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There is a critical unmet need for safe and efficacious neoadjuvant treatment for cisplatin-ineligible patients with muscle-invasive bladder cancer. Here we launched a phase 1b study using the combination of intravesical cretostimogene grenadenorepvec (oncolytic serotype 5 adenovirus encoding granulocyte–macrophage colony-stimulating factor) with systemic nivolumab in cisplatin-ineligible patients with cT2-4aN0-1M0 muscle-invasive bladder cancer. The primary objective was to measure safety, and the secondary objective was to assess the anti-tumor efficacy as measured by pathologic complete response along with 1-year recurrence-free survival. No dose-limiting toxicity was encountered in 21 patients enrolled and treated. Combination treatment achieved a pathologic complete response rate of 42.1% and a 1-year recurrence-free survival rate of 70.4%. Pathologic response was associated with baseline free E2F activity and tumor mutational burden but not PD-L1 status. Although T cell infiltration was broadly induced after intravesical oncolytic immunotherapy, the formation, enlargement and maturation of tertiary lymphoid structures was specifically associated with complete response, supporting the importance of coordinated humoral and cellular immune responses. Together, these results highlight the potential of this combination regimen to enhance therapeutic efficacy in cisplatin-ineligible patients with muscle-invasive bladder cancer, warranting additional study as a neoadjuvant therapeutic option. ClinicalTrials.gov identifier: NCT04610671.

Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches.

Genitourinary (GU) cancers have greatly benefited from immunotherapy treatments, such as immune checkpoint inhibitors. However, the durable clinical response rate for these agents remains relatively low, calling for more innovative immunotherapy approaches. Adoptive cell therapy has shown a significant advancement in the treatment of cancer in recent years and represents a great potential for the treatment of GU cancers. This review summarizes the current advancements in cellular therapy strategies for the treatment of renal cell carcinoma, bladder cancer, and prostate and penile cancers. Further, current and past clinical trials of adoptive cell therapy in GU tumors are reviewed. Finally, a perspective on the future of cell therapy in GU tumors is discussed.

Background: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa. Methods: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189). Results: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post–HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders. Conclusion: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

IMPORTANCE: Neoadjuvant chemotherapy (NAC) followed by radical cystectomy improves survival compared with cystectomy alone for patients with bladder cancer. Although gemcitabine with cisplatin has become a standard NAC regimen, a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) is being adopted at some institutions. OBJECTIVE: To assess the association of neoadjuvant ddMVAC vs standard regimens with downstaging and overall survival among patients treated with radical cystectomy for bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of data extracted from the medical records of a consecutive sample, after exclusions, of 1113 patients with bladder cancer of whom 824 had disease stage T2 or greater, who were treated with cystectomy at the Moffitt Cancer Center in Tampa, Florida, a tertiary care cancer center, between January 1, 2007, and May 31, 2017. Data were collected between November 14, 2016, and July 21, 2017, and analyzed between August 21, 2017, and December 8, 2017. Patients were compared based on type of NAC. Those who did not receive NAC were included as controls. MAIN OUTCOMES AND MEASURES: Comparative rates and the association of any downstaging, complete response, and overall survival with ddMVAC and other NAC regimens and surgery alone. Outcomes were examined using Kaplan-Meier, adjusted logistic, Cox regression, and propensity-weighted models. RESULTS: Of the 1113 patients who underwent cystectomy for bladder cancer, 861 (77.4%) were male, the median (interquartile range) age was 67 (60-74) years, 1051 (94.4%) were white, 27 (2.4%) black, 37 (3.3%) Hispanic/Latino, and 35 (3.1%) other race/ethnicity. Of 824 patients with muscle-invasive bladder cancer, 332 (40%) received NAC. Downstaging rates were 52.2% for ddMVAC, 41.3% for gemcitabine-cisplatin, and 27.0% for gemcitabine with carboplatin, and complete response (pT0N0) rates were 41.3% for ddMVAC, 24.5% for gemcitabine-cisplatin, and 9.4% for gemcitabine-carboplatin (2-sided P < .001). Adjusted analysis comparing ddMVAC with gemcitabine-cisplatin demonstrated a higher likelihood of downstaging (odds ratio [OR], 1.84; 95% CI, 1.10-3.09) and complete response (OR, 2.67; 95% CI, 1.50-4.77) with ddMVAC. Similar results were achieved with propensity score matching (OR, 1.52; 95% CI, 0.99-2.35). Patients who received ddMVAC had better overall survival than those treated with other chemotherapy regimens, although the observed survival benefit did not reach statistical significance in adjusted or propensity-matched models (hazard ratio, 0.44; 95% CI, 0.14-1.38; P = .16). CONCLUSIONS AND RELEVANCE: This study suggest that neoadjuvant ddMVAC followed by cystectomy is associated with a higher complete response (ypT0N0) rate than standard NAC. These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion.

Female primary urethral carcinoma is rare, and treatment standards are nonexistent, particularly for the use of multimodal therapy in locally advanced disease. We reviewed 39 patients with primary urethral carcinoma in regard to presentation, treatment, and outcomes. Multimodal therapy shows a nonsignificant interval increase in overall and recurrence-free survival, but the sequence, type, and delivery of multimodal therapy is poorly defined.

Although several guidelines have outlined the management options for patients with renal masses, these guidelines have largely been extrapolated from studies involving younger cohorts. We compared management strategies in an exclusively octogenarian population and found no differences in survival among active surveillance, partial nephrectomy, and radical nephrectomy for small renal masses. However, larger and clinically aggressive renal masses should undergo active treatment.

This study evaluated elderly patients with urothelial carcinoma of the bladder receiving neoadjuvant chemotherapy (NAC). Compared with a younger cohort of patients, NAC demonstrated equivalent toxicity and oncologic outcomes in our single-institution cohort. Although older patients had significantly poorer performance status and renal function, there were no differences in survival or response to NAC.

The treatment paradigm for stage I testicular cancer has changed in the setting of accurate staging, reliable followup and a greater understanding of treatment related side effects. We assessed the influences on management decisions in patients with stage I testicular cancer.

This article discusses the diagnostic and therapeutic options in the management of urethral cancer recurrence in patients treated with urethral sparing cystectomy as well as those who had urethral preservation following primary urethral carcinoma.

We assessed 126 patients with cT1-4, N0-2 urothelial carcinoma of the bladder who were treated with neoadjuvant chemotherapy followed by radical cystectomy. Twenty patients (16%) had squamous or glandular histological variation (HV). Significant pathologic downstaging (pT<2, N0) was seen in the HV patients (60% vs. 32%; P = .02) and this difference remained significant after controlling for other clinical and pathological confounders.

In an analysis of a large single-institution experience in the surgical management of renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus, the authors present the effect of RCC characteristics on survival, and aim to identify potential preoperative variables predictive of intraoperative complexity with regard to estimated blood loss, transfusion volume, surgical time, length of stay, and postoperative complication rates. Age, American Society of Anesthesiologists score, Charlson Comorbidity Index, preoperative calcium, preoperative creatinine, and IVC wall invasion were significantly related to complication rates.

Sarcomatoid histology in renal cell carcinoma (sRCC) is an indicator of poor prognosis. We conducted a single-institution retrospective review of sRCC cases and identified that the presence of 25% sarcomatoid change or more in the primary tumor of patients with nonmetastatic renal cell carcinoma is an independent predictor of poor overall survival. Patients with these features require vigilant follow-up.

To summarize the fundamental principles for technique of robot-assisted radical cystectomy (RARC) based on current peer reviewed literature. Also provide most recent evidence for the efficacy of RARC and Intracorporeal Ileal Conduit (ICIC).

As laser ablation of placental vascular communications gains acceptance as treatment option for severe twin-to-twin transfusion syndrome (TTTS), pathologists are increasingly confronted with the interpretation of laser-treated placentas. We present our preliminary institutional experience with the gross and microscopic analysis of these specimens. Patients underwent selective ablation for severe TTTS (Quintero stages II to V) between 16 and 25 wk gestation and the placentas were examined between < 24 h and 19 wk postoperatively. The placental vasculature was injected with gelatin-dye mixtures. The type and number of vascular anastomoses were recorded, followed by routine histopathological analysis of the placenta. Foci of laser impact were identified in all placentas examined within 1 month after laser coagulation. Located along the recipient side of the dividing membrane, the laser-treated vessels appeared hemorrhagic and showed a characteristic abrupt interruption of dye filling after vascular injection. In placentas examined more than 1 month after intervention, the most frequent gross finding was the absence or relative paucity of intertwin anastomoses, associated with subchorionic fibrin deposition. Microscopically, laser-treated vessels showed varying degrees of necrosis, associated with focal hemorrhage, avascular villi, and fibrin deposition in the underlying parenchyma. In some cases of intrauterine fetal demise or placental disruption, no definite laser scars were identified. As expected, the number of residual anastomoses (all types) was significantly smaller in laser-treated placentas than in control monochorionic placentas (2.4 ± 2.2 [ n = 10] vs. 6.2 ± 3.2 [ n = 70], P < 0.01). Velamentous cord insertion was noted in 50% of cases; markedly uneven placental sharing in 60%. Detailed analysis of laser-treated placentas and clinicopathological correlation may lead to a better understanding of the pathophysiology of TTTS and continued refinement of therapeutic approaches for this often lethal condition.

As laser ablation of placental vascular communications gains acceptance as treatment option for severe twin-to-twin transfusion syndrome (TTTS), pathologists are increasingly confronted with the interpretation of laser-treated placentas. We present our preliminary institutional experience with the gross and microscopic analysis of these specimens. Patients underwent selective ablation for severe TTTS (Quintero stages II to V) between 16 and 25 wk gestation and the placentas were examined between < 24 h and 19 wk postoperatively. The placental vasculature was injected with gelatin-dye mixtures. The type and number of vascular anastomoses were recorded, followed by routine histopathological analysis of the placenta. Foci of laser impact were identified in all placentas examined within 1 month after laser coagulation. Located along the recipient side of the dividing membrane, the laser-treated vessels appeared hemorrhagic and showed a characteristic abrupt interruption of dye filling after vascular injection. In placentas examined more than 1 month after intervention, the most frequent gross finding was the absence or relative paucity of intertwin anastomoses, associated with subchorionic fibrin deposition. Microscopically, laser-treated vessels showed varying degrees of necrosis, associated with focal hemorrhage, avascular villi, and fibrin deposition in the underlying parenchyma. In some cases of intrauterine fetal demise or placental disruption, no definite laser scars were identified. As expected, the number of residual anastomoses (all types) was significantly smaller in laser-treated placentas than in control monochorionic placentas (2.4 ± 2.2 [n= 10] vs. 6.2 ± 3.2 [n= 70], P< 0.01). Velamentous cord insertion was noted in 50% of cases; markedly uneven placental sharing in 60%. Detailed analysis of laser-treated placentas and clinicopathological correlation may lead to a better understanding of the pathophysiology of TTTS and continued refinement of therapeutic approaches for this often lethal condition.

ABSTRACTAdvanced bladder cancer patients have limited therapeutic options resulting in a median overall survival (OS) between 12 and 15 months. Adoptive cell therapy (ACT) using tumor infiltrating lymphocytes (TIL) has been used successfully in treating patients with metastatic melanoma, resulting in a median OS of 52 months. In this study, we investigated the feasibility of expanding TIL from the tumors of bladder cancer patients. Primary bladder tumors and lymph node (LN) metastases were collected. Tumor specimens were minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. Expanded TIL were phenotyped by flow cytometry and anti-tumor reactivity was assessed after co-culture with autologous tumor digest and IFN-gamma ELISA. Of the 28 transitional cell bladder or LN tumors collected, 14/20 (70%) primary tumors and all of the LN metastases demonstrated TIL expansion. Expanded TIL were predominantly CD3+(median 63%, range 10–87%) with a median of 30% CD8 + T cells (range 5–70%). TIL secreted IFN-gamma in response to autologous tumor. Addition of agonisitic 4-1BB antibody improved TIL expansion from primary bladder tumors regardless of pre-treatment with chemotherapy. This study establishes the practical first step towards an autologous TIL therapy process for therapeutic testing in patients with bladder cancer.