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Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small-cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts neurite-mediated cellular communication in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to docetaxel therapies. Moreover, t-NEPC-specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.

Context.--Low-risk (Gleason score 3 + 3 = 6) and intermediate-risk (Gleason score 3 + 4 = 7) prostate carcinoma cases diagnosed on needle biopsies are frequently referred for gene expression studies such as Oncotype DX to help validate the risk. Risk assessment helps in determining prognosis and therapeutic decision making. Objective.--To determine if addition of molecular testing is necessary, by evaluating its correlation with risk stratification provided by pathology report (Gleason score, Grade Group, proportion of positive cores) and serum prostate-specific antigen (PSA) level. Design.--Our institutional database was searched for cases that had Oncotype DX testing after prostate biopsy. The final risk category determined by molecular testing was compared to the risk stratification predicted by the pathology report and serum PSA levels. Cases were classified as concordant if they fell under the same National Comprehensive Cancer Network risk and recommended initial therapy group. Follow-up information on discordant cases was obtained and used to determine if risk stratification by molecular testing was superior to that obtained from the clinicopathologic data. Results.--A total of 4967 prostate biopsies (2015-2020) were screened. Of these, 131 prostate carcinoma cases (2.6%) had Oncotype DX testing and 111 of 131 cases (85%) had follow-up information. There was risk stratification concordance in 93 of 111 cases (84%). All 18 of 111 cases (16%) that were discordant had a follow-up course that matched the risk predicted by pathology data and serum PSA. Conclusions.--Risk stratification provided by information in the pathology report on routine biopsy assessment coupled with the serum PSA level is equivalent to that obtained by Oncotype DX testing. doi: 10.5858/arpa.2022-0225-OA, Clinical risk assessment for prostatic adenocarcinoma helps in determining prognosis and therapeutic decisions such as watchful waiting or active surveillance versus intervention. National Comprehensive Cancer Network (NCCN)-recommended traditional risk assessment [...]

Adenomatoid tumors are rare benign neoplasms arising from mesothelial cells, commonly found in the female genital system, particularly the uterus and fallopian tubes. The giant cystic variant of adenomatoid tumor is exceptionally rare and can cause massive growth mimicking malignant gynecological conditions. Histology and immunohistochemistry play a crucial role in confirming the diagnosis, with markers such as calretinin, D2‐40, CK7, BAP1, ER, and WT1 proving useful. A 51‐year‐old female with a history of breast cancer presented with pelvic pressure and vague pain. Imaging revealed an enlarged uterus with multiple heterogeneously enhancing masses and a predominantly cystic mass arising from the fundus, all believed to be leiomyomas. Surgical exploration and subsequent pathologic examination identified the cystic tumor as cystic adenomatoid tumor coexisting with leiomyomas, adenomyosis, and abdominal endometriosis. Diagnosing cystic adenomatoid tumor presents challenges, especially in patients with complex gynecologic histories. Cystic adenomatoid tumors typically have a favorable prognosis following surgical intervention. This case demonstrates one of the few reports of a giant cystic adenomatoid tumor (11.5 cm) and highlights diagnostic mimics. As these tumors are typically small and often seen only microscopically, the large size can confuse the pathologist who may be unaware of this feature leading to a misdiagnosis. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.

Purpose: Radiotherapy delivered at ultra‐high‐dose‐rates (≥40 Gy/s), that is, FLASH, has the potential to effectively widen the therapeutic window and considerably improve the care of cancer patients. The underlying mechanism of the FLASH effect is not well understood, and commercial systems capable of delivering such dose rates are scarce. The purpose of this study was to perform the initial acceptance and commissioning tests of an electron FLASH research product for preclinical studies. Methods: A linear accelerator (Clinac 23EX) was modified to include a non‐clinical FLASH research extension (the Clinac‐FLEX system) by Varian, a Siemens Healthineers company (Palo Alto, CA) capable of delivering a 16 MeV electron beam with FLASH and conventional dose rates. The acceptance, commissioning, and dosimetric characterization of the FLEX system was performed using radiochromic film, optically stimulated luminescent dosimeters, and a plane‐parallel ionization chamber. A radiation survey was conducted for which the shielding of the pre‐existing vault was deemed sufficient. Results: The Clinac‐FLEX system is capable of delivering a 16 MeV electron FLASH beam of approximately 1 Gy/pulse at isocenter and reached a maximum dose rate >3.8 Gy/pulse near the upper accessory mount on the linac gantry. The percent depth dose curves of the 16 MeV FLASH and conventional modes for the 10 × 10 cm2 applicator agreed within 0.5 mm at a range of 50% of the maximum dose. Their respective profiles agreed well in terms of flatness but deviated for field sizes >10 × 10 cm2. The output stability of the FLASH system exhibited a dose deviation of <1%. Preliminary cell studies showed that the FLASH dose rate (180 Gy/s) had much less impact on the cell morphology of 76N breast normal cells compared to the non‐FLASH dose rate (18 Gy/s), which induced large‐size cells. Conclusion: Our studies characterized the non‐clinical Clinac‐FLEX system as a viable solution to conduct FLASH research that could substantially increase access to ultra‐high‐dose‐rate capabilities for scientists. [ABSTRACT FROM AUTHOR]