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Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

PURPOSE We hypothesized that bevacizumab will potentiate activity of pembrolizumab. We conducted a phase Ib/II, single-arm, multisite clinical trial of the combination in metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS Patients with metastatic clear cell RCC who experienced progression after at least one systemic therapy (phase Ib) or were treatment naïve (phase II) were enrolled. In phase Ib, pembrolizumab (200 mg) and bevacizumab (10 or 15 mg/kg) were given intravenously every 3 weeks. The primary end point for phase II was overall response rate (ORR). With an 80% statistical power and a type I error probability of 0.1, 48 patients were to be accrued to detect an ORR of 42%. RESULTS Thirteen patients (ages 33-68 years; median, 55 years) were enrolled in the phase Ib study. No dose-limiting toxicities were reported. Pembrolizumab 200 mg and bevacizumab 15 mg/kg were chosen for phase II. Forty-eight patients (ages 42-84 years; median age, 61 years; 33 males) were accrued for the phase II study. The primary end point was met, with the ORR reaching 60.9% (95% CI, 45.4% to 74.9%), consisting of 1 complete response (CR), 2 CRs in target lesions, 25 partial responses, 18 responses of stable disease, 2 unevaluable responses. Median progression-free survival was 20.7 months (95% CI, 11.3 to 27.4 months). Median overall survival was not reached at the median follow-up of 28.3 months. The most common treatment-related grade 3 toxicities were hypertension and proteinuria. There were two grade 4 toxicities: duodenal ulcer and hyponatremia. Presence of tumor-infiltrating T cells, but not programmed death-ligand 1 expression, in tumor tissue correlated with response. CONCLUSION The combination of 200 mg of pembrolizumab and a 15 mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC.

Calf diarrhoea is the most commonly encountered disease syndrome and significant cause of economic losses in dairy industry. Present investigation was undertaken to find out the prevalence of causative agents of diarrhoea in the bovine calves for a period of one year. The effect of age, sex, season and parity of dam was also studied. E. coli was the major organism (86.00 %) observed in the faecal samples of the diarrhoeic calves followed by rotavirus, Eimeria spp. and Amphistomes (15.00 % each); Toxocara spp. (12.00 %); Strongyles (9.00 %); Cryptosporidium spp. (6.00 %); Trichuris spp. (5.00 %); and Salmonella spp. and Strongyloides spp. (3.00 % each). The prevalence of rotavirus, Cryptosporidium spp. and Eimeria spp. was found significantly higher in buffalo calves and crossbred calves than cow calves and Gir / local non-descript calves, respectively. The prevalence of Toxocara spp., Amphistomes and Strongyles in diarrhoeic buffalo calves was significantly higher than cow calves. Highest prevalence of E. coli and rotavirus was observed in faecal samples of diarrhoeic calves of 0-15 days age group. Rotavirus was not detected in faecal samples of diarrhoeic calves above 60 days age. The susceptibility of bovine calves for E. coli and rotavirus was found decreased with the advancement of the age. The prevalence of Salmonella spp. in diarrhoeic faecal samples of bovine calves was observed only in 16-60 days age whereas Cryptosporidium spp. was found only in 0-30 days age. The most of the parasitic infestations were observed after 30 days of age in calves. The calves of both sexes were equally susceptible to different causative agents of diarrhoea. The prevalence of E. coli and most of the helminth ova in the faecal samples of diarrhoeic calves was found maximum during rainy season whereas the rotavirus was observed mostly during winter season. The prevalence of E. coli, Salmonella spp., rotavirus and Cryptosporidium spp. was found highest in the faecal samples of the diarrhoeic calves of first or second parity dams.

An ecofriendly and solar light-responsive graphene oxide wrapped zinc oxide nanohybrid has been synthesized hydrothermally using lemon and honey respectively as chelating and complexing agents. By tuning the reaction conditions, a heterostructure between GO and ZnO has been formed during synthesis. The photocatalytic activity of the synthesized nanohybrid was investigated by degradation of hazardous organic textile dye (methylene blue) as well as wastewater under natural solar light. The nanohybrid exhibited excellent photocatalytic activity towards degradation (~ 89%) of methylene blue (MeB). Furthermore, along with decolorization, 71% of mineralization was also achieved. Interestingly, the nanohybrid has been found to be reusable up to 4 cycles without significant loss of photocatalytic activity. Along with this, the physicochemical parameters of the wastewater generated from textile industry have been also monitored before and after exposure to nanohybrid. The results revealed significant reduction in chemical oxygen demand (COD) (96.33%), biochemical oxygen demand (BOD) (96.23%), and total dissolved solids (TDS) (20.85%), suggesting its potential applicability in textile wastewater treatment.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms. Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor. Design, setting, and participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Intervention: Hybrid-capture–based CGP. Outcome measurements and statistical analysis: Descriptive analyses and differences between anatomic subgroups were reported. Results and limitations: In total, 39% of patients with UC harbored one or more tier 1–2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p = 0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p < 0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p = 0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p < 0.001). Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC. Patient summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

The present study reports a novel, simple, economic and ecofriendly method to synthesize Titanium dioxide (TiO2) nanoparticles using green alga Chlorella pyrenoidosa. Further, these TiO2 nanoparticles were deposited on GO sheets to form TiO2-GO nanocomposite. The crystalline information, morphological and optical properties of the synthesized TiO2-GO nanocomposite were studied using X-ray Diffraction (XRD), Scanning Electron Microscopy- Energy Dispersive X-ray Spectroscopy (SEM-EDX) and UV–Vis absorption spectroscopy. Crystal Violet (CV) dye was used as a model contaminant. The photocatalytic activity of TiO2 nanoparticles and the TiO2-GO nanocomposite were evaluated by the degradation of CV dye in aqueous medium under visible light. The result showed that the TiO2-GO nanocomposite exhibited higher photocatalytic efficiency compared to pristine TiO2 nanoparticles with three cycles reusability. The improved activity of the TiO2-GO nanocomposite might be attributed to enhanced charge separation, efficient charge transportation, extended light absorption range and increased adsorption of dye. This nanocomposite has a great potential in removing environmental contaminants and applicable in water purification.

BACKGROUND Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0-1) would correlate with shorter overall survival (OS) in patients receiving ICIs. METHODS In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013-2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested. RESULTS Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio [HR], 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04). CONCLUSIONS Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first-line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.

// Ming Yin 1, 6 , Petros Grivas 2, 7 , Hamid Emamekhoo 3 , Prateek Mendiratta 2 , Siraj Ali 4 , JoAnn Hsu 5 , Monali Vasekar 1 , Joseph J. Drabick 1 , Sumanta Pal 5 and Monika Joshi 1 1 Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA 2 Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 3 Department of Medicine, Division of Hematology-Oncology, University of Wisconsin Carbone Cancer Center, WI, USA 4 Foundation Medicine, Cambridge, MA, USA 5 Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 7 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA Correspondence to: Monika Joshi, email: mjoshi@pennstatehealth.psu.edu Keywords: biomarkers; prognosis; bladder cancer; genomic alterations; next generation sequencing Received: November 30, 2017 Accepted: March 02, 2018 Published: March 30, 2018 ABSTRACT Background: Mutations of DNA repair genes, e.g. ATM/RB1 , are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results: In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods: Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions: ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

BACKGROUND Lipid nanoparticles have attracted increased degree of scientific and commercial attention in the last decade. The lipidic nanoparticles have emerged as a potential alternative to other nano-scale systems due to their various advantages over them and also due to overcoming the shortcomings of the already available colloidal systems like liposomes, niosomes and polymeric nanoparticles. DESCRIPTION These have been investigated for delivery of macromolecules, genes, siRNA and other therapeutic agents for oral, topical, parenteral administration and target site specific delivery for various diseases like cancer, ocular diseases and brain disorders. The lipid nanoparticles have evolved from SLNs, then NLCs and lipid drug conjugates overcoming any issues related to production and formulation and adding advantages, if any. The current review article focuses on the lipid nanoparticles, their formulation approaches and current advancements in the field through recent clinical trials and patents. This manuscript embodies various patents, preclinical and clinical aspects related to the lipidic nanocarriers. CONCLUSION Over the years the lipidic nanoparticulate systems have evolved as significant carriers for improved therapeutics and in diagnostic field. The large number of patents and preclinical trials in the recent years suggests that these systems will find immense potential in near future.

Herein, iron oxide/titanium oxide nanocomposite (Fe3O4/TiO2) has been synthesized via an ultrasonic-assisted co-precipitation method. The synthesized nanocomposite has been characterized by X-ray diffractometer (XRD), scanning electron microscope (SEM), vibrating sample magnetometer (VSM), Fourier-transform infrared spectroscopy (FTIR), photoluminescence spectra, photocurrent response, and UV-Visible spectroscopy. The nanocomposite exhibited magnetic property with a saturation magnetization of 16.02 emu/g. The synergetic effect of magnetite and titanium oxide makes the nanocomposite highly efficient, stable and reusable for water remediation applications. The higher photocurrent response confirms more charge separation, which is responsible for the enhanced photocatalytic activity. Nanocomposite showed superior photocatalytic ability (~100%) than P-25 TiO2 (20% and 22%) to degrade the chlorinated organic pollutants like 2,4-dichlorophenol (2,4-DCP) and chlorobenzene (CB) respectively under visible irradiation within 50 min. The optimum performance has been achieved at pH 5 using 100 mg/L Fe3O4/TiO2 nanocomposite with 98% of reusability. The kinetics of photodegradation of 2,4-DCP and CB under visible irradiation of magnetic Fe3O4/TiO2 nanocomposite is well fitted with first-order reaction. A facile synthesis method, outstanding photocatalytic activity under visible as well as sunlight, synergistic effect between Fe3O4 and TiO2 and easy separation for reusability makes the nanocomposite a prospective material towards environmental remediation and solar energy harvesting.

We report a simple and nontoxic route for the synthesis of Zinc Oxide (ZnO) nanoflowers using commonly available water melon rind as a reducing agent. The structural properties of the synthesized samples were investigated using X-ray diffraction (XRD) and Fourier Transform Infrared Spectrum (FTIR) techniques. The morphology of the synthesized material has been studied using field effect scanning electron microscopy (FESEM) technique. The XRD and results proved wurtzite structure of ZnO nanostructures. Notably, Field emission electron microscopy (FESEM) results confirmed the formation of ZnO nanorods, which assembled to form flower like structures. Further, Energy dispersive X-ray spectroscopy (EDX) analysis confirmed the presence of the elemental signals of Zn and O. Optical characterization of the synthesized nanoflowers were carried out using UV–Vis spectroscopy. The synthesized nanoflowers exhibited excellent photocatalytic activities for the degradation of organic dye methylene blue (MeB). The photocatalytic efficiency of the sample remains almost the same up-to three cycles. In addition, by performing the optoelectronic studies in the ultraviolet region, the corresponding current–voltage ( I – V ) characteristics shows the samples have potential for photosensitive device. Therefore, considering the environment friendly and green approach for the synthesis of ZnO nanoflowers, the present investigation can be effectively used for various environmental and optoelectronic applications.

BACKGROUND In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

Herein, Ag/TiO2 nanocomposites were synthesized by simple chemical method. The structural parameters of the obtained Ag/TiO2 nanocomposites were investigated using Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray spectroscopy (EDX). The photocatalytic activity of Ag/TiO2 nanocomposite was investigated by studying the degradation of Methyl orange dye as a function of irradiation time under UV illuminator which is used as a model pollutant present in water.

Present work reports on the synthesis, characterization and photocatalytic activity of graphene oxide (GO). Recent studies have indicated GO to be a potential candidate for the treatment of textile wastewater. Here, GO was synthesized using solo-thermal method. Characterization of GO was performed using X-Ray Diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). The photocatalytic activity of GO was investigated for the degradation of the textile dye Methylene blue (MeB) under visible light. The result showed GO nanosheets exhibited 79% photocatalytic activity. The study suggested that GO nanosheets may be an excellent material for the treatment of wastewater for environment applications.

Agriculture is considered as a backbone for most of the developing countries around the world. Since the population is continuously increasing, it is necessary to use modern technologies of nano- and biotechnology in agricultural sciences. Nano-biotechnology offers solution in all stages of growth, processing, production, storing, packaging and transportation of agricultural products. Nano-biotechnology can revolutionize both food and agroindustries by proving better crop protection against several diseases, better shelf life, enhanced yield, more nutritional value and better resistance to harsh environmental conditions. Nanoparticles can now be easily synthesized via biological routes and can be instantly applied for agricultural purposes. Algae (macro/micro) are leading front runner in producing nanoparticles that can successfully provide several versatile applications. Algae play an important role in agriculture. Seaweeds (macroalgae) are used as fertilizers, resulting in less nitrogen and phosphorous run-off than the one from the use of livestock manure. This chapter provides an insight on various species of algae that can be used in nanoparticle synthesis and the advantages it can provide in agricultural activities.

TPS500 Background: Patients [pts] withlymph node positive (LN+), non-metastatic bladder cancer (BC) have a better prognosis than those with metastatic (M1) disease. However, this population is under-represented in advanced bladder trials and ineligible for bladder-sparing trials. Therefore, there have been no larger prospective trials establishing the standard of care in LN+ BC. Given the promise of immunotherapy in advanced BC and potential synergy between immunotherapy and radiation, INSPIRE was designed to determine the role of concurrent and adjuvant durvalumab (durva) in this patient population when treated with induction chemotherapy (IC) followed by concurrent chemoRT. Methods: This is a randomized phase II study that is enrolling BC pts with stage III (N1-2 M0), pure or mixed urothelial cancer. Pts must have received ≥3 cycles of IC [either before or after registration, prior to randomization] without progression. LN+ is defined as radiologically LN ≥1.0 cm in short axis, with or without biopsy prior to IC. As long as pts do not progress on induction chemotherapy, they will be randomized to chemoRT+/- durva using 5 stratification factors (Simon Pocock minimization method) a) IC prior vs. post registration b) cisplatin vs non-cisplatin regimen during RT c) LN size d) response to IC e) extent of TURBT. Pts on the chemoRT+durva arm will get chemotherapy per physician choice + IMRT + 3 x doses of Q3wk durva for 6.5-8 wks, whereas those on the control arm will get chemoRT alone. The primary end point is clinical complete response [CR], defined as no radiologically measurable disease in the LNs and negative cystoscopy and bladder biopsy 8-10 weeks post-chemoRT +/- durva. Pts on the chemoRT + durva arm who have a CR or clinical benefit (>T0 and ≤T2 in bladder per cystoscopy, biopsy + CR/PR/SD in LN by imaging) will get adjuvant Q4wk durva for 9 doses, while those on the chemoRT arm will undergo observation. Secondary end points include OS, PFS, bladder-intact event-free survival, rate of toxicity and salvage cystectomy. This study is designed to detect an improvement of 25% in clinical CR between both arms (37.5% to 62.5%). A total accrual of 114 pts (in order to enroll 92 evaluable pts) will provide 81% power to detect this difference using a Fisher’s exact test (assuming 10% drop out + anticipating that 20% chemotherapy-naïve pts will progress post IC). We are banking blood and primary tumor tissue pre- and post-chemoRT in both groups. The study was activated in August 2020 and accrual is ongoing. INSPIRE is the first prospective study designed for only LN+ BC and will define both short-term and long-term outcomes for bladder sparing in this patient population and has the potential to define a new treatment strategy for stage III BC. Clinical trial information: NCT04216290.

328 Background: Anti-PD1/PDL1 immune checkpoint inhibition (CPI) is active in advanced clear cell RCC, but not all patients benefit. Preclinical studies with the combination of hypomethylating agents and CPI resulted in reversal of immune evasion and tumor regression. We examined the combination of the hypomethylating agent guadecitabine (subcutaneously on Days 1-5), with the anti-PDL1 antibody durvalumab (intravenously at flat dose of 1500 mg on Day 8) in 28 day cycles in advanced RCC in a single arm trial. Methods: In the phase Ib portion (n=6; presented previously), guadecitabine dosing of 45 mg/m2/day was selected as maximum tolerated dose. For the phase II portion of Cohort 1 (36 pts with no prior CPIs), eligible patients had metastatic RCC with clear cell component, ECOG PS of 0-1, and measurable disease by RECIST 1.1. We present pooled efficacy and toxicity data for the 42 CPI-naive pts from the phase Ib and phase II portions. An exploratory Cohort 2 (N=16) consisting of CPI-refractory pts is enrolling. Results: Of the 42 pts, 71% were men, median age was 67 years, ECOG PS was 0 in 57%, IMDC risk group was intermediate in 83% and poor in 17%, and histology was mixed in 21%. At a median follow-up of 20.1 m, best RECIST 1.1 response was PR in 9 pts (22%); SD in 25 pts (61%); PD in 7 pts (17%); and non-evaluable in 1 pt. Response categories were identical by irRECIST. Clinical benefit defined as either PR or SD ≥6 months was seen in 66%. Median OS had not been reached and median PFS was 17 m. Treatment was generally well tolerated with asymptomatic neutropenia the most frequent AE attributed to guadecitabine (38.1%), and asymptomatic lipase elevation the most common AE from durvalumab (11.9%). Grade 4 AEs were noted in 50.0% pts, grade 3 59.5%. Immune-mediated AEs were generally mild (all ≤ grade 3), included pruritus (14.3%), rash (14.3%), asymptomatic amylase or lipase elevations (16.7%), hypothyroidism (11.9%), diarrhea (16.7%), dyspnea (16.7%), pneumonitis (4.8%), myalgia (4.8%), and transaminitis (9.6%). Laboratory peripheral blood profiling (done at baseline, C1D8, C2D8) was associated on univariate unadjusted analysis at baseline with response in two major PBMC subsets - MDSCs (negative) and ILCs (positive). Further functional analysis revealed that increased expression of IL-22 in both CD4 and CD8 positive T cells positively correlated with response. Associations were noted for toxicity with IL-22 expressed by CD8-CD4- T cells, and CTLs T-bet level. Baseline archival tumor tissue next generation sequencing results will be presented. Conclusions: Guadecitabine in combination with durvalumab was well tolerated and had reasonable activity in first-line advanced ccRCC. MDSCs and regulatory T lymphocytes decreased in responders, increased Th17 subpopulations of T cells were associated with immune-mediated toxicities. Further study of this combination in CPI-refractory RCC pts is ongoing. Clinical trial information: NCT03308396 .

398 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, or locally advanced and unresectable have limited treatment options. DUART investigates if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. We recently reported that the combination was safe, tolerable and disease control rate (DCR) was 92% post durvaRT. Here we present interim efficacy data of our phase II study. Methods: Pts with pure or mixed urothelial bladder cancer (T2-4 N0-2 M0) were enrolled if their tumor was unresectable (35%), were unfit for surgery (50%) and/or cisplatin ineligible (89%). Primary endpoints: a) PFS at 1-yr b) DCR post adjuvant durva; Secondary endpoints: a) CR post durvaRT b) median PFS c) median OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy. Sample size was based on assumption that this regimen would increase 1 yr PFS by 25% compared to RT alone (50% to 75%); we assumed DCR of 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Twenty-six pts (19 males, 7 females) were enrolled, median age 74 yr (51-94). Sixty two percent of pts had >T2 disease, 31% had positive lymph nodes; 62% with unresectable tumor or were unfit for surgery due to comorbidities. At data cut off (9/30/2020) 20/26 pts were evaluable for DCR post adjuvant durva (3 pts with CR post durvaRT, did not get adjuvant therapy; 1 pt withdrew after 3 cycles for adjuvant durva and was on f/u with unconfirmed CR; 2 pts are still on adjuvant durva) and 25/26 for PFS and all 26 pts for OS. Post completion of adjuvant durva, DCR was seen in 70 % (14/20 with 10 CR; 3 PR; 1 SD; 6 PD). One-year probability of PFS was 73% (95% CI 56.4%, 94.4%), median PFS was 18.5 months. One-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached. We did not observe any correlation between clinical outcome and baseline tumor PD-L1 expression. Conclusions: DurvaRT followed by adjuvant durva demonstrated promising efficacy with 1-year PFS probability of 73%, 1- year OS probability of 83.8% and DCR of 70% in MIBC and locally advanced BC pts with comorbidities. Results will be updated prior to the final presentation. Efficacy was also seen in node (+) pts which led to the design of prospective randomized NCTN study. Induction chemo followed by chemo+durvaRT+ adjuvant durva vs. chemoRT combination is being evaluated in the ongoing EA8185 clinical trial (ECOG-ACRIN/NRG study) for node (+) BC pts. Clinical trial information: NCT02891161.

39 Background: The presence of progressing cancer, male sex and advanced age have been shown to increase the severity of coronavirus disease 2019 (COVID-19). Given that the androgen regulated gene TMPRSS2 has been implicated in SARS-CoV-2 viral entry, we hypothesized that ADT may improve COVID-19 outcomes. This analysis evaluated clinical outcomes of pts with PCa with concurrent SARS-CoV-2 infection and investigated the impact of ADT on occurrence of severe-COVID-19 and mortality. Methods: Data was obtained via the COVID-19 and Cancer Consortium (CCC19), a multicenter registry including >120 cancer centers with de-identified data from pts with COVID-19 and cancer. Men with confirmed SARS-CoV-2 infection and a primary diagnosis of prostate cancer were included: data cutoff of July 31, 2020. The primary endpoint was the development of severe-COVID-19 (death, ICU admission, or mechanical ventilation) among pts on ADT vs. those not on ADT at time of COVID-19 infection. Secondary endpoints included 30-day mortality based on ADT use. Mortality and development of severe-COVID-19 were assessed in Pts grouped by therapy: 1st generation androgen receptor inhibitor (ARI-1), 2nd generation ARI (darolutamide, enzalutamide, apalutamide, ARI-2), abiraterone/prednisone, and chemotherapy. Propensity score matching was utilized. Logistic regression was utilized to adjust for age, ECOG PS, comorbidities, and race. Results: 589 pts were included; median follow-up was 42 days (IQR 25-90) and 62% (363/589) were hospitalized. Severe-COVID-19 developed in 28% of pts and the all-cause 30-day mortality rate was 19%. There was no significant difference in the development of severe-COVID-19 or 30-day mortality between Pts on ADT vs not on ADT, whether using descriptive statistics with the entire population or using the propensity score matched population (Table). Among the descriptive population, the numerical rates of severe-COVID-19 and mortality were lowest in Pts receiving ARI-2, but sample size was low. Conclusions: The overall 30-day mortality rate and percentage developing severe-COVID-19 were high. There was no statistical difference in the development of severe-COVID-19 or mortality based on receipt of ADT; however, this analysis is limited by the retrospective nature and small N after propensity-matching. [Table: see text]

426 Background: Erdafitinib (ERDA), a pan-FGFR kinase inhibitor, was US FDA approved for adults with mUC with susceptible FGFR3/2 alterations ( FGFRa) who progressed on ≥ 1 line of prior platinum-based chemotherapy based on primary results of the BLC2001 trial (NCT02365597). At final analysis (median 2-y follow-up), ERDA showed median OS of 11.3 mo and a manageable safety profile. Some FGFRi toxicities are distinct from those of other small-molecule TKIs. Proactive AE management can avoid treatment discontinuation, ensuring maximum benefit. We report the frequency and management of TEAEs of interest (central serous retinopathy [CSR], hyperphosphatemia [“on-target” FGFRi class effect], stomatitis, and skin and nail toxicities) for the optimal schedule of ERDA from the final analysis of BLC2001. Methods: The open-label, phase II BLC2001 study enrolled pts with measurable mUC, prespecified FGFRa, and progression during/after ≥ 1 line of prior chemotherapy or ≤ 12 mos of (neo)adjuvant chemotherapy or who were cisplatin ineligible, chemo naive. Optimal dose schedule in the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERDA 8 mg/d UpT) if prespecified serum phosphate level was not reached and no significant TEAEs occurred. ERDA 8 mg/d UpT safety results as of Aug 9, 2019 (final analysis) are summarized here. AEs were graded using NCI CTCAE v4.0. Results: Median follow-up for 101 pts treated with ERDA 8 mg/d UpT was 24.0 mos; median treatment duration was 5.4 mos. All pts had ≥ 1 TEAE. Hyperphosphatemia, stomatitis, nail disorders, skin disorders, and CSR TEAEs occurred in 78%, 59%, 59%, 55%, and 27% of pts, respectively (few were grade [gr] 3; none were gr ≥ 4; Table). TEAEs were mostly managed with concomitant treatment and dose modifications. As of data cutoff, hyperphosphatemia had resolved in 74/79 (94%) pts; stomatitis in 44/60 (73%); nail and skin TEAEs in 26/60 (43%) and 25/55 (45%), respectively; and CSR in 17/27 (63%). Most unresolved TEAEs were gr 1–2. No treatment-related deaths occurred. Conclusions: ERDA had measurable benefit in pts with advanced UC with FGFRa. As with other targeted therapies, exposure to ERDA is associated with a pattern of AEs. The most common and FGFRi class effect TEAEs were generally reversible and managed by supportive care and dose modification. Clinical trial information: NCT02365597 . Research Sponsor: Janssen Research & Development, LLC[Table: see text]

// Hong Zheng 1, * , Xin Liu 1, * , Jianhong Zhang 1 , Shawn J. Rice 1 , Matthias Wagman 1 , Yaxian Kong 2 , Liuluan Zhu 2 , Junjia Zhu 1 , Monika Joshi 1 , Chandra P. Belani 1 1 Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, USA 2 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China * These authors have contributed equally to this work Correspondence to: Chandra Belani, e-mail: cbelani@psu.edu Keywords: PD-1, peripheral blood, T cells, prognosis, NSCLC Received: February 12, 2016 Accepted: April 13, 2016 Published: May 12, 2016 ABSTRACT Recent success of using agents inhibiting the major immune check point, programmed cell death-1 (PD-1) pathway, offers a great promise for effective cancer therapy. Two blocking antibodies for PD-1, nivolumab and pembrolizumab have recently been approved for treating advanced recurrent non-small cell lung cancer (NSCLC). Activation of PD-1 on T cells and PD-L1 on tumor cells or antigen presenting cells leads to T cell exhaustion and ultimately tumor growth. In this study, we performed flow cytometry analysis of peripheral blood samples collected from patients with advanced NSCLC at initial diagnosis. We report that surface expression of PD-1 on CD4 + T cells has a prognostic value in NSCLC patients, as high expression of PD-1 is associated with a shorter progression-free survival and overall survival. Importantly, we also found that high PD-1 expression on peripheral CD4 + T cells is associated with inferior clinical response in a subset of patients who received anti-PD-L1 treatment, indicating a potential predictive value of this marker. This work highlights the potential of a non-invasive and effective method to determine prognostic and predictive biomarkers for inhibiting the PD-1 pathway in NSCLC patients.

Background Platinum-based neoadjuvant chemotherapy has been shown to improve survival outcomes in muscle-invasive bladder cancer patients. We performed a systematic review and meta-analysis to provide updated results of previous findings. We also summarized published data to compare clinical outcomes of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) versus gemcitabine and cisplatin/carboplatin (GC) in the neoadjuvant setting. Methods A meta-analysis of 15 randomized clinical trials was performed to compare neoadjuvant chemotherapy plus local treatment with the same local treatment alone. Because no randomized trials have investigated MVAC versus GC in the neoadjuvant setting, a meta-analysis of 13 retrospective studies was performed to compare MVAC with GC. Results A total of 3,285 patients were included in 15 randomized clinical trials. There was a significant overall survival (OS) benefit associated with cisplatin-based neoadjuvant chemotherapy (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96). A total of 1,766 patients were included in 13 retrospective studies. There was no significant difference in pathological complete response between MVAC and GC. However, GC was associated with a significantly reduced overall survival (HR, 1.26; 95% CI, 1.01-1.57). After excluding carboplatin data, GC still seemed to be inferior to MVAC in OS (HR, 1.31; 95% CI, 0.99-1.74), but the difference was no longer statistically significant. Conclusion These results support the use of cisplatin-based combination neoadjuvant chemotherapy in muscle-invasive bladder cancer. Although GC and MVAC had similar treatment response rates, the different survival outcome observed in this study requires further investigation. Implications for practice Platinum-based neoadjuvant chemotherapy (NCT) has been shown to improve survival outcomes in muscle-invasive bladder cancer (MIBC) patients, but the optimal neoadjuvant regimen has not been established. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and gemcitabine and cisplatin/carboplatin (GC) are two of the most commonly used chemotherapy regimens in modern oncology. In this two-step meta-analysis, an updated and more precise estimate of the survival benefit of cisplatin-based NCT in MIBC is provided. This study also demonstrated that MVAC might have superior overall survival compared with GC (with or without carboplatin data) in the neoadjuvant setting. The findings suggest that NCT should be standard care in MIBC, and MVAC could be the preferred neoadjuvant regimen.

The present investigation was focused to formulate semi-solid capsules (SSCs) of hydrophobic drug telmisartan (TLMS) by encapsulating semi-solid matrix of its solid dispersion (SD) in HPMC capsules. The combinational approach was used to reduce the lag time in drug release and improvise its dissolution. SDs of TLMS was prepared using hot fusion method by varying the combinations of Pluronic-F68, Gelucire 50/13 and Plasdone S630. A total of nine batches (SD1-SD9) were characterized for micromeritic properties, in vitro dissolution behavior and surface characterization. SD4 with 52.43% cumulative drug release (CDR) in phosphate buffer, pH 7.4, in 120 min, t50% 44.2 min and DE30min 96.76% was selected for the development of semi-solid capsules. Differential scanning calorimetry of SD4 revealed molecular dispersion of TLMS in Pluronic-F68. SD4 was formulated into SSCs using Gelucire 44/14 and PEG 400 as semi-solid components and PEG 6000 as a suspending agent to achieve reduction in lag time for effective drug dissolution. SSC6 showed maximum in vitro drug dissolution 97.49 % in phosphate buffer, pH 7.4 with in 20 min that was almost a three folds reduction in the time required to achieve similar dissolution by SD. Thus, SSCs present an excellent approach to enhance in vitro dissolution as well as to reduce the lag time of dissolution for poorly water soluble drugs especially to those therapeutic classes that are intended for faster onset of action. Developed approach based on HPMC capsules provided a better alternative to target delivery of telmisartan to the vegetarian population.

5015 Background: Erdafitinib (JNJ-42756493; ERDA) is the only pan-FGFR kinase inhibitor with US FDA approval for treatment of adults with mUC with susceptible FGFR3/2 alterations (alt) and who progressed on ≥ 1 line of prior platinum-based chemotherapy (chemo). Approval was based on data from the primary analysis of the pivotal BLC2001 trial1. Here we report long-term efficacy and safety data from the 8 mg/d continuous dose regimen in BLC2001. Methods: BLC2001 (NCT02365597) is a global, open-label, phase 2 trial of pts with measurable mUC with prespecified FGFR alt, ECOG 0-2, and progression during/following ≥ 1 line of prior chemo or ≤ 12 mos of (neo)adjuvant chemo, or were cisplatin ineligible, chemo naïve. The optimal schedule of ERDA determined in the initial part of the study was 8 mg/d continuous ERDA in 28-d cycles with uptitration to 9 mg/d (ERD 8 mg UpT) if a protocol-defined target serum phosphate level was not reached and if no significant treatment-related adverse events (TRAEs) occurred. Primary end point was the confirmed objective response rate (ORR=% complete response + % partial response). Key secondary end points were progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Results: Median follow-up for 101 patients treated with ERDA 8 mg UpT was ~24 months. Confirmed ORR was 40%. Median DOR was 5.98 mos; 31% of responders had DOR ≥ 1 yr. Median PFS was 5.52 mos, median OS was 11.3 mos. 12-mos and 24-mos survival rates were 49% and 31%, respectively. Median treatment duration was 5.4 mos. The ERDA safety profile was consistent with the primary analysis. No new TRAEs were seen with longer follow-up. Central serous retinopathy (CSR) events occurred in 27% (27/101) of patients; 85% (23/27) were Grade 1 or 2; dosage was reduced in 13 pts, interrupted for 8, and discontinued for 3. On the data cut-off date, 63% (17/27) had resolved; 60% (6/10) of ongoing CSR events were Grade 1. There were no treatment-related deaths. Conclusions: With a median follow-up of 2 yrs, ERDA in mUC + FGFR alt showed a manageable safety profile and consistent efficacy, with median OS of 11.3 mos. 31% had a DOR ≥12 mos and 31% were alive at 24 mos. ERDA monotherapy vs. immune checkpoint inhibitor (PD-1) or chemo is being further analyzed in a randomized control study (THOR; NCT03390504).Reference: Loriot Y, et al. N Engl J Med. 2019;381:338-48. Clinical trial information: NCT02365597 .

e17032 Background: Little is known about the patterns of racial and gender disparities in bladder cancer (BC). This study will use national large database to explore those disparities. Methods: Data from the National Cancer Institute’sSurveillance, Epidemiology, and End Results (SEER) Program for cancer registries was used. Patients > = 18 years diagnosed with BC in the years 2007-2016 were identified from SEER 18 database. We used the data year 2007 because that was the year when insurance status was first collected in SEER. Chi-square tests and multinomial logistic regression were used. Results: A total of 78,151 (females: 25.58%) patients were included, with 82.74% being non-Hispanic whites, 5.83% non-Hispanic blacks, 6.69 % Hispanics and 4.74% others. Distribution of stage 0 through stage IV at diagnosis was 51.97%, 23.21%, 12.11%, 4.10% and 8.61% respectively. Blacks (P < 0.0001) and females (P < 0.0001) were diagnosed at later stages as in Table. e.g., 14.54% of blacks were diagnosed at stage IV, compared to 7.97% of whites; and 11.03% of females at stage IV vs. 7.77% of males. Racial disparity exists for any given insurance status. Within every age group, gender disparity exists. For example, for those under 50 years of age, 12.81% of women vs. 8.16% of men were diagnosed at stage IV. After controlling for age, marital status and insurance type, both gender (P < 0.0001) and race (P < 0.0001) were statistically significant in predicting stage at diagnosis. Conclusions: Racial disparity in stage at BC diagnosis was strong, with blacks suffering most from the disparity. Females were more likely to be diagnosed at later stages, and this gender disparity exists in all age groups and was not due to women living longer. The existence of both racial and gender disparities in BC makes black women most vulnerable to late diagnosis than any other racial/gender group. Oncologists treating BC patients should be aware of the racial and gender disparity. More research needs to be done to help improve early access to health care amongst female and minority BC patients. [Table: see text]

Green microalga, Chlamydomonas sp. TRC-1 (C. TRC-1), isolated from the outlet of effluent treatment plant of textile dyeing mill, was investigated for its competence towards bioremediation. Algal biomass obtained after remediation (ABAR) was implied for bioelectricity and biofuel production. C. TRC-1 could completely decolorize the effluent in 7 days. Significant reduction in pollution-indicating parameters was observed. Chronoamperometric studies were carried out using cyclic voltammetry and electrochemical impedance spectroscopy (EIS). Maximum current density, power and power density of 3.6 A m–2, 4.13 × 10–4 W and 1.83 W m–2, respectively were generated in ABAR. EIS studies showed a decrease in resistance of ABAR, supporting better electron transfer as compared to algal biomass before remediation (ABBR). Its candidature for biofuel production was assessed by estimating the total lipid content. Results revealed enhancement in lipid content from 46.85% (ABBR) to 79.1% (ABAR). Current study advocates versatile potential of isolated C. TRC-1 for bioremediation of wastewater, bioelectricity production and biofuel generation.

447 Background: While ICI prolong OS after platinum chemotherapy in aUC, outcomes vary based on clinical confounders. We aimed to develop a prognostic model in pts receiving ICI in a non-clinical trial setting. Methods: We used a hypothesis driven approach of clinician selected covariates to develop a new prognostic model. Data source was a retrospective cohort of pts treated with ICI at 19 institutions. Demographics, clinicopathologic data, treatment patterns, and OS were collected. Univariate (UVA) Cox regression was done on 24 variables hypothesized to be associated with OS. Variables were retained for multivariate analysis (MVA) if they had statistical relationship with OS (p8x106/ul (upper limit of normal), and presence of bone or liver metastases (mets) were all associated with worse OS on UVA Cox regression; albumin8x106/uL, presence of bone or liver mets remained significant on MVA and were included in the prognostic model. Median (m)OS by new model and Bellmunt are shown in table. C-statistic of the new model was 0.67. Conclusions: Albumin8x106/ul, presence of bone or liver mets were negative prognostic factors in pts with aUC treated with ICI. This has comparable features to recently reported 5-factor model using clinical trial data, including LDH (unavailable in our cohort). External validation is being pursued. The proposed model may be used for prognostication, clinical trial design, eligibility and stratification. [Table: see text]

513 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, unresectable have limited treatment options. In this study, we investigate if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. Our results from phase (ph) Ib suggested that the combination was safe. Here we present the response rate post durvaRT and updated treatment related adverse events (TRAEs) amongst our evaluable pts in ph II. Methods: This is a single arm ph Ib-II study for T2-4 N0-2 M0 pts. The ph II primary endpoints a) PFS rate at 1 yr b) disease control rate (DCR); secondary endpoints were a) CR post durvaRT b) PFS c) OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy post durvaRT. We anticipated that durvaRT followed by durva would increase PFS at 1 yr from 50% to 75% when compared to RT; we assumed DCR of about 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Total N = 26 patients (male 19; female 7, median age 74yr). At the time of data cut off, 21/26 pts were evaluable for response post durvaRT. Post completion of durvaRT time point, clinical CR was seen in 15/21 pts (71.4%); PR 1/21 pts (4.7%); SD 4/21 (19%); PD 1/21 (4.7%). DCR was seen in 20/21 pts (95%) post durvaRT. Median follow up from D1 to last follow up was 6.1 mos. Grade ≥ 3 TRAE amongst 26 pts: anemia (1/26), lipase/amylase (1/26), immune nephritis (1/26), dyspnea (gr 4, copd/immune), fatigue (1/26), lymphopenia (6/26). Other TRAEs: Fatigue was the most common TRAE (16/26); UTI (5/26); cystitis (3/26). No fatal TRAEs were observed. Conclusions: DurvaRT demonstrated promising efficacy with clinical CR of 71.4% and DCR of 95% in unresectable, cisplatin ineligible locally advanced BC. It was generally well tolerated. Ph II study has completed accrual and longer-term results will further our understanding of this regimen’s efficacy in locally advanced BC. Clinical trial information: NCT02891161.

TPS771 Background: Over the last few years there has been a rapid increase in the clinically relevant agents available to treat metastatic renal cell carcinoma (mRCC). We note, however, that the vast majority of new agents available for mRCC do not exploit new clinical targets or pathways. We believe that the identification of new, clinically relevant targets in RCC will propel the field even further forward, expand treatment options, and lead to improved survival for mRCC patients. SGI-1776, a selective PIM1 kinase inhibitor, has previously been shown to induce reduction in tumor size as monotherapy and in combination with sunitinib in mouse pre-clinical studies of RCC. In our tissue microarray studies a subset of ~26% of RCC showed high staining for PIM1 kinase while only 1% of normal adjacent tissue showed similar high staining. Wildtype PIM1 is constitutively active, thus these data suggest that PIM1 activity is increased in a subset of RCC. Abemaciclib is a potent CDK4/6 inhibitor with an IC50 of 2 and 10 nM, respectively. It is also a potent PIM1 inhibitor with an IC50 of 50 nM. We have shown that abemaciclib decreases cell viability and increases apoptosis in RCC cell lines, and does so at greatest effect in combination with sunitinib. We have also shown that abemaciclib induces regression of RCC tumors in a mouse model of RCC, with the most rapid responses observed when abemaciclib is combined with sunitinib. Based on these data we have opened a phase Ib dose escalation study to determine the safety and tolerability of abemaciclib in combination with sunitinib in patients with mRCC. The study includes an expansion cohort at the recommended phase II dose to evaluate for a signal for efficacy. Pattern and intensity of PIM1 staining in tumor tissue will be evaluated as a potential biomarker of response. We are also collecting blood and urine to evaluate additional potential biomarkers of response. Methods: Clinical trial information: NCT03905889 .[Table: see text]

ObjectiveTo determine the feasibility of conducting creative writing workshops (CWW) for patients with cancer to promote improvement in mood.MethodWe piloted a prospective study to determine the feasibility of conducting CWW over a 4-week period. Patients were randomised 2:1 to either an intervention arm (IA) or to standard of care (SOC). Patients in the IA attended four 2-hour long weekly CWW × 4 weeks, whereas those receiving SOC did not participate in the CWW. We used a validated emotion thermometer scale (ETS) to assess changes in patient’s mental health before and after intervention. Patients with metastatic or unresectable cancer were included.Primary endpoint(1) Feasibility and (2) mood scores before and after CWW using ETS.ResultsA total of 16 patients were enrolled: 11 in the IA vs 5 in SOC. Seven out of 11 (63%) patients enrolled in the IA attended at least 75% of classes. Patients in the IA showed a trend towards mood improvement relative to the SOC when comparing initial and final ETS scores. Within the IA group significantly lower postclass total ETS scores were observed relative to preclass ETS scores. Also, a significant decreasing trend over time was observed in the preclass total ETS scores for participants in the IA group.ConclusionsIt is feasible for patients with cancer to attend CWW. Our results also show a positive effect on mood in the CWW arm. Further prospective clinical studies are needed to evaluate the effect of this intervention in patients with cancer.

Measures of mitotic activity predict behavior of noninvasive papillary urothelial carcinoma of the urinary bladder, but it is unclear what role these should have in tumor grading. In this article, we compare measures of mitotic activity to contemporary tumor grading, specifically in their association with recurrence of noninvasive papillary urothelial carcinoma. The study uses a retrospective cohort of 199 tumors from 124 patients. Mitotic activity was treated as a categorical variable (mitotic-inert, mitotic-low, or mitotic-high). Evaluating only first-occurrence tumors, recurrence was more frequent in mitotic-high (hazard ratio [HR], 8.8; P .0001, Cox model) and mitotic-low tumors (HR, 3.7; P = .017) compared with mitotic-inert tumors, when controlling for treatment with intravesical bacillus Calmette-Guerin, age, and sex. Recurrence was likewise more frequent in high-grade tumors (HR, 3.1; P = .00019, Cox model) compared with low-grade tumors, controlling for these factors. However, mitotic group, but not tumor grade, was significantly associated with recurrence in a multivariate Cox model including mitotic group, tumor grade, and treatment status (HR, 6.5 [P = .0025] for mitotic-high versus reference; HR, 3.7 [P = .018] for mitotic-low versus reference). Frailty models including both first-occurrence and recurrent tumors showed similar results. Isolating the analysis to first occurrence, low-grade tumors, recurrence was more frequent in mitotic-high (HR, 6.8; P = .0044, Cox model) and mitotic-low (HR, 3.4; P = .027) tumors compared with mitotic-inert tumors. The findings indicate that mitotic activity is associated with behavior of noninvasive papillary urothelial carcinoma and may be valuable as an adjunct to the contemporary grading system.

Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs.

Background Brain is a delicate organ, separated from general circulation and is characterized by the presence of relatively impermeable Blood Brain Barrier (BBB). The BBB maintains homeostasis in the brain thus restricting the entrance of foreign bodies and several molecules from reaching the brain. As a result several promising molecules do not reach the target site and fail to produce in vivo response. Nevertheless, lipid nanoparticles are taken up readily by the brain because of their lipophilic nature. The bioacceptable and biodegradable nature of lipid nanoparticles makes them less toxic and suited for brain targeting. Objective In the present review the BBB, mechanism of transport across the BBB, strategies to bypass the blood-brain barrier have been presented. The aptness of lipid nanoparticles for brain targeting has been highlighted. The proposed mechanism of uptake of the lipid nanoparticles, methods of prolonging the plasma retention and various methods of preparation for formulation of effective delivery systems for brain targeting have been included and dealt in this review. Conclusion Lipid based formulations can be designated as the current and future generation of drug delivery systems as these possess tremendous potential to bypass BBB and reach the target site due to their small size and ability to dodge the reticular endothelial system. However, these nanostructures need to be investigated intensively to successfully reach the clinical trials stage.

The photo-CIDNP effect has proven to be useful to strongly enhance NMR signals of photochemically active proteins simply by irradiation with light. The evolving characteristic patterns of enhanced absorptive and emissive NMR lines can be exploited to elucidate the photochemistry and photophysics of light-driven protein reactions. In particular, by the assignment of (13)C NMR resonances, redox-active amino acids may be identified and thereby electron-transfer pathways unraveled, in favorable cases, even with (13)C at natural abundance. If signal enhancement is weak, uniform (13)C isotope labeling is traditionally applied to increase the signal strength of protein (13)C NMR. However, this typically leads to cross relaxation, which transfers light-induced nuclear-spin polarization to adjacent (13)C nuclei, thereby preventing an unambiguous analysis of the photo-CIDNP effect. In this contribution, two isotope labeling strategies are presented; one leads to specific but ubiquitous (13)C labeling in tryptophan, and the other is based on fractional isotope labeling affording sets of isotopologs with low probability of next-neighbor isotope accumulation within individual tryptophan molecules. Consequently, cross relaxation is largely avoided while the signal enhancement by (13)C enrichment is preserved. This results in significantly simplified polarization patterns that are easier to analyze with respect to the generation of light-generated nuclear-spin polarization.

Candida albicans is a major fungal pathogen whose virulence is associated with its ability to transition from a budding yeast form to invasive hyphal filaments. The kinesin-14 family member Ca Kar3 is required for transition between these morphological states, as well as for mitotic progression and karyogamy. While kinesin-14 proteins are ubiquitous, Ca Kar3 homologs in hemiascomycete fungi are unique because they form heterodimers with noncatalytic kinesin-like proteins. Thus, Ca Kar3-based motors may represent a novel antifungal drug target. We have identified and examined the roles of a kinesin-like regulator of Ca Kar3. We show that orf19.306 (dubbed CaCIK1 ) encodes a protein that forms a heterodimer with Ca Kar3, localizes Ca Kar3 to spindle pole bodies, and can bind microtubules and influence Ca Kar3 mechanochemistry despite lacking an ATPase activity of its own. Similar to Ca Kar3 depletion, loss of Ca Cik1 results in cell cycle arrest, filamentation defects, and an inability to undergo karyogamy. Furthermore, an examination of the spindle structure in cells lacking either of these proteins shows that a large proportion have a monopolar spindle or two dissociated half-spindles, a phenotype unique to the C. albicans kinesin-14 homolog. These findings provide new insights into mitotic spindle structure and kinesin motor function in C. albicans and identify a potentially vulnerable target for antifungal drug development.

Biomarkers to identify subjects at high-risk for developing lung cancer will revolutionize the disease outlook. Most biomarker studies have focused on patients already diagnosed with lung cancer and in most cases the disease is often advanced and incurable. The objective of this study was to use proteomics to identify a plasma biomarker for early detection of lung lesions that may subsequently be the harbinger for cancer. Plasma samples were obtained from subjects without lung cancer grouped as never, current, or ex-smokers. An iTRAQ-based proteomic analysis was performed on these pooled plasma samples. We identified 31 proteins differentially abundant in current smokers or ex-smokers relative to never smokers. Western blot and ELISA analyses confirmed the iTRAQ results that demonstrated an increase of apolipoprotein E (APOE) in current smokers as compared to both never and ex-smokers. There was a strong and significant correlation of the plasma APOE levels with development of premalignant squamous metaplasia. Additionally, we also showed that higher tissue levels of APOE are seen with squamous metaplasia, supporting a direct relationship. Our analysis reveals that elevated plasma APOE is associated with smoking, and APOE is a novel predictive protein biomarker for early morphological changes of squamous metaplasia in the lung.

Targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in the tyrosine kinase (TKI) domain has led to a significant change in the management of this disease. The classic or sensitizing mutations are G719X mutation in exon 18, in-frame deletions or insertion of exon 19, L858R or L861Q mutation in exon 21. Approximately 90% of these mutations are exon 19 deletion or exon 21 L858R point mutation. Gefitinib and erlotinib are reversible first-generation inhibitors of mutant EGFR, and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5–13.7 months. However, the majority of these patients ultimately develop resistance to these drugs. Afatinib is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs. The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naïve and refractory NSCLC patients. The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib causes toxicities similar to those of the first-generation EGFR TKIs, such as diarrhea, rash, acne, and stomatitis, and overall is well tolerated. This article focuses on the clinical studies of afatinib in patients with NSCLC., Video abstract

The cycle process of the tidal force of celestial body for Lushan M7.0 earthquake, occurred in Lushan county of Sichuan, China on April 20, 2013 was calculated. The earthquake occurred at the lowest point phase. It indicated that the type of seismogenic fault that the tide force acted on belonged to the thrust fault. According to the tidal cycle, the abnormal air temperature change was analyzed based on NCEP satellite data around the whole China before and after the earthquake. The result showed that the air temperature changed evidently with the tide force changing. In temporal, the change went through: initial air temperature rise → strength→ reaching abnormal peak→ gradually decline; in spatial, the abnormal area winded its way along the margin of the southern Qinghai-Tibet Plateau and went through: scattered→ conversion→ scattered procession. The procession was similar to the change procession of a rock breaking under the stress loading. This shows that the stress change of rock may cause the air temperature change in the atmosphere before and after earthquake. It indicated that the tidal force of celestial body could trigger the earthquake, when the tectonic stress reaches its critical broken point and the air temperature anomaly was proportional to the seismic tectonic stress change. It was useful to combine air temperature and tidal force in earthquake precursory.

Semantic graph representation of text is an important part of natural language processing applications such as text summarisation. We have studied two ways of constructing the semantic graph of a document from dependency parsing of its sentences. The first graph is derived from the subject-object-verb representation of sentence, and the second graph is derived from considering more dependency relations in the sentence by a shortest distance dependency path calculation, resulting in a dense semantic graph. We have shown through experiments that dense semantic graphs gives better performance in semantic graph based unsupervised extractive text summarisation.

Several tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors and molecules inhibiting the mammalian target of rapamycin are being used for management of metastatic renal cell carcinoma (mRCC); however, there is still a potential for improvement. Immune checkpoint inhibitors like nivolumab and other PD-1/PD-L1 inhibitors provide an alternative approach for patients with mRCC. In this article, the authors review the safety profile and outcomes of phase 1, 2, and 3 clinical trials of nivolumab in mRCC.