The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study.

BACKGROUND: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.

The effect of chemotherapy in sarcomatoid bladder cancer patients treated with radical cystectomy.

INTRODUCTION: Data about the role of chemotherapy in sarcomatoid bladder cancer (SBC) are limited. We addressed the effect of chemotherapy in non-metastatic SBC patients treated with radical cystectomy (RC). METHODS: Using the Surveillance, Epidemiology, and End Results database (2001-2018), we identified 331 patients with non-metastatic muscle-invasive or higher SBC (T2-4N0-3M0). Kaplan-Meier plots and Cox regression models tested cancer-specific mortality (CSM ). Sample size and power analyses tested for power limitations. RESULTS: Of 331 SBC patients, 129 (38.9%) were exposed to chemotherapy. The rate of organ-confined stage (T2N0M0) was 33% in both chemotherapy-exposed and chemotherapy-naive patients. In the overall cohort, median CSM-free survival was 84 months (interquartile range [IQR] 21-NA) vs. 26 months (IQR 17-84) in chemotherapy exposed vs. chemotherapy-naive patients, respectively. In multivariable Cox regression models, chemotherapy was associated with lower CSM, without reaching statistical significance (hazard ratio [HR ] 0.72, confidence interval [CI] 0.51-1.01, p=0.054). In subgroup analyses, chemotherapy exposure in organ-confined (n=110) vs. non-organ-confined (n=221) patients resulted in a HR of 0.51 (p=0.12) vs. 0.77 (p=0.17), respectively. Power analyses, based on two-sided α=0.05, revealed values of 52%, 14%, and 43% in the entire population, organ-confined, and nonorgan-confined subgroups, respectively. CONCLUSIONS: In non-metastatic SBC treated with RC, the association between chemotherapy and lower CSM is particularly strong in organ-confined stage. A substantially larger cohort would be required to confirm the statistical significance of the recorded protective effect of chemotherapy.

Effect of inguinal lymph node dissection in lymph node negative patients with squamous cell carcinoma of the penis.

INTRODUCTION: The survival benefit of inguinal lymph node dissection (ILND) vs no ILND in patients with squamous cell carcinoma of the penis (SCCP) and the absence of lymph node invasion is unclear. We addressed this uncertainty within the Surveillance, Epidemiology and End Results (SEER 2000-2018) database. MATERIAL AND METHODS: We identified lymph node negative SCCP patients who either underwent ILND (pN0) or clinical examination only (cN0). We tested for the effect of ILND vs no ILND on cancer-specific mortality (CSM) in Kaplan-Meier plots, univariable and multivariable Cox regression analyses, in a pT stage-specific fashion, before and after 1:3 propensity score matching (PSM). Sensitivity analyses were conducted according to historical and contemporary treatment periods as well as geographic regions. RESULTS: Of 2520 SCCP patients, 369 (15%) underwent ILND (pN0) vs 2151 (85%) did not (cN0). The pN0 vs cN0 distribution according to pT stages was as follows: 80 (7%) vs 1092 (93%) in pT1b, and 289 (21%) vs 1059 (79%) in pT2-3. At 36 months, CSM-free survival in pT2-3 stage was 89% in ILND vs 74% in no ILND patients (multivariable hazard ratio: 0.42, CI 0.30-0.60, p < 0.001). This result was confirmed in sensitivity analyses, and after 1:3 PSM. The same analyses could not be completed in pT1b stage due to insufficient number of observations and events. CONCLUSIONS: In pT2-3 stage SCCP, a significantly lower CSM was recorded in lymph node negative patients treated with ILND than in their clinical lymph node negative counterparts who did not undergo ILND.

Efficacy of chemotherapy on overall survival in metastatic sarcomatoid bladder cancer patients.

Introduction: The role of chemotherapy in metastatic sarcomatoid bladder cancer (mSBC) is unknown. The current work aimed to test the effect of chemotherapy on overall survival (OS) in mSBC patients. Material and methods: Using the Surveillance, Epidemiology and End Results database (2001-2018), we identified 110 mSBC patients of all T and N stages (TanyNanyM1). Kaplan-Meier plots and Cox regression models were used. Covariates consisted of type of surgical treatment (no treatment vs radical cystectomy vs other), and patient age. The endpoint of interest was OS. Results: In 110 mSBC patients, 46 (41.8%) were exposed to chemotherapy vs 64 (58.2%) who were chemotherapy naive. Chemotherapy exposed patients were younger (median age 66 vs 70, p = 0.005). Median OS was 8 months in chemotherapy exposed vs 2 months in chemotherapy naive patients. In univariable Cox regression models, chemotherapy exposure was associated with a hazard ratio (HR) of 0.58 (p = 0.007).In multivariable Cox regression models adjusted for case mix, chemotherapy exposure was associated with a HR of 0.60 (p = 0.016). Conclusions: To the best of our knowledge, this is the first report of chemotherapy effect on OS in mSBC patients. OS is extremely poor. Nonetheless, it is improved in a statistically significant and clinically meaningful fashion, when chemotherapy is administered.