Association of Melanoma-Associated Antigen-A and Program-death ligand 1 Expression and Clinical Outcomes in Urothelial Carcinoma

Background: The melanoma-associated antigen-A (MAGE-A) and program-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We aim to assess survival outcomes in patients with MAGE-A and PD-L1 expression.Methods: Analysis of MAGE-A and PD-L1 expression on neoplastic cells was conducted using tissue microarrays from patients with UC. We compared differential expression between stage and grade. Co-expression of MAGE-A and PD-L1 were sub-categorized. Fisher’s exact test was done for categorical variables followed by analysis of univariable and multivariable assessment of recurrence and progression free survival (RFS, PFS).Results: Co-expression of MAGE+/PD-L1+ had a higher expression in advanced disease, however only MAGE+/PD-L1- group was associated with shorter RFS (HR 1.89, 95%CI 1.19-2.99; p=0.006). MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1, 95%CI 5.96-49.4; p=<0.001). MAGE-A expression was more prevalent high-grade (p=0.015), and higher stage ≥pT2 (p=0.001). The 5-year RFS in MAGE+ was 44%vs.58% for MAGE- samples. On multivariable analysis MP was also associated with shorter recurrence (HR 1.55, 95%CI 1.05-2.30; p=0.03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12, 95%CI 1.12-8.68; p=0.03). Conclusion: We report that the expression of MAGE-A and PD-L1 is increased in more advanced disease and associated with shorter PFS. Furthermore, expression of MAGE-A is significant in higher grade and stage, and was associated with shorter RFS and PFS. The finding of worse prognosis of MAGE-A/PD-L1 provides early evidence that a potential combinatorial treatment strategy of co-targeting MAGE/PD-L1 with respective agents might be feasible. Further studies are needed to validate these findings

Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma.

Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape

Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma

Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape

Oncologic outcomes in men with metastasis to the prostatic anterior fat pad lymph nodes: a multi-institution international study

BackgroundThe presence of lymph nodes (LN) within the prostatic anterior fat pad (PAFP) has been reported in several recent reports. These PAFP LNs rarely harbor metastatic disease, and the characteristics of patients with PAFP LN metastasis are not well-described in the literature. Our previous study suggested that metastatic disease to the PAFP LN was associated with less severe oncologic outcomes than those that involve the pelvic lymph node (PLN). Therefore, the objective of this study is to assess the oncologic outcome of prostate cancer (PCa) patients with PAFP LN metastasis in a larger patient population.MethodsData were analyzed on 8800 patients from eleven international centers in three countries. Eighty-eight patients were found to have metastatic disease to the PAFP LNs (PAFP+) and 206 men had isolated metastasis to the pelvic LNs (PLN+). Clinicopathologic features were compared using ANOVA and Chi square tests. The Kaplan-Meier method was used to calculate the time to biochemical recurrence (BCR).ResultsOf the eighty-eight patients with PAFP LN metastasis, sixty-three (71.6%) were up-staged based on the pathologic analysis of PAFP and eight (9.1%) had a low-risk disease. Patients with LNs present in the PAFP had a higher incidence of biopsy Gleason score (GS) 8-10, pathologic N1 disease, and positive surgical margin in prostatectomy specimens than those with no LNs detected in the PAFP. Men who were PAFP+ with or without PLN involvement had more aggressive pathologic features than those with PLN disease only. However, there was no significant difference in BCR-free survival regardless of adjuvant therapy. In 300 patients who underwent PAFP LN mapping, 65 LNs were detected. It was also found that 44 out of 65 (67.7%) nodes were located in the middle portion of the PAFP.ConclusionsThere was no significant difference in the rate of BCR between the PAFP LN+ and PLN+ groups. The PAFP likely represents a landing zone that is different from the PLNs for PCa metastasis. Therefore, the removal and pathologic analysis of PAFP should be adopted as a standard procedure in all patients undergoing radical prostatectomy

Prevention of erectile dysfunction after radiotherapy for prostate cancer

With increasing scrutiny of prostate cancer (PCa) diagnosis and treatment, much attention has been given to the morbidity caused by radical prostatectomy (RP) and/or radiotherapy (RT). One of the most common side-effects of either treatment is erectile dysfunction (ED). [1] Approximately, 40% of patients will experience ED after RT for PCa. The post-RT ED causes significant patient dissatisfaction with cancer treatment as well as decrease in patient and partner psychosocial function. [2] To address this issue in patients undergoing RT, Pisansky et al. [3] conducted a prospective, randomized, double-blinded, placebo-controlled trial to assess the efficacy of a phosphodiesterase enzyme-5 inhibitor (PDE5i), tadalafil, as a preventive measure for patients undergoing RT for PCa and found no difference in erectile function between the control and treatment groups

Intravesical Therapy for Non-muscle Invasive Bladder Cancer-Current and Future Options in the Age of Bacillus Calmette-Guerin Shortage.

Non-muscle invasive bladder cancer (NMIBC) is a common and burdensome malignancy. A substantial proportion of patients with intermediate- and high-risk disease will progress to invasive bladder cancer and are at a significant risk for metastasis and death. Bacillus Calmette-Guerin (BCG) therapy for selected cases has been the standard of care for nearly 40 years. Unfortunately, a world-wide shortage has made BCG challenging to obtain. Furthermore, recurrences and progressions do occur. With the US Food and Drug Administration creating a clear path to drug approval for novel treatments, many therapies have been tested, including intravesical cytotoxic chemotherapy, intravesical immunotherapy, systemic immunotherapy, and novel agents, such as gene therapy and targeted therapy. In this review, we highlight ongoing clinical trials

Overcoming Immune Resistance in Prostate Cancer: Challenges and Advances

The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer

Comparative analysis of the risk of radiation exposure and cost of reduced imaging intensity for surveillance of early-stage nonseminomatous germ cell tumors

OBJECTIVE: To evaluate the surveillance recommendations for early-stage testis cancer and the risk of secondary malignancies due to increased radiation exposure. MATERIALS AND METHODS: Using National Comprehensive Cancer Network (NCCN) guidelines 2012 and 2014 for early-stage testicular cancer, the numbers of abdominal and pelvic computed tomography scans (CTAPs) and chest radiographies were calculated, and lifetime attributable risk for secondary malignancy was estimated using Biologic Effects of Ionizing Radiation VII organ-specific model for solid organ malignancy based on the initial age of exposure. Cost was based on the Centers for Medicare and Medicaid Services' cost estimates of CTAP and magnetic resonance imaging (MRI). RESULTS: The 2012 NCCN protocol uses a maximum of 17 CTAPs over 6 years, whereas 2014 guidelines suggest a maximum of 13 CTAPs. The radiation dosage in 2014 guidelines is decreased by 25% compared to the 2012 NCCN guidelines. The minimum number of CTAPs under the 2014 NCCN protocol reduced radiation dose by 38% compared to the maximum number, this compared to about 50% decrease from the 2012 NCCN guidelines. The median cost for a single CTAP with contrast is $369.30; median cost for a single MRI with contrast is$772.18. As compared to the 2012 protocol, the 2014 guidelines reduced CTAP cost by approximately 24%-54% for minimum and maximum CTAPs allowed. CONCLUSION: There is low, however nonzero, risk of secondary malignancy for surveillance in stage I testicular cancer. There is also a significant cost difference between protocols as well as between CT and MRI modalities