Systemic therapy landscape of advanced prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in American men and 2nd leading cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. Over the past several decades a number of new therapeutics, such as novel androgen receptor pathway inhibitors, targeted agents and radionuclide therapies, have been introduced for the treatment of prostate cancers. These agents have been demonstrated to improve clinical outcomes of prostate cancer patients in randomized clinical trials. In addition, new therapeutic strategies, such as early intensification of ADT, novel treatment combinations, and treatment sequencing, are expected to improve outcomes further. In this clinical review, we discuss the changing treatment landscape for advanced prostate cancer with a focus on new therapeutics.

A TFEB-Amplified Renal Cell Carcinoma with Long-Term, Complete Immunotherapy Response: Retrospective Support for the Value of Molecular Classification.

Recent years have seen the recognition and establishment of numerous subtypes of renal cell carcinoma (RCC), including adoption of an entire category of "molecularly defined renal carcinomas" in the fifth Edition of World Health Organization Classification. To add value, new diagnostic entities should be clinicopathologically distinct, or better, imply specific management and treatment angles, especially if adjunctive testing is needed for diagnosis. One such promising future treatment angle for a molecularly defined subtype, TFEB-amplified RCC, is immunotherapy, for which recent scholarship has demonstrated frequent expression of PD-L1. Herein, we report a case of metastatic TFEB-amplified RCC, where the patient experienced a long-term, complete response to PDL1-directed therapy, which had been serendipitously used years ago under a renal tumor subtype-agnostic indication. This promising experience suggests formal exploration of immunotherapy for these tumors.

Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984.

PURPOSE: Cediranib, a pan-vascular endothelial growth factor receptor inhibitor, suppresses expression of homologous recombination repair (HRR) genes and increases sensitivity to poly-(ADP-ribose) polymerase inhibition in preclinical models. We investigated whether cediranib combined with olaparib improves the clinical outcomes of patients with prostate cancer. METHODS: Patients with progressive metastatic castration-resistant prostate cancer (mCRPC) were randomly assigned 1:1 to arm A: cediranib 30 mg once daily plus olaparib 200 mg twice daily or arm B: olaparib 300 mg twice daily alone. The primary end point was radiographic progression-free survival (rPFS) in the intention-to-treat patients. The secondary end points were rPFS in patients with HRR-deficient and HRR-proficient mCRPC. RESULTS: In the intention-to-treat set of 90 patients, median rPFS was 8.5 (95% CI, 5.4 to 12.0) and 4.0 (95% CI, 3.2 to 8.5) months in arms A and B, respectively. Cediranib/olaparib significantly improved rPFS versus olaparib alone (hazard ratio [HR], 0.617; 95% CI, 0.392 to 0.969; P = .0359). Descriptive analyses showed a median rPFS of 10.6 (95% CI, 5.9 to not assessed [NA]) and 3.8 (95% CI, 2.33 to NA) months (HR, 0.64; 95% CI, 0.272 to 1.504) among patients with HRR-deficient mCRPC, and 13.8 (95% CI, 3.3 to NA) and 11.3 (95% CI, 3.8 to NA) months (HR, 0.98; 95% CI, 0.321 to 2.988) among patients with BRCA2-mutated mCRPC in arms A and B, respectively. The incidence of grades 3-4 adverse events was 61% and 18% in arms A and B, respectively. CONCLUSION: Cediranib combined with olaparib improved rPFS compared with olaparib alone in men with mCRPC. This combination was associated with an increased incidence of grades 3-4 adverse events. BRCA2-mutated subgroups treated with olaparib with or without cediranib were associated with a numerically longer median rPFS.

Current Management of Urachal Carcinoma: An Evidence-based Guide for Clinical Practice.

Urachal carcinoma is a rare urological disease. The shortage of data about diagnosis and surgical treatment in literature makes it hard for clinicians to make a decision. Indeed, urachal carcinoma is an aggressive disease that requires prompt staging and treatment to ensure the best outcome for patients. We reviewed the last evidence about the management of urachal carcinoma to provide an easy-to-use guide for clinical practice. Patient summary: Urachal carcinoma is a rare malignancy. The literature on this challenging disease remains limited. Herein, we provide a practical guide for its management from diagnosis to treatment, which in most cases requires surgical intervention or chemotherapy.

Adverse Events of Immune Checkpoint Inhibitors Therapy for Urologic Cancer Patients in Clinical Trials: A Collaborative Systematic Review and Meta-analysis.

CONTEXT: Therapies based on immune checkpoint inhibitors (ICIs) are transforming the treatment landscape of urologic oncology. Nevertheless, an exhaustive overview of the toxicity spectrum of these novel therapies has yet to be provided. OBJECTIVE: To comprehensively investigate the incidence and profile of ICI therapy-related adverse events (AEs) across urologic cancers. EVIDENCE ACQUISITION: We searched for all clinical trials investigating the role of ICI therapy published between January 2010 and September 2021. Studies involving urologic cancers with reported overall incidence or tabulated data of treatment-related AEs (trAEs) or immune-related AEs (irAEs) were included. A systematic review and meta-analysis was performed after protocol registration in PROSPERO (CRD42021276435). EVIDENCE SYNTHESIS: We identified 2638 records, of which 92 studies (including 22942 participants) met the inclusion criteria. The pooled overall incidence was 81.6% (95% confidence interval [CI] 78.0-84.7) for any-grade trAEs and 29.3% (95% CI 24.9-34.1) for grade ≥3 trAEs. The pooled overall incidence was 34.3% (95% CI 28.5-40.7) for any-grade irAEs and 10.2% (95%CI 8.2-12.7) for grade ≥3 irAEs. On a multivariable analysis, cancer type, therapy combination, clinical settings (perioperative vs advanced/metastatic), and drug exposure were independently associated with the occurrence of trAEs or irAEs. The overall rate of treatment-related mortality was 0.94% (140 of 14 899 participants), with pneumonitis (9.3%), pneumonia (7.9%), and respiratory failure (7.1%) being the most common causes. Immune-related mortality occurred in 0.26% (28 of 10 723) patients, with pneumonitis (35.7%), hepatic failure (10.7%), and hepatitis (7.1%) being most common. CONCLUSIONS: Our study provides a comprehensive overview of ICI-associated AEs in urologic cancer patients. The spectrum and incidence of AEs vary across cancer types, ICI types, clinical settings, and therapy combinations. These findings provide important guidance to clinicians in counseling and management of patients with urologic cancers. PATIENT SUMMARY: A high proportion of patients experience immune checkpoint inhibitor-associated toxicity. Physician and patient education is critical for early recognition and proper management.

Trimodal therapy in muscle invasive bladder cancer management.

INTRODUCTION: Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC. EVIDENCE ACQUISITION: A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). EVIDENCE SYNTHESIS: The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported. CONCLUSIONS: Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.

New Antiandrogen Compounds Compared to Docetaxel for Metastatic Hormone Sensitive Prostate Cancer: Results from a Network Meta-Analysis.

PURPOSE: Docetaxel represent the standard of care in patients with metastatic, hormone sensitive prostate cancer. However, androgen receptor axis targeted therapies have also been shown to be effective. We aimed to analyze findings in randomized controlled trials investigating first-line treatment for hormone sensitive prostate cancer. MATERIALS AND METHODS: We systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and the PICO (Population, Intervention, Comparator, Outcomes) methodology. Outcomes of interest were overall and progression-free survival, and the rate of high grade adverse events. RESULTS: No treatment was superior to docetaxel in terms of overall survival. However, abiraterone (HR 0.89, 95% CI 0.76-1.05), enzalutamide (HR 0.90, 95% CI 0.69-1.19) and apalutamide (HR 0.90, 95% CI 0.67-1.22) showed nonstatistically significant lower overall mortality rates than docetaxel. Abiraterone (HR 0.71, 95% CI 0.59-0.86), enzalutamide (HR 0.61, 95% CI 0.49-0.75) and apalutamide (HR 0.74, 95% CI 0.57-0.95) also showed statistically significant lower disease progression rates than docetaxel. Furthermore, abiraterone (OR 0.83, 95% CI 0.56-1.21) showed no statistically significant lower rate of high grade adverse events compared to docetaxel. Finally, enzalutamide (OR 0.56, 95% CI 0.35-0.92) and apalutamide (OR 0.44, 95% CI 0.24-0.79) showed statistically significant lower rates of high grade adverse events compared to docetaxel. CONCLUSIONS: Treatment with androgen receptor axis targeted therapies combined with androgen deprivation therapy in patients with hormone sensitive prostate cancer did not offer a statistically significant advantage in overall survival compared to the standard, docetaxel. However, it was associated with a lower disease progression rate. Moreover, apalutamide and enzalutamide offer a better safety profile.

Testicular Swelling as an Initial Presentation of a Patient With Metastatic Gastric Cancer.

While signet-ring cell morphology in the testes might represent metastatic spread from an extragonadal adenocarcinoma, a rare variant of primary testicular neoplasms should be considered in a differential diagnoses as was seen in this rare occurrence of a testicular swelling as an initial presentation for a patient with metastatic gastric cancer.

Economic burden of renal cell carcinoma among older adults in the targeted therapy era.

OBJECTIVE: This study examined the economic burden of renal cell carcinoma (RCC) among older adults. The study also examined healthcare costs by types of resources used and stage at which RCC was diagnosed. METHODS: The study analyzed the Surveillance Epidemiology and End Result-Medicare linked data. We included a prevalent cohort of RCC patients from 2013, diagnosed and continuously enrolled in Medicare from 2005 to 2013. RCC patients were matched to controls selected from a 5% sample of noncancer beneficiaries using propensity score matching to calculate incremental costs. Total healthcare costs (THC) were calculated using a phase-based approach, which classified patients into early, continuing, and late phases of care. Costs were also examined by types of resources used and stage at which RCC was diagnosed. Generalized linear models estimated annual incremental costs per patient. The number of older RCC patients was calculated using SEER-Stat and ProjPrev software. The average incremental THC was multiplied by the estimated number of RCC patients to calculate the total economic burden of RCC among older adults. RESULTS: The study included 10,392 each of RCC and control patients. The average annual THC associated with RCC was $7,419 for all phases, $22,752 for the initial phase, $4,860 for the continuing phase, and $13,232 for the late phase of care. The average THC was $4,584 for patients diagnosed at stage I, $4,727 for stage II, $9,331 for stage III, and $31,637 for stage IV. For patients diagnosed at stages I to III, hospital cost (approximately $1,500-$3,400) was the largest component of THC. For stage IV patients, prescription drug cost ($11,747) was the largest component of THC. The projected number of older RCC patients in 2015 was 204,256. The annual economic burden of RCC after weighting for proportion of patients diagnosed at various stages was estimated to be $2.1 billion. CONCLUSIONS: RCC was associated with a significant economic burden on Medicare. Healthcare costs associated with RCC varied substantially between early stage and metastatic patients. This research provided a baseline that can be used to assess the economic value of emerging therapies among older RCC patients.

Sarcomatoid renal cell carcinoma: Biology and treatment advances.

Sarcomatoid transformation in renal cell carcinoma, so called sacromatoid RCC (sRCC), is associated with an aggressive behavior and a poor prognosis. Current therapeutic approaches are largely ineffective. Recent studies looking into the genomic and molecular characterization of sRCCs have provided insights into the biology and pathogenesis of this entity. These advances in molecular signatures may help development of effective treatment strategies. We herein present a review of recent developments in the pathology, biology, and treatment modalities in sRCC.

Immune Checkpoint Inhibitors for Urothelial Cancer: An Update on New Therapies.

Ongoing trials are evaluating immune checkpoint inhibitors-used alone, in combination with cytotoxic, targeted, radiation therapies, or with other such inhibitors-for therapy in patients with advanced bladder cancer.

Efficacy and pharmacogenomic biomarkers in breast cancer.

In patients with breast cancer, a number of biomarkers, such as estrogen receptor, progesterone receptor and HER2, are part of routine work-up and used to guide endocrine, cytotoxic and HER2-targeted treatment. Interaction among these markers may also impact on treatment response and is being investigated. Multigene assays have reached varying levels of validation and clinical use as predictive biomarkers of cytotoxic therapy in specific clinical situations. A number of pharmacogenomic biomarkers based on germline polymorphisms have reached some degree of validation for predicting variation in treatment response and treatment-associated adverse effects. The challenge of validating biomarkers will be exacerbated as the cost of nucleic acid sequencing rapidly declines and more potential biomarkers emerge. New, carefully designed approaches will be needed to address this issue and realize the potential of biomarkers in breast cancer.

Expression of HMP/AN2, a melanoma associated antigen, in murine cerebral gliomas: potential for radioimmunotargeting.

Human melanoma proteoglycan (HMP), a melanoma-associated antigen, is expressed in both human melanomas and gliomas. We used HMP-specific monoclonal antibody (mAb) VT68.2 to investigate whether murine GL261 cerebral gliomas express the HMP homologue AN2 and to determine whether AN2 could be targeted for selective delivery of radiation in vivo. HMP-specific mAb VT68.2 stained murine GL261 glioma cells grown in culture and intracerebrally in syngeneic C57BL/6 mice. Positron emission tomography with radiolabeled mAb VT68.2 showed high-contrast, positive images of gliomas against a negative background. At 96 h after injection, glioma uptake of radiolabeled mAb VT68.2 was 10x greater than that of the isotype control mAb and 20x greater than that detected in normal cerebral tissue. Our results show murine GL261 cerebral gliomas express AN2 and HMP-specific mAb VT68.2 accumulates selectively and specifically at high concentration and is retained within murine cerebral gliomas. Thus, HMP is a potential target for antibody-mediated selective delivery of radiation to cerebral gliomas in vivo.

Gated myocardial perfusion SPECT: basic principles, technical aspects, and clinical applications.

Electrocardiographically gated myocardial perfusion SPECT (GSPECT) is a state-of-the-art technique for the combined evaluation of myocardial perfusion and left ventricular function within a single study. It is currently one of the most commonly performed cardiology procedures in a nuclear medicine department. Automation of the image processing and quantification has made this technique highly reproducible, practical, and user friendly in the clinical setting. In patients with coronary artery disease, gating enhances the diagnostic and prognostic capability of myocardial perfusion imaging, provides incremental information over the perfusion data, and has shown potentials for myocardial viability assessment and sequential follow-up after therapy. After reading this article, the readers will understand (a) the general principles of GSPECT and quantitation, (b) the methods of the image acquisition and analysis, (c) validation of GSPECT with other cardiac imaging modalities, and (d) application of the GSPECT-derived functional parameters in the clinical practice.

Automatic determination of brain perfusion index for measurement of cerebral blood flow using spectral analysis and 99mTc-HMPAO.

Cerebral blood flow (CBF) can be non-invasively quantified using the brain perfusion index (BPI), determined from radionuclide angiographic data generated by technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO). We previously reported the use of a spectral analysis (SA) method using (99m)Tc-HMPAO to calculate the BPI. In this report, we demonstrate an automatic method for determining the optimal BPI value and compare the optimal BPI values with the absolute CBF values measured using H(2)(15)O positron emission tomography (PET). Bilateral cerebral hemispheres of 11 patients with various brain diseases were examined using (99m)Tc-HMPAO. In the automatic SA procedure, the radioactivity curve for the aortic arch ( C (a)) was shifted by 0-10 s. The radioactivity curve for the brain ( C (b)) was estimated using the shifted C (a), and the error value between the actually measured and the estimated C (b) (Err) was calculated. When the Err was at a minimum, the BPI value was defined as optimal BPI. The difference in BPI from the optimal BPI was calculated as |BPI - optimal BPI| / optimal BPIx100 (%). In all participants, an H(2)(15)O PET examination was also performed, and the BPI values were compared with the absolute CBF values measured using H(2)(15)O PET (mCBF(PET)). The difference between BPI and the optimal BPI increased significantly from 4.87%+/-1.69% to 18.38%+/-3.93% (mean+/-SD) when the Err value increased. The optimal BPI value ( y) was well correlated with the mCBF(PET) value ( x) ( y=0.21 x-0.0075, r=0.800). Our results suggest that this automatic SA method provides an accurate estimate of BPI that can be used for the quantification of CBF using (99m)Tc-HMPAO SA.