Current Landscape and Future Directions on Bladder Sparing Approaches to Muscle-Invasive Bladder Cancer.

OPINION STATEMENT: Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70-80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

High-Throughput Screen for Inhibitors of Androgen Receptor-RUNX2 Transcriptional Regulation in Prostate Cancer.

Runt-related transcription factor 2 (RUNX2) plays a critical role in prostate cancer progression. RUNX2 interacts with the androgen receptor (AR) and modulates its transcriptional activity in a locus-specific manner. RUNX2 and AR synergistically stimulate a subset of genes, including the pro-oncogene snail family zinc finger 2 (SNAI2). AR-RUNX2 signaling cooperatively induces invasiveness of prostate cancer cells via SNAI2; and coexpression of AR, RUNX2, and SNAI2 in prostate cancer biopsy samples predicts disease recurrence. Competitive inhibition of AR alone could not disrupt the synergistic activation of SNAI2. We therefore established a phenotypic cell-based screening assay for compounds that could inhibit AR-RUNX2 synergistic activity either directly or indirectly. This assay was used to screen 880 compounds as a proof of concept, resulting in identification of several compounds that disrupted the synergistic stimulation of genes. Further investigation suggested the involvement of epidermal growth factor receptor (EGFR) signaling in AR/RUNX2 synergistic activity. Our assay is amenable to high-throughput screening and can be used to identify inhibitors of the AR-RUNX2 interaction in prostate cancer cells.

Next-generation sequencing: unraveling genetic mechanisms that shape cancer immunotherapy efficacy.

Immunity is governed by fundamental genetic processes. These processes shape the nature of immune cells and set the rules that dictate the myriad complex cellular interactions that power immune systems. Everything from the generation of T cell receptors and antibodies, control of epitope presentation, and recognition of pathogens by the immunoediting of cancer cells is, in large part, made possible by core genetic mechanisms and the cellular machinery that they encode. In the last decade, next-generation sequencing has been used to dissect the complexities of cancer immunity with potent effect. Sequencing of exomes and genomes has begun to reveal how the immune system recognizes "foreign" entities and distinguishes self from non-self, especially in the setting of cancer. High-throughput analyses of transcriptomes have revealed deep insights into how the tumor microenvironment affects immunotherapy efficacy. In this Review, we discuss how high-throughput sequencing has added to our understanding of how immune systems interact with cancer cells and how cancer immunotherapies work.

Dosimetric comparison of deep-inspiration breath-hold and free-breathing treatment delivery techniques for left-sided breast cancer using 3D surface tracking.

INTRODUCTION: While radiation therapy has been shown to increase local control and overall survival for breast cancer, late cardiac toxicity remains a concern. Morbidity and mortality have been shown to increase proportionally to the mean heart dose. Deep inspiration breath-hold (DIBH) can reduce heart dose compared to free-breathing (FB) by increasing the heart-to-chest wall distance, especially in left-sided breast cancer. We present our clinical experience with DIBH in left breast and chest-wall irradiation using 3D optical surface tracking. MATERIALS & METHODS: 29 patients were treated with DIBH using a surface tracking system that provides a real time 3D surface image of the patient. Comparisons of maximum and mean heart dose, heart-chest wall separation, and the percentage of lung volume that receives 20 or more Gy (V20) between the DIBH and hypothetical FB treatment plans were conducted with the Student's t-test. Correlation coefficients were also calculated for heart-chest wall separation, heart volume, and lung volume. RESULTS: Comparing DIBH and FB plans showed a decrease in mean and maximum heart doses in all patients. Individual mean heart doses decreased by an average of 1.12 Gy, and the average mean heart dose for DIBH plans was significantly lower than corresponding FB plans (1.02 vs. 2.12 Gy; p < 0.0001). Maximum heart dose decreased by an average of 11.88 Gy and was significantly lower in DIBH versus FB plans (28.33 vs. 43.7 Gy; p = 0.0001). The average difference in heart to chest-wall separation between DIBH and FB images was 2.41 cm. DIBH left lung volume and measured increases in volume on inspiration inversely correlated with maximum heart dose (R = 0.39) and left lung V20 (R = 0.32). CONCLUSIONS: DIBH with 3D surface tracking can significantly benefit patients with left sided disease by limiting the mean and maximum heart dose. DIBH appears to viably reduce heart dose for left-breast cancer patients and thus potentially reduce long-term complications without prolonging treatment delivery.

Palliative radiotherapy for skin malignancies.

Palliative radiotherapy (PRT) improves patient quality of life (QoL) through alleviating cancer-associated symptoms such as pain, bleeding, and ulceration. Palliative management of patients with skin malignancies requires consideration of cosmetic and psychosocial outcomes as QoL measures. In this review, we highlight the current literature and advances in the use of PRT for patients with the three most commonly encountered forms of skin malignancies: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The disease course and sensitivity to radiation varies, thus dictating the palliative goal and scheduling for PRT.

Prognostic Significance of Neutrophilic Infiltration in Benign Lymph Nodes in Patients with Muscle-invasive Bladder Cancer.

BACKGROUND: Preclinical studies suggest that signal transducer and activator of transcription 3 (STAT3)-mediated recruitment of neutrophils to premetastatic tissue occurs prior to metastatic progression. OBJECTIVE: We sought to determine if neutrophilic infiltration in benign nodal tissue is associated with poor clinical outcome in patients with muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: Formalin-fixed, paraffin-embedded tissue was secured from 55 patients with muscle-invasive bladder cancer who had undergone cystectomy at our institution. Sections of benign lymph nodes were obtained and stained with primary antibodies against 3-fucosyl-N-acetyl-lactosamine, phosphorylated STAT3, and interleukin-17, the latter being a key mediator of neutrophil infiltration and STAT3 activation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Kaplan-Meier method was used to interrogate differences in overall survival (OS) in patients with high versus low biomarker expression. Cohorts stratified by receipt and nonreceipt of neoadjuvant chemotherapy were separately explored. RESULTS AND LIMITATIONS: Of the 55 patients examined, 19 patients (35%) had no prior neoadjuvant chemotherapy. Amongst these patients, median OS was improved in patients with low 3-fucosyl-N-acetyl-lactosamine+ cell counts (196 mo vs 37 mo; p=0.0062) and low phosphorylated STAT3+ cell counts (278 mo vs 106 mo; p=0.025). In the same cohort, a trend towards improved OS in patients with low interleukin-17+ cell count was observed (not reached vs 117 mo; p=0.18). No differences in OS were noted in biomarker-based subgroups amongst patients that had received prior neoadjuvant chemotherapy. CONCLUSIONS: The results herein support the hypothesis that bladder cancer metastasis may be driven by STAT3-mediated neutrophilic infiltration in premetastatic sites. Validation of these findings using tissues derived from a phase 3 surgical trial (Southwest Oncology Group 1011) is currently underway. PATIENT SUMMARY: Lymph node metastases occur in up to 25% of patients with muscle-invasive cancer and it represents one of the most frequent sites of bladder cancer metastasis. This report provides preliminary evidence that neutrophil levels in benign lymph nodes may predict clinical outcome.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies.

BACKGROUND: Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. MATERIALS AND METHODS: We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. RESULTS: A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). CONCLUSION: Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

Clinical and Translational Assessment of VEGFR1 as a Mediator of the Premetastatic Niche in High-Risk Localized Prostate Cancer.

Preclinical studies have suggested that VEGFR1-positive cells potentially foster the development of metastases by establishing a "premetastatic niche." We sought to test this hypothesis in high-risk localized prostate cancer and assess potential niche modulation by the VEGFR1-targeting drug axitinib. Formalin-fixed, paraffin-embedded tissue derived from benign lymph nodes was collected and VEGFR1-positive cell clustering was assessed in benign lymph nodes via IHC. Recursive partitioning was used to define a threshold for VEGFR1 clustering that could segregate patients based on time to biochemical recurrence (TTBR). Multivariate analyses were used to determine whether VEGFR1 clustering, age, pathologic T-stage, Gleason score, or baseline PSA could independently predict TTBR. A randomized, phase II clinical trial comparing axitinib for 28 days followed by radical prostatectomy and pelvic lymph node dissection (RP/PLND) to RP/LND alone was then conducted, with the primary endpoint of demonstrating downregulation of VEGFR1-positve cell clustering in benign lymph nodes. Our retrospective analysis assessed a cohort of 46 patients. A threshold of 1.65 VEGFR1-positive cells per high power field was identified, below which TTBR was delayed. VEGFR1 clustering was an independent predictor of TTBR in a multivariate analysis. Only 11 out of the planned 44 patients were accrued to the phase II trial. While preoperative axitinib was safe and well tolerated, there was no sign of clinical activity or VEGFR1 downregulation. Our results validate previous findings that suggest VEGFR1-positive cells in benign lymph nodes can predict clinical outcome. Further work is needed to develop a viable clinical strategy for modulating VEGFR1 in these tissues.

Radium-223 in metastatic castration resistant prostate cancer.

In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.