Citations

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

AbstractPulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis‐associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant‐free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan−Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was decreased. Decreased transplant‐free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant‐free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut‐offs with decreased transplant‐free survival in the SAPH population. Neither cut‐off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant‐free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.

Abstract Introduction During the Coronavirus (COVID‐19) pandemic, healthcare providers have overcome difficult experiences such as workplace violence. Nurses are particularly vulnerable to workplace violence. The objective of this study was to characterize violence and aggression against nurses during the COVID‐19 pandemic in Latin America. Methods An electronic cross‐sectional survey was conducted in 19 Latin American countries to characterize the frequency and type of violent actions against front‐line healthcare providers. Results Of the original 3544 respondents, 16% were nurses ( n = 567). The mean age was 39.7 ± 9.0 years and 79.6% ( n = 2821) were women. In total, 69.8% ( n = 2474) worked in public hospitals and 81.1% ( n = 2874) reported working regularly with COVID‐19 patients. Overall, about 68.6% ( n = 2431) of nurses experienced at least one episode of workplace aggression during the pandemic. Nurses experienced weekly aggressions more frequently than other healthcare providers (45.5% versus 38.1%, p < .007). Nurses showed a trend of lower reporting rates against the acts of aggression suffered ( p = .076). In addition, nurses were more likely to experience negative cognitive symptoms after aggressive acts (33.4% versus 27.8%, p = .028). However, nurses reported considering changing their work tasks less frequently compared to other healthcare providers after an assault event ( p = .005). Conclusion Workplace violence has been a frequent problem for all healthcare providers during COVID‐19 pandemic in Latin America. Nurses were a particularly vulnerable subgroup, with higher rates of aggressions and cognitive symptoms and lower rate of complaints than other healthcare providers who suffered from workplace violence. It is imperative to develop strategies to protect this vulnerable group from aggressions during their tasks.

Abstract Disclosure: S. Tella: None. J.C. Morris: None. M. Rivera: None. S. Gupta: None. M.M. Ryder: None. Introduction: NUT carcinoma is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT-fusion oncoproteins with a very dismal prognosis. Recent data showed that NUTM1 rearranged carcinoma of the thyroid can mimic other thyroid primaries but NSD3-NUTM1 fusions aid in the diagnosis. Other than systemic chemotherapy with ifosfamide-based therapies and bromodomain inhibitors, therapeutic options for metastatic NUTM1 rearranged carcinoma of thyroid are limited. Herein, we describe a case of NUTM1 carcinoma of thyroid that had an impressive response to lenvatinib. Clinical case: We describe a case of a 41-year-old Caucasian male who presented to urgent care with acute onset aphonia and was eventually diagnosed with poorly differentiated thyroid carcinoma of size 4 x 4 cms extending into the internal jugular vein. He was managed with partial resection of the mass, internal jugular vein ligation, and a right select neck dissection. He had R2 resection due to possible vascular or airway invasion. As such, he received external beam radiation 70 Gy with 35 fractions with concurrent cisplatin followed by 200 mci radio-iodine therapy. The radiation therapy was complicated by the formation of a tracheo-esophageal fistula. A follow-up FDG-avid PET scan demonstrated residual thyroid bed disease and oligometastatic disease in bones. He received a couple of Stereotactic Body Radiation Therapy twice for bone lesions. Unfortunately, he had rapid disease progression with large pleural-based nodules and histology showed poorly differentiated thyroid carcinoma. NUT1 IHC stain was negative. We simultaneously obtained next-generation sequencing (NGS) and started him on lenvatinib 20 mg. Interestingly, NGS showed NSD3-NUTM1 fusions favoring the diagnosis of NUTM1 rearranged carcinoma of thyroid. He had an impressive partial response to lenvatinib within 4 weeks of initiation of lenvatinib and the response is sustained on 8-month follow-up. He tolerated lenvatinib reasonably without any unexpected complications. In an event of progression, we intend to consider a clinical trial, chemotherapy in combination with bromodomain inhibitors, or another anti-angiogenic tyrosine kinase inhibitor therapy. Conclusions: We noticed an impressive and sustained partial response in NUTM1 rearranged carcinoma of thyroid with anti-angiogenic multi-kinase inhibitor, lenvatinib opening new avenues of targeted therapy in the therapeutic landscape of NUT1 carcinomas. Importantly, NUT1 stain could be negative and NGS is the gold standard for accurate diagnosis. Although our study is limited by one case report, we hope that by highlighting the spectrum of this disease that more cases will be recognized, facilitating risk stratification and improved treatment, and further enabling future studies to explore the clinical management and biology of NUTM1 rearranged carcinoma of thyroid. Presentation: Thursday, June 15, 2023

AbstractQuantifying tumor‐infiltrating lymphocytes (TILs) in breast cancer tumors is a challenging task for pathologists. With the advent of whole slide imaging that digitizes glass slides, it is possible to apply computational models to quantify TILs for pathologists. Development of computational models requires significant time, expertise, consensus, and investment. To reduce this burden, we are preparing a dataset for developers to validate their models and a proposal to the Medical Device Development Tool (MDDT) program in the Center for Devices and Radiological Health of the U.S. Food and Drug Administration (FDA). If the FDA qualifies the dataset for its submitted context of use, model developers can use it in a regulatory submission within the qualified context of use without additional documentation. Our dataset aims at reducing the regulatory burden placed on developers of models that estimate the density of TILs and will allow head‐to‐head comparison of multiple computational models on the same data. In this paper, we discuss the MDDT preparation and submission process, including the feedback we received from our initial interactions with the FDA and propose how a qualified MDDT validation dataset could be a mechanism for open, fair, and consistent measures of computational model performance. Our experiences will help the community understand what the FDA considers relevant and appropriate (from the perspective of the submitter), at the early stages of the MDDT submission process, for validating stromal TIL density estimation models and other potential computational models. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Abstract Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty‐seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non‐metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate‐sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS / RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non‐metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS / RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ ‐related germ cell tumors rather than non‐germ cell neoplasia in situ ‐derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Introduction: Genome-wide association studies (GWAS) have discovered >300 associations for CAD. Few loci are functionally characterized and may represent new mechanisms of disease. Hypothesis: Can an unbiased transcriptional screen for the >2000 candidate GWAS genes in endothelial cells (ECs) identify causal genes and disease-relevant pathways at CAD GWAS loci. Methods: We applied CRISPRi-Perturb-seq to knock down expression of genes within 500 Kb of coronary artery disease GWAS loci (2,300 genes in total) and measure their transcriptomic effects using single-cell RNA-seq. Validation of candidate causal genes was conducted in primary human ECs and zebrafish. Results: We identified 50 programs of co-expressed genes, which represent core cellular pathways (i.e. ribosome biogenesis) and 13 EC-specific pathways such as flow response and angiogenesis. The EC-specific programs show the greatest contribution to CAD heritability. 5 EC-specific programs have the greatest number of GWAS candidate genes. We find that 43 of 306 CAD GWAS signals converge onto these 5 gene programs, and all are regulated by genes in the cerebral cavernous malformations (CCM) pathway—which coordinates KLF2/4 transcriptional responses in endothelial cells, but has not been linked to CAD risk. The strongest regulator of these programs is TLNRD1 , which we show is a new CAD gene and novel regulator of the CCM pathway. TLNRD1 loss-of-function alters actin organization and barrier function in endothelial cells in vitro , and heart development in zebrafish in vivo . Conclusions: High-throughput functional analysis of 2,300 genes proximal to CAD GWAS loci prioritized pathways—such as angiogenesis and EC migration—that are regulated by multiple risk SNPs. Our study identifies new genes that likely influence risk for CAD, identifies convergence of CAD genes into certain pathways in endothelial cells, and prioritizes study of genes in the CCM-signaling pathway for contribution to CAD risk.

ABSTRACTObjectivesWe aimed to investigate the gender-based differences in idiopathic inflammatory myopathies (IIMs), with a particular focus on patient-reported outcomes, utilizing the data obtained through the international COVID-19 vaccination in autoimmune disease e-survey.MethodsPatient-reported outcomes including fatigue, pain, and physical function were extracted from the COVID-19 vaccination in autoimmune disease database and compared between genders, adjusting for demographics and IIM subgroups by multivariable analysis. Inclusion body myositis (IBM) was analysed separately because of the substantial differences in outcomes.ResultsA total of 1197 complete responses from patients with IIMs as of 31 August 2021 were analysed. Seventy percent were women. Women were younger (58 [48–68] vs. 69 [58–75] years old, median [interquartile range], P &lt; .001) and were more likely to suffer from autoimmune multimorbidity, defined as three or more autoimmune diseases in an individual patient (11.4% vs. 2.8%, P &lt; .001). In non-IBM IIMs, fatigue visual analogue scale scores were higher in women (5 [3–7] vs. 4 [2–6], median [interquartile range], P = .004), whereas no significant gender-based differences were noted in IBM. Multivariable analysis in non-IBM IIMs revealed that women, residence in high-income countries, overlap myositis, and autoimmune multimorbidity were independently associated with increased fatigue.ConclusionsWomen with IIMs suffer from autoimmune multimorbidity and experience increased fatigue compared to men.

ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.