Role of Lactate Dehydrogenase in Identifying Relapse for Patients With Stage I Testicular Cancer on Surveillance.

PURPOSE: Tumor markers alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase assume a key role in the management of testicular germ cell tumors. While alpha-fetoprotein and human chorionic gonadotropin have modest sensitivity and specificity for germ cell tumors, lactate dehydrogenase has weak sensitivity and specificity. We explored the utility of lactate dehydrogenase in identifying relapse among stage I seminomatous and nonseminomatous germ cell tumors on surveillance. MATERIALS AND METHODS: Patients with a history of stage I testicular germ cell tumors were identified from a prospectively maintained database at the Princess Margaret Cancer Centre from December 1980 to May 2021 and surveyed according to established institutional algorithm guidelines. The utility of lactate dehydrogenase elevation to independently detect germ cell tumor relapse was examined. RESULTS: Among 1,014 seminoma and 676 nonseminomatous germ cell tumor patients, 176 and 176 patients relapsed with a median time to relapse of 13.6 and 8.9 months, respectively. Imaging alone was the most common mode of relapse detection in 144 and 74 of seminoma and nonseminomatous germ cell tumor patients, respectively. Lactate dehydrogenase was elevated in 49 cases of seminoma and 38 cases of nonseminomatous germ cell tumors at relapse, but was never the sole relapse indicator. Among 350 seminoma and 311 nonseminomatous germ cell tumor patients who never relapsed, 210 and 233, respectively, had at least 1 elevated lactate dehydrogenase value. CONCLUSIONS: Lactate dehydrogenase alone did not independently contribute to early relapse detection in stage I seminoma or nonseminomatous germ cell tumor. Elevated lactate dehydrogenase values were documented in a high proportion of nonrelapsing seminoma and nonseminomatous germ cell tumor cases.

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer.

In urothelial bladder cancer (UBC), risk stratification remains an important unmet need. Limitless self-renewal, governed by TERT expression and telomerase activation, is crucial for cancer progression. Thus, telomerase activation through the interplay of mutations (TERTpMut ) and epigenetic alterations in the TERT promoter may provide further insight into UBC behavior. Here, we investigated the combined effect of TERTpMut and the TERT Hypermethylated Oncological Region (THOR) status on telomerase activation and patient outcome in a UBC international cohort (n = 237). We verified that TERTpMut were frequent (76.8%) and present in all stages and grades of UBC. Hypermethylation of THOR was associated with higher TERT expression and higher-risk disease in nonmuscle invasive bladder cancers (NMIBC). TERTpMut alone predicted disease recurrence (HR: 3.18, 95%CI 1.84 to 5.51, p < 0.0001) but not progression in NMIBC. Combined THORhigh /TERTpMut increased the risk of disease recurrence (HR 5.12, p < 0.0001) and progression (HR 3.92, p = 0.025). Increased THOR hypermethylation doubled the risk of stage progression of both TERTpwt and TERTpMut NMIBC. These results highlight that both mechanisms are common and coexist in bladder cancer and while TERTpMut is an early event in bladder carcinogenesis THOR hypermethylation is a dynamic process that contributes to disease progression. While the absence of alterations comprises an extremely indolent phenotype, the combined genetic and epigenetic alterations of TERT bring additional prognostic value in NMIBC and provide a novel insight into telomere biology in cancer.

Concordance of biopsy and prostatectomy diagnosis of intraductal and cribriform carcinoma in a prospectively collected data set.

AIMS: Intraductal and cribriform carcinoma of the prostate are increasingly recognised as independent prognosticators of poor outcome, both in prostate biopsies and surgical specimens. We studied the concordance of biopsy and prostatectomy diagnosis for these two subpathologies in relationship with pathological stage. METHODS AND RESULTS: Mandatory synoptic reporting of intraductal and cribriform carcinoma in prostate biopsies and prostatectomy specimens was adopted by two academic institutions in November 2015. Synoptic reports of 245 biopsy and corresponding prostatectomy specimens were interrogated to determine the prevalence of intraductal and cribriform carcinoma. Sensitivity and specificity were determined, with prostatectomy diagnosis as the gold standard. Associations with pathological stage as primary outcome parameter were determined using univariable and multivariable logistic regression analysis. Prevalence of the combination of intraductal and cribriform carcinoma was 26.9% in biopsies and 51.8% in prostatectomy specimens. Sensitivity and specificity at biopsy were 47.2% and 94.9%, respectively. Intraductal and cribriform carcinoma at biopsy were associated with advanced pathological stage independent of grade (P = 0.013). Among patients with grade group 2 prostate cancer at biopsy, the more advanced pathological stage distribution was similar for those with a false negative and a true positive biopsy diagnosis of intraductal and cribriform carcinoma (P = 0.29). CONCLUSION: In spite of low sensitivity, intraductal and cribriform carcinoma at biopsy was associated strongly with advanced stage at radical prostatectomy. As a false negative biopsy diagnosis was equally associated with advanced pathological stage, efforts should be undertaken to improve the sensitivity of biopsy diagnosis for intraductal and cribriform carcinoma.

Serum miRNA Predicts Viable Disease after Chemotherapy in Patients with Testicular Nonseminoma Germ Cell Tumor.

PURPOSE: Retroperitoneal lymph node dissection is recommended for residual masses greater than 1 cm after chemotherapy of nonseminomatous germ cell tumors. Currently there is no reliable predictor of post-chemotherapy retroperitoneal lymph node dissection histology. Up to 50% of patients harbor necrosis/fibrosis only so that a potentially morbid surgery has limited therapeutic value. In this study we evaluated the ability of defined serum miRNAs to predict residual viable nonseminomatous germ cell tumors after chemotherapy. MATERIALS AND METHODS: Levels of serum miRNA, including miR-371a-3p, miR-373-3p and miR-367-3p, were measured using the ampTSmiR (amplification targeted serum miRNA) test in 82 patients, including 39 in cohort 1 and 43 in cohort 2, who were treated with orchiectomy, chemotherapy and post-chemotherapy retroperitoneal lymph node dissection. miRNA levels were compared to clinical characteristics and serum tumor markers, and correlated with the presence of viable germ cell tumor vs fibrosis/necrosis and teratoma. ROC analysis was done to determine miRNA discriminative capacity. RESULTS: miRNA levels were significantly associated with disease extent at chemotherapy and they decreased significantly after chemotherapy. Conventional serum tumor marker levels were uninformative after chemotherapy. However, after chemotherapy miRNA levels remained elevated in patients harboring viable germ cell tumor in post-chemotherapy retroperitoneal lymph node dissection specimens. miR-371a-3p demonstrated the highest discriminative capacity for viable germ cell tumors (AUC 0.874, 95% CI 0.774-0.974, p <0.0001). Using an adapted hypothetical cutoff of 3 cm or less for surgical intervention miR-371a-3p correctly stratified all patients with viable residual retroperitoneal germ cell tumors with 100% sensitivity (p = 0.02). CONCLUSIONS: Our study demonstrates for the first time the potential value of miR-371a-3p to predict viable germ cell tumors in residual masses after chemotherapy. Prospective studies are required to confirm clinical usefulness.

Evaluation of an Aggressive Prostate Biopsy Strategy in Men Younger than 50 Years.

PURPOSE: Longitudinal cohort studies and guidelines demonstrate that prostate specific antigen 1 ng/ml or greater in younger patients confers an increased risk of delayed prostate cancer death. At our institution we have used an aggressive biopsy strategy in younger patients with prostate specific antigen 1 ng/ml or greater. Our objective was to determine the proportion of detected cancer and specifically clinically significant cancer by this strategy. MATERIALS AND METHODS: The prostate biopsy database at Princess Margaret Cancer Centre was queried for patients younger than 50 years who underwent a first prostate biopsy between 2000 and 2016. We included only patients who underwent prostate biopsy due to prostate specific antigen 1 ng/ml or greater and those with a suspicious digital rectal examination, a positive family history or a suspicious lesion on transrectal ultrasound. All clinical and pathological parameters were analyzed. Patients were stratified according to specific prostate specific antigen values. Multivariable logistic regression was performed to ascertain predictors of any prostate cancer diagnosis and of clinically significant prostate cancer. RESULTS: Of the 199 patients who met study inclusion criteria 37 (19%) were diagnosed with prostate cancer and 8 (22%) had a Gleason score of 7 or greater. Of those diagnosed with prostate cancer 25 (68%) had prostate specific antigen 1.5 ng/ml or greater and all men with a Gleason score of 7 or greater had prostate specific antigen 1.5 ng/ml or greater. Notably 19 patients (51%) had prostate cancer exceeding the Epstein criteria for active surveillance. Factors predicting prostate cancer included a positive family history, rising prostate specific antigen and lower prostate volume. CONCLUSIONS: Our results justify adopting an aggressive prostate biopsy strategy in men younger than 50 years with prostate specific antigen 1.5 ng/ml or greater while patients with prostate specific antigen less than 1.5 ng/ml are unlikely to have significant cancer. Special attention should be given to patients with a smaller prostate and a positive family history.

Gene expression signatures prognostic for relapse in stage I testicular germ cell tumours.

OBJECTIVES: To identify differentially expressed genes between relapsed and non-relapsed clinical stage I testicular germ cell tumours (TGCTs). MATERIALS AND METHODS: We reviewed patients with clinical stage I non-seminoma and seminoma from an institutional database (2000-2012) who were managed by active surveillance. Patients with non-relapsed non-seminoma and non-relapsed seminoma were defined as being relapse-free after 2 and 3 years of surveillance, respectively. RNA extraction and gene expression analysis was performed on archival primary tumour samples and gene-set enrichment analysis (GSEA) was conducted in order to identify differentiating biological pathways. RESULTS: A total of 57 patients (relapsed non-seminoma, n = 12; relapsed seminoma, n =15; non-relapsed non-seminoma, n = 15; non-relapsed seminoma, n = 15) were identified, with a median (range) relapse time of 5.6 (2.5-18.1) and 19.3 (4.7-65.3) months in the relapsed non-seminoma and relapsed seminoma cohorts, respectively. A total of 1 039 differentially expressed genes were identified that separated relapsed and non-relapsed groups. In patients with relapse, GSEA revealed enrichment in pathways associated with differentiation, such as skeletal development (i.e. FGFR1, BMP4, GLI2, SPARC, COL2A1), tissue (i.e. BMP4, SPARC, COL13A1) and bone remodelling (i.e. CARTPT, GLI2, MGP). A discriminative gene expression profile between relapsed and non-relapsed cases was discovered when combining non-seminoma and seminoma samples using 10- and 30-probe signatures; however, this profile was not observed in the seminoma and non-seminoma cohorts individually. CONCLUSION: A discriminating signature for relapsed disease was identified for clinical stage I TGCT that we were not able to identify by histology alone. Further validation is required to determine if this signature provides independent prognostic information to standard pathological risk factors.

Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?

AIMS: The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. METHODS AND RESULTS: Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. CONCLUSION: This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.

Lymph Node Yield in Primary Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumors.

PURPOSE: The number of lymph nodes removed at surgery for various malignancies has diagnostic and prognostic value. However, there are limited data on the significance of the number of nodes removed at retroperitoneal lymph node dissection performed for testicular nonseminoma germ cell tumors. MATERIALS AND METHODS: From 1979 to 2012 primary open retroperitoneal lymph node dissection was performed by a single experienced surgeon for clinical stage I/II testicular nonseminoma germ cell tumor in 157 patients. Node count was available in 111 cases (71%). Factors associated with total node count and nodes with viable cancer were assessed by linear regression. The association between node count and time to relapse was assessed by multivariate Cox proportional hazards models controlled for adjuvant chemotherapy. RESULTS: The median total lymph node count was 28 (IQR 19-38). Patient age, cancer laterality, body mass index, clinical stage, time from orchiectomy to retroperitoneal lymph node dissection, pathologist and lymph node dissection year were not associated with total lymph node count. A viable germ cell tumor was found in 70 patients (63%). Total node yield was not associated with nodal cancer metastasis. After lymph node dissection 17 patients (16%) received adjuvant chemotherapy. At a median 57-month followup 18 cases (17%) relapsed after primary retroperitoneal lymph node dissection. Increasing total node count was associated with a decreased risk of relapse on univariate and multivariate analysis (HR 0.96, 95% CI 0.92-0.99, p = 0.03 and HR 0.94, 95% CI 0.89-0.99, p = 0.017, respectively). CONCLUSIONS: No analyzed clinical or pathological variable was associated with the node yield of primary retroperitoneal lymph node dissection. However, there may be a relationship between the total node yield at retroperitoneal lymph node dissection and the risk of relapse.

PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade.

Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2-ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.

Treatment burden in stage I seminoma: a comparison of surveillance and adjuvant radiation therapy.

OBJECTIVE: To examine the management and outcomes of patients with stage I seminoma and to relate these to overall treatment burden. PATIENTS AND METHODS: A total of 764 patients with stage I seminoma underwent surveillance or adjuvant radiation therapy (RT) at a single institution. First relapse on surveillance was managed with RT alone, or with combination chemotherapy (ChT) for more extensive recurrence. Second relapse was managed with ChT. Relapse after adjuvant RT was treated with ChT. The treatment burden was measured, according to the specific treatment undertaken after orchiectomy, by defining treatment episodes as follows: surgery - one episode; one course of RT - one episode; one course of ChT - one episode. RESULTS: In all, 484 patients underwent surveillance and 280 received adjuvant RT. The 5- and 10-year overall survival rates were 98.6 and 97.7% for surveillance, and 97.2 and 91.4% for adjuvant RT. A total of 72 (15%) patients in the surveillance group relapsed; treatment for relapse was RT (n = 56), ChT (n = 15) and surgery (n = 1). Second relapse occurred in six patients; these patients were treated with ChT. Of the patients in the adjuvant RT group, 14 (5%) relapsed: salvage treatment was 10 - ChT (n = 10) surgery (n = 1) and further RT (n = 3). The overall treatment burden represented by number of treatment episodes per patient was 0.16 in the surveillance group and 1.05 in the adjuvant RT group. CONCLUSIONS: Surveillance reduces the overall treatment burden in patients with stage I seminoma and is the preferred management option. The selective use of RT at first relapse for patients on surveillance leads to a similar requirement for subsequent ChT to that for patients on adjuvant RT.

Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

PURPOSE: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. PATIENTS AND METHODS: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. RESULTS: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). CONCLUSIONS: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Utility of serum tumor markers during surveillance for stage I seminoma.

BACKGROUND: The serum tumor markers α-fetoprotein (AFP), ß-human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) are often measured as part of surveillance protocols in patients with stage I seminoma. In this study, the authors evaluated the utility of routine measurement of these markers in the detection of disease relapse. METHODS: Data were gathered from a prospectively maintained database of patients who underwent surveillance for stage I testicular seminoma diagnosed between 1982 and 2005 at Princess Margaret Hospital. Patients were followed on a predefined schedule with physical examination (PE), serum tumor markers, abdominopelvic computed tomography, and chest x-rays. The records of patients who relapsed were examined for details of imaging and serum tumor markers throughout the period of follow-up until the time of relapse. RESULTS: Of the 527 patients who were managed by surveillance, 75 patients (14%) relapsed at a median follow-up of 72 months. Of these, 65 patients relapsed within the first 3 years and had routine serum tumor markers measured. In total, 11 patients had abnormal tumor markers at the time of relapse (AFP, 0 patients; HCG, 6 patients; LDH, 4 patients; and HCG and LDH, 1 patient). Only 1 patient had an elevated tumor marker (LDH) before relapse, as defined by an abnormal imaging study (n = 64) or physical examination (n = 1), for which the treatment and outcome were not affected. CONCLUSIONS: Serum tumor marker levels did not aid in the early diagnosis of disease relapse in patients with stage I seminoma who were managed with surveillance. The current results indicated that routine measurement of serum tumor markers can be discontinued safely in seminoma surveillance schedules.

Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome.

UNLABELLED: What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ-confined (OC) to non-organ-confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0-8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6-4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES: To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS: Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992-2010) and University of Turku, Turku, Finland (1986-2005) were analysed. RESULTS: Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ-confined (OC) to non-organ-confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation (P= 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44-4.77), high grade disease (P= 0.01, OR = 2.85, 95% CI: 1.21-6.7), lymphovascular invasion (LVI) (P < 0.001, OR = 5.17, 95% CI: 3.48-7.68), female gender (P= 0.038, OR = 0.6, 95% CI: 0.38-0.97, and histological variants (P < 0.001, OR = 2.77, 95% CI: 1.6-4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10-year disease-specific mortality, P < 0.001). CONCLUSIONS: Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

Perineural invasion on prostate biopsy does not predict adverse pathological outcome.

INTRODUCTION: The clinical significance of perineural invasion (PNI) on prostate needle biopsy is controversial. The aim of this present study is to determine the role of PNI on prostate biopsy in predicting adverse findings at radical prostatectomy in a recent cohort of screen detected prostate cancer. MATERIALS AND METHODS: We analyzed 470 patients diagnosed with prostate cancer from a prospectively maintained database at Princess Margaret Hospital. Out of the 470 patients diagnosed with prostate cancer, 139 underwent radical prostatectomy. Pathological specimens were examined, and perineural invasion was identified as carcinoma tracking along or around a nerve in the perineural space. We investigated the predictive value of PNI on biopsy with PNI on radical prostatectomy as well as the ability of PNI on prostate biopsy to predict adverse findings at radical prostatectomy. RESULTS: Perineural invasion was present in 124 (26%) of biopsy specimens diagnosed with prostate cancer and 94 (68%) of those who chose radical prostatectomy. Perineural invasion on prostate needle biopsy was not predictive of radical prostatectomy Gleason score (p = .377), pathological stage (p = .852), extraprostatic extension (p = .258), surgical margin (p = .079), lymphovascular invasion (p = .499), and upgrading (p = .514) or downgrading (p = .208) at radical prostatectomy. The sensitivity, specificity, positive predictive value, and negative predictive value of PNI on biopsy for PNI on radical prostatectomy were 32%, 82%, 79%, and 37% respectively. The Cohen's Kappa correlation coefficient was .11. CONCLUSIONS: Perineural invasion on prostate needle biopsy is not predictive of radical prostatectomy outcome. Furthermore, perineural invasion on biopsy has limited predictive value for perineural invasion at radical prostatectomy.

Safety of Minimizing Intensity of Follow-up on Active Surveillance for Clinical Stage I Testicular Germ Cell Tumors.

Background: We have recommended active surveillance as the preferred management option for clinical stage I (CSI) testicular germ cell tumors (GCTs) since 1980. Over time, the recommended intensity of surveillance has decreased; however, the impact on relapse detection has not been investigated. Objective: To examine relapse rate, time to relapse, extent of disease, and burden of treatment at relapse across decreasing surveillance intensity over time. Design setting and participants: CSI GCT patients under active surveillance from 1981 to 2021 were included in this study. Outcome measurements and statistical analysis: Through four major iterations in both nonseminomatous (NSGCT) and seminoma surveillance schedules, visit frequency, blood testing, and imaging have been decreased successively. Low-dose, noncontrast computed tomography (CT) scans were adopted in 2011. Categorical variables and time to relapse were compared using chi-square and Fisher's exact or Kruskal-Wallis test, respectively. Results and limitations: A total of 1583 consecutive patients (942 with seminoma and 641 with NSGCT) were included. In seminoma, chest x-rays were reduced from 13 to one and CT scans were reduced from 20 to ten. Relapse rate, time to relapse, N or M category, and International Germ Cell Cancer Collaborative Group (IGCCCG) classification did not change. In NSGCT, chest x-rays were reduced from 27 to zero and CT scans were reduced from 11 to five. Relapse rate (from 46.2% to 21.2%, p = 0.002) and the median time to relapse (from 6.54 to 4.47 mo, p = 0.025) decreased. No difference in relapsed disease burden was identified by N, M, and S category or IGCCCG classification. Treatment burden at relapse and GCT cancer deaths remained similar for seminoma and NSGCT. Limitations include the retrospective design and large time period covered. Conclusions: Despite considerable reductions in surveillance intensity, we did not observe an increase in disease extent, treatment burden, or GCT cancer deaths upon relapse. These results support that our current lower-intensity active surveillance schedules are safe for managing CSI GCT. Patient summary: Our current reduced-intensity surveillance schedules for clinical stage I germ cell tumors appear to be safe.

Expansion of Lymphocytes from Prostatic Adenocarcinoma and Adjacent Nonmalignant Tissue.

Background: The evaluation of tumour-infiltrating lymphocytes (TILs) in solid malignancies has yielded insights into immune regulation within the tumour microenvironment and has also led to the development and optimisation of adoptive T cell therapies. Objectives: This study examined the in vitro expansion of TILs from prostate adenocarcinoma, as a preliminary step to evaluate the potential of TILs for adoptive T cell therapy. Design, Setting, and Participants. Malignant and adjacent nonmalignant tissues were obtained from fifteen men undergoing radical prostatectomy. Interventions. There were no study interventions. Outcome Measurements and Statistical Analysis. Expanded cells were analysed by flow cytometry, and the data was assessed for associations between cell subpopulations and expansion rate. Results: Tumour-infiltrating lymphocytes could be expanded to numbers that would be needed to generate a therapeutic infusion product from nine of 15 malignant specimens (60%). The CD4+ T cells predominated over CD8+ T cells (median 56.8% CD4+, 30.0% CD8+), and furthermore, faster TIL expansion was associated with a higher proportion of CD4+ T cells (median 69.8% in faster-growing cultures; 36.8% in slower-growing cultures). A higher proportion of CD3-CD56+ cells versus CD3+ cells was associated with slower TIL expansion in cultures from malignant specimens (median 13.3% in slower-growing cultures versus 2.05% in faster-growing cultures), but not from nonmalignant specimens. Conclusions: The expansion of TILs for potential therapeutic use is feasible. Our findings also indicate that further examination of TILs from prostate adenocarcinomas may yield insights into mechanisms of regulation of T cells within the tumour microenvironment. Further research is required to evaluate their therapeutic potential.

Long-term Surveillance of Patients with Complete Response Following Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumor.

BACKGROUND: There is controversy regarding the management of patients with normal markers and residual masses (≤1 cm) after chemotherapy for nonseminomatous germ cell tumors (NSGCTs). OBJECTIVE: To determine long-term outcomes of a surveillance strategy in such patients. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of our multidisciplinary testicular cancer database was performed. All patients who underwent primary chemotherapy for metastatic NSGCTs were identified between 1981 and 2016. A complete response (CR) was defined as normalization of serum tumor markers and a ≤1 cm residual mass in the largest axial dimension following chemotherapy. All such patients were surveilled. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome variables of interest were time to death, time to cancer-specific survival, and time to relapse. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, and the cumulative incidence of cause-specific survival rates was calculated using competing risk analysis. The impact of risk group and chemotherapy regimen on relapse-free survival was assessed using log-rank test. RESULTS AND LIMITATIONS: During the study period, 1429 metastatic germ cell tumor patients were treated with primary chemotherapy. CR was achieved in 191 (18.5%) NSGCT patients. The median age at diagnosis was 27.4 yr, with a median follow-up of 81.1 mo. The majority had American Joint Committee on Cancer stage II at diagnosis (I: 23.8%; II: 49.2%; III: 27%) and International Germ Cell Cancer Collaborative Group good-risk disease (good: 78%; intermediate: 17.8%; poor: 4.2%). Of the 191 patients with a CR, 175 (91.6%) never relapsed and remain disease free. Sixteen (8.4%) patients relapsed after a median of 11.3 mo (range 1-332 mo), with over half (nine patients; 4.7%) relapsing in the retroperitoneum only and salvaged successfully with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) alone. Of these nine patients, only two (1%) had viable disease in the PC-RPLND specimen. The remaining seven patients had relapses outside the retroperitoneum and received salvage chemotherapy ± postchemotherapy resection. Overall, nine (4.7%) patients have died, but only four (2.1%) from testis cancer. CONCLUSIONS: Our data, the largest series to date, confirm that surveillance is safe and effective for men who achieve a CR following chemotherapy for metastatic NSGCTs. PATIENT SUMMARY: Surveillance is a safe strategy for patients who achieve a complete response following chemotherapy for metastatic testis cancer.

Utility of Serum miR-371a-3p in Predicting Relapse on Surveillance in Patients with Clinical Stage I Testicular Germ Cell Cancer.

BACKGROUND: Optimal management of clinical stage I (CSI) testicular cancer is controversial due to lack of robust prognostic factors; miRNA-371a-3p holds promise as a biomarker, although its clinical utility for identifying patients at risk of relapse is unknown. OBJECTIVE: To explore the association between serum miR-371a-3p and CSI surveillance relapse. DESIGN, SETTING, AND PARTICIPANTS: Serial banked sera from 151 CSI (101 seminomas and 50 nonseminomatous germ cell tumors [NSGCTs]) samples from our Princess Margaret active surveillance cohort were tested. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Using the ampTSmiR test, miR-371a-3p was assayed. Multivariate logistic regression was used to assess the association between postorchiectomy miRNA and relapse. RESULTS AND LIMITATIONS: Thirty-four (23%) patients relapsed. There was no association between postorchiectomy miR-371a-3p (2.43 vs 2.74, p = 0.31) or percent decline from before to after orchiectomy (95.8% vs 93.1%, p = 0.14) and relapse. After adjustment for clinical prognostic factors, there remained no association between postorchiectomy miR-371a-3p and relapse (seminoma: odds ratio [OR] 1.33, 95% confidence interval [CI] 0.87-2.02, p = 0.18; NSGCT: OR 0.45, 95% CI 0.21-1.00, p = 0.05). Postorchiectomy miR-371a-3p levels rose as the date of miRNA assessment approached relapse. At relapse, serum markers alpha-fetoprotein and human chorionic gonadotropin were normal in 62%; yet, miR-371a-3p was elevated in 32/34 (94.1%). The magnitude of miR-371a-3p elevation at relapse correlated with disease burden (N1/M0 122.5 vs N2-N3/M0: 521.1; p = 0.05). Limitations include small numbers of relapses and variable time points of serum collection. CONCLUSIONS: In our cohort of CSI testis cancer patients on surveillance, postorchiectomy miR-371a-3p levels were not associated with relapse, suggesting that miR-371a-3p may not be a useful biomarker for guiding adjuvant therapy. Our data suggest that miR-371a-3p holds potential as an early relapse marker and warrants a prospective study, as this may allow a window for less morbid relapse therapy. PATIENT SUMMARY: The promising novel blood biomarker for testis cancer miR-371a-3p may not provide information at testicle removal, but serial monitoring may lead to earlier detection of relapse.

Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.

PURPOSE: Although enzalutamide (ENZ) has been widely used to treat de novo or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance. EXPERIMENTAL DESIGN: We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. RESULTS: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased. CONCLUSIONS: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.

Immunohistochemical examination of the mTORC1 pathway in high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinomas (PCa): a tissue microarray study (TMA).

BACKGROUND: The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase and a key regulator of protein synthesis and growth and is upregulated in many cancers. mTOR is activated by AKT phosphorylation (p-mTOR). p-mTOR associates with regulatory-associated protein of TOR (RAPTOR), forming the mTORC1 complex. mTORC1 promotes the activation of p70 ribosomal protein s6 kinase 1 (p70(S6K1)) and ribosomal protein s6 (RPS6). Upregulation of this pathway can lead to an aberrant increase in cell growth and metabolism characteristic of malignant transformation. METHODS: This study presents the immunohistochemical (IHC) expression of the mTORC1 pathway in prostate neoplasia. The expression of p-mTOR and RAPTOR and p-p70(S6K1) and p-RPS6 were examined in HGPIN and PCa using tissue microarrays (TMA). Since each case in our TMAs was represented by three tissue cores, we quantified the IHC intratumoral heterogeneity of mTOR expression. This extensive analysis is the first detailed assessment documenting the IHC heterogeneity of mTOR expression in HGPIN and prostate cancer and represents the first IHC description of the mTORC1 pathway in HGPIN and PCa. RESULTS: A Cochran-Armitage analysis demonstrated decreasing p-mTOR activity progressing from PIN through GL6 and GL7 to HG PCa. There was considerable intratumoral IHC heterogeneity within an individual patient. However, a statistically significant correlation was observed between p-mTOR, p-p70(S6K1), and p-RPS6 in each representative core. CONCLUSION: mTOR inhibitors may be an effective treatment for HGPIN and PCa. The extent of mTOR expression in an individual patient would determine the effective use of mTOR inhibitors as a potential therapeutic strategy.