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Objective: To review the presentation and long-term oncologic outcomes of patients with regressed ("burnt out") primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes., Methods: We queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990 to 2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method., Results: Fifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n = 5) or first-line chemotherapy (n = 34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively., Conclusion: Patients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP., Patients and Methods: Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score., Results: Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively., Conclusion: TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner., (© 2021. The Author(s).)

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions., Competing Interests: Competing interest statement: C.L.S. is on the board of directors of Novartis, is a cofounder of ORIC Pharmaceuticals, and serves on the scientific advisory boards of the following biotechnology companies: Agios, Arsenal, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ Therapeutics, and PMV Pharma. He is a coinventor of the prostate cancer drugs enzalutamide and apalutamide, covered by US patents 7,709,517, 8,183,274, 9,126,941, 8,445,507, 8,802,689, and 9,388,159 filed by the University of California, Los Angeles., (Copyright © 2021 the Author(s). Published by PNAS.)

Background: The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience., Material and Methods: Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data., Results: Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events., Conclusion: EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care., Implications for Practice: Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2., (© 2021 AlphaMed Press.)

Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies., Competing Interests: Declaration of Interests C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharmaceuticals. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals, and received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. D.E.R. reports having consulting or advisory role (uncompensated) from Genentech/Roche, Janssen Oncology, and TRACON Pharma, and received research funding from: AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Medivation/Astellas/Pfizer (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst). W.R.K. is a coinventor on patent WO2012168930A2 filed by Koninklijke Nederlandse Akademie Van Wetenschappen that covers organoid technology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The relapse rate after primary retroperitoneal lymph node dissection (RPLND) for patients with pathologic stage (PS) IIA nonseminomatous germ cell tumors (NSGCTs) is 10%-20% but increases to ≥ 50% for PS IIB disease. We report our experience with 2 cycles of adjuvant etoposide plus cisplatin (EP×2) after therapeutic primary RPLND., Patients and Methods: All patients with PS II NSGCT seen at Memorial Sloan Kettering Cancer Center from March 1989 to April 2016 and who were planned to receive EP×2 were included. Each cycle consisted of cisplatin 20 mg/m 2 and etoposide 100 mg/m 2 on days 1 through 5 at 21-day intervals. Demographic characteristics, histopathologic features, therapeutic and survival outcomes were recorded., Results: Of 156 patients, 30 (19%) had pathologic N1, 122 (78%) had pathologic N2 (pN2), and 4 (3%) had pathologic N3 (pN3) disease. The median number of involved lymph nodes was 3 (range, 1-37 nodes), and the median size of the largest involved node was 2.0 cm (range, 0.4-7.0 cm); extranodal extension was present in 69 patients (45%). Embryonal carcinoma was the most frequent RPLND histology, present in 143 patients (92%). One hundred fifty patients (96%) received EP×2, five received EP×1 and one received EP×4. With a median follow-up of 9 years, 2 patients (1.3%; 1 patient each with pN2 and pN3 disease) experienced relapse; both patients remain continuously disease free at more than 5 and 22 years after salvage chemotherapy. Three patients died, all unrelated to NSGCT, yielding 10-year disease-specific, relapse-free, and overall survival rates of 100%, 98%, and 99%, respectively., Conclusion: Adjuvant EP×2 for PS II NSGCT is highly effective, has acceptable toxicity, and incurs less drug cost than 2 cycles of bleomycin, etoposide, and cisplatin. Inclusion of bleomycin in this setting is not necessary.

Genomic rearrangements leading to the aberrant expression of ERG are the most common early events in prostate cancer and are significantly enriched for the concomitant loss of PTEN. Genetically engineered mouse models reveal that ERG overexpression alone is not sufficient to induce tumorigenesis, but combined loss of PTEN results in an aggressive invasive phenotype. Here, we show that oncogenic ERG repressed PI3K signaling through direct transcriptional suppression of IRS2, leading to reduced RTK levels and activity. In accordance with this finding, ERG-positive human prostate cancers had a repressed AKT gene signature and transcriptional downregulation of IRS2. Although overexpression of IRS2 activated PI3K signaling, promoting cell migration in a PI3K-dependent manner, this did not fully recapitulate the phenotype seen with loss of PTEN as PI3K signaling is not as robust as observed in the setting of loss of PTEN. Importantly, deletions of the PTEN locus, which promotes active PI3K signaling, were among the most significant copy-number alterations that co-occurred with ERG genomic rearrangements. This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote oncogenic signaling during tumor evolution. SIGNIFICANCE: This work provides insight on how initiating oncogenic events may directly influence the selection of secondary concomitant alterations to promote tumorigenesis., (©2020 American Association for Cancer Research.)

On the basis of our previous work defining the molecular rationale for combined targeting of the PI3K and AR pathways in PTEN loss prostate cancer, the first clinical trial was recently reported demonstrating a significant benefit for combination therapy in patients with metastatic prostate cancer. In this phase II trial, loss of PTEN was a biomarker predictive of response to combined AKT and AR inhibition. Given that PTEN loss prostate cancers are significantly enriched for ERG genomic rearrangements, we evaluated how the aberrant expression of ERG may impact response to PI3K/AR-targeted therapy. Here, we show that overexpression of ERG in the setting of Pten loss promotes resistance to combined PI3K and AR pathway inhibition with associated maintenance of AR target gene expression. Importantly, following AR knockout in the setting of ERG overexpression, there is maintenance of a subset of AR lineage-specific target genes, making AR dispensable in this context. This has important clinical implications as even in the setting of the androgen-regulated TMPRSS2:ERG genomic rearrangement, ERG expression is never abolished following AR inhibition and may allow for cell survival following AR (lineage)-targeted therapies., (©2019 American Association for Cancer Research.)

The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: To characterize clinical and pathologic outcomes of cisplatin-refractory or relapsed germ cell tumor (GCT) patients who underwent retroperitoneal lymph node dissection (RPLND) following salvage chemotherapy with either conventional or high dose regimens., Methods: Data were reviewed to identify all patients treated with TIP or TICE salvage chemotherapy between 1994 and 2011(n = 184) at our institution. We report clinicopathologic and outcomes data on 131 patients who were further managed with surgical resection. Using Cox-proportional hazards models, predictors of disease-specific survival (DSS) were analyzed., Results: Median follow-up was 7.3 years. Of the 112 patients who underwent postsalvage chemotherapy RPLND, histology was reported as viable GCT in 30 (27%), teratoma only in 26 (23%) and fibrosis in 56 (50%). 5-year DSS for the entire cohort was 74% (95% confidence interval 63%-80%). On multivariable analysis, viable GCT histology at RPLND or extra-RPLND resection predicted for worse DSS (hazard ratio 7.37, P = .003)., Conclusions: Our data suggest that approximately half of the patient with cisplatin-refractory or relapsed GCT salvaged with TIP or TICE chemotherapy and evidence of residual disease are at risk of harboring either viable GCT or teratoma. This finding underlines the critical role of surgery in the multimodality approach to the management of this advanced disease entity. If retroperitoneal disease exists prior to salvage chemotherapy, we recommend postchemotherapy resection in all eligible patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate the oncologic outcomes and histologic concordance of postchemotherapy residual liver mass resection with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND)., Methods: Retrospective review of our prospectively maintained germ cell tumor (GCT) surgical database identified patients with nonseminomatous GCT who underwent both postchemotherapy residual liver mass resection and PC-RPLND between 1990 and 2015., Results: A total of 36 patients were identified, of whom 29 (81%) presented with a liver mass at initial diagnosis and 17 (47%) received second-line chemotherapy before liver resection. Teratoma was found in 8 (22%) and 5 (14%) of PC-RPLND and liver resection specimens, respectively. Viable GCT was found in 5 (14%) and 4 (11%) of PC-RPLND and liver resection specimens, respectively. Histologic discordance was observed in 4 of 19 patients (21%; 95% confidence interval [CI] 6.1%-46%); in all cases, liver resection specimens contained teratoma or viable GCT while PC-RPLND revealed only fibrosis or necrosis. At 3 years after surgical intervention, the Kaplan-Meier estimated probability of cancer-specific survival was 75% (95% CI 55%-85%) and the probability of progression-free survival was 75% (95% CI 56%-87%)., Conclusion: In this contemporary cohort, clinically significant discordance was observed between the histology of metastatic liver masses and that of retroperitoneal lymph nodes. The benefit of postchemotherapy liver mass resection for patients with advanced nonseminomatous GCT is supported by favorable survival outcomes. Until more reliable predictors of postchemotherapy histology exist, complete surgical resection of all sites of residual disease should be performed whenever feasible., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background MLN0128 is a first-in-class, dual mTOR inhibitor with potential to outperform standard rapalogs through inhibition of TORC1 and TORC2. This phase II study was designed to assess antitumor activity of MLN0128 in metastatic castration-resistant prostate cancer (mCRPC). Methods Eligible patients had mCRPC previously treated with abiraterone acetate and/or enzalutamide. Five patients started MLN0128 at 5 mg once daily, subsequently dose reduced to 4 mg because of toxicity. Four subsequent patients started MLN0128 at 4 mg daily. Primary endpoint was progression-free survival at 6 months. Results Nine patients were enrolled and median time on treatment was 11 weeks (range: 3-30). Best response was stable disease. All patients had a rise in PSA on treatment, with a median 159% increase from baseline (range: 12-620%). Median baseline circulating tumor cell count was 1 cell/mL (range: 0-40); none had a decrease in cell count posttreatment. Grade ≤ 2 adverse events included fatigue, anorexia, and rash. The most common serious adverse events were grade 3 dyspnea and maculopapular rash. Eight patients discontinued treatment early because of radiographic progression (n = 1), grade 3 toxicity (n = 5), or investigator discretion (n = 2). Four patients had immediate PSA decline following drug discontinuation, suggesting MLN0128 could cause compensatory increase of androgen receptor (AR) activity. Correlative studies of pretreatment and posttreatment biopsy specimens revealed limited inhibition of AKT phosphorylation, 4EBP1 phosphorylation, and eIF4E activity. Conclusions Clinical efficacy of MLN0128 in mCRPC was limited likely due to dose reductions secondary to toxicity, PSA kinetics suggesting AR activation resulting from mTOR inhibition, and poor inhibition of mTOR signaling targets.

Objective: To determine the pathologic findings and clinical outcome of patients with pure embryonal carcinoma (EC) of the testis who were diagnosed with testis cancer from January 1989 to January 2013 who underwent an orchiectomy, cisplatin-based chemotherapy and a postchemotherapy retroperitoneal lymph node dissection (PC-RPLND)., Methods: We compared those patients with 100% EC with those with mixed nonseminomatous germ cell tumor pathology who underwent a PC-RPLND., Results: Of 1105 patients who underwent a PC-RPLND, 145 had pure EC. Twenty-six percent of patients presented with metastatic disease outside the retroperitoneum. Patients with mixed histologies tended to have worse International Germ Cell Cancer Collaborative Group risk compared to those with EC at orchiectomy (P = .037). Histology at PC-RPLND revealed fibrosis or necrosis in 76%, mature teratoma in 19% and viable cancer in 4%. Over one-third of the patients had a residual mass of <1 cm prior to RPLND; of whom 15% harbored mature teratoma in PC-RPLND histology. The Kaplan-Meier estimated probability of recurrence at 5 years of follow-up was 3.1% (95% CI 1.2%, 8.0%) for EC histology, 7.3% lower than mixed histology. For cancer-specific mortality, the Kaplan-Meier estimated probability at 5 years was 4.6% (95% CI 3.3%, 6.3%) and 1.7% (95% CI 0.4%, 6.8%) for mixed and pure EC histologies, respectively., Conclusion: Approximately 20% of patients with pure EC had teratoma at PC-RPLND. We have shown that those with a maximum node size of <1 cm should not be precluded from RPLND., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of PTEN loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K-Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA-PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging., (© 2018 Kaittanis et al.)

A multigenic locus at 3p13-14, spanning FOXP1 to SHQ1, is commonly deleted in prostate cancer and lost broadly in a range of cancers but has unknown significance to oncogenesis or prognosis. Here, we report that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate oncogenesis and that loss of component genes correlates with prostate, breast, and head and neck cancer recurrence. We demonstrate that Foxp1-Shq1 deletion accelerates prostate tumorigenesis in mice in combination with Pten loss, consistent with the association of FOXP1-SHQ1 and PTEN loss observed in human cancers. Tumors with combined Foxp1-Shq1 and Pten deletion show increased proliferation and anaplastic dedifferentiation, as well as mTORC1 hyperactivation with reduced Akt phosphorylation. Foxp1-Shq1 deletion restores expression of AR target genes repressed in tumors with Pten loss, circumventing PI3K-mediated repression of the androgen axis. Moreover, FOXP1-SHQ1 deletion has prognostic relevance, with cancer recurrence associated with combined loss of PTEN and FOXP1-SHQ1 genes.

Objective: To describe clinical management and outcomes of a cohort of patients with malignant mesothelioma of the tunica vaginalis testis (MMTVT) who received treatments beyond radical orchiectomy., Methods: Patients with confirmed MMTVT at a single tertiary care institution were identified. Treatments, pathologic outcomes, and survival were recorded. Prognostic variables associated with survival were analyzed with a Cox proportional hazards model and Kaplan-Meier curves., Results: Overall, 15 patients were included. Initial presentation was a scrotal mass in 7 of 15 (47%) and hydrocele in 5 of 15 (33%) patients. Clinical staging revealed enlarged nodes in 5 of 15 (33%) patients. Radical orchiectomy was the initial treatment in 5 of 15 (33%) patients. Positive surgical margins were found in 6 of 14 (43%) radical orchiectomies and were associated with worse survival (P = .007). The most frequent histologic subtype was epithelioid, associated with better survival (P = .048). Additional surgeries were performed on 12 of 15 (80%) patients. Pathologic examination revealed MMTVT in 6 of 12 (50%) hemiscrotectomies, 7 of 8 (88%) retroperitoneal lymph node dissections, 1 of 7 (14%) pelvic lymph node dissections, and 10 of 10 (100%) groin dissections. Five patients received adjuvant chemotherapy. Two also received adjuvant radiation therapy. Three patients with lymph node involvement remain no evidence of disease over 6 years after diagnosis. After a median follow-up of 3.5 years (interquartile range: 1.2-7.2), 5 patients have died, all of MMTVT; the median overall survival has not been reached. Common sites of relapse were lungs (5 of 7) and groin (3 of 7)., Conclusion: The pattern of metastatic spread of MMTVT is predominantly lymphatic. Nodes in the retroperitoneum and the groin are commonly involved. Prognosis is poor, but there may be a role for aggressive surgical resection including hemiscrotectomy, and inguinal and retroperitoneal lymph nodes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To characterize the incidence, presentation, management, and relapse of a large population of bilateral testicular germ cell tumors (TGCT) from a single institution., Patients and Methods: We identified bilateral TGCT diagnosed between January 1989 and February 2014. We categorized synchronous and metachronous TGCT, noting time between first and second TGCT, histology (seminoma vs nonseminoma [NSGCT]), stage, and treatments. Kaplan-Meier survival estimates characterized relapse., Results: Of 5132 patients with TGCT, 128 (2.5%) had bilateral TGCT. Bilateral TGCT increased over time-1.7% in 1989-1994 up to 3.8% in 2010 to February 2014. The 35 (27%) synchronous cases of TGCT had 20 (57%) concordant seminoma, 5 (14%) concordant NSGCT, and 10 (29%) discordant NSGCT. The 93 (73%) metachronous cases had median time interval to second TGCT of 73 months (range: 5 months-28.6 years). Compared with first TGCT, 39 (42%) had discordant histology, 29 (31%) had concordant seminoma, and 25 (27%) had concordant NSGCT. Stage at first tumor was statistically similar to second TGCT (second stage I, II, II in 69%, 22%, 10%). Increasing duration between first and second TGCT was not associated with higher stage (II or III) at second TGCT (P = .09). Treatment at first tumor was not associated with stage at second tumor. Relapse following bilateral diagnosis was 16.8% (95% confidence interval 10.5%-26.2%) at 5 years., Conclusion: Incidence of bilateral TGCT increased with >25% of metachronous TGCT presenting ≥10 years after first TGCT; possible causes include increased survivorship and referral bias. Stage was statistically similar at first and second tumor; stage at second tumor was not associated with time interval between tumors or prior treatment modality at first tumor., (Published by Elsevier Inc.)

Purpose: Fibrosis accounts for approximately 50% of histological findings at post-chemotherapy retroperitoneal lymph node dissection, and is associated with reported relapse rates of 10% to 15%. We characterized patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection and identified predictors of adverse outcomes in this group., Materials and Methods: We reviewed the medical records of men who underwent post-chemotherapy retroperitoneal lymph node dissection between 1989 and 2013 with histological findings of necrosis/fibrosis. With few exceptions post-chemotherapy retroperitoneal lymph node dissection after 1999 was performed with a bilateral template. Clinical, pathological and treatment related data were reported. Cox regression models were built to identify predictors of disease recurrence., Results: The study cohort included 598 men with a median age of 32 years (IQR 25-38). Most cases (397 of 547, 73%) were classified as IGCCCG good risk, with no significant differences in risk classification before and after 1999 (p=0.55). Median followup was 7.3 years (IQR 3.2-12.3). The 5-year recurrence-free and overall survival rates were 94% and 96%, respectively. Overall 36 patients had disease recurrence, most of which was distant or outside the retroperitoneal lymph node dissection template. Procedures performed after 1999 and the presence of embryonal cell carcinoma on primary histology were associated with improved recurrence-free survival on multivariate analysis (p <0.01)., Conclusions: Disease recurrence in patients with fibrosis at post-chemotherapy retroperitoneal lymph node dissection is an uncommon yet significant event, which is less likely to occur in patients treated after 1999 and in those with embryonal carcinoma on primary histology., Competing Interests: and Disclosure Statement All authors have nothing to disclose., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the pathologic findings and clinical outcome data for patients undergoing pelvic lymph node dissection (PLND) in the course of management of testicular germ cell tumors at Memorial Sloan Kettering Cancer Center (MSKCC)., Patients and Methods: Following institutional review board approval, data on 2186 patients who underwent retroperitoneal lymph node dissection (RPLND) at MSKCC between 1989 and 2011 were retrospectively reviewed. Of these 2186 patients, we analyzed data for 44 patients (2%) who underwent PLND at the time of RPLND., Results: PLND was performed in 14/44 (31%) patients at time of primary RPLND (P-RPLND), and in 21/44(48%) patients at time of postchemotherapy RPLND (PC-RPLND), usually for suspicious radiologic or intraoperative findings, whereas 9/44 (21%) underwent PLND for treatment of relapse. Positive pelvic findings on imaging included pelvic disease ≤5 cm in 17/44 (39%) patients and >5 cm in 11/44 (25%) patients (median size = 4 cm). At the time of PC-RPLND, alpha-fetoprotein and beta human chorionic gonadotropin were elevated in 6/21 (29%) and 4/21 (19%) patients, respectively. Histology revealed teratoma in 15/44 (34%) and viable tumor in 5/44 (11%) patients. At a median follow-up of 46 months, 40/44 (91%) patients were living without disease, 3/44 (7%) were living with disease (1 after PC-RPLND and 2 after relapse), and 1/44 (2%) died of other causes., Conclusion: PLND was performed infrequently in our series of patients who underwent RPLND for testis cancer. Teratoma was the dominant tumor histology in the resected tissue., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In this issue of Cancer Cell, Lee and colleagues (2016) define the biologic role of MYCN in promoting prostate tumorigenesis and development of a neuroendocrine phenotype. This has important implications for the clinical management of neuroendocrine prostate cancer as Aurora A kinase inhibitors promoting N-Myc destabilization progress in the clinic., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Patients with persistently elevated serum tumor markers should be monitored for marker kinetics and evaluated for nonviable cancer causes of marker elevation. Desperation postchemotherapy retroperitoneal lymph node dissection is performed in select patients following second-line chemotherapy. Adjuvant postoperative chemotherapy is not indicated in patients following second-line chemotherapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Germ cell tumors of the testis have an overall survival rate greater than 90% as a result of a successful multidisciplinary approach to management. Late relapse affects a subset of patients however, and tends to be chemorefractory and the overall prognosis is poor. Surgery is the mainstay in management of late relapse but salvage chemotherapy can be successful. In this review, the clinical presentation and detection of late relapse, clinical outcomes, and predictors of survival in late relapse and the importance of a multidisciplinary treatment approach for successful management of late relapse are discussed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members, such as ERG, ETV1, ETV4, and ETV5, are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here, we show that ETS family members, such as ERG and ETV1, directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell-cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia into prostatic invasive carcinoma in Pten(+) (/-) mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications., Significance: Genetic translocation and aberrant expression of ETS family members is a common event in different types of human tumors. Here, we show that through the transcriptional repression of CHK1, ETS factors may favor DNA damage accumulation and consequent genetic instability in proliferating cells. Importantly, our findings provide a rationale for testing DNA replication inhibitor agents in ETS-positive TP53-proficient tumors., (©2015 American Association for Cancer Research.)

Purpose: Patients with good risk nonseminomatous germ cell tumors received induction chemotherapy with 4 cycles of etoposide and cisplatin (EPx4) or 3 cycles of bleomycin, etoposide and cisplatin (BEPx3). We report the histological results at post-chemotherapy retroperitoneal lymph node dissection after induction chemotherapy in patients treated with etoposide and cisplatin or bleomycin, etoposide and cisplatin for good risk nonseminomatous germ cell tumors., Materials and Methods: Post-chemotherapy retroperitoneal lymph node dissection was performed in 579 patients after induction chemotherapy. Of these patients 505 were treated with EPx4 and 74 were treated with BEPx3 or BEPx4. Clinical and pathological features are reported., Results: No difference in the frequency of viable residual cancer was observed with bleomycin, etoposide and cisplatin vs etoposide and cisplatin (5% vs 6%, respectively, p=not significant). Teratoma was more prevalent in the bleomycin, etoposide and cisplatin group vs etoposide and cisplatin group (57% vs 34%, respectively, p <0.001). On multivariate analysis patients who received induction bleomycin, etoposide and cisplatin had a twofold greater risk of harboring teratoma at post-chemotherapy retroperitoneal lymph node dissection (OR 2.0; 95% CI 1.0, 4.0; p=0.04). When excluding patients from analysis who received BEPx4, those who received BEPx3 still had a 3.7-fold increased risk of teratoma in the retroperitoneum (OR 3.7; 95% CI 1.5, 8.9; p=0.004). Relapse-free and disease specific survival was not different between the 2 regimens., Conclusions: Viable cancer was equally uncommon after treatment with both regimens. Overall, relapse-free and disease specific survival did not differ between the groups. The discrepancy between regimens in the frequency of teratoma is not explained but may be due to an unrecognized selection bias rather than an effect of the regimen., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

In PTEN-mutated tumors, we show that PI3Kα activity is suppressed and PI3K signaling is driven by PI3Kβ. A selective inhibitor of PI3Kβ inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3Kβ only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3Kα and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3Kα and PI3Kβ. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Copy-number alterations (CNA) are among the most common molecular events in human prostate cancer genomes and are associated with worse prognosis. Identification of the oncogenic drivers within these CNAs is challenging due to the broad nature of these genomic gains or losses which can include large numbers of genes within a given region. Here, we profiled the genomes of four genetically engineered mouse prostate cancer models that reflect oncogenic events common in human prostate tumors, with the goal of integrating these data with human prostate cancer datasets to identify shared molecular events. Met was amplified in 67% of prostate tumors from Pten p53 prostate conditional null mice and in approximately 30% of metastatic human prostate cancer specimens, often in association with loss of PTEN and TP53. In murine tumors with Met amplification, Met copy-number gain and expression was present in some cells but not others, revealing intratumoral heterogeneity. Forced MET overexpression in non-MET-amplified prostate tumor cells activated PI3K and MAPK signaling and promoted cell proliferation and tumor growth, whereas MET kinase inhibition selectively impaired the growth of tumors with Met amplification. However, the impact of MET inhibitor therapy was compromised by the persistent growth of non-Met-amplified cells within Met-amplified tumors. These findings establish the importance of MET in prostate cancer progression but reveal potential limitations in the clinical use of MET inhibitors in late-stage prostate cancer., (©2014 American Association for Cancer Research.)

Cancer is responsible for many deaths and is a major source of healthcare expenditures. The identification of new, non-invasive biomarkers might allow improvement of the direct diagnostic or prognostic ability of already available tools. Here, we took the innovative approach of interrogating the activity of exopeptidases in the serum of cancer patients with the aim of establishing a distinction based on enzymatic function, instead of simple protein levels, as a means to biomarker discovery. We first analyzed two well-characterized mouse models of prostate cancer, each with a distinct genetic lesion, and established that broad exopeptidase and targeted aminopeptidase activity tests reveal proteolytic changes associated with tumor development. We also describe new peptide-based freeze-frame reagents uniquely suited to probe the altered balance of selected aminopeptidases, as opposed to the full array of exopeptidases, and/or their modulators in patient serum or plasma. One particular proteolytic activity was impaired in animals with aggressive disease relative to cancer-free littermates. We identified the protease in question as dipeptidyl peptidase 4 (DPP4) by analyzing selected knockout mice and evaluating the effect of specific inhibitors. DPP4 activity was also reduced in the sera of patients with metastatic prostate cancer relative to patients with localized disease or healthy controls. However, no significant differences in DPP4 serum levels were observed, which established the loss of activity as the result of impaired enzymatic function. Biochemical analysis indicated that reduced activity was the result not of post-translational modifications or allosteric changes, but instead of a low-molecular-weight inhibitor. After we adjusted for age and total prostate-specific antigen, reduced DPP4 activity remained a significant predictor of cancer status. The results of this proof-of-principle study suggest that DPP4 activity might be a potential blood-based indicator of the presence of metastatic cancer of prostatic origin, either by itself or, more likely, as a means to improve the sensitivity and specificity of existing markers., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

SLUG represses E-cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19(Arf) (p14(ARF) in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19(Arf) reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14(ARF) stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14(ARF) are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

Androgen receptor (AR) signaling plays a critical role in prostate cancer cell proliferation, survival, and differentiation. Therapeutic strategies targeting the androgen receptor have been developed for the treatment of metastatic hormone-naïve prostate cancer; however, despite effective targeting recent studies have demonstrated that during progression to a castrate-resistant phenotype there is restoration of AR target gene expression. On the basis of this observation, second-generation therapeutics have been developed to target AR in the castrate-resistant setting resulting in a survival benefit. In this review we will discuss the mechanisms promoting AR signaling and the development of second-generation therapeutics targeting AR in castrate-resistant prostate cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: We evaluated pathological variables of testicular sex cord-stromal tumors, management options and clinical outcomes., Materials and Methods: We retrospectively reviewed the records of 48 patients with testicular sex cord-stromal tumors treated at Memorial Sloan-Kettering Cancer Center between 1997 and 2012. Clinical outcomes were compared based on treatment and previously described pathological factors associated with metastatic potential., Results: Of the 48 patients 37 underwent surveillance without retroperitoneal lymph node dissection, including 34 with no high risk feature and 3 with 1. Median followup was 14.5 months (IQR 6.9-32.5). No patient experienced recurrence. Retroperitoneal lymph node dissection was performed in 11 patients, including 6 with clinical stage I disease and 2 or more high risk features who underwent early dissection, 2 with clinical stage IIa disease at diagnosis who underwent early dissection and 3 with clinical stage I disease and 2 or more high risk features who were observed elsewhere but referred to our institution due to retroperitoneal disease. Six patients with clinical stage I disease underwent early dissection, 4 had no evidence of disease at a median followup of 6.6 years and 2 experienced recurrence and died of disease. Neither of the 2 patients with IIa disease at diagnosis experienced relapse. All 3 patients with delayed dissection experienced relapse and 1 died of disease., Conclusions: Patients with testicular sex cord-stromal tumors and 1 or no high risk feature can be safely observed without retroperitoneal lymph node dissection but longer followup is needed. Given the lack of effective alternative treatments, early retroperitoneal lymph node dissection may be beneficial in those with 2 or more high risk features, or clinical stage IIa disease., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.

The receptor tyrosine kinase inhibitor cabozantinib (XL184, BMS-907351 Cometriq) has displayed impressive clinical activity against several indications, culminating in its recent approval for medullary thyroid cancer. Among malignancies with tropism for the bone (prostate, breast), one striking feature of early clinical reports about this drug has been the rapid and complete resolution of bone scans, a phenomenon almost never observed even among therapies already shown to confer survival benefit. In castration-resistant prostate cancer, not all conventional response indicators change as dramatically posttreatment, raising the possibility that cabozantinib may impair the ability of bone-seeking radionuclides to integrate within the remodeling bone. To test this hypothesis, we surgically induced bone remodeling via physical insult in non-tumor-bearing mice and performed 18F-sodium fluoride (18F-NaF) positron emission tomographic (PET) and technetium 99m-methylene diphosphonate (99mTc-MDP) single-photon emission computed tomographic (SPECT) scans pre- and posttreatment with cabozantinib and related inhibitors. A consistent reduction in the accumulation of either radiotracer at the site of bone remodeling was observed in animals treated with cabozantinib. Given that cabozantinib is known to inhibit several receptor tyrosine kinases, we drugged animals with various permutations of more selective inhibitors to attempt to refine the molecular basis of bone scan resolution. Neither the vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib, the MET inhibitor crizotinib, nor the combination was capable of inhibiting 18F-NaF accumulation at known bioactive doses. In summary, although the mechanism by which cabozantinib suppresses radionuclide incorporation into foci undergoing bone remodeling remains unknown, that this phenomenon occurs in tumor-naïve models indicates that caution should be exercised in interpreting the clinical significance of this event.

Objective: To evaluate, in detail, the histopathologic features of metastatic testicular germ cell tumors to retroperitoneal lymph nodes treated with primary retroperitoneal lymph node dissection (RPLND) and correlate the findings with patients' outcomes., Materials and Methods: We studied 183 patients with documented pathologic stage II disease with or without elevated serum tumor markers, selected from 453 patients who underwent primary RPLND at our institution from 1989 to 2002. Tumor type(s), size and extent of disease, and amount of tumor necrosis were assessed and correlated with outcome., Results: Embryonal carcinoma was the most common tumor type, present as the only component in 99 cases (54%) and the predominant tumor type (>50%) in 142 (78%). The number of positive lymph nodes ranged from 1 to 40 from a total of 2-80 lymph nodes examined (median, 28). Extranodal extension (ENE) was identified in 120 cases (66%). Among 73 patients followed up expectantly and with normal serum tumor markers, 19 experienced relapse, the probability of which was higher in patients with more positive nodes, larger metastases, and presence of ENE. However, none of these differences was statistically significant (all P >.2). The predominance of embryonal carcinoma and the presence of tumor necrosis were not significantly associated with outcome., Conclusion: In this cohort, most patients treated with primary RPLND and with positive lymph nodes also had ENE. We did not identify any variables to be significantly associated with relapse after RPLND in patients managed expectantly. Additional studies with more patients are needed to validate our findings., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining., Significance: We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer., (©2013 AACR.)

Androgen receptor (AR) signaling plays a critical role in the physiology of the prostate and thus the biology of prostate cancer. Agents targeting the AR pathway have been the mainstay of treatment for patients with locally advanced and metastatic prostate cancer. In this review we will cover the role of androgen signaling in prostate cancer mouse models with an emphasis on how tumorigenic molecular alterations impact response to AR pathway inhibition and downstream AR target gene expression. Both of these concepts have meaningful implications for the management of patients with prostate cancer.

Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

Unlabelled: Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The effect of advancing age on the clinicopathological outcomes of men with germ cell testicular cancers remains uncertain. Through the review and comparison of the present large cohort of men with testis cancer, we report on our experience in men aged ≥50 years. Our results showed similar clinical and pathological characteristics, and survival outcomes that compare favourably with those of men aged <50 years., Objective: To determine the impact of age on clinicopathological findings and disease recurrence in men with nonseminomatous germ cell tumour (NSGCT) undergoing retroperitoneal lymph node dissection (RPLND)., Patients and Methods: We identified 1246 patients with NSGCT who underwent either primary or post-chemotherapy-RPLND (PC-RPLND) between 1989 and 2006 from our prospective testis cancer database. • Perioperative characteristics were compared among men aged < or ≥50 years. • Multivariable models were used to evaluate the association of age with disease-free survival, controlling for established clinical and pathological features., Results: Of 514 men undergoing primary and 732 men undergoing PC-RPLND, 12 (2.3%) and 23 (3.1%) were aged ≥50 years, respectively. • There were no significant differences between men aged < or ≥50 years for perioperative clinicopathological characteristics, with the exception of pre-RPLND CT nodal size. • The pathological distributions at primary RPLND were similar in men aged < or ≥50 years. After PC-RPLND, there were no differences in RPLND histology, number of lymph nodes resected, estimated blood loss, hospital stay, or perioperative complication rate. • Age at surgery was not a significant predictor of disease recurrence when subjected to a multivariable analysis., Conclusions: Our data suggests that age at RPLND does not predict for disease recurrence and men aged ≥50 years had similar pre- and postoperative characteristics to those aged <50 years. • We conclude that RPLND can be safely performed in men aged ≥50 years and these patients should be offered optimal treatment regimens for NSGCT as directed according to established guidelines., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Objective: To compare the survival outcomes of patients with advanced nonseminoma and extraretroperitoneal (ERP) disease observed for a clinical complete response (CCR) with those demonstrating a pathologic complete response (PCR)., Methods: From 1989 to 2003, 237 patients with clinical Stage III nonseminoma underwent induction chemotherapy followed by retroperitoneal lymph node dissection. After chemotherapy, 107 demonstrated a CCR to treatment at the ERP disease site. Of the remaining 130 patients with radiographic evidence of residual ERP disease, 86 (66%) had fibrosis only on pathologic review (ie, PCR). The probability of progression-free and disease-specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression analysis was used to determine the prognostic significance of risk factors for progression and survival., Results: The median follow-up was similar for both CCR and PCR patients (44.5 and 50.7 months, respectively). Overall, the 5-year probability of freedom from progression (93% vs 72%, respectively; P = .0005) and disease-specific survival (96% vs 87%, respectively; P = .08) rates were far better for men with a PCR. The predictors of disease progression included residual retroperitoneal nodal size after chemotherapy (P = .05), and resection of the residual disease at the ERP site was protective (P = .02)., Conclusion: A CCR at the ERP disease site is associated with a greater likelihood of relapse compared with a PCR, underscoring the limitations of radiographic imaging after chemotherapy in detecting microscopic residual disease and need for rigorous monitoring of patients observed after a CCR. Furthermore, until more accurate clinical predictors of ERP histologic features are identified, we advocate for complete surgical resection of all sites of residual disease, when feasible., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To determine whether body mass index (BMI) is associated with lymph node counts in patients treated with a primary retroperitoneal lymph node dissection (RPLND). Lymph node counts are a proposed measure of quality assurance for numerous malignancies. Investigation of patient factors associated with lymph node counts are lacking., Methods: Using the Memorial Sloan-Kettering Testis Cancer Database, we identified 255 patients treated with a primary RPLND for nonseminomatous germ cell tumors (NSGCT) from 1999-2008. The associations between BMI and node counts were evaluated using linear regression models in univariate and multivariable models adjusting for features reported to predict higher node counts (year of surgery, stage, and surgeon volume)., Results: Median BMI (IQR) was 26.1 (23.4-28.7) and median (IQR) total node count was 38 (27-53). Median total node count for patients with a BMI<25, 25 to 29, and ≥30 was 35, 42, and 44 nodes, respectively. In a univariate analysis, higher BMI was significantly associated with higher total node counts (coefficient 0.7 nodes for each 1-U increase in BMI; P=.026). Features associated with higher node count on multivariate analysis included high-volume surgeon (P=.047), pathologic stage (P=.017), more recent year of surgery (P<.001), and higher BMI (P=.009)., Conclusion: Our results suggest for the first time that BMI is independently associated with higher lymph node counts during a lymph node dissection. If confirmed by others, these results may be important when using lymph node counts as a surrogate for adequacy of a lymph node dissection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Integration of platinum-based chemotherapy and surgical resection of residual masses is essential in the management of advanced nonseminomatous germ cell tumors (NSGCT). We reviewed our institutional experience in patients undergoing resection of extraretroperitoneal (ERP) residual masses after chemotherapy to assess its impact on cancer progression and survival., Methods: Between 1989 and 2003, 532 patients with advanced NSGCT underwent postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) with a median follow-up of 41 months. Survival probabilities were estimated by the Kaplan-Meier method. Cox proportional hazards regression analysis was used to determine the prognostic significance of risk factors for progression and survival., Results: Of 532 patients, 402 (76%) underwent PC-RPLND alone, and 130 (24%) underwent resection of ERP residual disease concurrently or in a staged fashion within 6 weeks. Concordance between retroperitoneal (RP) and ERP sites of disease was 83% in the presence of fibrosis, 42% for teratoma, and 47% for viable NSGCT. Overall, 34% of patients undergoing resection of ERP residual disease had either teratoma or viable disease on final pathology. Five-year probability of freedom from progression was 74% (95% CI 65%, 82%) and disease-specific survival was 84% (95% CI 75%, 89%). On multivariable analysis the histologic findings at the ERP site were significant predictors of disease progression, independent of the RP findings., Conclusion: Our data suggest that teratoma or viable NSGCT is present in approximately one-third of patients undergoing resection of residual ERP disease. The presence of residual ERP teratoma and viable NSGCT predicts for cancer progression independent of RP histology., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To report the retroperitoneal histologic findings from a contemporary series of patients with pure seminoma at orchiectomy with an elevated serum α-fetoprotein (AFP) level. These patients underwent treatment on the assumption that the lesion was nonseminomatous germ cell tumor (NSGCT)., Methods: We identified 22 patients from 1989 to 2009 with pure seminoma diagnosed at orchiectomy with an elevated serum AFP level (>15 ng/mL) either before or after orchiectomy. The retroperitoneal histologic and relapse data are reported., Results: The median preorchiectomy and prechemotherapy serum AFP level was 248 ng/mL (interquartile range 48-4693) and 279 ng/mL (interquartile range 66-5311), respectively. The percentage of patients with clinical Stage I, II, and III disease was 5%, 50%, and 45%, respectively. The percentage of patients with a good, intermediate, and poor risk status according to the International Germ Cell Cancer Collaborative Group was 32%, 32%, and 36%, respectively. Of the 22 patients, 21 underwent induction chemotherapy followed by retroperitoneal lymph node dissection. Overall, 67% of patients had NSGCT elements in the retroperitoneum. The histologic findings were pure teratoma in 38%, malignant transformation in 14%, and viable NSGCT in 14%. Also, 59% had some component of teratoma in the retroperitoneum. Only 1 patient (5%) had any seminoma in the retroperitoneum, but this patient also had retroperitoneal teratoma. Of the 22 patients, 7 developed a relapse and received salvage chemotherapy. The actuarial relapse-free survival rate at 5 and 10 years was 76% and 61%, respectively, reflecting the high percentage of patients with Stage II-III disease., Conclusions: Pure seminoma at orchiectomy with an elevated serum AFP level portends a high likelihood of NSGCT elements in the retroperitoneum., (Copyright © 2011. Published by Elsevier Inc.)

Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)