Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review

Advancements in the understanding of tumor immunology in urothelial carcinoma (UC) have led to U.S Food and Drug Administration (FDA) approval of five novel anti-programmed cell death protein-1/ligand 1 (PD-1/L1) checkpoint inhibitors. In 2017, the anti-PD-L1 antibody atezolizumab and the anti-PD-1 antibody pembrolizumab gained approval for use in cisplatin-ineligible patients with locally advanced and metastatic UC. These approvals were based on single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). Since then, additional checkpoint inhibitors, including avelumab, durvalumab, and nivolumab, have gained approval. Preliminary results suggest additional benefits with combinations of these agents in both first- and subsequent-line therapies, inferring a paradigm shift in the future treatment approach in advanced UC. Ongoing clinical trials will investigate how to utilize predictive biomarkers for optimal patient selection and to incorporate immunotherapy into earlier lines of multimodal treatment. In this comprehensive review, we summarize the evidence supporting the use of checkpoint inhibitors for patients with UC, and highlight ongoing clinical trials that are investigating novel combinations of immunotherapy in various disease settings.ope

Comparison of prostate cancer detection rates of various prostate biopsy methods for patients with prostate-specific antigen levels of <10.0 ng/mL in real-world practice

Purpose: Several strategies of prostate biopsy (PBx) have been introduced to improve prostate cancer (PCa) detection rates. However, studies comparing cancer detection rates (CDRs) according to biopsy methods in real-world practice are scarce. This study aimed to investigate CDRs according to the biopsy methods for patients with prostate-specific antigen (PSA) <10.0 ng/mL. Materials and Methods: From 2006 to 2015, patients who underwent PBx were initially selected. All patients were categorized according to the biopsy methods performed (magnetic resonance imaging targeted biopsy [MR-TBx], 12+2 hypoechoic lesion target biopsy, saturation biopsy [sPBx], extended biopsy, and 12-core PBx). The CDR of MR-TBx was compared to that of sPBx and other protocols. Volume per core (VPC) was defined as prostate volume divided by the number of biopsy cores. Patients previously diagnosed with PCa were excluded. Results: Of the 1,598 patients (median PSA, 5.41 ng/mL), 401 (25.1%) were diagnosed with PCa. Among the biopsy methods, MR-TBx has the highest CDR and proportion of Gleason score ≥7 (3+4). Biopsy methods, VPC, age, prostate volume, and PSA were associated with PCa detection. In the sub-analysis for initial biopsy, MR-TBx had no significant difference with sPBx, but had higher CDR than the other biopsy protocols. For repeat biopsy, VPC, rather than the biopsy method, was associated with CDR. Conclusions: This study reaffirmed the efficacy of MR-TBx on CDR in real-world practice. In cases with barriers to performing magnetic resonance imaging, VPC might be useful for adjusting the optimal number of biopsy cores in repeat biopsy.ope

Is targeted biopsy really needed when performing systematic prostate biopsy to raise the detection rate for prostate cancer in patients with prostate-specific antigen ≤10 ng/mL?

Targeted biopsy with multiparametric magnetic resonance imaging and hypoechoic lesions on transrectal ultrasound has been implemented to increase prostate cancer detection rate.We compared the detection abilities of systematic prostate biopsy, hypoechoic lesion-targeted biopsy (HL-TBx), and cognitive magnetic resonance imaging-targeted biopsy (MRI-TBx) in patients with suspected prostate cancer. Between September 2014 and August 2016, 193 patients with a prostate-specific antigen level of 3 to 10 ng/mL underwent HL-TBx or MRI-TBx. In patients who refused magnetic resonance imaging examination before prostate biopsy, HL-TBx was performed. We compared cancer detection rates and pathologic outcomes between systematic prostate biopsy and HL-TBx or MRI-TBx.The cancer detection rates for HL-TBx and MRI-TBx were 40.8% and 43.8%, respectively, without a significant difference (P = .683). Of the 81 patients diagnosed with prostate cancer, most patients (77 patients, 95.1%) were diagnosed with prostate cancer by systematic prostate biopsy. The detection ability for prostate cancer was significantly better for systematic prostate biopsy than for HL-TBx or MRI-TBx (P < .001).The detection abilities for clinically significant prostate cancer similar between HL-TBx and systematic prostate biopsy. Systematic prostate biopsy alone should be recommended for detection prostate cancer in patients with a prostate-specific antigen ≤10 ng/mL.ope

Treatment of Oligometastatic Hormone-Sensitive Prostate Cancer: A Comprehensive Review

With advancements in diagnostic techniques, including molecular and clinical imaging, that directly target cancer cells, oligometastatic prostate cancer (PCa) is being diagnosed in patients who were, in the past, considered to have localized disease. With accumulating evidence, there has been a paradigm shift in considering aggressive treatments targeted at both the primary tumor and metastatic lesions in an aim to avoid and delay the need for palliative treatments and, ultimately, to achieve survival benefits. However, many questions still remain unanswered regarding the understanding of oligometastatic PCa, from its definition to optimal treatment strategies for each individual. Limited retrospective studies have suggested that interventions, including local and/or metastasis-directed therapy using surgery and radiation therapy (RT), can improve survival outcomes with minimal risk of adverse effects. Such treatments have been shown to decrease the risks of subsequent palliative interventions and to delay the start of androgen-deprivation therapy. Nevertheless, available data are insufficient to draw a reliable conclusion regarding their effect on quality of life measures and overall survival. This comprehensive review overviews data from contemporary literature that have investigated treatments, including surgery and RT, for patients with oligometastatic PCa, namely pelvic lymph node positive disease and limited distant metastases, and summarizes ongoing trials that are evaluating the feasibility of aggressive multimodal treatments.ope

Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.ope

Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition.ope

The Association of A Number of Predictive Factors for The Recurrence of Papillary Urothelial Neoplasm of Low Malignant Potential: Prognostic Analysis From Multiple Academic Centers.

PURPOSE: To identify clinically useful predictors for the recurrence of papillary urothelial neoplasm of low malignant potential (PUNLMP), we reviewed the clinical information of patients who were diagnosed and treated in multiple tertiary-care academic facilities. MATERIALS AND METHODS: Between February 2007 and April 2015, 95 patients diagnosed with PUNLMP after transurethral resection of bladder (TURB) were included in this study. Age, gender, body mass index, smoking history, the presence or absence of previous history of urothelial neoplasm, the presence or absence of gross hematuria, cytological results at the time of diagnosis, tumor diameter, and multiplicity of tumor were estimated as variablesfor analysis. Cox regression tests were used for identifying predictive factors for recurrence of PUNLMP. RESULTS: Sixty-nine cases of PUNLMP were de novo primary bladder PUNLMPs without known urothelial lesions in the urinary tract, and 26 PUNLMPs were identified on surveillance biopsies of patients with a previous history of urothelial neoplasm. During the follow-up period, recurrences developed in 13 patients (13.7%). Recurrence rates were 4.2% and 9.5% at 12 and 24 months, respectively. On univariate and multivariate Cox regression analyses, previous history of urothelial neoplasm [95% confidence interval (CI): 0.057-0.604, hazard ratio (HR) = 0.185, P = .005] and multiplicity of tumors [95% CI = 0.064-0.584, HR = 0.193, P = .004] were identified as independent predictors for recurrence-free survival of patients with PUNLMP. CONCLUSION: Tumor multiplicity and previous history of urothelial neoplasm are independent prognostic factors forprediction of recurrence of PUNLMP. More careful and closer follow-up should be recommended for PULNMPpatients with tumor multiplicity or a previous history of urothelial neoplasm.ope

Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

The clinical spectrum of prostate cancer (PCa) varies from castration-naive to metastatic castration-resistant disease. Despite the administration of androgen synthesis inhibitors and chemotherapy regimens for castration-resistant prostate cancer, the treatment options for this entity are limited. The utilization of the immune system against cancer cells shows potential as a therapeutic modality for various solid tumors and hematologic malignancies. With technological advances over the last decade, immunotherapy has become an integral treatment modality for advanced solid tumors. The feasibility of immunotherapy has shown promise for patients with PCa, and with advances in molecular diagnostic platforms and our understanding of immune mechanisms, immunotherapy is reemerging as a potential treatment modality for PCa. Various combinations of individualized immunotherapy and immune checkpoint blockers with androgen receptor-targeted therapies and conventional cytotoxic agents show promise. This article will review the current status of immunotherapy, including new discoveries and precision approaches to PCa, and discuss future directions in the continuously evolving landscape of immunotherapy.ope

Current Status and Application of Metformin for Prostate Cancer: A Comprehensive Review

Metformin, an oral biguanide used for first-line treatment of type 2 diabetes mellitus, has attracted attention for its anti-proliferative and anti-cancer effects in several solid tumors, including prostate cancer (PCa). Liver kinase B1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) activation, inhibition of the mammalian target of rapamycin (mTOR) activity and protein synthesis, induction of apoptosis and autophagy by p53 and p21, and decreased blood insulin level have been suggested as direct anti-cancer mechanisms of metformin. Research has shown that PCa development and progression are associated with metabolic syndrome and its components. Therefore, reduction in the risk of PCa and improvement in survival in metformin users may be the results of the direct anti-cancer mechanisms of the drug or the secondary effects from improvement of metabolic syndrome. In contrast, some research has suggested that there is no association between metformin use and PCa incidence or survival. In this comprehensive review, we summarize updated evidence on the relationship between metformin use and oncological effects in patients with PCa. We also highlight ongoing clinical trials evaluating metformin as an adjuvant therapy in novel drug combinations in various disease settings.ope

Physical Activity and Subjective Vitality in Older Adults From Community-and Assisted-Living Settings

Purpose: There is a growing number of older adults moving into assisted-living facilities to maintain their independence while being assisted with certain tasks and having convenient access to services. Physical activity (PA) and vitality play an important role in independence, as well as in mental health, of older adults. However, no research has examined the difference in older adults' levels of vitality (defined as the state of feeling alive and alert) between those living in assisted-living facilities and those from community-living settings. This study also explored sociodemographic predictors of PA and vitality among older adults living in two different types of housing. Methods: This cross-sectional study examined differences in PA levels and vitality between older adults (aged ≥ 60 years; n = 148, mean age = 74.70 years) living in assisted-living facilities (n = 85, mean age = 77.46 years) and those in community-living settings (n = 63, mean age = 70.98 years). PA was assessed by accelerometry, and vitality was measured using the subjective vitality scale. Results: Engagement in light PA and moderate to vigorous PA was higher in individuals living in community-living settings after controlling for sociodemographic variables. However, vitality was not significantly different between the two types of housing after controlling for sociodemographic variables. Marital status, education, and number of diagnosed diseases were associated with vitality. Conclusion: The support is needed for designing strategies to increase PA in older adults living in assisted-living facilities. More attention should be paid to increasing subjective vitality of older adults in both types of housing to promote healthy aging.ope