudinal evidence for an association of the infant gut microbiota with later ADHD development.

Low-grade oncocytic tumour of the kidney is characterised by genetic alterations of TSC1, TSC2, MTOR or PIK3CA and consistent GATA3 positivity.

Low-grade oncocytic tumour (LOT) of the kidney has recently emerged as a potential novel tumour type. Despite similarity to oncocytoma or eosinophilic chromophobe renal cell carcinoma, it shows diffuse keratin 7 immunohistochemistry (IHC) and negative KIT (CD117), which differs from both. We aimed to identify the molecular characteristics of these tumours. Seventeen tumours (one male, 16 female, nine previously published) fitting the original description of this entity (solid eosinophilic cell morphology, often with areas of tumour cells loosely stretched in oedematous stroma, and the above IHC features) were analysed with a next-generation sequencing panel of 324 cancer-associated genes from formalin-fixed, paraffin-embedded tissue. All tumours harboured at least one alteration in either TSC1 (n = 7, 41%), TSC2 (n = 2, 12%), MTOR (n = 5, 29%) or PIK3CA (n = 4, 24%). Four tumours harboured a second alteration, including two NF2, one each in conjunction with MTOR and TSC2 alterations, one PTEN with TSC1 alteration and one tumour with both MTOR and TSC1 alterations. No other renal cancer-related or recurring gene alterations were identified. In addition to the previously described IHC findings, 16 of 16 were positive for GATA3. Eleven patients with follow-up had no metastases or recurrent tumours. Recurrent tuberous sclerosis/MTOR pathway gene alterations in LOT support its consideration as a distinct morphological, immunohistochemical and genetic entity. PIK3CA is another pathway member that may be altered in these tumours. Further study will be necessary to determine whether tumour behaviour or syndromic associations differ from those of oncocytoma and chromophobe carcinoma, warranting different clinical consideration.

Clear cell renal cell carcinoma with focal psammomatous calcifications: a rare occurrence mimicking translocation carcinoma.

AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumours consistent with clear cell RCC that contain focal psammomatous calcifications. METHODS AND RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in-situ hybridisation (FISH and RNA ISH). Twenty-one tumours were identified: 12 men, nine women, aged 45-83 years. Tumour size was 2.3-14.0 cm (median = 6.75 cm). Nucleolar grade was 3 (n = 14), 2 (n = 4) or 4 (n = 3). In addition to clear cell pattern, morphology included eosinophilic (n = 12), syncytial giant cell (n = 4), rhabdoid (n = 2), branched glandular (n = 1), early spindle cell (n = 1) and poorly differentiated components (n = 1). Labelling for CA9 was usually 80-100% of the tumour cells (n = 17 of 21), but was sometimes decreased in areas of eosinophilic cells (n = 4). All (19 of 19) were positive for CD10. Most (19 of 20) were positive for AMACR (variable staining = 20-100%). Staining was negative for keratin 7, although four showed rare positive cells (four of 20). Results were negative for cathepsin K (none of 19), melan A (none of 17), HMB45 (none of 17), TFE3 (none of 5), TRIM63 RNA ISH (none of 13), and TFE3 (none of 19) and TFEB rearrangements (none of 12). Seven of 19 (37%) showed chromosome 3p deletion. One (one of 19) showed trisomy 7 and 17 without papillary features. CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.