bluuebunny/crossref_metadata_2025 huggingface dataset:
Axitinib and avelumab (AA) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in the Northwest of England, United Kingdom.
Authors: Allison Jennifer , Charnley Natalie , Stevenson Robert , Waddell Tom , Pillai Manon Rhys
Published: March 2021

294

Background: The combination of the immune checkpoint inhibitor avelumab and VEGF-targeted, antiangiogenic tyrosine kinase inhibitor axitinib (AA) has demonstrated superior PFS and ORR compared to sunitinib in patients with mRCC and is an option for first line treatment across all IMDC risk scores. In this retrospective review we report our real world experience of this combination in three cancer centres in the Northwest of England. Methods: Treatment naïve mRCC patients receiving AA through the Early Access to Medicine Scheme at 3 cancer sites in the UK between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), adverse events (AEs) and preliminary survival observations. Results: A total of 44 patients were identified with a median follow up of 6.9 months (0.8-13.5 mo). Median age was 68 (48-81); 68% were male. The patients’ adult comorbidity evaluation score (ACE-27) was calculated: 0 = 43%, 1 = 30%, 2 = 7% and 3 = 20% . 45%, 48% and 7% of patients had favourable (F), intermediate (I) and poor (P) IMDC risk scores respectively. All had clear cell histology with 16% demonstrating sarcomatoid change. Most patients had undergone a nephrectomy (70%) and 36% had a single organ site of metastatic disease. ORR in the whole cohort was 60% (CR 5%, PR 55%, SD 25%, PD 2%, NE 13 %). Median time to first response was 2.6 months (0.6- 8.2mo). At time of data cut-off, 64% of patients remain on treatment (80% F, 48% I and 67% P). 14% of patients discontinued treatment due to disease progression while 22% stopped due to toxicity. The majority of patients (68%) continued axitinib at the starting dose of 5mg BD. Dose escalation of axitinib was possible in 9% patients while 23% needed a dose reduction due to toxicities. AEs were observed in 36 (82%) patients (G3 36%); the commonest being mucositis 30%; hypertension 23% (G3 11%); fatigue 25%; thyroid dysfunction 18%; diarrhoea 20% (G3 5%); hepatitis 20% (G3 11%). 9% of patients experienced an infusion reaction to avelumab. Overall, 9 (20%) patients received steroids for suspected immune related adverse events (irAEs); 6 (14%) were managed as G3≤ irAEs. 9 (20%) patients required inpatient admission due to AEs; 5 (11%) were associated with irAEs. Of the patients who discontinued AA treatment, 50% received subsequent therapy (12.5%, 75% and 12.5% receiving combination checkpoint inhibitor therapy, other VEFG TKi and TKi/MTOR combination respectively). 4 patients remain on active surveillance with no evidence of progression. Conclusions: Our early experience of AA in this real world setting reports comparable clinical responses to the published data. Treatment is well tolerated, with lower than expected levels of G3 or above AEs which is reassuring in a non-trial selected population. Follow-up is ongoing and updated efficacy and safety outcomes will be presented.
Feasibility study of gallium-68 citrate PET as a bone-tropic imaging biomarker in mCRPC.
Authors: de Kouchkovsky Ivan , Behr Spencer , Zhang Li , Foye Adam , Vanbrocklin Henry , Small Eric Jay , Feng Felix Y , Friedlander Terence W. , Li Patricia , Frey Natalie , Chung Andy , Lui Austin , Subramanian Aishwarya , Rodvelt Tammy J. , Barlesi Brigid , Evans Michael , Aggarwal Rahul Raj
Published: March 2021

31

Background: Transferrin receptor (TFRC) expression is controlled by the PI3K and MYC signaling pathways, which are frequently dysregulated in prostate cancer (PC). Gallium-68 citrate (68Ga-citrate) is an iron biomimetic, which can be used to image PC in a TFRC dependent fashion. We performed a single-center pilot imaging study to investigate the use of 68Ga-citrate PET in patients with metastatic castration-resistant PC (mCRPC). Methods: Following written informed consent, mCRPC patients were prospectively enrolled and underwent 68Ga-citrate PET imaging. Optional metastatic tumor biopsies were undertaken at the time of imaging. Results: 34 mCRPC patients underwent 68Ga-citrate PET imaging. The median age was 67.5 years old. Median duration of castration resistance was 17.5 months; 14.7% of patients were post-docetaxel. Median serum PSA was 35.2 ng/dL. A total of 483 lesions were detected on conventional imaging (CT, 99mTc-HDP) or 68Ga-citrate PET, including 420 osseous and 63 soft tissue (nodal and visceral) lesions (Table). 67.3% of all lesions were detected on 68Ga-citrate PET, including 74.5% of all osseous lesions but only 19.0% of all soft tissue lesions (p<0.0001). Eight (1.7%) lesions were detected on 68Ga-citrate PET imaging only. Per-lesion average SUVmax (SUVmax,avg) was 6.7. Metastatic biopsies of PET avid lesions were performed in 20 patients (59%); adenocarcinoma histology was confirmed in 14 (70%) cases, treatment-emergent small cell neuroendocrine cancer (t-SCNC) in 6 (30%). There was no significant difference in SUVmax,avg between patients with adenocarcinoma or t-SCNC (SUVmax,avg 7.3 vs 7.6, respectively; Table). Serial 68Ga-citrate PET perfomed in a patient with biopsy-confirmed t-SCNC after 2 cycles of carboplatin/cabazitaxel demonstrated an early metabolic response (28.5% decrease in average SUVmax) confirmed on subsequent conventional imaging. Conclusions: 68Ga-citrate PET detects mCRPC bone metastases in patients with biopsy-proven prostatic adenocarcinoma or t-SCNC, distinguishing it from lineage dependent agents such as PSMA tracers. Detection of an early metabolic response in the bone of a treated t-SCNC patient was observed. Further prospective studies are ongoing coupling serial Ga-citrate PET with investigational agents targeting the MYC signaling pathway. Clinical trial information: NCT02391025. [Table: see text]
Efficacy of VEGFR-TKI plus immune checkpoint inhibitor (ICI) in metastatic renal cell carcinoma (mRCC) patients with favorable IMDC prognosis.
Authors: Ciccarese Chiara , Iacovelli Roberto , Bria Emilio , Schinzari Giovanni , Rossi Ernesto , Astore Serena , Cannella Maria Antonella , D'Angelo Tatiana , Cicala Carlo Maria , Maratta Maria Grazia , Tortora Giampaolo
Published: March 2021

318

Background: Combinations of a PD-1/PD-L1 immune checkpoint inhibitor (ICI) with a VEGFR-TKI as front-line/treatment-naïve therapy significantly improve the outcome of metastatic renal cell carcinoma (mRCC) patients. The benefit of these combinations is well evident in IMDC intermediate- and poor-risk population, while it is unclear in the subgroup of mRCC patients with favorable prognosis. We performed a meta-analysis with the aim to evaluate whether the addition of ICIs to VEGFR-TKIs is able to improve the outcome compared to VEGFR-TKIs alone in mRCC patients with favorable IMDC prognosis. Methods: This meta-analysis searched MEDLINE/PubMed, the Cochrane Library and ASCO Meeting abstracts for phase II or III randomized clinical trials (RCTs) testing the combination of VEGFR-TKI+ICI in mRCC. Data extraction was conducted according to the PRISMA statement. The hazard ratios (HRs) for PFS and OS with the relative 95% CIs were extracted from each study. Summary HRs was calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. Results: Three RCTs were selected for the final analysis, with a total of 605 patients (306 treated with VEGFR-TKI+ICI combinations and 299 who received sunitinib in the control arms). The combination of VEGFR-TKI+ICI improved PFS compared to sunitinib, with a 30% reduction of the risk of progression (fixed-effect, HR=0.70; p = 0.003). However, VEGFR-TKI+ICI combinations did not significantly prolong OS (fixed-effect; HR = 0.94; 95% CI 0.62–1.43; p = 0.77). Conclusions: Our analysis demonstrates a PFS benefit without an OS advantage for VEGFR-TKI+ICI combinations as first-line therapy for mRCC patients with favourable prognosis according to IMDC. Longer follow-up is required to definitely confirm the best therapy for treatment-naïve mRCC patients with favorable prognosis. [Table: see text]
Phase I with expansion clinical trial of seleno-l-methionine (SLM) in combination with axitinib in patients with relapsed clear cell renal cell carcinoma (ccRCC): Bench to bedside.
Authors: Zakharia Yousef , Reis Ryan , Garje Rohan , Swami Umang , Born Janelle M , Brown James A. , Nepple Kenneth Gerard , Abuqayas Bashar , Rajput Maheen , Bellizzi Andrew , Sieren Jessica C , Rustum Youcef M.
Published: March 2021

322

Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .
Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).
Authors: Barata Pedro C. , Gulati Shuchi , Elliott Andrew , Rao Arpit , Hammers Hans J. , Quinn David I. , Gartrell Benjamin Adam , Zibelman Matthew R. , Wei Shuanzeng , Geynisman Daniel M. , Zhang Tian , Darabi Sourat , Dawson Nancy Ann , Hauke Ralph J. , Poorman Kelsey Anne , Nabhan Chadi , Ryan Charles J. , Heath Elisabeth I.
Published: March 2021

343

Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.
Assessing the impact of the COVID-19 pandemic on patients with genitourinary malignancies.
Authors: Borno Hala , Zhang Sylvia , Gomez Scarlett Lin , Kaplan Celia , Miaskowski Christine , Hong Julian , Idossa Dame , Bailey Adina , Small Eric Jay
Published: March 2021

38

Background: The COVID-19 pandemic has vast implications on the health system. Patients with a cancer diagnosis may face greater challenges in the context of the current COVID-19 pandemic. Methods: We sought to assess the impact of the COVID-19 pandemic among patients with genitourinary malignancies. We performed a cross-sectional survey study at a Comprehensive Cancer Center during the current pandemic. Results: A total of 86 participants were recruited to the study to date, 72.1% had prostate, 19.8% had kidney, and 12.8% had bladder cancer. A subset (n = 5) had more than one primary tumor. The mean time from diagnosis was 6.47 years (std dev 6.01, range from 0 to 27 years). Overall, 73% reported having metastatic disease and prior treatment with surgery (62%), radiation (71%), or systemic therapy (68%), with 68.6% currently receiving cancer treatment. In the study, 78.9% of patients were >65 years of age and 88.2% were White. The majority of participants had a bachelor’s degree or higher level of education (74.4%), were legally married (82.6%), were homeowners (91.9%), and reported an annual household income of >$100,000 (56.0%). Among respondents, 7% reported loss/change of health insurance and 30% reported a decrease in household income. Among patients with reduced household income, 23% reported a reduction of more than 50%. In this study, 28% of patients reported that the pandemic impacted their cancer treatment. Overall 7% reported decrease in frequency of labs, 11% reported a delay in obtaining a scan, 5% reported treatment delays, and 96% reported use of telemedicine (video or telephone) visit. Overall, 59% reported fear of hospitalization, 23% reported delays in seeking medical care, and 16% reported missing required medications. Conclusions: The negative impact of the COVID-19 pandemic on patients with genitourinary malignancies is extensive. Ongoing research is evaluating the impact across socio-demographically groups and examine clinical outcomes associated with delays in care and medication non-adherence.
Impact of equal access healthcare on race disparities in bladder cancer.
Authors: Kotha Nikhil V. , Kumar Abhishek , Qiao Edmund M. , Cherry Daniel R. , Nalawade Vinit , Kader A. Karim , McKay Rana R. , Stewart Tyler Francis , Rose Brent S.
Published: March 2021

399

Background: Outcomes in bladder cancer are disproportionately worse for black patients compared to white patients. We hypothesize these disparities arise in part due to differences in access to healthcare and therefore may be mitigated in an equal access healthcare system, such as the Veterans Affairs’ (VA) system. Here, we examine outcomes by race for patients with bladder cancer within the VA system and then compare these outcomes to those in the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We performed a retrospective cohort study using VA Informatics and Computing Infrastructure (VINCI) and SEER. We included all patients diagnosed with bladder cancer, American Joint Committee on Cancer (AJCC) stage 0-4 diagnosed between 2000 and 2018. Endpoints of overall survival (OS), bladder cancer-specific survival (BCS), and non-bladder cancer-specific survival (NCS) were evaluated in multivariable Cox and Fine-Gray models. Results: Using the VA dataset, we identified 36322 veterans (9.0% black, 91.0% white) with bladder cancer. Black veterans were more likely to have more comorbidities, reside in zip codes with lower median income and education levels, and present with higher stage disease (AJCC stages 2-4) than white veterans (23.3% vs 19%). In multivariable models accounting for disease stage among other covariables, there were no statistically significant differences in any survival endpoint (Table). Using the SEER dataset, we identified 130998 patients (5.9% black, 94.1% white) with bladder cancer. In similar multivariable models, SEER’s black patients had statistically significant inferior outcomes in all survival endpoints compared to SEER’s white patients (Table). Conclusions: While racial disparities for patients with bladder cancer in the SEER database were observed, no differences in survival outcomes between black and white patients were observed in the VA healthcare system. Of note, black veterans presented with more advanced stage, suggesting a delay in diagnosis or a more aggressive cancer phenotype compared to white patients. Our findings underscore the need to bridge healthcare disparities across diverse racial groups. Our study highlights the beneficial impact of an equal access healthcare system in reducing financial and social barriers to healthcare to counteract racial health disparities. Further research is required to delineate these disparities and guide appropriate screening strategies. [Table: see text]
Combinatorial biomarkers to predict responses to immune checkpoint therapy in metastatic urothelial cancer.
Authors: Goswami Sangeeta , Chen Yulong , Anandhan Swetha , Szabo Peter M , Basu Sreyashi , Blando Jorge M , Liu Wenbin , Zhang Jan , Natarajan Seanu , Xiong Liangwen , Guan Baoxiang , Singh Shalini , Saci Abdel , Allison James Patrick , Galsky Matt D. , Sharma Padmanee
Published: March 2021

488

Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of immune checkpoint therapy in mUCC, we lack predictive biomarkers to guide patient selection. Therefore, there is a critical need to develop clinically useful biomarkers to refine patient selection. The single biomarker studies either focused on tumor mutations or immune response biomarkers, which may limit predictive power due to lack of integration between cancer cell biology and immune cell responses. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Methods: We performed retrospective multi-platform immuno-genomic analyses of pre-treatment tumor tissues in a discovery cohort (n = 31). Next, we tested the clinical relevance of ARID1A mutation and pre-treatment CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). Additionally, we performed reverse translational studies using murine model of bladder cancer to demonstrate direct association of the biomarkers in anti-PD-(L)-1 mediated anti-tumor immunity. Results: We identified genomic mutation of AT-rich interactive domain-containing protein 1A ( ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the pre-treatment tumor tissues as two predictors of clinical responses. We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). Further, reverse translational studies revealed that CXCL13−/− tumor-bearing mice were resistant to immune checkpoint therapy whereas ARID1A knockdown enhanced sensitivity to immune checkpoint therapy in a murine model of bladder cancer. We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to immune checkpoint therapy in CheckMate275 and IMvigor210. Combination of the 2 biomarkers in baseline tumor tissues showed improved OS compared to either single biomarker. Conclusions: Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A mutation may improve patient selection in mUCC for immune checkpoint therapy.
The potential role of frailty in modifying quality-of-life related outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel, abiraterone, enzalutamine, and radium 223.
Authors: Kim Seungyeon , Breunis Henriette , Timilshina Narhari , Yang Helen , Alibhai Shabbir M.H.
Published: March 2021

63

Background: As the arsenal of therapeutic agents for mCRPC expands, frailty-informed care is emerging as a strategy for tailoring management decisions. Yet, data to guide this approach and to ascertain its impact on the mood, fatigue, pain, and quality of life (QoL) experienced by older men with mCRPC remain lacking. We examined patient-reported outcomes, stratified by a validated frailty index (FI), for mCRPC treatment with docetaxel chemotherapy (CHEMO), abiraterone (ABI), enzalutamide (ENZA), or radium 223 (RAD). Methods: Older (aged 65+) men starting one of four approved therapies for mCRPC were enrolled in a multicenter prospective cohort study. Assessing their mood, fatigue, pain, and QoL with PHQ-9, ESAS tiredness, ESAS pain, and FACT-G total as well as subscale scores, we used linear mixed effect models to determine change in each outcome over time (0, 3, 6 months). At end of treatment, we administered the Decisional Regret Scale. We then constructed a FI from 34 variables that span laboratory abnormalities, geriatric syndromes, instrumental activities of daily living, social support, as well as emotional, cognitive, and physical deficits. Following established cut-offs, we categorized patients as non-, pre-, and frail, then performed stratified linear mixed effects regression analyses to identify differences in outcomes by frailty status. Results: A total of 198 men (mean age 75.1) starting CHEMO (n = 70), ABI (n = 38), ENZA (n = 67), and RAD (n = 29) were included, of which 9.6%, 1.5%, 5.6%, and 2.5%, respectively, were determined frail. Frailty correlated only modestly with age (Pearson r = 0.27). Independent of frailty status, patients across treatment cohorts were similar in terms of baseline QoL-related measures, with the exceptions of mood (p = 0.033) and pain (p = 0.034). Over time, no significant change in QoL was reported, although all four therapies resulted in generally low levels of decisional regret and similar trends of improved pain but worsened mood (p = 0.006 and 0.02, respectively). At baseline, frailty status correlated with worse FACT-G total (p < 0.001) and functional well-being (p < 0.001), as well as worse depression scores (p < 0.001). According to FI-stratified analysis, frail patients experienced similar QoL-related outcomes to fit patients for all measures aside from mood (p < 0.001). Contrary to our hypotheses, frailty was not associated with significant worsening in emotional well-being or functional well-being in response to mCRPC treatment. Conclusions: Of the older men receiving care for mCRPC, frail patients may experience generally similar trends in QoL as fit patients. Interestingly, frailty status, rather than treatment modality, may play more of a contributory role to changes in QoL-related outcomes over time.
Comparative analysis of sarcopenia induced by long-term abiraterone (A) versus enzalutamide (E) therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Naimi Mahdi Farzad , Khan Maira , Briones Carvajal Juan Rodrigo , Emmenegger Urban
Published: March 2021

69

Background: Androgen deprivation therapy induces osteosarcopenia, which in turn is associated with prostate cancer related morbidity, mortality and health expenditures. Although bone and skeletal muscle health are interconnected at multiple levels, clinical guidelines focus on the prevention and management of osteoporosis while largely ignoring skeletal muscle health. Due to the paucity of studies investigating the impact of A or E therapy on skeletal muscle loss, we decided to compare the effects of the two agents on sarcopenia development among men with mCRPC. Methods: In this retrospective single-centre study we identified a total of 58 mCRPC patients (pts) who (i) had received treatment with A (n = 29) or E (n = 29) for > 1.5 years, (ii) had an available routine abdominopelvic CT scan at baseline, and (iii) had at least one follow-up CT scan 12 and/or 24 months after treatment initiation. Using the contour tool of the eUnity imaging platform, we obtained the total contour area of the left and right psoas muscle at the inferior endplate of L3 in order to calculate the Psoas Muscle Index (PMI; defined as the total contour area divided by patients’ height in meters) as a measure of sarcopenia. Results: The median age of men undergoing A or E therapy was 75 (range 70-79) versus 69 (67-75) years (p = 0.09), with A use for first line mCRPC therapy in 65.5% of pts, and of E in 69.0% of pts. The median time on A was 30.3 (95%CI 27.2-46.0) months, compared to 42.8 (27.4-49.9) months for men on E (p = 0.96). Using a PMI cut-off for sarcopenia of < 5.7, the rate of sarcopenia increased from 34.5% at baseline to 39.3% at 24 months in pts undergoing A therapy (p = 0.71); the median PMI of A pts at baseline was 6.79 (95%CI 5.48-7.22) and steadily decreased to 5.86 (5.46-6.42) at 24 months (p = 0.0002). As for E, the rate of sarcopenia increased from 24.1% to 39.3% after 24 months of treatment (p = 0.21), with a concurrent PMI decrease from 6.73 (95%CI 5.87-7.64) to 6.32 (5.25-6.90; p = 0.001). There were no significant PMI differences between the A and E cohorts at baseline, month 12, or month 24. Furthermore, the presence versus absence of baseline sarcopenia was not significantly associated with the time on A or E therapy (p = 0.15 and p = 0.54, respectively). Conclusions: A sizeable number of men with mCRPC are sarcopenic at start of A or E therapy. In addition, the use of both agents is associated with an increase in the rate of sarcopenia, and with significant PMI decreases over time. The sarcopenia-inducing potential of A and E is comparable, while baseline sarcopenia seems not to predict time on A or E.
Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Feng Felix Y , Aguilar-Bonavides Clemente , Lucas Justin , Thomas Shibu , Gormley Michael , McCarthy Sharon Anne , Brookman-May Sabine Doris , Triantos Spyros , Mundle Suneel , Smith Matthew Raymond , Small Eric Jay
Published: March 2021

8

Background: SPARTAN, a phase 3 placebo (PBO)-controlled study in patients (pts) with nmCRPC, showed that APA plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival compared with PBO + ADT. This exploratory analysis investigated potential biological signatures of pts with long-term responses to APA and PBO. Methods: The biomarker cohort of SPARTAN was characterized as long-term responders (LTR) or early progressors (EP) based on time to metastasis, and separated into quartiles for APA and PBO groups. Pts progressing in the first quartile (APA, 21; PBO, 17), with shortest time to metastatic event, were classified as EP, those progressing in the last quartile (APA, 39; PBO, 20) as LTR. Gene expression profiles were generated from 233 archival primary prostate tumors. Predefined gene signatures indicative of cancer biology were compared between LTR and EP groups within the APA and PBO arms using 2 sample t tests. Signatures associated with LTR and EP were identified using p values of less than 0.05. Results: Median time to metastatic progression was 40.5 months in APA pts and 22 months in PBO pts in the LTR group and 7.3 and 3.6 months in APA and PBO pts, respectively, in the EP group. Signatures categorized into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) associated with LTR on APA included increased T cell activity reflected by T cell activation ( p = 0.0045), stimulation ( p = 0.0642), cytokine response ( p = 0.0489), and interferon production (gamma response p = 0.0227 ), and decreased T cell exclusion ( p = 0.0652), low proliferative capacity ( p = 0.0435), and increased hormonal dependence ( p = 0.0485). High risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors ( p = 0.0125) were associated with early progression on treatment with PBO. Conclusions: Although the data require confirmation in larger studies, these molecular determinants may have utility in selecting pts with nmCRPC who may derive the most benefit from APA and other androgen signaling inhibitors. Clinical trial information: NCT01946204.
Fractionated docetaxel and radium-223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A phase I trial.
Authors: Connell Brendan James , Folefac Edmund , Hwang Clara , Lawlor Christian , Mathew Paul
Published: March 2021

TPS175

Background: Disease progression following highly-active androgen-axis therapy (HAAT) in CRPC remains bone-dominant and docetaxel-responsive. Combination bone-homing Ra223 isotope therapy with docetaxel would be a logical combination therapy to follow but myelosuppression is dose-limiting. With 3-weekly bolus schedules of docetaxel (D), dose-reduction to 60mg/m2 Q3wkly and Ra223 to every 6 weeks has been required representing a reduction in the dose-intensity of both agents. Fractionated schedules of docetaxel Q2wkly (DQ2) have comparable activity to D 75mg/m2 Q3wkly (DQ3) with mitigated myelosuppression. We hypothesize that a fractionated dose-schedule of DQ2 in combination with standard Ra223 dosing will be feasible without reduction in dose-intensity of Ra-223 or D. Methods: Outcomes: The primary objective is to determine the feasibility and maximal tolerated dose (MTD) of the combination. Secondary objectives include PSA kinetics, objective response, bone marker outcomes, progression free and overall survival, and description of toxicity and quality of life. Eligibility: Progressive bone-metastatic CRPC, ECOG PS 0-2 with no prior Ra223, no prior docetaxel for CRPC, and no bulky visceral disease. Design: Phase I (6+6) design; 4 week lead-in with DQ2. Dose-level 1a: 40mg/m2; 2a: 50mg/m2, both with PEGylated G-CSF on Day 16. If tolerated (≤ Grade 2 toxicity, ANC ≥ 1500, Platelets ≥ 100,000), lead-in is followed by C1D1 of DQ2 plus Ra223 Q4wkly x 6 doses. Dose level 1a has accrued 6 subjects without DLT. Enrollment to Dose Level 2a began in August, 2020. An expansion cohort of 25 subjects is planned after the MTD is determined. Clinical trial information: NCT03737370.
Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): The phase III KEYNOTE-991 study.
Authors: Gratzke Christian , Niu Cuizhen , Poehlein Christian Heinrich , Burgents Joseph E.
Published: March 2021

TPS184

Background: The combination of pembro, an anti–PD-1 antibody, added to enza, a nonsteroidal antiandrogen agent, has shown antitumor activity in abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC) in the KEYNOTE-365 trial (NCT02861573) and in pts with mCRPC for whom enza was ineffective in the KEYNOTE-199 trial (NCT02787005). The efficacy of enza may be proimmunogenic, suggesting that it may be additive or synergistic in antitumor activity when combined with pembro. These data indicate that pembro + enza with ADT warrants phase 3 evaluation. Methods: KEYNOTE-991 (NCT04191096) is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial evaluating the efficacy and safety of enza + ADT (luteinizing hormone-releasing hormone agonist/antagonist during study treatment or bilateral orchiectomy) + pembro or placebo in pts with mHSPC. Eligibility criteria include age ≥18 years, mHSPC, ≥2 bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and ECOG PS 0 or 1. Pts must provide tissue for biomarker analysis. Approximately 1232 pts will be randomized in a 1:1 ratio to receive enza 160 mg orally once daily + ADT + pembro 200 mg intravenously (IV) every 3 weeks (Q3W) or enza 160 mg orally once daily + ADT + placebo IV Q3W. Treatment will continue with pembro up to 35 cycles and treatment with enza will proceed continuously from day 1 of cycle 1 until disease progression, unacceptable toxicity, or withdrawal of consent. The stratification factors are prior docetaxel therapy (yes or no) and presence of high-volume disease (yes or no). Computed tomography or magnetic resonance imaging and radionuclide bone imaging will be used to assess response according to Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) every 12 weeks (Q12W) from the date of randomization. Imaging will continue until the end of treatment and will resume Q12W during the posttreatment period. The dual-primary endpoints are BICR-assessed radiographic progression-free survival (rPFS; according to PCWG3-modified RECIST v1.1) and overall survival (OS). Key secondary endpoints are time to first subsequent anticancer therapy (TFST) and time to symptomatic skeletal-related event (TTSSRE). Safety and tolerability will be evaluated using a tiered approach. The dual-primary (rPFS and OS) and key secondary (TFST and TTSSRE) endpoints will be evaluated using a stratified log-rank test. Event rates will be summarized using the Kaplan-Meier method, and hazard ratios will be estimated using a stratified Cox regression model. KEYNOTE-991 is enrolling at 40 sites in Australia, Chile, Colombia, Germany, Israel, Japan, Poland, South Korea, Spain, Switzerland, Taiwan, and the United States. Clinical trial information: NCT04191096.
P3BEP (ANZUP 1302): An international randomized phase III trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate and poor-risk metastatic germ cell tumors (GCTs).
Authors: Subramaniam Shalini , Toner Guy C. , Stockler Martin R. , Martin Andrew James , Pashankar Farzana D. , Tran Ben , Jeffery Mark , Mazhar Danish , Huddart Robert A , Walpole Euan Thomas , Stevanovic Amanda Gwendolyn , Wyld David , Hanning Fritha J. , Wheater Matthew James , Balagtas Jay R. , Troon Simon , Birtle Alison Jane , White Jeff D. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2021

TPS390

Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 is standard first-line chemotherapy for metastatic GCT categorised as intermediate risk or poor risk. Acceleration of standard regimens by shortening the cycle length improved cure rates in other cancers. We aim to determine the superiority of accelerated BEP versus standard BEP in this setting. Methods: This open label, randomised, phase III trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) is complete response (CR); and for stage II (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide >80% power with a two-sided type error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage II) and of 7% in the PFS2y (stage II). The target population is males and females aged 11 to 45 with intermediate-risk or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomised (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments are 30 days after completing chemotherapy, 6 months from randomisation, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour tissue and baseline blood samples are collected for translational substudies including assessment of favourable versus unfavourable rates of decline in the novel biomarker miR-371. As of 13 October 2020, 140 participants have been recruited from 25 ANZ sites, 14 UK sites (led by Cambridge Clinical Trials Unit), and 140 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. The stage I analysis is anticipated mid-2021. This international randomised trial of chemotherapy for intermediate and poor-risk metastatic GCT is the first to include adults and children of both sexes. ClinicalTrials.gov: NCT02582697 Clinical trial information: NCT02582697.
A kinetic generator for classical field theories with conservation laws
Authors: Otomo Hiroshi , Boghosian Bruce M. , Succi Sauro
Published: March 2021

In this study, we demonstrate that, by suitably modifying the equilibrium distribution, the Bhatnagar-Gross-Krook form of the Boltzmann equation can serve as a generator of a broad class of nonlinear partial differential equations via a suitable generalization of the Chapman-Enskog method. We achieve this by properly choosing the relaxation time and moments of the equilibrium state in such a way as to suppress the dynamics of the zeroth moment, density, at increasingly faster time scales. As concrete examples, explicit analytical formulations of the Burgers', Korteweg-de Vries and Kuramoto-Sivashinsky equations are presented, along with a discussion of the associated conservation laws of the corresponding moments. The concept is numerically demonstrated by solving the BGK Boltzmann equation with the finite-element method. Because the Boltzmann-BGK equation can be equipped with a H-theorem, the framework developed in this work indicates a path towards the development of new algorithms for the numerical solution of the aforementioned equations with enhanced stability.
Enhancement of Unruh effect near hyperbolic metamaterials
Authors: Smolyaninov Igor
Published: March 2021

Laser fields acting on free electrons were proposed to create sufficiently large accelerations to enable detection of Unruh radiation. However, the currently achievable electron accelerations are not large enough. Here we demonstrate that the Unruh effect in laser fields is strongly enhanced near hyperbolic metamaterials, so that many orders of magnitude smaller accelerations may be used to detect Unruh radiation.
Extending Postpartum Medicaid: State and Federal Policy Options during and after COVID-19
Authors: Daw Jamie R. , Eckert Emily , Allen Heidi L. , Underhill Kristen
Published: March 2021

The United States is facing a maternal health crisis with rising rates of maternal mortality and morbidity and stark disparities in maternal outcomes by race and socioeconomic status. Among the efforts to address this issue, one policy proposal is gaining particular traction: extending the period of Medicaid eligibility for pregnant women beyond 60 days after childbirth. The authors examine the legislative and regulatory pathways most readily available for extending postpartum Medicaid, including their relative political, economic, and public health trade-offs. They also review the state and federal policy activity to date and discuss the impact of the COVID-19 pandemic on the prospects for policy change.
Extensive crosstalk of G protein-coupled receptors with the Hedgehog signalling pathway
Authors: Saad Farah , Hipfner David R.
Published: March 2021

Hedgehog (Hh) ligands orchestrate tissue patterning and growth by acting as morphogens, dictating different cellular responses depending on ligand concentration. Cellular sensitivity to Hh ligands is influenced by heterotrimeric G protein activity, which controls production of the second messenger 3′,5′-cyclic adenosine monophosphate (cAMP). cAMP in turn activates Protein kinase A (PKA), which functions as an inhibitor and (uniquely in Drosophila) as an activator of Hh signalling. A few mammalian Gαi- and Gαs-coupled G protein-coupled receptors (GPCRs) have been shown to influence Sonic hedgehog (Shh) responses in this way. To determine whether this is a more-general phenomenon, we carried out an RNAi screen targeting GPCRs in Drosophila. RNAi-mediated depletion of more than 40% of GPCRs tested either decreased or increased Hh responsiveness in the developing Drosophila wing, closely matching the effects of Gαs and Gαi depletion, respectively. Genetic analysis indicated that the orphan GPCR Mthl5 lowers cAMP levels to attenuate Hh responsiveness. Our results identify Mthl5 as a new Hh signalling pathway modulator in Drosophila and suggest that many GPCRs may crosstalk with the Hh pathway in mammals.
Social immunity in honey bees: royal jelly as a vehicle in transferring bacterial pathogen fragments between nestmates
Authors: Harwood Gyan , Salmela Heli , Freitak Dalial , Amdam Gro
Published: March 2021

Social immunity is a suite of behavioral and physiological traits that allow colony members to protect one another from pathogens, and includes the oral transfer of immunological compounds between nestmates. In honey bees, royal jelly is a glandular secretion produced by a subset of workers that is fed to the queen and young larvae, and which contains many antimicrobial compounds. A related form of social immunity, transgenerational immune priming (TGIP), allows queens to transfer pathogen fragments into their developing eggs, where they are recognized by the embryo's immune system and induce higher pathogen resistance in the new offspring. These pathogen fragments are transported by vitellogenin (Vg), an egg-yolk precursor protein that is also used by nurses to synthesize royal jelly. Therefore, royal jelly may serve as a vehicle to transport pathogen fragments from workers to other nestmates. To investigate this, we recently showed that ingested bacteria are transported to nurses' jelly-producing glands, and here, we show that pathogen fragments are incorporated into the royal jelly. Moreover, we show that consuming pathogen cells induces higher levels of an antimicrobial peptide found in royal jelly, defensin-1.
Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis
Authors: Thiagarajan Sasinthiran , Tan Joey Wee-Shan , Zhou Siqin , Tan Qiu Xuan , Hendrikson Josephine , Ng Wai Har , Ng Gillian , Liu Ying , Tan Grace Hwei Ching , Soo Khee Chee , Teo Melissa Ching Ching , Chia Claramae Shulyn , Ong Chin-Ann Johnny
Published: March 2021

Background

The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs.

Methods

Data were collected from a prospectively maintained database of PC patients treated at the authors’ institution from April 2001 to March 2019. The platelet–lymphocyte ratio (PLR), the neutrophil–lymphocyte ratio (NLR), and the lymphocyte–monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan–Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters.

Results

The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4–7), high postoperative NLR (days 8–21), and high postoperative PLR (days 22–56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57–90) and low postoperative LMR (days 8–21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC.

Conclusions

The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.
TreeSummarizedExperiment: a S4 class for data with hierarchical structure
Authors: Huang Ruizhu , Soneson Charlotte , Ernst Felix G.M. , Rue-Albrecht Kevin C. , Yu Guangchuang , Hicks Stephanie C. , Robinson Mark D.
Published: March 2021

Data organized into hierarchical structures (e.g., phylogenies or cell types) arises in several biological fields. It is therefore of interest to have data containers that store the hierarchical structure together with the biological profile data, and provide functions to easily access or manipulate data at different resolutions. Here, we present TreeSummarizedExperiment, a R/S4 class that extends the commonly used SingleCellExperiment class by incorporating tree representations of rows and/or columns (represented by objects of the phylo class). It follows the convention of the SummarizedExperiment class, while providing links between the assays and the nodes of a tree to allow data manipulation at arbitrary levels of the tree. The package is designed to be extensible, allowing new functions on the tree (phylo) to be contributed. As the work is based on the SingleCellExperiment class and the phylo class, both of which are popular classes used in many R packages, it is expected to be able to interact seamlessly with many other tools.
Digitalization and Accounting
Authors: Mislavskaya N.
Published: March 2021

Th e article attempts to investigate and establish the relationship and mutual infl uence of the digitalization process in the economy and the accounting system. Th e author, based on a detailed analysis of the process of analog-todigital conversion and on the prevailing approaches to the defi nition of the concept of «digital economy» today, draws certain parallels with accounting. Digitalization is considered as a prerequisite for synthesizing new methodological and methodological approaches to solving the problems of refl ecting economic reality in the accounting system.
How becoming self-sufficient can improve non-surgical and surgical outcomes
Authors: Spang Angela
Published: March 2021

As a follow-up to a 2017 article, Angela Spang expands on the idea of learning curves by detailing the ways in which both surgical and non-surgical practitioners can become self-sufficient