We reviewed the clinical characteristics of male patients with MEN2B associated medullary thyroid cancer (MTC) with prostate lesions and analyzed available imaging and pathology data.Patients were enrolled on a National Cancer Institute (NCI) natural history protocol (NCT01660984) and a University of Texas (UT) MD Anderson Cancer Center study (DR09-0507).Thirty-six male patients (median age of MEN2B diagnosis 12.0 years, range 1.3-25.6) with the RET p.Met918Thr germline mutation were identified.Pelvic imaging was available for 28/36 (78%) patients. Prostate lesions and/or calcifications were noted in eight patients (28.6%). Lesions were identified at a median age of 20.5 years (range 13-30.5 years). Biopsies in three patients with prostate neoplasms were histologically indistinguishable from primary MTC. Two of these patients did not have other sites of distant disease at the time of prostate biopsy. Prostate lesions in males with MEN2B and MTC are more frequent than previously described. Lesions were identified in patients as young as 14 years and often contained calcifications. The prostate is a more common site of disease in patients with MEN2B than previously appreciated and may represent a distant site of metastatic MTC metastasis or a second primary calcitonin-secreting neuroendocrine tumor. Imaging of the prostate should be considered in post-pubertal MEN2B males, especially in case of unexplained increase in calcitonin or onset of urinary tract symptoms.

PURPOSE:Active surveillance (AS) is an increasingly used strategy for managing localized prostate cancer, yet reliable biomarkers for predicting disease progression remain limited. Low testosterone has been associated with aggressive prostate cancer features at diagnosis, but its role in Grade Group (GG) progression during AS remains unclear. Our objective was to evaluate the association between baseline serum testosterone levels and GG progression in men undergoing AS for localized prostate cancer. MATERIALS AND METHODS:We conducted a retrospective cohort study of 924 men enrolled in an AS program between 2005 and 2024, with a median follow-up of 46.1 months among those who did not progress. Serum testosterone levels were categorized as low if they met a threshold of ≤ 300 ng/dL based on guideline recommendations. Primary outcomes were biopsy progression to GG2 or "extreme" progression to GG3 or higher disease. Multivariable Cox proportional hazards models were used to assess associations between testosterone levels and progression, adjusting for age, PSA density, and biopsy tumor volume. Potential clinically significant confounding by BMI, smoking status, and ethnicity was also considered. RESULTS:Among 924 men, the mean age was 63.6 years (SD 8.1), and the mean PSA density was 0.13 ng/mL2 (SD 0.14). The average baseline testosterone was 394 ng/dL (SD 160.4), with 29.4% (n = 272) of men having a testosterone level ≤ 300 ng/dL. Low testosterone was associated with a statistically significant increased risk of GG3 progression (HR 1.61, 95% CI 1.02-2.54, P = .04). Furthermore, evidence suggested that low testosterone was not associated with risk of GG2 progression (HR 1.25, 95% CI 0.93-1.67, P = .13). Findings were consistent when employing alternative cut points for testosterone and when considering other potential confounders. CONCLUSIONS:These findings suggest that while low testosterone is not clearly associated with moderate progression (GG2), it may increase the risk of higher-grade "extreme" progression to GG3 or higher. Future studies should focus on prospective validation of our findings to elucidate the biological relationship between androgens and prostate cancer progression.

To compare perioperative and survival outcomes of patients undergoing robotic versus open post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testicular cancer. Analyzing data from patients who underwent PC-RPLND at eleven academic centres between 1990 and 2023, we used propensity score matching (PSM) to create a 1:1 (open-RPLND: robotic-RPLND) matched cohort. The primary endpoint was time to relapse. Secondary endpoints included operative time, length of stay, estimated blood loss, and surgical complications. Relapse free survival rates were calculated using the Kaplan-Meier methodology, and Cox proportional hazards model was used to compare perioperative outcomes between robotic vs. open PC-RPLND after adjusting for template and pathology. A total of 134 robotic cases were propensity score matched to 134 open cases. At a median follow-up of 2.2 years, estimated relapse-free survival at 3 years was similar between robotic and open PC-RPLND (92.8

PURPOSE:Somatic-type malignancy (SM) of germ cell tumor (GCT) is rare but demonstrates aggressive behavior. Differences by primary site, time to transformation, and mutational status remain poorly characterized. PATIENTS AND METHODS:We reviewed all SM patients between June 2016 and May 2025 at a tertiary referral center. Time to somatic transformation (TST) was defined from the initial GCT diagnosis to SM detection. SM were classified based on time of detection- at initial diagnosis (de novo), at consolidative surgery, at relapse within 5 years, and evolved SM at relapse after 5 years. Descriptive statistics, Kaplan-Meier estimates, and Cox regression analyses were used. RESULTS:72 patients were identified: 40 (56%) with testicular, 24 (33%) with mediastinal, and 8 (11%) with other primaries. 22/24 (92%) mediastinal tumors with SM had sarcomatous transformation. Sarcoma was seen in 25/42 (60%) of de novo SM while adenocarcinoma was detected as an evolved entity in 5/6 (83.3%) cases. Embryonic type neuroectodermal tumor (ENET) histology carried poor prognosis compared to non-ENET histology (median, OS 1.8 vs 8 years; HR, 1.94; P = 0.1). Genomic data available showed PTEN-AKT-mTOR pathway mutations (33%) and TP53 mutations (33%), enriched in extra-gonadal sarcomatous SM. CONCLUSIONS:SM exhibits temporal, histologic, and molecular distinctions across primary sites. Response to frontline therapy and survival outcomes are poor. Future direction includes the exploration of underlying predictors of transformation and identification of targetable alterations in the relapsed setting.

PURPOSE:Sequential high-dose chemotherapy (HDC) using carboplatin/etoposide with autologous stem cell transplant can be curative in relapsed germ cell tumors (GCT). However, outcomes are poor for multiply relapsed/refractory tumors. We studied gemcitabine/docetaxel/melphalan/carboplatin (GemDMC), which exploits DNA damage repair inhibition. We hypothesized that concurrent bevacizumab, targeting the high vascularity of GCT, would synergize with HDC. PATIENTS AND METHODS:Trial eligibility included second or later relapse or poor-risk first relapse and adequate end-organ function. Treatment consisted of sequential bevacizumab-GemDMC (HDC cycle 1) and bevacizumab-ifosfamide/carboplatin/etoposide (C2) in three consecutive cohorts: bevacizumab/full-dose GemDMC (cohort 1), bevacizumab/reduced-dose GemDMC (cohort 2), and no bevacizumab/reduced-dose GemDMC (cohort 3). The trial was powered to distinguish a target 50% 2-year relapse-free survival rate from an expected <25%. We validated its results in an off-trial fourth cohort treated the same as cohort 3. RESULTS:We treated 165 male patients (65 trial and 100 cohort 4 patients), after a median of three prior therapy lines, mostly with cisplatin-refractory tumors at relapse (45% refractory and 23% absolutely refractory) and 19% primary mediastinal tumors. The overall response rate was 84.5% (77% complete response/partial response with negative markers). The treatment-related mortality rates in cohorts 1 to 4 were 13%, 8%, 4%, and 4%, respectively. Resection of residual lesions in 74 patients found no viable GCT in 76%. The 5-year relapse-free survival and overall survival rates were 57.1% and 58.3%, respectively, without differences between trial and cohort 4 patients or between patients receiving bevacizumab (cohorts 1 and 2) and those not receiving it (cohorts 3 and 4). CONCLUSIONS:Sequential GemDMC-carboplatin/etoposide with or without ifosfamide shows outcomes that exceed the anticipated results in multiply, poor-risk relapsed GCT. Bevacizumab did not improve outcomes. See related commentary by Kollmannsberger et al., p. 257.

Background Marker-negative germ cell tumors (GCT) account for up to 40% of metastatic disease, making treatment monitoring and surveillance challenging. The utility of circulating tumor DNA (ctDNA) in teratoma and somatic-type malignancies (SM) remains undefined. Methods In this retrospective study, the GCT database at a tertiary referral center was queried to identify patients with available ctDNA reports and evidence of radiological progression without tumor marker elevation, or normal pre-orchiectomy tumor markers. ctDNA, stratified as either positive or negative was studied in conjunction with radiology and histology status to determine concordance. Serial trends of mean tumor molecules/ml across various therapeutic interventions and relapse were also investigated. Results Between December 2024 and February 2026, 34 patients with marker-negative germ cell tumors (GCTs) and 70 ctDNA assessments were identified. The most common histology was seminoma (15, 44%), followed by somatic-type malignancy (SM) (6, 18%). Pure teratoma was present in 3 patients (9%). ctDNA was undetectable in 35/38 (92.1%) assessments of response and detectable in 23/25 (92.0%) assessments of progression. One patient each with neuroendocrine somatic transformation and growing teratoma syndrome progressed with undetectable ctDNA. Conclusion ctDNA demonstrates high concordance with disease status in marker-negative non-teratomatous GCT, with potential utility in SM.

The Gleason score (GS) is a fundamental predictor of prostate cancer (PCa) behavior and cancer-specific survival. The GS is determined by analyzing the tumor cell architecture in tissue samples. As PCa exhibits significant heterogeneity within any single tumor, whole-prostate tissue specimens enable a comprehensive assessment of the tumor’s GS. However, a biopsy, upon which treatment decisions are made, is inherently prone to sampling bias. Thus, a more accurate method to predict tumor biology and clinical disease progression is needed. To address this unmet critical demand, we propose the concept of virtual Gleason Score (vGS). The vGS consists of a personalized prediction of the local map of GS over the 3D tumor morphology extracted from MRI and informed by biomechanistic markers that characterize spatiotemporal tumor dynamics. The vGS is obtained through a three-step pipeline hybridizing physics-driven and data-driven models. First, we personalize a biomechanistic model of PCa growth using MRI and serum PSA data collected as part of routine management of the disease. Second, we calculate a panel of biomechanistic biomarker maps probing quantities and mechanisms included in the model that have shown strong correlation with GS. Finally, a machine learning algorithm leverages the local values of these biomechanistic markers to render a spatiotemporally-resolved map of vGS over the tumor geometry. Here, we present preliminary results in a cohort with 16 PCa cases that were longitudinally monitored with PSA and MRI in the context of active surveillance. The underlying biomechanistic model was the Fisher-Kolmogorov equation, and we used logistic classifiers to build the vGS. Our study shows that local proliferation activity and tumor cell density weighted by the ratio of tumor to prostate volume achieve an AUC of 0.96 as well as optimal sensitivity and specificity of 86.4% s and 90.7% for predicting GS. Despite the coarse nature of the vGS predictions obtained from the biomechanistic model used herein, these forecasts accurately anticipated the emergence of higher GS more than one year earlier than standard PCa monitoring. Future work will seek to advance the biomechanistic and data-driven models to enhance local vGS forecasts, as well as leveraging them to optimize disease management on a patient-specific basis. Guillermo Lorenzo Gomez, Chengyue Wu, Joshua P. Yung, John F. Ward, Hector Gomez, Thomas E. Yankeelov, Aradhana M. Venkatesan, Thomas J. Hughes. Virtual Gleason score: Towards personalized predictive identification of prostate cancer risk via integration of clinical and imaging data into spatiotemporal, biomechanistically-informed classifiers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3685.

e17153 Background: Focal therapy (FT) for prostate adenocarcinoma (PCa) aims to minimize adverse effects while achieving tumor control. While FT is becoming more prevalent, there is no consensus on treatment after FT failure. The goal of this study was to measure the toxicity and oncological outcomes of external beam radiation therapy (EBRT) after cryosurgery (CS) or high-intensity focused ultrasound (HIFU) to evaluate its role as a salvage treatment option for FT failure. Methods: Institutional databases were queried to identify patients diagnosed with PCa from 2002 to 2024 who were treated with CS or HIFU as the initial treatment. Patients who underwent intensity-modulated radiation therapy (IMRT) or proton therapy (PT) for recurrent localized PCa were included. Patients received concurrent androgen deprivation therapy (ADT) as recommended. Primary outcomes were acute and late genitourinary (GU) and gastrointestinal (GI) toxicity from EBRT using the modified Radiation Therapy Oncology Group (RTOG) scale. Acute and late toxicities were defined as events occurring during and up to 3 months after EBRT and after 3 months, respectively. Secondary outcomes were biochemical recurrence-free survival (bFS), metastasis-free survival (MFS), and overall survival (OS). Biochemical recurrence was defined as a PSA increase of ≥2 ng/mL above the nadir. Toxicity outcomes were reported using descriptive statistics, and survival outcomes were analyzed using Kaplan-Meier analysis. Results: 36 patients were included in this study (23 CS, 12 HIFU, and 1 both). 28 patients received IMRT and 8 patients proton therapy. 30 patients underwent confirmation biopsy before the radiation therapy with the following Gleason scores: 7 (3+4) in 15 patients, 7 (4+3) in 6 patients, 8 (4+4) in 10 patients, ≥9 in 3 patients. The median dose was 76 Gy (range 72-79.2 Gy) in 1.8 Gy (24 patients) or 2.0 Gy (12 patients) per fraction. 32 patients received ADT with radiation for a median duration of 6 months (range 4-24). Median follow-up period was 38 months (IQR 20.5–61.8). Acute genitourinary (GU) toxicities of grade 1 and grade 2 were observed in 11 patients (30.6%) and 7 patients (19.4%), respectively. Acute gastrointestinal (GI) toxicities of grade 1 and grade 2 were reported in 7 patients (19.4%) and 1 patient (2.8%), respectively. There were no grade 3 or higher acute GU or GI toxicities seen. Late GU toxicities included grade 1 and grade 2 in 2 patients each (8.3%), with grade 3 late GU toxicity (hematuria) occurring in 1 patient (4.2%). Grade 1 late GI toxicity was observed in 2 patients (8.3%). There was no grade 2 or higher late GI toxicity. bFS, MFS, and OS were 94.1%, 100%, and 100% at 5 years and 70.6%, 83.3%, and 75.8% at 10-years, respectively. Conclusions: Our data demonstrate that EBRT after FT failure is a safe and effective treatment. Studies with larger patient cohorts are required to further validate the use of EBRT as a salvage treatment.

Detail of manually curated full or partial copy number/ transcript loss

Background: Current fiducial markers (FMs) in external-beam radiotherapy (EBRT) for prostate cancer (PCa) cannot be positively visualized on magnetic resonance imaging (MRI) and create dose perturbation and significant imaging artifacts on computed tomography (CT) and MRI. We report our initial experience with clinical imaging of a novel multimodality FM, NOVA. Methods: We tested Gold Anchor [G-FM], BiomarC [carbon, C-FM], and NOVA FMs in phantoms imaged with kilovoltage (kV) X-rays, transrectal ultrasound (TRUS), CT, and MRI. Artifacts of the FMs on CT were quantified by the relative streak artifacts level (rSAL) metric. Proton dose perturbations (PDPs) were measured with Gafchromic EBT3 film, with FMs oriented either perpendicular to or parallel with the beam axis. We also tested the performance of NOVA-FMs in a patient. Results: NOVA-FMs were positively visualized on all 4 imaging modalities tested. The rSAL on CT was 0.750 ± 0.335 for 2-mm reconstructed slices. In F-tests, PDP was associated with marker type and depth of measurement (p < 10−6); at 5-mm depth, PDP was significantly greater for the G-FM (12.9%, p = 10−6) and C-FM (6.0%, p = 0.011) than NOVA (4.5%). EBRT planning with MRI/CT image co-registration and daily alignments using NOVA-FMs in a patient was feasible and reproducible. Conclusions: NOVA-FMs were positively visible and produced less PDP than G-FMs or C-FMs. NOVA-FMs facilitated MRI/CT fusion and identification of regions of interest.

Percentage of reads matching with mouse DNA

Fusion genes expression levels. CNV details on TMPRSS2-ERG fusion and AR enhancer region. Putative PCa drivers in models lacking alterations in four major genes

Fusions identified in MDA PCa PDX cohort

T200.1 panel: genes implicated in the pathogenesis of solid cancers

Clinical, morphological and molecular features of MDA PCa PDXs pairs derived from the same patient

Comparison between adenocarcinoma and neuroendocrine carcinoma

STR Profiling of samples derived from the same patient

General copy number profile and association with expresion for PTEN and RB1