In testicular germ cell tumors (TGCTs), staging is a major determinant of disease-specific outcomes and dictates clinical management. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual recommends that tumor deposits in the spermatic cord that are discontinuous with the primary tumor be considered pathologic stage M1 (clinical stage [CS] III). This recommendation is controversial because, if patients do not show other metastases, it results in upstaging from CS I to III. This is relevant because CSI patients are candidates for active surveillance, whereas chemotherapy represents the standard treatment of CSIII patients. In this study, we describe the clinicopathologic findings and disease outcomes of TGCT patients presenting with discontinuous cord involvement no other concurrent metastases (ie, otherwise CS I). A total of 19 patients were assessed: 16 nonseminomas and 3 seminomas. When the focus of discontinuous spermatic cord invasion was excluded from staging, 10 tumors were pT3, 8 were pT2, and 1 was pT1. Adjuvant chemotherapy was given to 15 patients, 10 of whom developed disease recurrence (8 of them showing metastases in the retroperitoneum). None of the 4 patients kept on active surveillance showed evidence of recurrence at last follow-up, which is incompatible with the natural history of untreated CS III TGCTs. If the focus of discontinuous cord involvement was excluded from staging, these 4 cases were all pT2. Our data support that discontinuous cord invasion should not be considered pM1, since this practice may result in overtreatment of patients that could be kept on surveillance. We suggest staging these tumors as pT3(disc), considering this finding a risk factor for recurrence.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4-Precursor Lesions of the Testis-focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that "seminoma with intratubular nonseminoma" is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Adverse events in CA-3 vs vehicle treated mice

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4—Precursor Lesions of the Testis—focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that “seminoma with intratubular nonseminoma” is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Inhibition of α2 reduces invasiveness of PNE and PAC cells

Divergence of the proteomes of ECMs obtained from TRAMP and WT prostates

Polarized light analysis of ECM linearization in human prostate cancer specimen

769 Background: Standard-of-care treatment for MIBC is radical cystectomy (RC) with neoadjuvant chemotherapy (CT), but ~50% of patients (pts) are ineligible for/refuse CT and survival for RC alone is poor. Neoadjuvant Pembro and SG monotherapies showed activity in MIBC within PURE-01 and SURE-01 studies. SURE-02 (NCT05535218) is a phase 2 study of neoadjuvant SG+Pembro and adjuvant Pembro, including a bladder-sparing approach depending on clinical response. We report results of primary analysis and final biomarker analyses. Methods: Pts age ≥18 y, ECOG PS 0-1, with histologically confirmed cT2-T4N0M0 MIBC, ineligible/refusing CT, and scheduled for RC received 4 cycles of Pembro 200 mg on D1 and SG 7.5 mg/Kg on D1 and D8, Q3W, followed by postsurgical Pembro x 13 cycles, Q3W. A reTURBT was allowed instead of RC, followed by Pembro x 13 cycles, for pts achieving a clinical complete response (cCR), stringently defined as a negative magnetic resonance imaging (MRI) and no residual viable tumor at reTURBT (ypT0). Primary outcome measure was cCR rate with 19 cCR required to meet the endpoint in a 2-stage design. Transcriptome-wide analyses (Decipher Bladder, Veracyte, Inc) and comprehensive genomic profiling (CGP, Foundation Medicine, Inc) assays were performed on baseline tumor samples. Results: From 10/23 to 02/25, 49 pts were treated and efficacy evaluable. 33 (67.3%) had a cT2 stage, 19 (38.8%) had a centrally confirmed variant histology. The cCR-rate was 38.8% (N = 19; 95%CI: 25.2-53.8); all these pts underwent a reTURBT; ypT≤1N0-x rate was 51% (N = 25). 12m Event-free survival (EFS: defined as any high-grade relapse, progression, further therapy to the bladder or death) was 71% (95%CI: 56.7-88.8); 12m-EFS in cCR was 90.9% vs 59.6% in non-cCR. All cCR pts were metastases-free after a median follow-up of 14 months; 2 pts developed an intravesical relapse. Grade ≥3 treatment-related adverse-events (TRAE) occurred in 8 pts (16.3%). No Grade 5 TRAE occurred. CGP revealed ERBB2 mutations/amplifications in 42.1% of cCR vs 13.7% non-cCR pts. Median TMB was 12.1 in cCR vs 7.9 in non-cCR pts. Variance by subtype showed that Luminal tumors had higher TROP2 and ERBB2 expression, as well as higher KEGG mismatch repair deficiency (MMR) signature. Molecular subtyping revealed higher cCR rates for Luminal subtypes (62% vs 31% in non-Luminal). Higher MMR KEGG signature was significantly associated with longer EFS (100% at 12 months). Conclusions: Perioperative SG+Pembro revealed a compelling cCR rate, with a manageable safety profile, allowing a bladder preservation with sustained remission in ~40% of pts. Pre-treatment biomarker analyses revealed an enrichment of putative biomarkers of response and outcome in Luminal subtypes. Clinical trial information: NCT05535218 .

INTRODUCTION:Immune checkpoint inhibitors (ICI) have demonstrated meaningful activity as neoadjuvant therapy in muscle-invasive bladder cancer (MIBC). Identifying patients most likely to respond to ICI-based neoadjuvant strategies remains an unmet need. MATERIALS AND METHODS:Tumor mutational burden (TMB) from baseline transurethral resection of bladder (TURB) tumor samples of MIBC patients treated with neoadjuvant ICI across PURE-01 (NCT02736266), SURE-02 (NCT05535218), and NURE-Combo (NCT04876313) trials was analyzed. Probabilities of complete response ( CR; yT0N0‑x at radical cystectomy or re-TURB tumor), event‑free survival, and overall survival were assessed across different TMB cutoffs. Logistic regression models evaluated predictors of CR. RESULTS:202 patients (85% male, median age 66) were included. 57% had cT2 disease. Median TMB was 10.5 mut/Mb; 88 patients (44%) achieved CR. Optimal TMB threshold for CR was 13 mut/Mb with a predicted probability (PP) of 43% (95% confidence interval [CI]: 36.6-50.6); higher TMB showed incremental PP. At TMB ≥ 20 threshold, PP was 54% (95% CI: 43.7-63.1), with significant association with CR at multivariable analysis (AUC: 0.65). No significant effect by therapeutic regimen was observed. With a median follow-up of 63 months (interquartile range 25-77), 60m-event‑free survival for TMB ≥ 20 pts was 97% (95% CI: 90.4-100) versus 73% (95% CI: 65.6-80.7), P=0.03, and 60m-overall survival was 100% versus 78.8% (95% CI: 71.9-86.4), P = .01. CONCLUSIONS:Our analysis support TMB as a clinically informative biomarker in MIBC patients treated with neoadjuvant ICI, identifying a subset of exceptional responders associated with higher TMB levels.

Differentially expressed matrisome genes discriminate human NEPC and CRPC-Adeno