A phase II trial of apalutamide for intermediate-risk prostate cancer and molecular correlates.

OBJECTIVES: To determine whether 6 months of preoperative apalutamide for intermediate-risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. PATIENTS AND METHODS: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b-c or prostate-specific antigen level of 10-20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single-arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post-apalutamide RP specimens, and assessed for associations with clinical outcomes. RESULTS: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3-year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3-years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. CONCLUSIONS: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre-specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high-risk PCa.

A west African ancestry-associated SNP on 8q24 predicts a positive biopsy in African American men with suspected prostate cancer following PSA screening.

BACKGROUND: African American (AA) men have the highest incidence and mortality rates of prostate cancer (PCa) among all racial groups in the United States. While race is a social construct, for AA men, this overlaps with west African ancestry. Many of the PCa susceptibility variants exhibit distinct allele frequencies and risk estimates across different races and contribute substantially to the large disparities of PCa incidence among races. We previously reported that a single-nucleotide polymorphism (SNP) in 8q24, rs7824364, was strongly associated with west African ancestry and increased risks of PCa in both AA and Puerto Rican men. In this study, we determined whether this SNP can predict biopsy positivity and detection of clinically significant disease (Gleason score [GS] ≥ 7) in a cohort of AA men with suspected PCa. METHODS: SNP rs7824364 was genotyped in 199 AA men with elevated total prostate-specific antigen (PSA) (>2.5 ng/mL) or abnormal digital rectal exam (DRE) and the associations of different genotypes with biopsy positivity and clinically significant disease were analyzed. RESULTS: The variant allele carriers were significantly over-represented in the biopsy-positive group compared to the biopsy-negative group (44% vs. 25.7%, p = 0.011). In the multivariate logistic regression analyses, variant allele carriers were at a more than a twofold increased risk of a positive biopsy (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.06-4.32). Moreover, the variant allele was a predictor (OR = 2.26, 95% CI = 1.06-4.84) of a positive biopsy in the subgroup of patients with PSA < 10 ng/mL and normal DRE. The variant allele carriers were also more prevalent in cases with GS ≥ 7 compared to cases with GS < 7 and benign biopsy. CONCLUSIONS: This study demonstrated that the west African ancestry-specific SNP rs7824364 on 8q24 independently predicted a positive prostate biopsy in AA men who were candidates for prostate biopsy subsequent to PCa screening.

The association of body mass index with tumor aggression among men undergoing radical prostatectomy.

OBJECTIVES: To evaluate the association of preoperative body mass index (BMI) on adverse pathology in peripheral (PZ) and transition zone (TZ) tumors at time of prostatectomy for localized prostate cancer. METHODS: Clinical and pathologic characteristics were obtained from up to 100 consecutive prostatectomy patients from 10 prostate surgeons. BMI groups included normal (18.5-24.9), overweight (25-29.9) and obese (> 29.9). "Aggressive" pathology was defined as the presence of Grade Group (GG) 3 or higher and/or pT3a or higher. Pathologic characteristics were evaluated for association with BMI using univariate analyses. Our primary outcome was the association of BMI with adverse pathology, which was assessed using logistic regression accounting for patient age. We hypothesized that obese BMI would be associated with aggressive TZ tumor. RESULTS: Among 923 patients, 140 (15%) were classified as "normal" BMI, 413 (45%) were "overweight", and 370 (40%) were "obese." 474 patients (51%) had aggressive PZ tumors while 102 (11%) had aggressive TZ tumors. "Obese" BMI was not associated with aggressive TZ tumor compared to normal weight. Increasing BMI group was associated with overall increased risk of aggressive PZ tumor (HR 1.56 [95CI 1.04-2.34]; P = 0.03). Among patients with GG1 or GG2, increasing BMI was associated with presence of pT3a or higher TZ tumor (P = 0.03). CONCLUSIONS: Increased BMI is associated with adverse pathology in PZ tumors. TZ adverse pathology risk may be increased among obese men with GG1 or GG2 disease, which has implications for future studies assessing behavioral change among men whose tumors are actively monitored.

Surgical Management and Considerations for Patients with Localized High-Risk Prostate Cancer.

OPINION STATEMENT: Localized high-risk (HR) prostate cancer (PCa) is a heterogenous disease state with a wide range of presentations and outcomes. Historically, non-surgical management with radiotherapy and androgen deprivation therapy was the treatment option of choice. However, surgical resection with radical prostatectomy (RP) and pelvic lymph node dissection (PLND) is increasingly utilized as a primary treatment modality for patients with HRPCa. Recent studies have demonstrated that surgery is an equivalent treatment option in select patients with the potential to avoid the side effects from androgen deprivation therapy and radiotherapy combined. Advances in imaging techniques and biomarkers have also improved staging and patient selection for surgical resection. Advances in robotic surgical technology grant surgeons various techniques to perform RP, even in patients with HR disease, which can reduce the morbidity of the procedure without sacrificing oncologic outcomes. Clinical trials are not only being performed to assess the safety and oncologic outcomes of these surgical techniques, but to also evaluate the role of surgical resection as a part of a multimodal treatment plan. Further research is needed to determine the ideal role of surgery to potentially provide a more personalized and tailored treatment plan for patients with localized HR PCa.

Longitudinal GFR trends after neoadjuvant chemotherapy prior to nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: Renal function dictates sequencing and eligibility for definitive therapy in upper tract urothelial carcinoma. We investigated longitudinal glomerular filtration rate (GFR) changes after neoadjuvant chemotherapy (NAC) and nephroureterectomy (RNU). MATERIALS AND METHODS: Patients treated with ≥3 cycles of chemotherapy prior to RNU for UTUC from 2000 to 2019 were included. GFR was calculated by CKD-Epi before chemotherapy, before RNU, 1 to 3 months, and 12 months post-RNU. Pathologic stage and overall survival were compared in those with stable GFR (+/-10% of baseline) to the rest of the cohort. RESULTS: One hundred and fifty-two patients received ≥3 cycles of NAC, with 121 (79%) receiving at least 1 cycle of cisplatin. Renal function dropped by mean of 22.3 ml/min/1.73 m2 from the beginning of chemotherapy to 1-year post-surgery. In patients receiving cisplatin, a mean decline of 26.2 ml/min/1.73 m2 was observed vs. 8.8 ml/min/1.73 m2 without cisplatin-based NAC (P < 0.01). GFR after RNU was unchanged between 3 and 12 months postoperatively. At 1 to 3 months after RNU, 19% of patients had GFR<30 ml/min/1.73m2. Improvement in GFR during NAC was associated with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049). CONCLUSIONS: In patients managed with NAC prior to RNU, renal function stabilizes at 1 to 3 months post-operatively and remains clinically similar for cisplatin or non-cisplatin-based therapy. Improvement in GFR during NAC was associated with higher pathologic stage and poorer survival, especially in those receiving non-cisplatin-based therapy, an observation that requires further investigation.

Contemporary outcomes following robotic prostatectomy for locally advanced and metastatic prostate cancer.

While radical prostatectomy (RP) plays a prominent role in the management of localized prostate cancer, its role in high risk or metastatic disease is less clear. Due to changes in prostate cancer screening patterns, particularly those made by the United States Preventive Services Task Force, data is suggesting increasing incidences of high risk and metastatic disease, underlying the importance of continued research in this area. While past approaches to management may have discouraged surgical intervention, more contemporary approaches have attempted to evaluate its effectiveness and utility. The purpose of this review is an updated discussion of the current literature regarding surgical approaches to high risk prostate cancer. The PubMed and Medline databases were queried for English language articles related to the surgical management of high-risk prostate adenocarcinoma. In this review, we examine the utility of surgery as a single or multimodal approach to management with patients with high risk, locally advanced, and metastatic prostate cancer. Outcomes measures are reviewed including data on survival and recurrence rates. Functional outcomes are an important consideration in prostate cancer management and while data is more limited, this review examines some of the key findings. Finally, a discussion regarding surgical complication rates and ongoing clinical trials is addressed. While surgery appears to be promising in this patient cohort, there remains significant heterogeneity in the data that ongoing trials may be able to address. At its current level of understanding, surgery should be considered as a potential tool in patient management, but may play a more prominent role in a multi-modality setting for optimal outcomes.

Predicting Adherent Perinephric Fat Using Preoperative Clinical and Radiological Factors in Patients Undergoing Partial Nephrectomy.

BACKGROUND: The decision to perform a partial nephrectomy (PN) relies largely upon the complexity of the renal mass and its surrounding anatomy. The presence of adherent perinephric fat (APF) can increase surgical complexity and extend operative times. The accurate prediction of APF may improve surgical planning and aid in decision making for the surgical approach. OBJECTIVE: We sought to develop and externally validate a score that predicts APF based on preoperative clinical and radiological prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed 495 consecutive patients who underwent open or minimally invasive PN. APF was defined as the presence of "dense," "adherent," or "sticky" perinephric fat at the time of dissection by the surgeon, and this did not require subcapsular dissection. Additionally, we analyzed an independent cohort of 285 patients for external validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A score model was developed using multivariate logistic regression analysis. Calibration of the fitted model was assessed graphically with a plot of the predicted versus the actual probability of APF, and discrimination was assessed by calculating the area under the receiver operating characteristic curve. RESULTS AND LIMITATIONS: Of the 495 patients, 95 (19%) had APF. Patients with APF had longer operative (p=0.02) and arterial clamp (p=0.01) times than non-APF patients. On multivariate analyses, diabetes mellitus (p=0.009), posterior perinephric fat thickness (p<0.001), and perinephric stranding (p<0.001) were predictors of encountering APF in PN. A risk score ranging from 0 to 4 was developed based on these three variables to predict APF. The scoring system demonstrated good discrimination of 0.82 and 0.84 for the development and external validation cohorts, respectively. CONCLUSIONS: The APF score can accurately predict the presence of APF in patients with a small renal mass who are planning to undergo PN. This score could aid in pre- and intraoperative planning and impact the surgical approach. PATIENT SUMMARY: The presence of "sticky" fat surrounding the kidney in patients undergoing partial nephrectomy has previously been linked to longer operative times, intraoperative complications, and surgical conversion. In our study, we found that this feature is more often presented in patients with diabetes mellitus, and thicker and more inflammatory fat on renal imaging. Based on these findings, we developed a risk score that can accurately predict this feature before surgery, in order to improve surgical planning and better counsel the patients.

18F-Fluciclovine Uptake in a Ureterocele.

A 60-year-old man with prostate adenocarcinoma status post radical prostatectomy and bilateral pelvic lymph node dissection referred for restaging F-fluciclovine PET/CT due to rising serum prostate-specific antigen levels (1.1 ng/mL at that time of imaging). PET/CT images were obtained from the proximal thighs to the vertex of the skull approximately 3 to 5 minutes after the IV administration of 347.8 MBq (9.4 mCi) of F-fluciclovine. PET/CT imaging demonstrated a focus of abnormally increased F-fluciclovine uptake at the right ureterovesical junction. Subsequent MRI of the pelvis revealed that this focus corresponded to a benign ureterocele.

The Effects of Neoadjuvant Axitinib on Anthropometric Parameters in Patients With Locally Advanced Non-metastatic Renal Cell Carcinoma.

OBJECTIVE: To examine the effect that neoadjuvant axitinib for the treatment of localized renal cell carcinoma has on body compartment composition. MATERIALS AND METHODS: The study was based on a single-institution, single-arm clinical trial that enrolled 24 patients with locally advanced non-metastatic biopsy-proven clear cell renal cell carcinoma. Patients received axitinib orally for up to 12 weeks. Computed tomography scans were completed before the start of treatment, after 7 weeks of treatment and at the completion of 12 weeks of treatment. Patients underwent nephrectomy after axitinib treatment. The primary outcome of the current study was change in body compartment composition. Secondary outcomes included development of new-onset sarcopenia and changes in body weight. RESULTS: A total of 23 patients had a complete set of imaging for evaluation, of which 19 (82.6%) lost weight. Median weight loss was 4.5 kg (P <.001). Seven patients (30.4%) had sarcopenia before treatment, with an additional 5 (21.7%) developing sarcopenia during treatment. Median decrease in skeletal muscle was 2.9 cm2/m2 (P <.001), visceral adipose tissue was 4.9 cm2/m2 (P = .132), and subcutaneous adipose tissue was 1.0 cm2/m2 (P = .043). Ten of the 16 patients (62.5%) without baseline sarcopenia achieved a partial response, whereas only 1 of the 7 patients (14.3%) with baseline pretreatment sarcopenia achieved a partial response (P = .069). CONCLUSION: Neoadjuvant axitinib resulted in a decrease in skeletal muscle and subcutaneous adipose tissue, as well as weight loss. Patients with baseline sarcopenia tended to have a lower response rate to neoadjuvant axitinib.

Cytoreductive nephrectomy for metastatic renal cell carcinoma.

The incidence of renal cell carcinoma is increasing, with up to one-third of patients presenting with metastatic disease. Combination therapy is used to prolong survival in patients with metastatic renal cell carcinoma, which carries a poor prognosis. Although two pivotal phase 3 trials have demonstrated the efficacy of immunotherapy after cytoreductive nephrectomy for metastatic disease, for now, targeted therapy has replaced immunotherapy as the preferred systemic treatment in these patients. Two ongoing phase 3 trials are evaluating the role of cytoreductive nephrectomy prior to targeted therapy. Proper patient selection is paramount in achieving successful outcomes.

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer.

BACKGROUND: The TMPRSS2-ERG gene fusion is detected in approximately half of primary prostate cancers (PCa) yet the prognostic significance remains unclear. We hypothesized that ERG promotes the expression of common genes in primary PCa and metastatic castration-resistant PCa (CRPC), with the objective of identifying ERG-associated pathways, which may promote the transition from primary PCa to CRPC. METHODS: We constructed tissue microarrays (TMA) from 127 radical prostatectomy specimens, 20 LuCaP patient-derived xenografts (PDX), and 152 CRPC metastases obtained immediately at time of death. Nuclear ERG was assessed by immunohistochemistry (IHC). To characterize the molecular features of ERG-expressing PCa, a subset of IHC confirmed ERG+ or ERG- specimens including 11 radical prostatectomies, 20 LuCaP PDXs, and 45 CRPC metastases underwent gene expression analysis. Genes were ranked based on expression in primary PCa and CRPC. Common genes of interest were targeted for IHC analysis and expression compared with biochemical recurrence (BCR) status. RESULTS: IHC revealed that 43% of primary PCa, 35% of the LuCaP PDXs, and 18% of the CRPC metastases were ERG+ (12 of 48 patients [25%] had at least one ERG+ metastasis). Based on gene expression data and previous literature, two proteins involved in calcium signaling (NCALD, CACNA1D), a protein involved in inflammation (HLA-DMB), CD3 positive immune cells, and a novel ERG-associated protein, DCLK1 were evaluated in primary PCa and CRPC metastases. In ERG+ primary PCa, a weak association was seen with NCALD and CACNA1D protein expression. HLA-DMB association with ERG was decreased and CD3 cell number association with ERG was changed from positive to negative in CRPC metastases compared to primary PCa. DCLK1 was upregulated at the protein level in unpaired ERG+ primary PCa and CRPC metastases (P = 0.0013 and P < 0.0001, respectively). In primary PCa, ERG status or expression of targeted proteins was not associated with BCR-free survival. However, for primary PCa, ERG+DCLK1+ patients exhibited shorter time to BCR (P = 0.06) compared with ERG+DCLK1- patients. CONCLUSIONS: This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression. We determined expression of DCLK1 correlates with ERG expression and may play a role in primary PCa progression to metastatic CPRC. Prostate 76:810-822, 2016. © 2016 Wiley Periodicals, Inc.

Limited Panniculectomy for Adult Buried Penis Repair.

Patients with buried or hidden penis may be unable to carry out normal hygiene, void with a directable urine stream, or be sexually active as a result of the condition. Although these patients are nearly always obese, weight loss often does not reverse the problem, as the mons pannus may remain after weight loss. Furthermore, associated penile skin changes such as lichen sclerosus or stenosis of the penile shaft skin are often irreversible. Treatment includes removal of the diseased shaft skin surrounding the penis, in combination with a limited panniculectomy. The authors present their technique for this procedure in a typical patient with buried penis that prevented him from voiding effectively.

The Role of Postchemotherapy Surgery in Germ Cell Tumors.

Retroperitoneal lymph node dissection after chemotherapy has a proved role in the staging and treatment of metastatic testicular cancer. Complete removal of all postchemotherapy residual masses in nonseminomatous germ cell tumor should be performed. Complete removal of positron emission tomography-avid masses greater than 3 cm in pure seminoma should be performed. Outcomes depend on patient selection and extent of surgery.

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer.

PURPOSE: The neuroendocrine phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the neuroendocrine phenotype in CRPC. EXPERIMENTAL DESIGN: Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by IHC in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole-genome microarrays. REST splicing was verified by PCR. RESULTS: Coexpression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR(+)/PSA(+) (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR(-)/PSA(-). By IHC, of the 71 metastases analyzed by whole-genome microarrays, 5 metastases were CHGA(+)/SYP(+)/AR(-), and 5 were CHGA(+)/SYP(+)/AR(+). Only CHGA(+)/SYP(+) metastases had a neuroendocrine transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the neuroendocrine signature in CHGA(+)/SYP(+) metastases and all CHGA(+)/SYP(+) LuCaP xenografts. In addition, expression of SRRM4 in LuCaP neuroendocrine xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. CONCLUSIONS: (i) Metastatic neuroendocrine status can be heterogeneous in the same patient, (ii) the CRPC neuroendocrine molecular phenotype can be defined by CHGA(+)/SYP(+) dual positivity, (iii) the neuroendocrine phenotype is not necessarily associated with the loss of AR activity, and (iv) the splicing of REST by SRRM4 could promote the neuroendocrine phenotype in CRPC.

Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways.

Cancer dormancy refers to the prolonged clinical disease-free time between removal of the primary tumor and recurrence, which is common in prostate cancer (PCa), breast cancer, esophageal cancer, and other cancers. PCa disseminated tumor cells (DTC) are detected in both patients with no evidence of disease (NED) and advanced disease (ADV). However, the molecular and cellular nature of DTC is unknown. We performed a first-in-field study of single DTC transcriptomic analyses in cancer patients to identify a molecular signature associated with cancer dormancy. We profiled eighty-five individual EpCAM⁺/CD45⁻ cells from the bone marrow of PCa patients with NED or ADV. We analyzed 44 DTC with high prostate-epithelial signatures, and eliminated 41 cells with high erythroid signatures and low prostate epithelial signatures. DTC were clustered into 3 groups: NED, ADV_1, and ADV_2, in which the ADV_1 group presented a distinct gene expression pattern associated with the p38 stress activated kinase pathway. Additionally, DTC from the NED group were enriched for a tumor dormancy signature associated with head and neck squamous carcinoma and breast cancer. This study provides the first clinical evidence of the p38 pathway as a potential biomarker for early recurrence and an attractive target for therapeutic intervention.

Circulating microRNA profiling identifies a subset of metastatic prostate cancer patients with evidence of cancer-associated hypoxia.

MicroRNAs (miRNAs) are small (∼22 nucleotide) non-coding RNAs that regulate a myriad of biological processes and are frequently dysregulated in cancer. Cancer-associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. Here we used miRNA profiling to identify cancer-associated miRNAs that are differentially expressed in sera from patients with metastatic castration resistant prostate cancer (mCRPC) as compared to healthy controls. Of 365 miRNAs profiled, we identified five serum miRNAs (miR-141, miR-200a, miR-200c, miR-210 and miR-375) that were elevated in cases compared to controls across two independent cohorts. One of these, miR-210, is a known transcriptional target of the hypoxia-responsive HIF-1α signaling pathway. Exposure of cultured prostate cancer cells to hypoxia led to induction of miR-210 and its release into the extracellular environment. Moreover, we found that serum miR-210 levels varied widely amongst mCRPC patients undergoing therapy, and correlated with treatment response as assessed by change in PSA. Our results suggest that (i) cancer-associated hypoxia is a frequent, previously under-appreciated characteristic of mCRPC, and (ii) serum miR-210 may be further developed as a predictive biomarker in patients with this distinct disease biology.