The Utility of 68Ga-PSMA PET/CT in Decisions Regarding Administering Salvage Radiotherapy to Men with Prostate Cancer.

BACKGROUND: Numerous papers have described 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)'s sensitivity in identifying prostate cancer (PCa) recurrence. This study aimed to characterize the role of 68Ga-PSMA PET/CT in deciding to re-irradiate pelvic structures. METHODS: 68Ga-PSMA PET/CT scans performed at Sheba Medical Center over seven years in 113 men were reviewed. All had undergone radiation to the prostate (70, 61.9%) or post-radical prostatectomy radiation to the prostate fossa (PF) (43, 48.1%), and had local or oligometastatic PCa recurrence and received salvage radiotherapy (SRT) based on PET/CT findings. RESULTS: Mean age was 70.7 years. The mean grade group was 2.9; the mean prostate-specific antigen was 9.0. The 68Ga-PSMA PET/CT positive findings included: 37 (32.7%) in the prostate, 23 (20.4%) in seminal vesicles, 7 (6.2%) in the PF, and 3 (2.7%) in the seminal vesicle fossa. The mean standardized uptake value was 10.6 ± 10.2 (range: 1.4-61.6); the mean lesion size was 1.8 ± 3.5 mm (range: 0.5-5.1). SRT was directed toward the prostate and seminal vesicles in 48 (42.5%), PF in 18 (15.9%), and intrapelvic lymph node and bone in 47 (41.6%). Toxicities were mostly mild to moderate. CONCLUSION: 68Ga-PSMA PET/CT-identified relapse with targeted SRT was well-tolerated and may result in less onerous treatments.

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.

BACKGROUND: The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up. METHODS: Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory. RESULTS: Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.75; 95% CI, 0.62-0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61-0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77-1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46-0.54), and more patients achieved complete response (10.1%-12.8% vs 1.4%-5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports. CONCLUSIONS: NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months' minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response. TRIAL REGISTRATION NUMBER: NCT02231749.

Isolated autoimmune adrenocorticotropic hormone deficiency: From a rare disease to the dominant cause of adrenal insufficiency related to check point inhibitors.

OBJECTIVE: Immune checkpoint inhibitors have introduced a new and heterogeneous class of immune-related adverse effects, with the endocrine system being a predominant target for autoimmunity. Autoimmune hypothalamic-pituitary-adrenal axis (HPA) diseases induced by checkpoint inhibitors are being increasingly recognized. We aimed to characterize the spectrum of checkpoint associated hypothalamic-pituitary-adrenal axis endocrinopathies. DESIGN: A retrospective cohort study of a tertiary cancer center. METHODS: Patients were characterized for HPA axis abnormalities based on clinical and pituitary axes evaluation. The risk for developing HPA endocrinopathies was compared by log- rank test, by the time since checkpoint inhibitors initiation. Additionally, the risk for developing HPA endocrinopathies after adjusting for covariates was assessed using multivariable logistic regression analysis. RESULTS: Among 1615 patients, fourteen (0.87%) patients developed isolated adrecocorticotrophic hormone deficiency (IAD), six (0.37%) - hypophysitis and no case of adrenalitis was identified. IAD presented with mild and non-specific symptoms, mainly asthenia. In multivariable analysis, exposure to both PD-1/PD-L1 and Ipilimumab and female gender were associated with an increased odds ratio (OR) for developing IAD (6.98 [95% CI 2.38-20.47, p < .001] and 3.67 [95% CI 1.13-11.84, p = .03]), respectively. CONCLUSIONS: IAD, a rare disease before the immunotherapy era, has become a predominant checkpoint related HPA axis autoimmune injury. Despite its life threatening potential, IAD may be missed due to its subtle presentation. Patients exposed to Ipilimumab and PD-1/PD-L1 in combination or sequentially and women have an increased risk for developing IAD.

Checkpoint Genes at the Cancer Side of the Immunological Synapse in Bladder Cancer.

Immune checkpoint inhibitors have revolutionized cancer therapy, but not all cancers respond to the currently available drugs, and even within cancers considered responsive to such modality, response rates range between 15 and 40%, depending on the cancer type, the line of treatment, and yet unknown clinical/molecular factors. Coordinated expression of checkpoint proteins was shown to occur on T cells, probably allowing fine-tuning of the signal transmitted to the cell. We performed a bioinformatic analysis of the expression of putative checkpoint mRNAs at the cancer side of the immunological synapse from the bladder cancer tumorgenome atlas (TCGA) database. Fifteen mRNAs, corresponding to both coinhibitory and costimulatory checkpoints, were shown to be expressed above a designated threshold. Of these, seven mRNAs were found to be coexpressed: CD277, PD-1L, CD48, CD86, galectin-9, TNFRSF14 (HVEM), and CD40. The expression of 2 of these mRNAs-BTN3A1 (CD277) and TNFRSF14 (HVEM)-was positively correlated with overall survival in the TCGA database. All these seven mRNA share putative binding sites of a few transcription factors (TFs). Of these, the expression of the TF BACH-2 was positively correlated with the expression of checkpoint mRNAs from the network. This suggests a joint transcriptional regulation on the expression of checkpoint mRNAs at the bladder tumor side of the immunological synapse.

Acute vascular events as a possibly related adverse event of immunotherapy: a single-institute retrospective study.

AIM: Immune-related toxicities of immune checkpoint inhibitors (CPIs) require prompt diagnosis and treatment. Atherosclerosis has an inflammatory component; we speculated this inflammation could be enhanced by CPIs. We aimed to evaluate the risk of acute vascular events (AVEs) on CPIs. METHODS: Patients treated by CPIs in Sheba Medical Center (Israel) between January 2015 and May 2018 were retrospectively identified from electronic medical records. AVEs were identified and verified by chart review. Age, sex, diabetes, hypertension, smoking, dyslipidemia, previous AVE, renal failure, cancer type and specific treatments were evaluated as potential risk factors. AVE rate on CPIs was compared with that on chemotherapy or on combined chemo-immunotherapy in patients with lung adenocarcinoma. Survival of patients with AVEs was compared with that of patients without AVEs. RESULTS: CPI was administered to 1215 patients. AVEs within six months after CPI initiation occurred in 2.6% (95% confidence interval [CI]: 1.8-3.6) of patients, more common than in later time periods. In lung adenocarcinoma, event rate was 5.2% (95% CI: 2.8-9.2). Lung adenocarcinoma, prior AVE, hypertension and dyslipidemia were correlated with AVEs. AVE rate in patients with non-small cell lung cancer adenocarcinoma was similar whether on chemotherapy or on CPI. Survival of patients with AVEs was worse than that of those without AVEs. CONCLUSION: The similarly increased rates of AVEs for patients on CPI, on chemotherapy or on both suggest that although CPI may not augment the risk of AVE over that of chemotherapy, it carries a similar and significant risk of such adverse event. Caution should be exercised for patients with risk factors for AVEs.

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma.

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial.

BACKGROUND: Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon neoplasms with high morbidity in advanced stages. Effective systemic treatments are limited. METHODS: A multisite phase 2 trial evaluated sunitinib in patients with progressive PCC/PGL. Patients received 50 mg orally for 4-6 weeks. RESULTS: Between May 2009 and May 2016, 25 patients were enroled. The median age was 50 years and 56% were male. Three patients (12%) received prior chemotherapy and 16 (64%) prior surgery. The DCR was 83% (95% CI: 61-95%) and median PFS 13.4 (95% CI: 5.3-24.6) months. Of 23 evaluable patients, 3 (13%) with germline mutations (SDHA, SDHB, RET) achieved a PR. The patient with mutated RET and MEN2A remains on treatment after 64 cycles. The median time on treatment was 12.4 (1-88.0) months. Grade 3 or 4 toxicities were as expected and manageable; fatigue (16%) and thrombocytopenia (16%) were most common. One patient with grade 3 hypertension and 2 with grade 3 cardiac events discontinued treatment. CONCLUSION: Although the primary endpoint of disease control was met, the overall response rate of sunitinib was low in unselected patients with progressive PCC/PGL. Patients with germline variants in RET or in the subunits of SDH may derive greatest benefit.

Accelerated Hypofractionated Radiation Therapy for Elderly Frail Bladder Cancer Patients Unfit for Surgery or Chemotherapy.

PURPOSE/OBJECTIVES: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. MATERIALS AND METHODS: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. RESULTS: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). CONCLUSIONS: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT.

The Prognostic Role of the Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Chemotherapy in Patients with Muscle-Invasive Bladder Cancer: A Retrospective, Multi-Institutional Study.

BACKGROUND: The impact of the change in the neutrophil-to-lymphocyte ratio (NLR) during neoadjuvant chemotherapy (NAC) on outcomes in patients with muscle-invasive bladder cancer (MIBC) is poorly understood. OBJECTIVE: To evaluate the prognostic impact of the change in NLR during NAC for patients with MIBC. METHODS: Patients referred to academic, community, and quaternary referral centres in Alberta, Canada from 2005 to 2015, Ontario, Canada from 2005 to 2013, and Southampton, UK from 2004 to 2010 were evaluated. 376 eligible patients were treated with NAC for clinical T2-4aN0M0 disease, and 296 were evaluable for the change in NLR. A high NLR was defined as being an NLR > 3. Relationships between the change in NLR from baseline to mid-NAC (pre-cycle 3) and outcomes were analyzed using multivariable Cox regression. Kaplan-Meier analysis was used with the log-rank test for group comparisons. RESULTS: Median follow-up was 22.0 months (95% confidence interval [CI]: 14.9-30.0). Patients with a sustained high NLR had a median disease-free survival (DFS) of 12.6 months, compared to 34.8 months for those with a sustained low NLR (log-rank test p = 0.0025; hazard ratio [HR] 0.61 [95% CI: 0.44-0.84]). Median overall survival (OS) was 19.4 months for patients with a sustained high NLR, compared to 44.0 months for patients with a sustained low NLR (log-rank test p = 0.0011; HR 0.54 [95% CI: 0.38-0.77]). CONCLUSIONS: A sustained high NLR from baseline to mid-NAC is an independent prognostic factor for patients with MIBC.

High-Throughput Architecture for Discovering Combination Cancer Therapeutics.

PURPOSE: The amount of available next-generation sequencing data of tumors, in combination with relevant molecular and clinical data, has significantly increased in the last decade and transformed translational cancer research. Even with the progress made through data-sharing initiatives, there is a clear unmet need for easily accessible analyses tools. These include capabilities to efficiently process large sequencing database projects to present them in a straightforward and accurate way. Another urgent challenge in cancer research is to identify more effective combination therapies. METHODS: We have created a software architecture that allows the user to integrate and analyze large-scale sequencing, clinical, and other datasets for efficient prediction of potential combination drug targets. This architecture permits predictions for all genes pairs; however, Food and Drug Administration-approved agents are currently lacking for most of the identified gene targets. RESULTS: By applying this approach, we performed a comprehensive study and analyzed all possible combination partners and identified potentially synergistic target pairs for 38 approved targets currently in clinical use. We further showed which genes could be synergistic prediction markers and potential targets with MAPK/ERK inhibitors for the treatment of melanoma. Moreover, we integrated a graph analytics technique in this architecture to identify pathways that could be targeted synergistically to enhance the efficacy of certain therapeutics in cancer. CONCLUSION: The architecture and the results presented provide a foundation for discovering effective combination therapeutics.

Positive surgical margin following radical nephrectomy is an independent predictor of local recurrence and disease-specific survival.

BACKGROUND: Positive surgical margins (PSM) are recognized as an adverse prognostic sign and are often associated with higher rates of local and systemic disease recurrence. The data regarding the oncological outcome for PSM following radical nephrectomy (RN) is limited. We examined the predictive factors for PSM and its influence on survival and site of recurrence in patients treated with RN for renal cell carcinoma (RCC). METHODS: Clinical, pathologic and follow-up data on 714 patients undergoing RN for kidney cancer were analyzed. Secondary analysis included 44 patients with metastatic RCC upon diagnosis who underwent cytoreductive nephrectomy (CRN). Univariate and multivariable logistic regression models were fit to determine clinicopathologic features associated with PSM. A Cox proportional-hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS: PSM was documented in 17 cases (2.4%). PSM were associated with tumour size, advanced pathologic stage (pT3 vs. ≤ pT2) and presence of necrosis. On multivariate analysis, cancer-specific survival (CSS) was associated with tumour stage, size, presence of necrosis and PSM. PSM was also associated with local recurrence but not distant metastasis or overall survival (OS). CSS and OS were comparable between the PSM and metastatic RCC groups, but significantly lower than the negative margin group. CONCLUSIONS: The prevalence of PSM following RN is rare. Pathological data, including advanced stage (> pT2), tumour necrosis and tumour size, are associated with the presence of PSM. PSM is associated with tumour recurrence and CSS. Patients with PSM are a potential group for adjuvant therapy or for more careful and thorough follow-up following surgery.

Classifying high-risk versus very high-risk prostate cancer: is it relevant to outcomes of conformal radiotherapy and androgen deprivation?

OBJECTIVE: To evaluate outcomes in prostate cancer patients classified as high-risk (HR) or very high-risk (VHR) who were treated with conformal radiation therapy (CRT) and androgen deprivation therapy (ADT). METHODS: Between 11/2001 and 3/2012, 203 patients with HR disease received CRT to the prostate (78-82 Gy) and pelvic lymph nodes (46-50 Gy) with ADT (6 m-2 years). Median follow-up was 50 months (12 m-142 m). Biochemical failure was defined according to Phoenix definition. Imaging studies were used to identify local, regional or metastatic failure. Four different VHR/HR groupings were formed using the 2014 and revised 2015 NCCN guidelines. Differences were examined using Kaplan Meier (KM) estimates with log rank test and uni- and multivariate Cox regression analysis (MVA). RESULTS: Failure occurred in 30/203 patients (15%). Median time to failure was 30 m (4 m-76 m). KM estimate of 4 year biochemical disease free survival (b-DFS) for the entire cohort was 87% (95%CI: 82-92%). Four year KM survival estimates for b-DFS, PCSS and OS were comparable for each NCCN subgroup. On univariate analysis, the NCCN subgroups were not predictive of b-DFS at 4 years, however, DMFS was worse for both VHR subgroups (p = .03and .01) respectively. Cox univariate analysis was also significant for: PSA ≥40 ng/ml p = 0.001; clinical stages T2c p = .004, T3b p = .02 and > 4 cores with Gleason score 8-10 p < .03. On MVA, only PSA ≥ 40 ng/ml was predictive for b-DFS or MFS at 4 years (HR: 3.75 and 3.25, p < 0.005). CONCLUSION: Patients with HR and VHR disease treated with CRT and ADT had good outcomes. Stratification into HR and VHR sub-groups provided no predictive value. Only PSA ≥40 ng/ml predicted poor outcomes on MVA. Distant failure was dominant and local recurrence rare, suggesting that improved systemic treatment rather than intensification of local therapy is needed. Patients with high-risk prostate cancer are most often treated with conformal dose escalated radiation therapy with androgen deprivation. Stratification into high versus very high-risk subgroups using 2014 or revised 2015 National Comprehensive Cancer Network (NCCN) criteria did not impact treatment outcomes. Only Prostate Serum Antigen (PSA) ≥40 ng/ml was predictive of poor prognosis. Distant failure was dominant and local recurrence uncommon which challenges the notion that intensification of local therapy will further improve outcomes in patients with high-risk disease.

Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial.

BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.

Is there a "Trial Effect" on Outcome of Patients with Metastatic Renal Cell Carcinoma Treated with Sunitinib?

PURPOSE: Studies suggested the existence of a 'trial effect', in which for a given treatment, participation in a clinical trial is associated with a better outcome. Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC). We aimed to study the effect of clinical trial participation on the outcome of mRCC patients treated with sunitinib, which at present, is poorly defined. MATERIALS AND METHODS: The records of mRCC patients treated with sunitinib between 2004-2013 in 7 centers across 2 countries were reviewed. We compared the response rate (RR), progression free survival (PFS), and overall survival (OS), between clinical trial participants (n=49) and a matched cohort of non-participants (n=49) who received standard therapy. Each clinical trial participant was individually matched with a non-participant by clinicopathologic factors. PFS and OS were determined by Cox regression. RESULTS: The groups were matched by age (median 64), gender (male 67%), Heng risk (favorable 25%, intermediate 59%, poor 16%), prior nephrectomy (92%), RCC histology (clear cell 86%), pre-treatment NLR (>3 in 55%, n=27), sunitinib induced hypertension (45%), and sunitinib dose reduction/treatment interruption (41%). In clinical trial participants versus non-participants, RR was partial response/stable disease 80% (n=39) versus 74% (n=36), and progressive disease 20% (n=10) versus 26% (n=13) (p=0.63, OR 1.2). The median PFS was 10 versus 11 months (HR=0.96, p=0.84), and the median OS 23 versus 24 months (HR=0.97, p=0.89). CONCLUSIONS: In mRCC patients treated with sunitinib, the outcome of clinical trial participants was similar to that of non-participants who received standard therapy.

Promoter-Associated RNAs Regulate HSPC152 Gene Expression in Malignant Melanoma.

The threshold of 200 nucleotides (nt) conventionally divides non-coding RNAs (ncRNA) into long ncRNA (lincRNA, that have more than 200 nt in length) and the remaining ones which are grouped as "small" RNAs (microRNAs, small nucleolar RNAs and piwiRNAs). Promoter-associated RNAs (paRNAs) are generally 200-500 nt long and are transcribed from sequences positioned in the promoter regions of genes. Growing evidence suggests that paRNAs play a crucial role in controlling gene transcription. Here, we used deep sequencing to identify paRNA sequences that show altered expression in a melanoma cell line compared to normal melanocytes. Thousands of reads were mapped to transcription start site (TSS) regions. We limited our search to paRNAs adjacent to genes with an expression that differed between melanoma and normal melanocytes and a length of 200-500 nt that did not overlap the gene mRNA by more than 300 nt, ultimately leaving us with 11 such transcripts. Using quantitative real-time PCR (qRT-PCR), we found a significant correlation between the expression of the mRNA and its corresponding paRNA for two studied genes: TYR and HSPC152. Ectopic overexpression of the paRNA of HSPC152 (designated paHSPC) enhanced the expression of the HSPC152 mRNA, and an siRNA targeting the paHSPC152 decreased the expression of the HSPC152 mRNA. Overexpression of paHSPC also affected the epigenetic structure of its putative promoter region along with effects on several biologic features of melanoma cells. The ectopic expression of the paRNA to TYR did not have any effect. Overall, our work indicates that paRNAs may serve as an additional layer in the regulation of gene expression in melanoma, thus meriting further investigation.

MiR-377 targets E2F3 and alters the NF-kB signaling pathway through MAP3K7 in malignant melanoma.

BACKGROUND: The incidence of cutaneous malignant melanoma continues to rise, and once the disease metastasizes it is almost inevitably fatal. We recently reported that a large miRNAs cluster on human chromosome 14q32, implicated in many types of cancers, is significantly down-regulated in melanoma. miR-377, one of the miRNAs located within this cluster, was studied here. METHODS: qRT-pCR was used to quantify miR-377 levels in melanoma cell lines and samples. Melanoma cell lines ectopically expressing miR-377 were generated by stable transfection, mRNA expression was assessed using mRNA arrays and protein expression was assessed by Western blot analysis. Potential targets of miR-377 were identified through luciferase reporter assays. Cellular proliferation, migration and soft-agar colony formation were monitored in control and miR-377-expressing cells using cell biology techniques. RESULTS: miR-377 is expressed in normal melanocytes but not in melanoma cell lines or samples. Its ectopic stable expression in melanoma cell lines decreased their proliferative and migratory capacity and their colony-forming capability. mRNA arrays of melanoma cells over-expressing miR-377 pointed to several down-regulated mRNAs that have putative binding sites for miR-377 in their 3'UTR, of which both E2F3 and MAP3K7 were found to be direct targets of miR-377. E2F3, a potent transcriptional inducer of cell-cycle progression, was found to be elevated in melanoma cell lines, but decreased following ectopic expression of miR-377. Ectopic miR-377 also led to a decrease in the activity of a reporter plasmid containing three E2F DNA-binding sites linked to a luciferase cDNA sequence, demonstrating that miR-377 down-regulates E2F3-induced transcription. MAP3K7 (known as TAK1), a serine/threonine kinase along the MAPK signaling pathway, was over-expressed in melanoma but decreased following ectopic expression of miR-377. MAP3K7 is involved in the activation of NF-κB. MiR-377 over-expression led to decreased activity of a reporter plasmid containing two NF-κB DNA-binding sites and to decreased output along the NF-kB signaling pathway. CONCLUSION: Our results suggest that miR-377 is an important negative regulator of E2F and MAP3K7/NF-kB signaling pathway in melanoma cells; it is tempting to speculate that its silencing in melanoma promotes the tumorigenic and metastatic potential of the cells through activation of these pathways.

Neutrophil-Lymphocyte Ratio and Pathological Response to Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NC) improves overall survival in muscle-invasive bladder cancer (MIBC), but there are currently no predictive biomarkers of response to NC in MIBC. An increased peripheral blood neutrophil to lymphocyte ratio (NLR) is a marker of systemic inflammation and is linked to poor prognosis in some solid tumors. We evaluated whether NLR is associated with pathological response (pathR) in MIBC patients who receive NC. PATIENTS AND METHODS: MIBC patients treated with NC and radical cystectomy (RC) between July 2006 and April 2013 were retrospectively reviewed. The primary end point was to find variables associated with pathR in the RC specimen after NC. Potential predictive markers were analyzed using logistic regression. NLR values before NC, midway through NC, and before RC were collected and compared between patients who achieved pathR ('responders') and those who did not ('nonresponders'). RESULTS: In 26 evaluable patients, age, sex, performance status, smoking status, stage, hydronephrosis, NLR before NC, midway through NC, and before RC were not significantly associated with pathR, but the pattern of NLR change between responders and nonresponders was significantly different (P = .038). Responders exhibited a sustained decrease in NLR during NC until RC, and nonresponders exhibited a transient decrease in NLR which then increased to above its baseline before RC. CONCLUSION: The pattern of change in NLR during NC varied significantly between responders and nonresponders. We hypothesize that a sustained decrease in inflammatory burden during NC is associated with pathR. Despite limitations of a small retrospective study, our observations might have clinical implications and warrant further basic and clinical research.

Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer.

OBJECTIVE: To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age >80 compared to younger men. METHODS: Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan-Meier method and log-rank tests. RESULTS: Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4months) or OS (14.0 vs 20.7months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p=0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p=0.004). CONCLUSIONS: Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity.