Characterizing different motility-induced regimes in active matter with machine learning and noise.

We examine motility-induced phase separation (MIPS) in two-dimensional run-and-tumble disk systems using both machine learning and noise fluctuation analysis. Our measures suggest that within the MIPS state there are several distinct regimes as a function of density and run time, so that systems with MIPS transitions exhibit an active fluid, an active crystal, and a critical regime. The different regimes can be detected by combining an order parameter extracted from principal component analysis with a cluster stability measurement. The principal component-derived order parameter is maximized in the critical regime, remains low in the active fluid, and has an intermediate value in the active crystal regime. We demonstrate that machine learning can better capture dynamical properties of the MIPS regimes compared to more standard structural measures such as the maximum cluster size. The different regimes can also be characterized via changes in the noise power of the fluctuations in the average speed. In the critical regime, the noise power passes through a maximum and has a broad spectrum with a 1/f^{1.6} signature, similar to the noise observed near depinning transitions or for solids undergoing plastic deformation.

Social environmental impact of COVID-19 and erectile dysfunction: an explorative review.

BACKGROUND: To date, no attempt has been made to collate literature on the relationship between the social environmental impact of COVID-19 and erectile dysfunction. The aim of this explorative review was to assess and compare the prevalence of erectile dysfunction (ED) in male healthcare workers and males during the COVID-19 pandemic. METHODS: A systematic review of major databases from inception to February 2021 was conducted. Prevalence data were extracted, and a random-effects meta-analysis was undertaken. OUTCOMES: The pooled prevalence of ED amongst healthcare workers working in COVID-19 specific environments, and non-healthcare during the COVID-19 pandemic. RESULTS: Of 52 initial studies, six were included for the final analysis. The pooled prevalence of ED in healthcare workers working in a COVID-19 environment was 63.6% (95% CI 20.3-92.3%), and in non-healthcare workers during the COVID-19 pandemic was 31.9% (95% CI 19.5-47.6%). CONCLUSION: The prevalence of ED in healthcare workers working in COVID-19 environments was higher than representative samples and is of concern. Sexual health (and by extension, overall health), should be a priority when considering ways to care for this population. Considering the social environmental impact of COVID-19 on sexual health and in particular on ED, it is important to provide adequate psychological support systems and to promote quality of life with particular attention to sexual health.

The development and validation of the secondary exercise addiction scale.

OBJECTIVES: Exercise addiction can be secondary to eating disorders, or a primary condition in the absence of another disorder. Currently, to determine secondary exercise addiction, two screening tools must be administered. The aim of this study was to validate a novel screening tool able to stratify between primary and secondary exercise addiction, called the secondary exercise addiction scale (SEAS). METHODS: Phase 1 (n = 339) described the statistical reduction of an initial pool of scale items. Phase 2 (n = 382) used a confirmatory factor analysis (CFA) to examine the robustness of the latent structure. Phase 3 (n = 721) determined cut off scores for the eating disorder and exercise addiction sections of the SEAS and determine concurrent reliability with the exercise addiction inventory (EAI) and the SCOFF questionnaires. Phase 4 (n = 45) determined test-retest reliability. RESULTS: Phase 1 extracted two components: exercise addiction and eating disorder symptomology, with 11 items retained. The CFA in Phase 2 showed an acceptable fit to the proposed model (comparative fit index = 0.93, Tucker Lewis Index = 0.91). Phase 3 determined cut off scores of ≥ 28 (specificity = 91.97%), and ≥ 20 (specificity = 96.27%) in the respective exercise addiction and eating disorders sections of the SEAS. The respective sections also correlated well with the EAI (r = 0.70, p = < 0.001) and the SCOFF (r = 0.72, p = < 0.001). Phase 4 showed excellent test-retest reliability (exercise addiction r = 0.95, p = < 0.001, eating disorders r = 0.93, p = < 0.001). CONCLUSION: The SEAS appears to be a valid and reliable tool for measuring primary and secondary exercise addiction. Further studies are warranted to further validate this tool amongst clinical populations. LEVEL OF EVIDENCE: Level III: evidence obtained from cohort or case-control analytic studies.

Checkpoint inhibitors in metastatic papillary renal cell carcinoma.

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.

A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆.

BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts.

BACKGROUND: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. MATERIALS AND METHODS: We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. RESULTS: Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. CONCLUSION: A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice.

Detecting depinning and nonequilibrium transitions with unsupervised machine learning.

Using numerical simulations of a model disk system, we demonstrate that a machine learning generated order-parameter-like measure can detect depinning transitions and different dynamic flow phases in systems driven far from equilibrium. We specifically consider monodisperse passive disks with short range interactions undergoing a depinning phase transition when driven over quenched disorder. The machine learning derived order-parameter-like measure identifies the depinning transition as well as different dynamical regimes, such as the transition from a flowing liquid to a phase separated liquid-solid state that is not readily distinguished with traditional measures such as velocity-force curves or Voronoi tessellation. The order-parameter-like measure also shows markedly distinct behavior in the limit of high density where jamming effects occur. Our results should be general to the broad class of particle-based systems that exhibit depinning transitions and nonequilibrium phase transitions.

Syndemic effects of HIV risk behaviours: results from the NHANES study.

The aim of the present study is to use the syndemic framework to investigate the risk of contracting HIV in the US population. Cross-sectional analyses are from The National Health and Nutrition Examination Survey. We extracted and aggregated data on HIV antibody test, socio-demographic characteristics, alcohol use, drug use, depression, sexual behaviours and sexually transmitted diseases from cycle 2009-2010 to 2015-2016. We carried out weighted regression among young adults (20-39 years) and adults (40-59 years) separately. In total, 5230 men and 5794 women aged 20-59 years were included in the present analyses. In total, 0.8% men and 0.2% women were tested HIV-positive. Each increasing HIV risk behaviour was associated with elevated odds of being tested HIV-positive (1.15, 95% CI 1.15-1.15) among young adults and adults (1.61, 95% CI 1.61-1.61). Multi-faceted, community-based interventions are urgently required to reduce the incidence of HIV in the USA.

Dynamic phases, stratification, laning, and pattern formation for driven bidisperse disk systems in the presence of quenched disorder.

Using numerical simulations, we examine the dynamics of driven two-dimensional bidisperse disks flowing over quenched disorder. The system exhibits a series of distinct dynamical phases as a function of applied driving force and packing fraction, including a phase-separated state as well as a smectic state with liquid-like or polycrystalline features. At low driving forces, we find a clogged phase with an isotropic density distribution, while at intermediate driving forces the disks separate into bands of high and low densities with either liquid-like or polycrystalline structure in the high-density bands. In addition to the density phase separation, we find that in some cases there is a fractionation of the disk species, particularly when the disk size ratio is large. The species phase-separated regimes form a variety of patterns such as large disks separated by chains of smaller disks. Our results show that the formation of laning states can be enhanced by tuning the ratio of disk radius of the two species, due to the clumping of small disks in the interstitial regions between the large disks. This system could be experimentally realized using sterically interacting colloidal particles suspended in a viscous fluid driven over random pinning arrays or granular matter suspended in fluid moving over a random landscape.

Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMSM registry.

BACKGROUND: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. METHODS: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIMSM registry data base was assessed utilizing the International Metastatic RCC Database Consortium (IMDC) risk criteria. Median follow-up is 23.4 months (mo.) (range 0.2-124 mo.). Subgroup evaluations were performed by separating patients by prior or no prior therapy, IL-2 alone, or therapy subsequent to IL-2. Some patients were in two groups. We will focus on the 356 patients who received IL-2 alone, and evaluate outcome by risk factor categories. RESULTS: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. CONCLUSIONS: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. TRIAL REGISTRATION: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.

Dynamic phases, clustering, and chain formation for driven disk systems in the presence of quenched disorder.

We numerically examine the dynamic phases and pattern formation of two-dimensional monodisperse repulsive disks driven over random quenched disorder. We show that there is a series of distinct dynamic regimes as a function of increasing drive, including a clogged or pile-up phase near depinning, a homogeneous disordered flow state, and a dynamically phase separated regime consisting of high-density crystalline regions surrounded by a low density of disordered disks. At the highest drives the disks arrange into one-dimensional moving chains. The phase separated regime has parallels with the phase separation observed in active matter systems, but arises from a distinct mechanism consisting of the combination of nonequilibrium fluctuations with density-dependent mobility. We discuss the pronounced differences between this system and previous studies of driven particles with longer-range repulsive interactions moving over random substrates, such as superconducting vortices or electron crystals, where dynamical phase separation and distinct one-dimensional moving chains are not observed. Our results should be generic to a broad class of systems in which the particle-particle interactions are short ranged, such as sterically interacting colloids or Yukawa particles with strong screening driven over random pinning arrays, superconducting vortices in the limit of small penetration depths, or quasi-two-dimensional granular matter flowing over rough landscapes.

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK.Cancer. 2015 Oct 1;121(19):3435-43. [Epub 2015 Jun 8]. doi: 10.1002/cncr.29503.

BACKGROUND: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. METHODS: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had>10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with≤10% sarcomatoid histology (P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). CONCLUSIONS: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation.

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC-A Possible Path Forward.

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms.

BACKGROUND: Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making. MATERIALS AND METHODS: Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach. RESULTS: The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria. CONCLUSION: In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

Avalanches, plasticity, and ordering in colloidal crystals under compression.

Using numerical simulations we examine colloids with a long-range Coulomb interaction confined in a two-dimensional trough potential undergoing dynamical compression. As the depth of the confining well is increased, the colloids move via elastic distortions interspersed with intermittent bursts or avalanches of plastic motion. In these avalanches, the colloids rearrange to minimize their colloid-colloid repulsive interaction energy by adopting an average lattice constant that is isotropic despite the anisotropic nature of the compression. The avalanches take the form of shear banding events that decrease or increase the structural order of the system. At larger compression, the avalanches are associated with a reduction of the number of rows of colloids that fit within the confining potential, and between avalanches the colloids can exhibit partially crystalline or anisotropic ordering. The colloid velocity distributions during the avalanches have a non-Gaussian form with power-law tails and exponents that are consistent with those found for the velocity distributions of gliding dislocations. We observe similar behavior when we subsequently decompress the system, and find a partially hysteretic response reflecting the irreversibility of the plastic events.

International cancer seminars: a focus on kidney cancer.

Recent years have seen important advances in our understanding of the etiology, biology and genetics of kidney cancer. To summarize important achievements and identify prominent research questions that remain, a workshop was organized by IARC and the US NCI. A series of 'difficult questions' were formulated, which should be given future priority in the areas of population, genomic and clinical research.

Safety and clinical activity of vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors after programmed cell death 1 inhibitor treatment in patients with metastatic clear cell renal cell carcinoma.

BACKGROUND: Emerging agents blocking the programmed cell death 1 (PD-1) pathway show activity in metastatic clear cell renal cell carcinoma (mRCC). The aim of this study was to evaluate the efficacy and safety of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy after PD-1 inhibition. PATIENTS AND METHODS: Patients with mRCC treated with anti-PD-1 antibody (aPD-1) monotherapy or in combination (with VEGFR-TKI or ipilimumab) that subsequently received VEGFR-TKI were retrospectively reviewed. The efficacy end points were objective response rate (ORR) and progression-free survival (PFS) stratified by the type of prior PD-1 regimen. Safety by the type and PD-1 exposure was also evaluated. RESULTS: Seventy patients were included. Forty-nine patients received prior therapy with immune checkpoint inhibitors (CPIs) alone and 21 had combination therapy of aPD-1 and VEGFR-TKI. Overall, ORR to VEGFR-TKI after PD-1 inhibition was 28% (19/68) and the median PFS was 6.4 months (mo) (4.3-9.5). ORR to VEGFR-TKI after aPD-1 in combination with VEGFR-TKI was lower than that in patients treated with VEGFR-TKI after CPI alone (ORR 10% versus 36%, P = 0.039). In the multivariable analysis, patients treated with prior CPI alone were more likely to achieve an objective response than those treated with aPD-1 in combination with VEGFR-TKI (OR = 5.38; 95% CI 1.12-26.0, P = 0.03). There was a trend toward numerically longer median PFS in the VEGFR-TKI after the CPI alone group, 8.4 mo (3.2-12.4) compared with 5.5 mo (2.9-8.3) for those who had VEGFR-TKI after aPD-1 in combination with VEGFR-TKI (P = 0.15). The most common adverse events (AEs) were asthenia, hypertension, and diarrhea. CONCLUSIONS: The efficacy and safety of VEGFR-TKIs after PD-1 inhibition were demonstrated in this retrospective study. The response rate was lower and the median progression-free survival was shorter in those patients who received prior PD-1 in combination with VEGFR-TKI. PD-1 exposure does not seem to significantly influence the safety of subsequent VEGFR-TKI treatment.

PD-L1 expression in nonclear-cell renal cell carcinoma.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown. METHODS: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data [time to recurrence (TTR) and overall survival (OS)] were correlated with PD-L1 staining. RESULTS: Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively). CONCLUSION: In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.

A phase I study of cabozantinib (XL184) in patients with renal cell cancer.

BACKGROUND: Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). PATIENTS AND METHODS: This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. RESULTS: The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. CONCLUSION: Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. ClinicalTrials.gov identifier: NCT01100619.

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients.

BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.