Molecular tumor heterogeneity in muscle invasive bladder cancer: Biomarkers, subtypes, and implications for therapy Despite years of slow progress, muscle invasive bladder cancer (MIBC) is finally entering the era of molecularly guided targeted therapy. However, tumor heterogeneity is high in MIBC and may impact treatment response and resistance. The objective of this review is to dissect recent insights into inter- and intratumor heterogeneity (ITH) in MIBC, with emphasis on the clinical implications of this heterogeneity for biomarker-driven strategies and the development of new therapies.
Introduction to the seminar series: Optimal management during ADT to mitigate complications In this special edition of Urologic Oncology, we are addressing the effects of androgen deprivation therapy (ADT) for men with prostate cancer. The contributors to this edition were invited based their areas of expertise and willingness to present updated and practical information for providers involved in the care of prostate cancer patients. Drs. Melloni and Roe present current data on androgen deprivation therapy and cardiovascular disease. Management of bone and metabolic effects is reviewed by Drs.
Renal cell carcinoma and brain metastasis: Questioning the dogma of role for cytoreductive nephrectomy The increased utilization of cross-sectional imaging is at least partially responsible for the growing incidence of renal cell carcinoma (RCC) throughout the last 30 years. It has been estimated for 2018 that approximately 65,340 new patients will be diagnosed with RCC, over 60% incidentally, and about 14,970 patients will die from RCC . Even with the increased detection of incidental renal masses, approximately 30% of patients still present with metastatic disease .
Re: “Monopolar vs. bipolar transurethral resection for nonmuscle invasive bladder carcinoma: A post hoc analysis from a randomized controlled trial” The authors have published a valuable article that compares safety and efficacy between monopolar transurethral resection of bladder (mTURB) and bipolar (bTURB) for patients with primary nonmuscle invasive bladder cancer. They have found no evident advantages of bTURB over mTURB with respect to operation time, perioperative and postoperative complication rates, and recurrence rates at 12 months . The mainstay for the diagnosis and initial treatment of bladder cancer is TURBT, aiming at reaching a definitive diagnosis and removing all visible lesions including a part of underlying muscle .
Proton therapy for prostate cancer: A review of the rationale, evidence, and current state Men diagnosed with localized prostate cancer have many curative treatment options including several different radiotherapeutic approaches. Proton radiation is one such radiation treatment modality and, due to its unique physical properties, offers the appealing potential of reduced side effects without sacrificing cancer control. In this review, we examine the intriguing dosimetric rationale and theoretical benefit of proton radiation for prostate cancer and highlight the results of preclinical modeling studies.
Analyzing the current practice patterns and views among urologists regarding focal therapy for prostate cancer The widespread use of prostate-specific antigen screening has led to an earlier and increased diagnosis of low-risk prostate cancer (CaP) [1,2]. While urologists have increasingly been using active surveillance for very low-risk and low-risk disease, whole gland treatment (WGT) by means of radical prostatectomy and radiation therapy is still widely used for high volume low-risk and low volume intermediate-risk CaP. However, the risk of CaP mortality in these populations is low [3,4]. These patients may ultimately receive WGT because of several reasons, including, but not limited to, concerns of the patient and physician, young patient age, and strong family history [3,5].
Role of serum cholinesterase in patients treated with salvage radical prostatectomy Serum cholinesterase (ChE) a serine hydrolase that catalyses the hydrolysis of esters of choline, is involved in cellular proliferation and differentiation, therefore affecting carcinogenesis. The aim of this study was to understand the prognostic role of preoperative serum ChE in patients with radiation-recurrent prostate cancer (CaP) treated with salvage radical prostatectomy (SRP).
A delay ≥8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging Bladder cancer is the fifth most common cancer in the United States with an estimated incidence of 81,190 in 2018 . Approximately 25% of new cases present as muscle invasive disease, which is associated with a higher risk of developing metastasis and death. Studies have suggested that a delay in radical cystectomy (RC) is associated with a decrease in overall survival (OS) [2–5] and it is now recommended to perform radical surgery within 3 months from diagnosis . However, after RC, the 5-year survival is only 50% .
Preoperative apolipoprotein B/A1 ratio is an independent prognostic factor in metastatic renal cell carcinoma Kidney cancer is among the 10 most common human malignancies in men and women [1,2]. According to statistics, approximately 65,340 new cases and 14,970 deaths are related to this malignancy in 2018 in the United States . Renal cell carcinoma (RCC), which is derived from renal tubular epithelial cells, is the most common histological type and accounts for over 80% of all cases [1,2,4,5]. Approximately more than 15% of all RCC patients are diagnosed with metastatic renal cell carcinoma (mRCC) [1,3,6], and over 20% of patients with localized RCCs have metastases after partial or radical nephrectomy .
Utilizing precision medicine to modulate the prostate tumor microenvironment and enhance immunotherapy The last two decades of cancer research have seen two major advancements in our ability to treat cancer: precision medicine and immunotherapy. While these approaches have shown striking anticancer efficacy in numerous malignancies, they have not shown similar success and applicability in advanced prostate cancer patients. The fields of precision medicine and immunotherapy have come to realize that targeted therapies are capable of not only inhibiting tumor cell growth, but also promoting antitumor immunity by modulating the tumor microenvironment.
Assessing trends in urinary diversion after radical cystectomy for bladder cancer in the United States In the United States, bladder cancer will be diagnosed in an estimated 81,000 patients in 2018 . Radical cystectomy (RC) with a thorough pelvic lymph node dissection is the treatment of choice for muscle-invasive bladder cancer [2,3]. Following RC, reconstruction of the urinary system can be performed using a variety of techniques. The critical distinction of different diversion options is between incontinent diversions (ID) and continent diversions (CD), such as catheterizable continent cutaneous pouches and the most common form, the orthotopic neobladder.
Prognostic significance of serum γ-glutamyltransferase in patients with advanced urothelial carcinoma Urothelial carcinoma (UC), including bladder UC (90%–95%) and upper urinary tract UC (5%–10%), are estimated to account for 85,000 new cancer cases and 18,000 deaths in the United States in 2018, making UC the fourth and twelfth most common cancer in men and women, respectively . Patients with advanced UC (aUC) generally show poor prognosis with median overall survival (OS) of 3 to 6 months without treatment and 13 to 16 months with systemic chemotherapy . The first prognostic model predicting survival of patients with aUC was developed by Bajorin et al., which consisted of Karnofsky performance status (KPS) and the presence of visceral metastasis as dual independent predictors of OS .
Mutations in renal cell carcinoma Renal cell carcinoma (RCC) is a commonly diagnosed and histologically diverse urologic malignancy. Clear cell RCC (ccRCC) is by far the most common, followed by the papillary and chromophobe subtypes. Sarcomatoid differentiation is a morphologic change that can be seen in all subtypes that typically portends a poor prognosis. In the past, treatment options for RCC were limited to cytokine-based therapy with a high-toxicity profile and low response rate. An increased understanding of the molecular basis of RCC has led to substantial improvement in treatment options in the form of targeted therapy and immunotherapy.
Development and translation of novel therapeutics targeting tumor-associated macrophages Tumor-associated macrophages (TAMs) regulate an array of tumor functions and have critical roles in both the progression and the eradication of cancer. Numerous therapies targeting TAMs are under development in cancer and many have demonstrated success at the preclinical and clinical levels. Most of these therapies fall within 3 main categories: systemic depletion of TAMs, inhibition of TAM recruitment and polarization, and promoting the antitumor functions of TAMs. In this article, the rationale behind these various therapies and approaches is reviewed along with supporting preclinical and clinical data.
Frailty as a predictor of complications after radical cystectomy: A prospective study of various preoperative assessments In the United States in 2018, it is estimated 81,190 patients will be diagnosed with bladder cancer, and 17,240 patients will die due to the disease . Both men and women are usually diagnosed at an advanced age, with an average age of 69 years for men and 71 years for women . The 5-year cause-specific survival rate for those 60 to 65 years old is 84% and decreases to 60% in those 85 years and older . While radical cystectomy is the gold standard treatment for muscle-invasive bladder cancer, this procedure carries significant morbidity, with reported 30-day complication rates ranging from 31.5% to 58% [4–9] and 90-day complication rates from 47% to 78% .
EGFR mono-antibody salvage therapy for locally advanced and distant metastatic penile cancer: Clinical outcomes and genetic analysis For locally advanced (including inguinal and pelvic lymph node metastatic disease) and distant metastatic penile squamous cell carcinoma (PSCC), multimodal treatments utilizing surgery, chemoradiotherapy and/or chemotherapy continue to be the most popular treatment regimen. Although several chemotherapy regimens combined with surgery have achieved encouraging short-term efficacies, long-term survival for those patients remains poor [1,2]. For patients with chemotherapy-failed experience, therapeutic options are even more limited.
Propensity-score-matched comparison of soft tissue surgical margins status between open and robotic-assisted radical cystectomy Open radical cystectomy (ORC) with pelvic lymph node dissection is the standard of care treatment for very high-risk non–muscle-invasive and muscle-invasive urothelial carcinoma of the bladder (UCB), providing durable local cancer control [1–3]. Even when performed by experienced surgeons, it is associated with significant morbidity including bleeding, pain associated with the incision and prolonged abdominal wall retraction, as well as major fluid shifts . Additionally, visibility of the surgical field can be difficult in the deep pelvic and retrovesical spaces [5–9].
Mutational landscape of non-muscle-invasive bladder cancer Non-muscle-invasive bladder cancer (NMIBC) includes stage Ta and stage T1 tumors and carcinoma in situ (CIS). Grading of Ta tumors subdivides these lesions into papillary urothelial neoplasms of low malignant potential and low- and high-grade noninvasive papillary urothelial carcinoma. CIS is by definition high-grade and the majority of stage T1 tumors are of high-grade. This pathologic heterogeneity is associated with divergent clinical outcome, with significantly worse prognosis for patients with T1 tumors or CIS.
The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer Immunotherapy—particularly immune checkpoint blockade—has seen great success in many tumor types. However, checkpoint-based therapies have not demonstrated high levels of success in prostate cancer, and there is much to be learned from both the successes and failures of these treatments. Here we review the evidence that composition of infiltrating immune cells in the tumor microenvironment is fundamental to the response to immunotherapy. Additionally, we discuss the emerging idea that the organization of these immune cells may also be crucial to this response.
Exercise medicine for the management of androgen deprivation therapy-related side effects in prostate cancer Androgen deprivation therapy (ADT) is associated with considerable adverse side effects which compromise the health and wellbeing of many men with prostate cancer. Exercise has been identified as a therapy to help manage ADT-related treatment toxicities. This paper systematically reviews the scientific literature investigating the impact of exercise on men receiving ADT and discusses strategies to effectively implement exercise in clinical practice. The findings of this review demonstrate that exercise has therapeutic benefit for the management of ADT-related side effects.
Management of bone and metabolic effects of androgen deprivation therapy Androgen Deprivation Therapy (ADT) has established roles in the neoadjuvant treatment of high risk localized prostate cancer (CaP) together with radiotherapy, and in biochemically recurrent nonmetastatic, and metastatic disease. Use of gonadotrophin-releasing hormone (GnRH) analogs as a means of blocking testosterone production is currently the most commonly used ADT modality. As long-term survival in men receiving ADT is the norm, it is appropriate to focus on identification and mitigation of adverse effects of this therapy.
Trends and outcomes of lymphadenectomy for nonmetastatic renal cell carcinoma: A propensity score-weighted analysis of the National Cancer Database Kidney cancer is the third most common genitourinary malignancy, with an estimated 65,340 new diagnoses and 14,970 deaths in 2018 . The vast majority of kidney cancers are renal cell carcinoma (RCC), accounting for over 90% of renal parenchymal tumors . RCC is associated with significant morbidity and mortality, and an especially poor prognosis when there is lymph node (LN) involvement. For example, numerous studies have identified both clinical and pathologic lymphadenopathy as independent adverse prognostic factors for cancer-specific survival (CSS) and all-cause mortality (ACM) .
Molecular footprints of muscle-invasive bladder cancer in smoking and nonsmoking patients Bladder cancer is one of the most common cancers in the United States and occurs in men more frequently than in women . About 70% of bladder cancers are nonmuscle invasive, while the remaining patients have muscle invasive (MIBC) or metastatic tumors, with significantly reduced survival [2,3]. Smoking is recognized as the most important risk factor for bladder cancer, and smokers are 4 to 7 times more likely to develop bladder cancer than nonsmokers [4–6]. Tobacco consumption may increase the risk of bladder cancer because of the accumulation of tobacco-derived chemicals in the urine, which in turn cause DNA damage in the urothelium [6,7].
Current controversies on the role of retroperitoneal lymphadenectomy for testicular cancer Retroperitoneal lymph node dissection (RPLND) is an important component of the multimodal treatment which cures most patients diagnosed with testicular germ cell tumors. Considering the high cure rates achieved, research focus in recent years has been directed toward improving quality of life and decreasing long-term treatment related sequelae. Consequently, the role of RPLND has evolved over the past 3 decades in both low-stage and advanced testicular cancer.The use of RPLND in clinically stage I and low volume stage II disease may offer the advantages of treating retroperitoneal teratoma which is present in 15% to 20% of patients, avoiding chemotherapy and reducing the need for frequent imaging during follow-up.
Post-translational modifications in bladder cancer: Expanding the tumor target repertoire Bladder cancer (BCa) is the second most common urological malignancy after prostate cancer and a major cause of morbidity and death with enormous health-related cost. Approximately, 75% of newly diagnosed BCa patients have non-muscle invasive bladder cancer (NMIBC). Of this group, 70% of patients experience post-treatment recurrence that requires lifelong monitoring and up to 25% progress to more advanced disease [1,2]. In contrast to NMIBC, muscle-invasive bladder cancer (MIBC) is highly metastatic with a 5-year survival rate of approximately 50% in patients undergoing treatment .
Current controversies and developments on the role of lymphadenectomy for penile cancer Penile squamous cell carcinoma is a rare cancer in men. The main prognosticators of survival for penile cancer patients remain the presence and the extent of lymph node metastasis. While radical inguinal lymphadenectomy has been the cornerstone of regional lymph node management for many years, it is still associated with significant morbidity and psychological distress. Recent developments in penile squamous cell carcinoma management have been met with some controversy in the urologic oncology community.
Prostate cancer tissues with positive TMPRSS2-ERG-gene-fusion status may display enhanced nerve density Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue. In parallel, we measured several members of the neuropilin/plexin/semaphorin family (NRP, PLXN, and SEMA) as possible targets mediating innervation.
Mechanisms and funding opportunities in genitourinary cancer clinical research Progress in the prevention, diagnosis, and treatment of genitourinary cancers is dependent on well-conducted clinical trials. The complexity and cost of clinical research continues to escalate, and success is dependent on adequate funding. Opportunities to fund such research include federal, industry, and private sources. The mechanisms whereby larger trials are conducted include contract research organizations, publically- and privately funded consortia, and the National Clinical Trials Network of the National Cancer Institute.
Current controversies on the role of lymphadenectomy for bladder cancer Significant evidence exists regarding the diagnostic and therapeutic roles of pelvic lymph node dissection at the time of radical cystectomy for patients with bladder cancer. Despite this, lymphadenectomy for bladder cancer is still underutilized and even where performed, controversies exist in regard to what defines an adequate dissection and whether or not the indications for lymphadenectomy have changed now that we are firmly entrenched in the neoadjuvant chemotherapy era. A comprehensive literature review was performed to touch on these important issues and highlight future directions and current trials that will soon provide more clarity for surgeons and patients dealing with bladder cancer.
Lifestyle and nutritional modifiable factors in the prevention and treatment of bladder cancer Bladder cancer is one of the top 5 most common cancers diagnosed in the U.S. It is also one of the most expensive cancers to treat through the life course given its high rate of recurrence. While cigarette smoking and occupational exposures have been firmly established as risk factors, it is less certain whether modifiable lifestyle factors such as diet and physical activity play roles in bladder cancer etiology and prognosis. This literature review based on a PubMed search summarizes the research to date on key dietary factors, types of physical activity, and smoking in relation to bladder cancer incidence, and discusses the potential public health implications for formalized smoking cessation programs among recently diagnosed patients.
Role of lymph node dissection in renal cell cancer Lymph node metastasis in renal cell cancer (RCC) portends an extremely poor prognosis. Despite proven staging benefit, the therapeutic value of lymph node dissection in RCC remains questionable. The only prospective randomized trial examining its role failed to show any benefit. However, subsequent retrospective publications have attempted to identify high-risk cohorts and clinical scenarios where removal of nodes may improve survival. The aim of this article is to provide a comprehensive review looking at the role of lymph node dissection in RCC if any, the ideal extent of dissection, and also tools a clinician could employ to identify those who would most likely benefit from this exercise.
Key design and analysis principles for quality of life and patient-reported outcomes in clinical trials Cancer researchers have increasingly aimed to incorporate the patient’s perspective in examinations of new treatments or interventions . Central to this effort is the use of patient-reported outcomes (PROs), which are designed specifically to reflect the patient’s experience with respect to disease, treatment symptoms, and quality of life (QOL), as well as treatment tolerability and toxicity. PROs augment clinical outcomes through more comprehensive assessment of symptoms and side effects associated with investigational therapies and provide alternative endpoints (such as QOL) that may impact the overall evaluation of new therapies.
Contribution of bladder cancer pathology assessment in planning clinical trials Bladder cancer is a heterogeneous disease that demonstrates a wide spectrum of histologic features. The modern classification of bladder cancer is largely based on pathologic analysis, which assesses tumor grade, stage, type, size, and other features that are essential for understanding the biological behavior of bladder cancer. Bladder cancers with similar histologic features are likely to show comparable responses to a new therapeutic agent in clinical trial. Furthermore, pathologic analysis also evaluates the quality of tissue samples in clinical trial to ensure the integrity of various molecular tests.
Optimizing androgen deprivation therapy with radiation therapy for aggressive localized and locally advanced prostate cancer Radiation therapy with androgen deprivation therapy (ADT) has historically been one of the mainstays of treatment for intermediate- and high-risk prostate cancer. The benefit of ADT likely derives from both enhancing local control and inhibiting micrometastatic disease. While level 1 evidence has demonstrated the benefits of 4–6 months of ADT for all men with intermediate-risk disease, further stratification of intermediate-risk prostate cancer into favorable and unfavorable subgroups indicates that ADT may not be necessary for favorable intermediate-risk disease but likely still provides a survival advantage for unfavorable intermediate-risk disease, even in the dose escalation era.
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