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.
View Article and Find Full Text PDFPurpose: 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.
To gain insight into how ERG translocations cause prostate cancer, we performed single cell transcriptional profiling of an autochthonous mouse model at an early stage of disease initiation. Despite broad expression of ERG in all prostate epithelial cells, proliferation was enriched in a small, stem-like population with mixed-luminal basal identity (called intermediate cells). Through a series of lineage tracing and primary prostate tissue transplantation experiments, we find that tumor initiating activity resides in a subpopulation of basal cells that co-express the luminal genes and (called Basal) but not in the larger population of classical + luminal cells.
View Article and Find Full Text PDFPrevious 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.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
August 2021
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.
View Article and Find Full Text PDFBackground: 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.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFDespite 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.
View Article and Find Full Text PDFPurpose: 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.
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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFOn the basis of our previous work defining the molecular rationale for combined targeting of the PI3K and AR pathways in 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 loss prostate cancers are significantly enriched for genomic rearrangements, we evaluated how the aberrant expression of ERG may impact response to PI3K/AR-targeted therapy.
View Article and Find Full Text PDFObjective: 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.
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.
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.
View Article and Find Full Text PDFObjective: 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.
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.
View Article and Find Full Text PDFA 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.
View Article and Find Full Text PDFObjective: 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.
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.
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.
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.
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.
View Article and Find Full Text PDFGerm 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.
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