bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of the RANK/RANKL/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma.
Authors: Sasaki Bianca Ribeiro de Souza , Reis Ianny Brum , Oliveira Gabriela , Duran Nelson , Fávaro Wagner José
Published: March 2021

462

Background: The activity of the receptor activator of nuclear factor-kβ RANK/RANKL in cancer cells has been correlated with tumor progression and poor prognosis in solid tumors including bladder cancer. Regulatory T cells (Tregs), often identified by FOXP3 biomarker, suppress the anti-tumor response and allow immune tolerance through suppression of T cells. Immunomodulator OncoTherad is an inorganic phosphate nanocomplex associated with glycosidic protein, developed by the University of Campinas/Brazil, with antitumor effects. Previous reports have demonstrated immune activation and antitumor effects of Platelet Rich Plasma (PRP). We evaluated the effects of OncoTherad associated with PRP in the RANK/RANKL system and Tregs in a mouse model of non-muscle invasive bladder cancer (NMIBC). Methods: C57BL/6J mice were assigned to groups (n = 42): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 consecutive weeks after induction. Results: After NMIBC induction, all animals in the Cancer group showed flat carcinoma in situ (pTis) and both percentages of RANK, RANKL, OPG, and FOXP3 positive cells and the intensity of immunoreaction for these antigens were significantly higher in comparison with healthy animals. In addition to ensuring this NMIBC model, these results indicated the involvement of RANK/RANKL in urothelial carcinogenesis and the presence of Tregs in a suppressed immune tumor microenvironment. Mice treated with PRP only showed a 28.6% rate of tumor progression inhibition (TPI) and exhibited papillary urothelial carcinoma (pTa) and pTis. In this group, the intensity of the RANKL and FOXP3 immunoreaction was weaker when compared to the Cancer group. Thus, PRP showed immunomodulatory effects, reducing Tregs that are sources of RANKL. Oncotherad immunotherapy led to an TPI of 85.7%, and benign flat hyperplasia was the most frequent diagnosis. Oncotherad reduced the total RANK and RANKL immunoreactivities and decreased the intensity of RANKL immunostaining in comparison to the Cancer. In the OncoTherad+PRP 10 mg/ml or 20 mg/ml group, TPI was 71.4%, with a predominance of non-malignant lesions such as flat hyperplasia, low-grade intraurothelial neoplasia, and reactive atypia. Treatments with Oncotherad and Oncotherad plus PRP decreased the percentage of FOXP3+ cells and reduced the intensity of FOXP3 immunoreaction compared to the Cancer and PRP groups. Conclusions: The tumor inhibition obtained with Oncotherad plus PRP was related to the alteration of the immune profile of the tumor microenvironment by decreasing RANK/RANKL expression and Tregs, resulting in an effective immune response against the tumor.
Bladder tumor metabolic alterations in response to IFNα gene therapy.
Authors: Miest Tanner , Mitra Anirban P , Narayan Vikram M , Dinney Colin P.N. , Mokkapati Sharada
Published: March 2021

468

Background: Intravesical interferon-alpha (IFNα) gene therapy with Nadofaragene firadenovec has shown clinical efficacy in patients with non-muscle invasive bladder cancer (NMIBC) in a phase III clinical trial, highlighting the therapeutic potential of this approach in a disease with significant unmet clinical need. Optimizing the clinical efficacy of IFNα gene therapy requires an understanding of the underlying therapeutic mechanisms. Here, we investigate the impact of IFNα gene therapy on tumor metabolism using in vitro and orthotopic murine preclinical models and clinical trial data to elucidate mechanisms of tumor resistance and identify predictive biomarkers. Methods: In vitro murine bladder cancer cell lines treated with recombinant IFNα (rIFNα) and lentiviral IFNα (LV-IFNα) were analyzed by whole-transcriptome sequencing, glucose uptake, and lactate production. Preclinical murine bladder cancer models were treated with LV-IFNα (orthotopic tumor model) or Poly(I:C) (flank tumor model), a potent IFN inducer. Disease response was monitored by in vivo real-time luciferase imaging. Tumors were harvested and whole-transcriptome sequencing performed to assess effects of IFNα therapy on tumor metabolism and lipidomics. Lipidomic profiling was performed on patient urine samples from a phase II clinical trial of intravesical Nadofaragene firadenovec (7 clinical responders and 6 non-responders) to assess for clinically-relevant differences in lipid metabolism. Results: Following IFNα therapy in vitro and in murine orthotopic bladder cancer models, we identified downregulation of genes involved in fatty acid synthesis and upregulation of genes involved in glycolysis by whole-transcriptome sequencing. This was confirmed by higher glucose uptake and lactate production by IFNα-treated cells in vitro. These findings were recapitulated in whole-transcriptome sequencing data of human bladder tumors treated with intravesical Nadofaragene firadenovec. Lipidomics performed on murine MB49 tumors treated with poly(I:C) identified 79 upregulated lipids, including phosphotidyl choline, spingomyelin and phosphatidyl ethanolamine, and 12 downregulated lipids, notably the cardiolipin class. Lipidomics performed on patient urine samples collected pre- and post-treatment with intravesical Nadofaragene firadenovec detected >592 lipids with distinct expression profiles differentiating clinical responders and non-responders at both timepoints. Conclusions: We describe novel modulation of glucose and lipid metabolism by bladder tumor cells in response to IFNα gene therapy. These metabolic changes were reproducible across in vitro, in vivo and clinical trial studies and improve our mechanistic understanding of IFNα gene therapy, identify tumor escape pathways targetable with combination therapy regimens, and identify a new class of biomarkers for predicting clinical response of NMIBC to IFNα gene therapy.
CDKN2A alterations as markers of immune checkpoint blockade (ICB) resistance in urothelial carcinoma (UC).
Authors: Nassar Amin , Adib Elio , Akl Elie W. , Abou Alaiwi Sarah , Nuzzo Pier Vitale , Mouhieddine Tarek H. , Sonpavde Guru , Haddad Robert I. , Giannakis Marios , Hodi F. Stephen , Choueiri Toni K. , Kwiatkowski David J.
Published: March 2021

475

Background: ICB has shown clinical benefit across several metastatic carcinomas; however, predictive biomarkers are still lacking. CDKN2A is one of the most commonly altered genes across human cancers. With prior studies giving conflicting evidence regarding the association between CDKN2A alterations and ICBs, we examined the impact of CDKN2A alterations on clinical outcomes in UC patients treated with ICBs. Methods: Of 809 patients at the Dana Farber Cancer institute (DFCI) treated with ICBs only and with relevant cancer types and targeted exome sequencing data (Oncopanel), 235 (29%) had loss-of-function (LOF) mutations or homozygous deletions in CDKN2A. Overall survival (OS) was compared by Cox logistic regression between CDKN2A altered and CDKN2A wild type (WT) patients. Hazard ratio (HR) was derived using multivariable analysis (MVA), adjusted for prior lines of therapy and tumor mutational burden (TMB). A validation cohort from Memorial Sloan Kettering Cancer Center (MSKCC) (Samstein et al., Nature Genetics, 2019) of 811 cancer patients treated with ICBs was analyzed in a similar manner, adjusted for TMB. As a control, the association between CDKN2A alterations and OS was examined in a cohort of platinum-treated UC patients (N = 56) to determine whether CDKN2A alterations were predictive of response to ICIs. Results: For the DFCI and MSKCC cohorts, median follow-up was 26.9 and 24 months (m), respectively. In the DFCI and MSKCC cohorts, CDKN2A alterations were found in 32/90 (35%) and 22/104 (21.2%) of UC, respectively; 4/55 (7.3%) and 3/131 (2.3%) of renal cell carcinoma, respectively; 73/178 (41%) and 45/194 (23.2%) of melanoma tumors, respectively; 86/370 (23.2%) and 26/260 (10%) of non-small cell lung cancer (NSCLC) tumors, respectively; 18/66 (27.2%) and 4/53 (7.5%) of esophagogastric tumors, respectively; and 22/50 (44%) and 11/69 (15.9%) of head and neck, respectively. CDKN2A alterations were significantly associated with shorter OS and TTF in the DFCI UC and melanoma cohorts by MVA, and showed a trend towards significance in the MSKCC UC cohort (Table). There was no significant association between CDKN2A alterations and OS for the other cancer types in both cohorts; and no association with OS or TTF was seen in the DFCI cisplatin-treated UC cohort. Conclusions: CDKN2A alteration status may serve as a predictive biomarker in patients with UC treated with ICBs. Further studies are needed to examine the mechanism of this clinical effect. [Table: see text]
Transcriptome analysis of low-risk and high-risk non-muscular invasive bladder cancer patients to reveal disease progression related genes.
Authors: Fu Zhichao , Liu Shenghua , Wang Jianfei , Zhang Yiqun , Yang Yadong , Xu Tianyuan , Anil Shrestha , Yan Yang , Li Cheng , Zheng Zongtai , Li Xin , Yao Xudong
Published: March 2021

483

Background: According to the EAU prognostic risk classes, non-muscle invasive bladder cancer (NMIBC) is divided into low, medium, and high risk. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression.Our specific aim was to investigate the biomarkers associated with progression and recurrence in NMIBC. Methods: Tumor tissue were collected from 70 patients with bladder cancer, including high-risk NMIBC (n = 44),low-risk NMIBC (n = 10) and (n = 16) MIBC. mRNA sequenced using the ABclonal Whole RNA-seq Lib Prep kit.The differentially expressed genes were identified using DESeq2 and the analysis of the association between genes expression and patient survival with NMIBC cohorts data(Jakob et al., 2016). RNAseq data of human bladder cancer cell lines were achieved from the Cell Model Passports website (https://cellmodelpassports.sanger.ac.uk/). Results:A total of 456 genes are significantly high expressed in high-risk NMIBC group compared with the low-risk NMIBC group. Combined with MIBC expression data,we found 16 genes with consistently increasing expression from the low-risk NMIBC group to high-risk NMIBC group and MIBC group using a fold change of at least 2, and a false discovery rate (FDR) of 0.05.Among these genes,14 genes were also highly expressed in human bladder cancer cell lines. Survival analysis by Kaplan-Meier,we finally identified 13 high-expressed genes, including KRT6A、SPHK1、S100A9、SLC16A1、CDC25B、NELL2、PREX1、C15orf48、AKR1B10、CERCAM、PKMYT1、UCHL1、SLC16A1, were significantly associated with poor progression-free survival(p<0.05). Conclusions: We identified a set of 13 genes that may predict the progression of NMIBC and may serve as molecular targets for NMIBC therapy. these study results need to be confirmed in larger research studies.
Circulating tumor DNA analysis of genomic alterations in metastatic urothelial carcinoma from NCT03113266 study.
Authors: Chen Haige , Zhang Ruiyun , Xie Feng , Du Pan , Zhang Yue , Jia Shidong , Zhuang Guanglei , Huang Yiran
Published: March 2021

486

Background: Recent studies have suggested the predictive value of liquid biopsies for immune checkpoint inhibitors. NCT03113266 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-PD-1) in metastatic urothelial carcinoma (mUC). Here we report the initial circulating tumor DNA (ctDNA) analysis of genomic alterations from a single-institution biomarker cohort. Methods: Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled and consented to Institutional Review Board-approved protocols permitting biomaterial collection and genetic sequencing. Serial plasma specimens were obtained at baseline and every two cycles. The 600-gene panel (PredicineATLAS) liquid biopsy assay was applied to assess somatic variants and blood tumor mutational burden (bTMB). Results: The ctDNA assays were performed successfully for 100% of baseline samples (n = 27) with average read depth of 24,389 (range 14,000-31,700). A total of 571 non-synonymous mutations were identified, demonstrating prevalent aberrations in TP53 (63%), TERT promoter (30%), KDM2D (26%), PPM1D (26%), and KDM6A (26%). In 5 patients, FGFR3 variants were detected, including 6 missense sites and 4 FGFR3- TACC3 fusion events. Copy number gain ( FGFR1, ERBB2) and loss ( PTEN, BRCA2, CDKN2A) were pinpointed. TMB estimation revealed one case with an exceptionally high bTMB (62.6 mutations/Mb) and genomic features of microsatellite instability (MSI). Concordance with tumor-based genotyping and ctDNA kinetics during toripalimab treatment are being determined. Conclusions: Prospective ctDNA analysis using the PredicineATLAS liquid biopsy assay is feasible and represents a minimally invasive approach to detecting cancer-specific genetic landscape and potentially guiding personalized therapeutic decisions in mUC patients. Clinical trial information: NCT03113266 . Research Sponsor: Shanghai Junshi BioSciences; Huidu Shanghai Medical Sciences Ltd
Retrospective cohort analysis of real-world clinical outcomes in nonmetastatic (M0) castration-resistant prostate cancer (CRPC) treated with novel androgen receptor pathway inhibitors (ARPI).
Authors: Gagnon Richard , Alimohamed Nimira S. , Watson Alexander , Batuyong Eugene , Chow Alyssa , Lee-Ying Richard M.
Published: March 2021

51

Background: The landscape of M0 CRPC has changed with the recent demonstration of metastasis-free survival (MFS) and overall survival (OS) improvements with the use of ARPIs in clinical trial settings. However, the extrapolation of this data to clinical practice is limited by strict exclusion criteria in these trials, including prior or concurrent malignancy, cardiovascular disease, or hypertension. The purpose of this study was to assess real-world outcomes in patients with M0 CRPC treated with ARPIs compared to historical controls. Methods: We designed a retrospective cohort study with the inclusion of patients in Alberta, Canada diagnosed with M0 CRPC between 2001-2020. Via chart review, we identified baseline characteristics, potential confounders, treatment details, and clinical outcomes. The primary outcome of interest was MFS. Secondary outcomes included: second progression-free survival (PFS2) and OS. Median survival times were measured using the Kaplan-Meier method and the log-rank test was used for comparison of outcomes based on ARPI exposure. Cox proportional hazard regression models were used to calculate hazard ratios (HR) accounting for impact of PSA doubling time (PSADT), use of osteoclast inhibiting agents, and presence of pelvic lymphadenopathy. Results: We identified 211 patients across multiple centres in Alberta with M0 CRPC, with 54 having received apalutamide (40/54), enzalutamide (7/54), or darolutamide (7/54). Median age at M0 CRPC diagnosis was 74 years; median PSADT was 4.4 months; and 19% of patients (40/211) had pelvic lymphadenopathy at diagnosis. Median MFS in patients treated with ARPIs was 47.5 months compared to 20.6 months in those not treated with ARPIs (HR, 0.23; 95% confidence interval [CI], 0.11-0.49; p < 0.001). Median PFS2 in ARPI treated patients was 66.3 months compared with 35.6 months (HR, 0.40; 95% CI, 0.18-0.87; p = 0.022). Median OS for patients treated with ARPI was not reached. Conclusions: Given the older age of men with advanced prostate cancer, real-world outcomes that include patients with comorbidities are important adjuncts to the interpretation of clinical trials exploring the benefit of novel therapeutics. Here, we demonstrate that in a real-world, unselected population of men with M0 CRPC, apalutamide, enzalutamide, and darolutamide seem to confer similar MFS and PFS2 benefits to those demonstrated in the SPARTAN, PROSPER, and ARAMIS studies. Real-world OS data remain immature and will be an important addition to these findings.
Association of health-related quality of life (HRQOL) variations with biological biomarkers for patients with metastatic castrate-resistant prostate cancer (MCRPC) treated by abiraterone/prednisone combination or prednisone.
Authors: Goujon Morgan , Anota Amelie , Frontczak Alexandre , Charton Emilie , Maurina Tristan , Almotlak Hamadi , Nguyen Thierry , Fabien Calcagno , Stein Ulrich , Mouillet Guillaume , Thiery-Vuillemin Antoine
Published: March 2021

54

Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p < 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p < 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p < 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p < 0.001) and shorter time in case of progression (p < 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.
Use of bone modifying agents in patients with metastatic castrate-sensitive prostate cancer.
Authors: Mitchell Aaron Philip , Mishra Akriti A. , Bach Peter B , Morris Michael J.
Published: March 2021

68

Background: Bone modifying agents (BMAs) do not prevent skeletal related events (SREs) among patients with metastatic, castration-sensitive prostate cancer (mCSPC). Within this population, BMAs are recommended for prevention of osteoporotic fractures but not for SRE prevention. Utilization patterns of BMAs among patients with mCSPC have not been described, and it is unknown whether these patients may receive BMAs intended for SRE prevention unnecessarily. We conducted this study to measure BMA use among mCSPC patients who are unlikely to have an indication for osteoporotic fracture prevention. Methods: We used linked SEER-Medicare data. Our cohort included men newly diagnosed with de-novo stage IV prostate adenocarcinoma during 2007-2015. We included those age > = 66 at diagnosis, who lived at least 60 days after diagnosis, had continuous enrollment in Medicare Parts A and B from 180 days prior to diagnosis through the outcome period and Part D from diagnosis through outcome period, and who received androgen deprivation or antiandrogen therapy after diagnosis. We excluded patients who had previously received BMAs, or who had existing osteoporosis, osteopenia, hypercalcemia, or prior bone fracture. Our primary outcome was receipt of a BMA (zoledronic acid or denosumab) within 180 days of prostate cancer diagnosis, during which time the development of castrate-resistant disease is unlikely to arise. We also assessed receipt of BMAs within 90 days of diagnosis as a secondary outcome. We used multivariable logistic regression to assess patient factors associated with BMA use. Results: Our sample included 2,998 patients. Median age at diagnosis was 77. 77% of patients were white, 12% were Black, and 11% were of other race/ethnicity. 77% of patients were treated in the physician office setting and 23% the hospital outpatient setting. Overall, 24% received a BMA within 180 days of diagnosis; 18% did within 90 days. BMA therapy was more common among patients treated in the hospital outpatient vs. physician office setting (OR 1.25, 95%CI 1.03-1.52). Age, race/ethnicity, comorbidity, and renal disease were not associated with likelihood of BMA therapy. There was substantial variation across the study period: 19% of patients received BMAs from 2007-2009 (19% zoledronic acid, 0% denosumab), and 29% from 2012-2015 (9% zoledronic acid, 21% denosumab). Conclusions: Use of BMAs among patients with mCSPC is common. In this cohort of mCSPC patients, who were unlikely to have a BMA indication for osteoporotic fracture prevention based on the absence of history of osteoporosis, osteopenia, or fracture, nearly one-quarter received BMAs. The increase in BMA use which occurred during the 2007-2015 study period appears to have been driven by increased utilization of denosumab following its approval in 2010. Use of BMAs in patients with mCSPC without a need for osteoporotic fracture prevention may constitute overuse.
TALAPRO-1: Phase II study of talazoparib (TALA) in patients (pts) with DNA damage repair alterations (DDRm) and metastatic castration-resistant prostate cancer (mCRPC).
Authors: De Bono Johann S. , Mehra Niven , Higano Celestia S. , Saad Fred , Buttigliero Consuelo , van Oort Inge M. , Mata Marielena , Chen Hsiang-Chun , Healy Cynthia G. , Czibere Akos , Fizazi Karim
Published: March 2021

93

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) show antitumor activity in mCRPC/DDRm pts treated with novel hormonal therapy (NHT). TALAPRO-1 is an open-label study evaluating TALA (a potent PARP inhibitor/trapper) in men with mCRPC/DDRm. We report a planned interim analysis (IA; Dec 2019). Updated results at a Sep 4 2020 cut-off, available in November 2020, will be presented at the meeting. Methods: TALAPRO-1 (NCT03148795) is enrolling pts (N ≈ 100) with measurable soft tissue disease, progressive mCRPC, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received 1–2 chemotherapy regimens (≥1 taxane-based) for metastatic disease and progressed on ≥1 NHT (enzalutamide/abiraterone acetate) given for mCRPC. DDRm are defined as known/likely pathogenic variants or homozygous deletions. Pts receive oral TALA 1 mg/day (moderate renal impairment 0.75 mg/day) until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Primary endpoint is objective response rate (ORR). Secondary endpoints: time to objective response; response duration; prostate-specific antigen (PSA) decrease ≥50%; circulating tumor cell (CTC) count conversion (to CTC = 0 and <5 per 7.5 mL blood); time to PSA progression; radiographic progression-free survival (rPFS); overall survival; safety. A planned efficacy/safety IA was done when 60 pts with DDRm and measurable disease completed ≥6 months of TALA/no longer followed. Radiographic responses are based on investigator assessments. Results: 113 pts received TALA (cut-off Dec 12 2019); 75 pts were evaluable for IA, with DDRm, had measurable disease, received ≥16 weeks’ treatment, and were assessed for ORR (54.7% BRCA1/2, 4.0% PALB2, 22.7% ATM; 18.7% other DDRm).All pts evaluable for IA had prior docetaxel; 45.3% cabazitaxel. Confirmed ORR, rPFS, and composite response (investigator-assessed) in pts who received TALA for ≥16 weeks are in the table. Most common treatment-emergent adverse events: anemia (42.5%); nausea (32.7%). Conclusions: TALA monotherapy has encouraging antitumor activity in docetaxel-pretreated mCRPC pts with BRCA1/2 alterations and was generally well tolerated. Funding: Pfizer Inc. Clinical trial information: NCT03148795. [Table: see text]
Open-label, phase II study of ladiratuzumab vedotin (LV) for castration-resistant prostate cancer (SGNLVA-005, trial-in-progress).
Authors: Sher Amna Falak , Bruce Justine Yang , Gabrail Nashat Y. , Anderson Ian Churchill , Patrikidou Anna , Sanborn Rachel E. , Cho Jae Yong , Lee Arielle Shebay , Lee Jong-Seok , Nott Louise M. , Oh Do-Youn , Oh Sang Cheul , Oh Sung Yong , Wang Yinghui , Wang Zejing , Guthrie Troy H.
Published: March 2021

TPS185

Background: LIV-1 is a transmembrane protein expressed in a variety of cancer types. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death. In a phase 1 study, LV was tolerable and active in heavily pretreated patients with metastatic breast cancer (Modi 2017). This study is currently evaluating the safety and efficacy of LV in different advanced solid tumors with various LIV-1 expression, including metastatic castration-resistant prostate cancer (mCRPC), advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (squamous and nonsquamous), head and neck squamous cell carcinoma, and melanoma. Methods: SGNLVA-005 (NCT04032704) is an open-label, phase 2 study evaluating LV monotherapy in patients with previously treated, locally advanced unresectable or metastatic advanced solid tumors, including mCRPC. Patients with mCRPC will receive LV administered as a 30 minute intravenous infusion (IV) at 1.25 mg/kg every 1 week. Up to 30 patients with mCRPC will be enrolled. Patients in the mCRPC cohort must have metastatic castration-resistant disease, have received no more than 1 prior line of androgen receptor-targeted therapy, have ≥28 days between androgen receptor-targeted therapy and start of study treatment, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. In addition, mCRPC patients with measurable and non-measurable disease are eligible if the protocol-defined criteria are met. mCRPC patients must not have BRCA gene mutations, prior cytotoxic chemotherapy in the metastatic mCRPC setting, prior radioisotope therapy, or radiotherapy to ≥30% of bone marrow. Patients are not preselected based on tumor LIV-1 expression. Their tumor samples will be analyzed for correlation between LIV-1 expression and response. Safety and efficacy will be monitored throughout the study. Study objectives include objective tumor response rate per RECIST 1.1 and prostate-specific antigen (PSA) response rate per Prostate Cancer Clinical Trials Working Group 3 (both primary); safety and tolerability, disease control rate, duration of response, progression-free and overall survival, and pharmacokinetics and immunogenicity (all secondary); and pharmacodynamics. Study accrual is ongoing in the USA, Italy, South Korea, Taiwan, Australia, and the UK. Clinical trial information: NCT04032704.
Clinical-pathological characterization and outcomes of metastatic urothelial cancer in Latin America: Retrospective and translational multicenter database (LACOG 1518).
Authors: Souza Vinicius Carrera , Luz Murilo , Bastos Diogo Assed , Freitas Marcelo Roberto Pereira , Dauster Pereira E Silva Breno , Monteiro Fernando Sabino M. , Fernandes Roni , Caitano Manuel , Trindade Karine , Nogueira Lucas , Herchenhorn Daniel , Sade Juan , Nunes Galvão de Oliveira Fernando , Fay Andre P. , Werutsky Gustavo , Maluf Fernando C. , Fabricio Vanessa Carvalho , Gidekel Rosemarie , Pacheco Patricia , Soares Andrey
Published: March 2021

TPS497

Background: There is lack of high-quality and comprehensive data on advanced urothelial cancer in Latin America. Pathological and clinical outcomes information of this cancer can help the scientific community to understand the current standard of treatment and identify possible gaps for optimal care. Very few translational studies were performed in advanced urothelial cancer in developing countries describing the prevalence of key biomarkers for targeted agents and immunotherapy. Methods: LACOG 1518 is a large multi-institutional retrospective study that will collect information about sociodemographic data, treatment and outcome of patients diagnosed with recurrent/ metastatic urothelial cancer in Latin America between January 2016 and December 2019. Socio-demographic characteristics, clinical-pathological features, treatment patterns and outcomes will be extracted from medical charts. Tumor tissue will be collected for fibroblast growth factor receptor (FGFR) gene mutation or fusion test in a central laboratory. A biorepository will be built for future translational research including PD-L1 test and next generation sequencing. Primary endpoint consists on characterize demographic, socioeconomic factors, medical and oncological history of patients diagnosed with recurrent/metastatic urothelial cancer. This study aim to describe treatment sequence, duration, best response and progression time in each line of therapy as well as survival at 1 and 2 years. Translational research endpoints are biomarkers prevalence and association with treatment responses and outcomes.
TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy.
Authors: Grivas Petros , Tagawa Scott T. , Bellmunt Joaquim , De Santis Maria , Duran Ignacio , Goebell Peter-Juergen , Necchi Andrea , Sridhar Srikala S. , Sternberg Cora N. , Aziz M Usman , Pichardo Cabilia C. , Loriot Yohann
Published: March 2021

TPS498

Background: Treatment options are limited for patients with locally advanced unresectable or metastatic urothelial carcinoma (mUC) who progress following prior platinum-based and checkpoint inhibitor (CPI) therapy. Sacituzumab govitecan (SG) is an antibody-drug conjugate consisting of an anti–Trop-2 monoclonal antibody coupled to SN-38 (an active metabolite of irinotecan, a topoisomerase-I inhibitor) via a unique hydrolyzable linker. A phase II registrational study, TROPHY-U-01 study, confirmed the initial positive efficacy signal in mUC. SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months in patients with mUC (median 3 prior lines of therapy and 87% with ≥1 Bellmunt risk factors) who progressed after prior platinum-based and CPI therapies (n=113; Loriot ESMO 2020). The results compared favorably with historic single-agent chemotherapy (ORR ~10%; OS ≤7 months). A phase III trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in patients with locally advanced unresectable or mUC who progressed after prior platinum-based and CPI therapies (with Eastern Cooperative Oncology Group performance status 0–1 and adequate hematologic, hepatic, and renal function). Patients will be randomized 1:1 to receive SG 10 mg/kg intravenously (IV) on day 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in patients deemed to be receiving clinical benefit per investigator assessment. Approximately 482 patients will be enrolled to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors v1.1), safety, and quality of life. Study initiation is ongoing and enrollment begins in Q4 2020 across ~90 sites. Clinical trial information: NCT04527991.
Sub-urothelial durvalumab injection-1 (SUBDUE-1): A novel approach to immunotherapy for bladder cancer.
Authors: Viswambaram Pravin , Moe Andrew , Liow Elizabeth Chien Hern , Redfern Andrew David , Swarbrick Nicole , Ferguson Tom , Davis Ian D. , Hayne Dickon
Published: March 2021

TPS503

Background: Bladder cancer progression may be influenced by the host immunological response to the tumour. Cells strongly associated with this immunological response include Tumour Infiltrating Lymphocytes (TILs) and Tumour-Associated Macrophages (TAMs). Several solid tumours, including bladder cancer can demonstrate good responses to systemic immuno-oncology (IO) agents, however, the efficacy of IO agents in localised bladder carcinoma remains less clear, although numerous trials are underway. One such IO agent is durvalumab, an antibody against the immune checkpoint protein programmed cell death ligand 1 (PD-L1). The sub-urothelial administration of immune therapeutic agents has not been reported. This method of administrating other agents such as Botulinum toxin has shown excellent feasibility and efficacy. Local delivery could have a number of therapeutic advantages and aligns more closely with the intra-vesical therapies commonly adopted in this clinical scenario. It remains unknown whether systemic effects (both beneficial and adverse) of PD-L1 blockade would be reduced by this mode of delivery. Our aim was to establish: a protocol for the sub-urothelial administration of durvalumab. the safety and tolerability of sub-urothelial administration of durvalumab to identify an appropriate dose for future phase II studies the local immunological efficacy of sub-urothelial administration of durvalumab by assessing the quantity and distribution of TILs and TAMs in pre- and post-administration biopsies Methods: This dose-finding Phase Ib trial is currently recruiting patients with invasive, high-grade bladder cancer (≥pT1) already scheduled for radical cystectomy. Cystoscopy under general anaesthesia and sub-urothelial injection of durvalumab will be performed a minimum of 2 weeks prior to cystectomy, utilising a 3+3 dose escalation design (25mg, 75mg, 150mg). The selected dose of durvalumab is diluted into 25mL of normal saline, and administered to the bladder using a 5Fr Bonee needle via 22Fr rigid cystoscope. PROMS, blood specimens, and tumour histopathology and immunohistochemistry at allocated times pre- and post-cystectomy are being collected for translational end-points. Analysis of safety and tolerability will be primarily descriptive in nature. This trial is registered with the Australian Clinical Trials Registry (ACTRN12620000063910, funded by ANZUP Below the Belt and has been approved by the appropriate institutional HREC. To date, four patients have been recruited. This study has a two-year recruitment target and is expected to finish recruiting in 2022. Clinical trial information: ACTRN12620000063910.
European Health Care Systems and the Emerging Influence of European Union Competition Policy
Authors: Morton Andrew J. B.
Published: March 2021

Context: Since the 1990s, the EU's influence over national health care policy has been limited to European internal market law or social policy coordination mechanisms. The introduction of EU competition law into health care is more recent and underdeveloped; however, its introduction would potentially be much more far-reaching and disruptive.

Methods: Three EU competition law (state-aid) cases are used and comprise both Court of Justice and European Commission decisions. One is from Ireland, one is from the Netherlands, and the third is from Belgium.

Findings: The Belgian (Iris-H) case sees EU institutions scrutinize a clearly “social” (nonmarket) health care model with EU competition law for the first time. This is a highly significant development. It is clear, however, that the European Commission is more reluctant to use EU competition law to scrutinize health care systems than the European courts are.

Conclusions: This intent on the part of EU institutions will have to be assessed in future cases, as considerable uncertainty about its shape and outer contours remains. However, EU competition law, and the EU's state-aid investigation apparatus, encroaching into the national health care systems for the first time is highly significant.
High-dimensional immunotyping of tumors grown in obese and non-obese mice
Authors: Wogsland Cara E. , Lien Hilde E. , Pedersen Line , Hanjra Pahul , Grondal Sturla M. , Brekken Rolf A. , Lorens James B. , Halberg Nils
Published: March 2021

Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine whether tumors evolving in obese environments adapt differential interactions with immune cells and whether this can be connected to disease outcome. Most of these studies have been limited to single-cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T-cell-suppressive cell types and a decrease in CD8 T cells.
Theory of change: Drama and arts-based community engagement for malaria research and elimination in Cambodia
Authors: Ean Mom , Sanann Nou , Callery James J. , Pell Christopher , Peto Thomas J. , Tripura Rupam , Cheah Phaik Yeong
Published: March 2021

Background: Across the Greater Mekong Sub-region, malaria persists in isolated communities along international borders. Arts and drama have been used to reach to communities in Cambodia to engage them in malaria research, prevention and control. The “Village Drama Against Malaria” (VDAM) project was conducted in north eastern and western Cambodia: Stung Treng; Battambang and Pailin provinces during 2016 to 2019.  In total, VDAM reached 55 rural villages, 2,378 student participants and 43,502 audience members.

Methods: This article presents the results of two stakeholder-led evaluation workshops in which participants collaboratively developed theories of change to better understand the potential and actual impact of arts and drama-based activities on malaria in these communities. The workshops had a particular focus on identifying areas for monitoring and evaluation so that impact can be measured. Workshop participants included village malaria workers, community leaders, professional and student drama performers, and representatives from the local health authorities and the national malaria control programme.

Results: Five broad areas were identified as relevant for monitoring and evaluation: logistical and practical challenges; embeddedness and reach of engagement; health knowledge and confidence of young people; community-level malaria outcomes; impact on malaria. These areas align well with the monitoring and evaluation conducted to date and point to additional opportunities for data collection.

Conclusions: The findings from these workshops will inform future engagement strategies, for example, we may engage a smaller number of young people but over a longer period and more in-depth.
Cost Accounting in the Production of Commodity Output
Authors: Grachev A.
Published: March 2021

Th is article discusses the organization, accounting and cost management of a manufacturing enterprise. To do this, the relationship between accounting accounts and cost centers, items and elements is shown. Particular attention is paid to the compilation of the consolidated calculation and the consolidated budget, as well as the construction of the balance of commodity output.
Accounting and Analytical Mechanism for Managing Accounts Receivable in Construction
Authors: Gerasimova L.
Published: March 2021

Th e article considers the mechanisms of accounting and analysis of accounts receivable in the construction industry. Th e author highlighted the accounting tools that are used by construction companies, depending on the territorial and technological features of the industry. Th e issue of determining the size of the construction company’s own funds, taking into account diff erent types of receivables, is considered. A methodology for analyzing accounts receivable in the construction industry is proposed in order to optimize the size of accounts receivable of construction companies.
Dermal fillers: a brief background and overview for injectors
Authors: Haq Alexandra Mills
Published: March 2021

Going back to basics and visiting one of the backbones of the medical aesthetics sector, Alexandra Mills Haq details important information on dermal fillers
Türkiye’deki Güzel Sanatlar Liselerinin müzik dersi öğretim programlarının öğrenci alan seçimi üzerindeki etkileri üzerine bir araştırma
Authors: Şengün Taşçı Aylin
Published: March 2021

Tanzimat sonrası Osmanlı batılılaşmasında göze çarpan en önemli yeniliklerden biri eğitimalanında yapılmıştır. Çağın gerektirdiği eğitim modellerinin uygulanması için modernokulların açılması on dokuzuncu asrın sonlarına doğru hız kazanmıştır. Bunlar arasındaüniversite ve lise dengi birçok müzik okulu yer alıyor. Batı müziği ekseninde verilen eğitimprogramları günümüze kadar benzer program ve müfredat dahilinde ulaşmıştır. Özellikleİstanbul ve Ankara merkezli müzik yüksek okullarının belirlemiş olduğu ders içerikleri müzikeğitiminde etkin rol oynamıştır. Bu durum ülkemizde yer alan güzel sanatlar liselerindede benzerlik gösteriyor. Türkiye’deki güzel sanatlar liselerinin ilki 1989 yılında döneminMilli Eğitim Bakanı Avni Akyol tarafından İstanbul’da kurulmuştur. Güzel Sanatlar Liseleribugün orta öğretim düzeyindeki müzik eğitiminin öncü kurumlarıdır. Konservatuvar ve güzelsanatlar fakültelerinde geçmişten bu yana uygulanan Batı eksenli müzik eğitim modelleribu liselerde de görülmektedir. Bu araştırmada, ülkemizdeki Güzel Sanatlar Liselerinin müziköğretim programında yer alan Batı Müziği, Türk Müziği ve Halk Müziği türlerindeki derssayısı planlamalarının, müzik bölümündeki öğrenci sayılarına yansımasının incelenmesiamaçlanmıştır. Buna yönelik olarak Millî Eğitim Bakanlığı Öğrenci İşleri Daire Başkanlığındanalınan Güzel Sanatlar Liseleri öğrenci verileri ve 19.02.2018 tarihinde Talim ve TerbiyeKurulu Başkanlığı tarafından yayımlanan Güzel Sanatlar Liseleri müzik öğretim programıderslerine ait haftalık ders çizelgelerindeki ders dağılımları incelenmiştir.
The Impact of Microwave Irradiation Reaction in Medicinal Chemistry: A Review
Authors: Pal Ashutosh , Gayen Krishnanka Shekhar
Published: March 2021

The present review collects an update of the reactions in the area of medicinal chemistry using microwave irradiation. This review come up with an overview of most salient reactions performed under microwave irradiation in the field of drug discovery. Moreover, chemists are preferring to use this reaction rapidly in the academic as well as pharmaceutical laboratory during their drug discovery and making library of compounds. This reaction is much greener using less amount and readily recyclable solvents or sometimes reaction process without solvents and product become much cleaner, often yields are better than the conventional heating. Microwave irradiation is now very robust instrument used in company in the field of drug discovery, due to reduce the reaction time from hour to minute or even second and efficiently creation of compound libraries through combinatorial methodology associated with drug discovery so that new therapeutic agents bring to the market quicker. Hopefully, we will observe in the future the use of microwave irradiation drugs for the patients and this technology will utilize increase in number extensively in the field of medicinal chemistry. As this is an exceedingly rapid evolution area, this review offers significant expertise to the interested readers.
Photocatalytic Degradation of Naphthalene By UV/Zno: Kinetics, Influencing Factors and Mechanisms
Authors: Khatibi Aram Dokht , Chandrika Kethineni , Mostafapour Ferdos Kord , Sajadi Ali Akbar , Balarak Davoud
Published: March 2021

Conventional wastewater treatment is not able to effectively remove Aromatic hydrocarbons such as Naphthalene, so it is important to remove the remaining antibiotics from the environment. The aim of this study was to evaluate the efficiency of UV/ZnOphotocatalytic process in removing naphthalene antibiotics from aqueous solutions.This was an experimental-applied study that was performed in a batch system on a laboratory scale. The variables studied in this study include the initial pH of the solution, the dose of ZnO, reaction time and initial concentration of Naphthalene were examined. The amount of naphthalene in the samples was measured using GC.The results showed that by decreasing the pH and decreasing the initial concentration of naphthalene and increasing the contact time, the efficiency of the process was developed. However, an increase in the dose of nanoparticles to 0.8 g/L had enhance the efficiency of the process was enhanced, while increasing its amount to values higher than 0.8 g/L has been associated with a decrease in removal efficiency.The results of this study showed that the use of UV/ZnOphotocatalytic process can be addressed as a well-organized method to remove naphthalene from aqueous solutions.
Pentafluorophenylammonium triflate: A Mild, Efficient and Reusable Catalyst for the Synthesis of 2-Arylbenzothiazole and 2-Arylbenzothiazoline Derivatives in a Green Chemical Approach
Authors: Datta Arup
Published: March 2021

In this work, one pot, simple and environmentally benign effective synthesis of 2-substituted benzothiazole and benzothiazoline derivatives are described in presence of PFPAT (pentafluorophenylammonium triflate) catalyst in water successfully. A series of benzothiazole derivative were synthesized by the reaction between 2-aminothiophenol and various aldehydes in good yields. Recyclability of the catalyst is observed for four times without loss of its activity in aqueous medium.
Synthesis and Characterization of Strontium Oxide Nano Particle by Sol-Gel Method
Authors: Alimuddin Alimuddin , Rafeeq Mohd
Published: March 2021

Synthesis of strontium oxide nanoparticles was carried out by sol –gel method using strontium nitrate and sodium hydroxide at room temperature which is very simple and cost effective. The characterization of strontium oxide nanoparticles was done using X-ray diffraction, scanning electron microscopy (SEM) and Fourier transform infra-red (FTIR). X-ray diffraction pattern indicates that the nanoparticles are crystalline in nature. The crystalline size of strontium oxide nanoparticle was calculated by Debye-Scherrer formula. The crystalline sizes are about 80nm. The morphology of nanoparticles was observed and investigated using SEM. The material at room temperature, calcined at 2000C, 400 0C and 6000C respectively shows pseudo spherical shape, cubic form and finally it becomes cylindrical this shows that there is a agglomeration with increase in temperature. FTIR spectrum of strontium oxide shows the peak at 854.64 cm-1 which is due to Sr -O bond.