bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of CSF proteins with tau and amyloid β levels in asymptomatic 70-year-olds
Authors: Remnestål Julia , Bergström Sofia , Olofsson Jennie , Sjöstedt Evelina , Uhlén Mathias , Blennow Kaj , Zetterberg Henrik , Zettergren Anna , Kern Silke , Skoog Ingmar , Nilsson Peter , Månberg Anna
Published: March 2021

Background

Increased knowledge of the evolution of molecular changes in neurodegenerative disorders such as Alzheimer’s disease (AD) is important for the understanding of disease pathophysiology and also crucial to be able to identify and validate disease biomarkers. While several biological changes that occur early in the disease development have already been recognized, the need for further characterization of the pathophysiological mechanisms behind AD still remains.

Methods

In this study, we investigated cerebrospinal fluid (CSF) levels of 104 proteins in 307 asymptomatic 70-year-olds from the H70 Gothenburg Birth Cohort Studies using a multiplexed antibody- and bead-based technology.

Results

The protein levels were first correlated with the core AD CSF biomarker concentrations of total tau, phospho-tau and amyloid beta (Aβ42) in all individuals. Sixty-three proteins showed significant correlations to either total tau, phospho-tau or Aβ42. Thereafter, individuals were divided based on CSF Aβ42/Aβ40 ratio and Clinical Dementia Rating (CDR) score to determine if early changes in pathology and cognition had an effect on the correlations. We compared the associations of the analysed proteins with CSF markers between groups and found 33 proteins displaying significantly different associations for amyloid-positive individuals and amyloid-negative individuals, as defined by the CSF Aβ42/Aβ40 ratio. No differences in the associations could be seen for individuals divided by CDR score.

Conclusions

We identified a series of transmembrane proteins, proteins associated with or anchored to the plasma membrane, and proteins involved in or connected to synaptic vesicle transport to be associated with CSF biomarkers of amyloid and tau pathology in AD. Further studies are needed to explore these proteins’ role in AD pathophysiology.
Among the shapeshifters: parasite-induced morphologies in ants (Hymenoptera, Formicidae) and their relevance within the EcoEvoDevo framework
Authors: Laciny Alice
Published: March 2021

As social insects, ants represent extremely interaction-rich biological systems shaped by tightly integrated social structures and constant mutual exchange with a multitude of internal and external environmental factors. Due to this high level of ecological interconnection, ant colonies can harbour a diverse array of parasites and pathogens, many of which are known to interfere with the delicate processes of ontogeny and caste differentiation and induce phenotypic changes in their hosts. Despite their often striking nature, parasite-induced changes to host development and morphology have hitherto been largely overlooked in the context of ecological evolutionary developmental biology (EcoEvoDevo). Parasitogenic morphologies in ants can, however, serve as “natural experiments” that may shed light on mechanisms and pathways relevant to host development, plasticity or robustness under environmental perturbations, colony-level effects and caste evolution. By assessing case studies of parasites causing morphological changes in their ant hosts, from the eighteenth century to current research, this review article presents a first overview of relevant host and parasite taxa. Hypotheses about the underlying developmental and evolutionary mechanisms, and open questions for further research are discussed. This will contribute towards highlighting the importance of parasites of social insects for both biological theory and empirical research and facilitate future interdisciplinary work at the interface of myrmecology, parasitology, and the EcoEvoDevo framework.
A multicenter retrospective analysis examining the effect of dipeptidyl protease 4 (DPP4) inhibitors on progression-free survival in patients with prostate cancer.
Authors: Pan Kelsey , Skelton William Paul , Elzeneini Mohammed , Nguyen Thu-Cuc , Franke Aaron J , ali azka , Patel Sandip , Bishnoi Rohit , Shah Chintan , Dang Long H. , Dang Nam H. , Kish Julie Ann
Published: March 2021

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Background: Dipeptidyl peptidase IV (DPP4), also known as Cluster of differentiation 26 (CD26) is a commonly expressed cell surface protein found in many cell types that can function as a tumor suppressor or activator, depending on the cancer type its interactions with the tumor microenvironment. DPP4 has been studied as a tumor biomarker due to its expression in various primary tumors and metastases. Recent literature established benefits of DPP4 inhibitors on progression free survival (PFS) of diabetic patients with advanced colorectal and airway cancers. In this study, we examine the effect of DPP4 inhibitors on PFS in diabetic patients (pts) with advanced-stage prostate cancer. Methods: We performed a multi-center retrospective analysis at Moffitt Cancer Center and the University of Florida of diabetic pts with advanced stage (III or IV) prostate cancer. All pts were on anti-hyperglycemic therapy and received either surgery, radiation therapy, or both for their prostate cancer. The control group included pts on metformin and a sulfonylurea, and the study group included pts on a DPP4 inhibitor and metformin. PFS was calculated for both groups, and Cox proportional hazards regression was used to determine statistical significance. Kaplan-Meier survival analysis was done to predict the effect of DPP4 inhibition and radiation therapy on PFS. Results: Our study population consisted of 161 pts, with 120 pts in the control group and 41 in the study group. No significant difference in progression of prostate cancer was found between those on DPP4 inhibitor vs. Metformin. Specifically, 24 of 41 (59%) of patients on DPP4 inhibitors progressed, while 73 of 120 (61%) of patients on Metformin had progression of prostate cancer (HR 1.01, 95% CI 0.64 to 1.61, p= 0.955). Median time to progression was 3.3 years in the DPP4 group versus 3.5 years in the Metformin group. However, radiation therapy was associated with improved PFS (HR 0.56, 95% CI 0.37 to 0.84, p= 0.0006). Conclusions: Contrary to what has been shown in pts with diabetes and advanced colorectal or airway cancers, exposure to DPP4 inhibitors did not lead to statistically significant improvement in PFS in pts with advanced stage prostate cancer. Recent data suggests that DPP4 may act as a tumor suppressor gene to the androgen receptor (AR) pathway, and that DPP4 inhibition can result in emergence of resistance to androgen deprivation therapy (ADT). Further analysis with larger sample sizes is necessary to elucidate if this is applicable to prostate cancer as a whole, or if this effect is specific to castrate-sensitive prostate cancer (CSPC) vs. castrate-resistant prostate cancer (CRPC).
Pilot study of anti-prostate-specific membrane antigen (PSMA) antibody J591 for men with metastatic castration-resistant prostate cancer (mCRPC) and unfavorable circulating tumor cell (CTC) count.
Authors: Lebenthal Justin M , Sun Michael , Nauseef Jones T. , Niaz Muhammad Junaid , Imad Dunya , Christos Paul J. , Fernandez Escarleth , Singh Sharon , Chamberlain Tessa A , Osborne Joseph , Babich John , Molina Ana M. , Sternberg Cora N. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: March 2021

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Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was observed to have CTC count decline following imaging with 111In-J591, so a prospective study was launched to test the hypothesis that “naked” J591 leads to CTC count decline. Methods: In a Simon 2-stage dose de-escalation study, men with progressive mCRPC and unfavorable CTC count (CellSearch > 4) received a single dose of J591. Initial dose cohort 300 mg with de-escalation to 20 mg. CTC count was re-assessed 4, 8, and 12 weeks following therapy along with PSA and standard imaging. An optional PSMA PET was included prior to treatment. The primary endpoint was proportion of subjects with conversion to favorable CTC count ( < 5 CTCs/7.5 mL blood) and/or > 30% decline from baseline within 12 weeks post-treatment. Results: 10 men were enrolled, 9 of whom were evaluable (1 died of progressive mCRPC prior to post-treatment CTC count). Median age was 71.5 years (range 60-81), 78% had prior chemo, ECOG PS 1 in 45% and 2 in 55%. 7 of 9 (78%) evaluable subjects were Halabi CALGB prognostic poor risk category and 2 (22%) intermediate. 6 of 9 had pre-treatment PSMA PET/CT (three 89Zr-J591 and three 68Ga-PSMA11). Though not required, all scans showed > 1 lesion with SUVmax > liver SUV (range 9.12-70.15). 2 of 6 in the 300 mg cohort had CTC count decline; 1 of 6 converted to favorable count (9 to 0 with decrease of 35 to 12 in other). 3 were treated with 20 mg; 1 had CTC count decline of 316 to 112, but 0 converted to favorable count. Across both cohorts, 3 of 9 had a CTC count decline at any point in time, ranging from 65-100% decline. With the pre-specified 2-stage design, enrollment was halted for futility based upon the primary endpoint of 12-week CTC count. PSA values post-treatment increased in 8 (89%) patients and remained unchanged in 1 (11%) patient. Conclusions: Single-agent anti-PSMA antibody J591 may lead to decline in CTC count, though the study did not meet its primary endpoint. A combination or maintenance approach might be preferable and is worthy of exploration.
Baseline and post-treatment circulating tumor cell (CTC) counts with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sun Michael , Lebenthal Justin M , Nauseef Jones T. , Niaz Muhammad Junaid , Guervil Sabrina , Fernandez Escarleth , Patel Amie , Tan Angela , Vlachostergios Panagiotis J. , Osborne Joseph , Molina Ana M. , Sternberg Cora N. , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: March 2021

158

Background: CTC counts are an independent prognostic factor in men with mCRPC; certain changes following treatment (conversion from detectable to undetectable or unfavorable to favorable) are associated with improved overall survival. Most PSMA-TRT efficacy data have focused on PSA or imaging changes. Here, we describe baseline and post-treatment CTC counts from subjects receiving PSMA-TRT. Methods: Men with mCRPC treated on prospective clinical trials of PSMA-TRT and with available CTC counts (CellSearch) were included in our analysis. Depending upon the era of the trial, post-treatment counts were performed at 4-6 (initial era) or 12 weeks (recent era) after a single cycle of PSMA-TRT (individual trial data reported elsewhere). We describe CTC counts at baseline and compare pre-treatment counts to those after PSMA-TRT. Results: 116 men treated with PSMA-TRT had baseline CTC count (90 with both pre- and post-treatment CTC). Forty-four patients (37.9%) received 177Lu-J951, 46 (39.7%) received 177Lu-PSMA-617, and 26 (22.4%) received 225Ac-J591. Median age was 71.5. Fifty-eight patients (50%) had previously received taxane chemotherapy, median PSA was 82.98 ng/mL, and 66 (56.9%) were in the high-risk Halabi (CALGB) prognostic group. Eighty-nine out of one hundred sixteen (76.7%) had detectable baseline CTC and 58/116 (50%) had unfavorable baseline CTC count. Forty-nine out of seventy (70%) had post-treatment CTC count decline, 23/70 (32.9%) converted from detectable to undetectable, and 17/47 (36.2%) converted from unfavorable to favorable. CTC changes stratified by type of PSMA-TRT are reported in the table. Conclusions: This is the largest analysis of CTC changes in patients who have received PSMA-TRT. In addition to PSA changes and other previously reported outcomes, even when low doses of radionuclide therapy as part of dose-escalation studies are included, the majority with detectable CTC counts have post-treatment CTC count decline. A significant portion of patients experience favorable CTC changes. [Table: see text]
CTC counts as a biomarker of prognosis and response in metastatic castration-resistant prostate cancer (mCRPC) from the CARD trial.
Authors: De Bono Johann S. , Pantel Klaus , Efstathiou Eleni , Sternberg Cora N. , Castellano Daniel , Fizazi Karim , Tombal Bertrand , Wulfing Christian , Schonhoft Joseph D. , Gill Audrey , Chu Lincy , Wenstrup Rick , Ozatilgan Ayse , Geffriaud-Ricouard Christine , Macé Sandrine , De Wit Ronald
Published: March 2021

161

Background: In the prospective CARD trial (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and progressed within 12 months with the alternative androgen-signaling-targeted inhibitor. Here we analyzed circulating tumor cell (CTC) counts as a biomarker of prognosis and response to therapy. Methods: Blood samples collected at screening (SC), Cycle 2 (C2) Day 1, and end of therapy were sent to Epic Sciences for CTC analysis. The association between CTC counts, defined as any cytokeratin-positive, CD45-negative cell, and clinical outcomes were pre-specified and analyzed using a multivariate Cox model for time-to-events (rPFS, OS) or a Χ2 test for categorical outcomes (objective tumor response). Results: Of the 255 patients randomized, 237 (92.9%) had evaluable samples at SC and 213 (83.5%) at C2. CTCs ≥ 1 were detected in 204 samples at SC (86%) and 178 samples at C2 (84%), with a median (interquartile range) count per mL of blood of 4.1 (1.3–14.2) and 5.2 (1.5–17.3), respectively. At baseline, higher CTC counts were associated with higher values of lactate dehydrogenase (P = 0.014), alkaline phosphatase (P < 0.001), and prostate-specific antigen (P < 0.001). High CTC counts, measured as a continuous variable at SC (all arms combined) were associated with a shorter OS (P = 0.03), but not rPFS (P = 0.7). However, favorable changes in absolute CTC count from SC to C2, all arms combined, were associated with longer rPFS (P = 0.03). Conversion from high (≥ 3) to low (< 3) CTC count at C2 or maintenance of a low CTC count at C2 was associated with objective tumor response (P = 0.007). Analysis of the associations of CTC androgen receptor variant 7, chromosomal instability, heterogeneity status (Shannon Index), single-cell genotypes (e.g. retinoblastoma/phosphatase and tensin homolog copy-loss), and the presence of CTCs with small-cell/neuroendocrine morphology is ongoing. Conclusions: This preplanned analysis of the CARD trial confirms that baseline CTC counts, measured by Epic Sciences platform, are prognostic. Moreover, early favorable changes in CTC counts from baseline to C2 are associated with response to therapy. Funding: Sanofi. Clinical trial information: NCT02485691.
Implementation of clinician-facing prostate cancer therapeutic clinical trial decision tool at a comprehensive cancer center.
Authors: Borno Hala , Li Patricia , Zhang Sylvia , Idossa Dame , Desai Arpita , Rodvelt Tammy J. , Bose Rohit , Koshkin Vadim S , Chou Jonathon , Friedlander Terence W. , Huang Franklin W. , Small Eric Jay , Aggarwal Rahul Raj
Published: March 2021

19

Background: The conventional model for clinical trial (CT) recruitment relies on clinicians to identify potential CTs for patients. Internet technology can be leveraged as a decision tool to enhance the CT recruitment process. Methods: An internet-based, clinician-facing decision tool was developed in genitourinary medical oncology clinic at a Comprehensive Cancer Center (CCC). The tool provided access to a real-time, tailored list of treatment CTs actively recruiting patients with PCa at the CCC based on clinical characteristics inputted by user. The clinical data was summarized. All clinicians (n = 9) with access to the decision tool completed a survey to assess effectiveness and satisfaction. Results: During a 9-month pilot period, user engagement increased from a baseline of 36 to 136 cases per month, with a total of 644 cases overall. Among cases, 525 had metastatic disease, 436 of which were metastatic castration resistant PCa (mCRPC). Overall, 145 cases were classified as having oligo-metastatic ( < = 3) PCa, 93 of whom were also mCRPC. Prior treatments received included abiraterone in hormone-sensitive PCa (HSPC 19.3%, CRPC 48.7%); enzalutamide (HSPC 3.7%, CRPC 34.9%) apalutamide (HSPC 1.3%, CRPC 6.9%), taxane (HSPC 17.2%, CRPC 27.8%), radium-223 (6.1%), sipuleucel-T (18.3%), parp inhibitors (4%), or check-point inhibitors (6%). Clinician-inputted genomics of cases included CDK12 (20.9%), MSI-high disease (13.6%), BRCA1/2 (32.7%), ARID1a (7.3%), ATM (21.8%), FANCA (4.5%), or CHEK2 (6.4%) and HDAC2 (0.9%). Among survey respondents, use of tool in clinic was reported sometimes (22%), often/always (78%). Results of decision tool were reported to inform treatment sometimes (22%) or often/always (78%). Respondents confidence in often/always knowing all available CTs increased from a baseline of 0% to 89%, and 89% of users reported very/complete satisfaction with decision tool. Conclusions: An internet-based CT decision tool for provides detailed clinical characteristics of patients for whom CTs are being considered at a CCC. Clinicians using the decision tool report high levels of satisfaction. The tool was effective in increasing confidence in knowledge of current available CTs. Data gathered in the decision tool may inform future CT development. Future research with expanded use of decision tool among referring clinicians will assess its impact in promoting diversity among CT participants.
Factors influencing noncompletion of radiotherapy among men with localized prostate cancer.
Authors: Dee Edward Christopher , Muralidhar Vinayak , Arega Melaku A , Kishan Amar Upadhyaya , Spratt Daniel Eidelberg , Dess Robert Timothy , King Martin T. , Sha Sybil , Santos Patricia Mae G , Butler Santino , Sanford Nina Niu , Nguyen Paul L. , Mahal Brandon Arvin Virgil
Published: March 2021

199

Background: Treatment non-completion may occur with radiotherapy (RT), especially with protracted treatment courses such as RT for prostate cancer, and may affect the efficacy of RT. For men with localized prostate cancer managed with primary RT, we evaluated associations between rates of treatment non-completion and RT fractionation schedules. Methods: The National Cancer Database identified men diagnosed from 2004-2014 treated with primary RT. Patients receiving 180cGy/fraction (conventional), 200cGy/fraction (conventional), 250cGy/fraction (moderate hypofractionation), and 300cGy/fraction (moderate hypofractionation) were defined as having completed radiotherapy if they received ≥40 fractions, ≥37 fractions, ≥28 fractions, and ≥19 fractions, respectively. Stereotactic body radiotherapy (SBRT) was defined as 5-8 fractions of 600-800cGy/fraction. Odds ratios compared rates of treatment noncompletion, adjusting for various sociodemographic covariates. Propensity-adjusted multivariable Cox regression assessed the association between treatment completion and overall survival. Results: Of 93,079 patients, 90.5% (N = 84,260) received conventional fractionation, 2.3% (N = 2,181) received moderate hypofractionation, and 7.1% (N = 6,638) received SBRT. Rates of non-completion were 10.0% (N = 8,406) among patients who received conventional fractionation, 7.5% (N = 163) among patients who received moderate hypofractionation, and 1.7% (N = 115) among patients who received SBRT (OR versus conventional: 0.214, 95%CI 0.177-0.258, P < 0.001). The rate of non-completion among 15,417 African American patients was 11.8%, compared to 8.8% among 74,189 white patients (OR 1.39, 95%CI 1.31-1.47, P < 0.001). On subgroup analysis, the disparity in non-completion persisted for conventional fractionation (12.4% vs. 9.4%, OR 1.36, 95%CI 1.29-1.44, P < 0.001) and moderate hypofractionation (13.6% vs. 6.6%, OR 2.24, 95%CI 1.52-3.29, P < 0.001), but not for SBRT (2.0% vs. 1.6%, OR 1.25, 95%CI 0.76-2.06, P = 0.384). Non-completion was associated with worse survival on propensity-adjusted multivariate analysis (HR 1.37, 95%CI 1.31-1.43, P < 0.001). Conclusions: SBRT was associated with lower rates of RT non-completion among men with localized prostate cancer. African American race was associated with greater rates of treatment non-completion, although the disparity may be decreased among men receiving SBRT.
Myocardial perfusion PET imaging to evaluate coronary microvascular dysfunction in men with prostate cancer receiving androgen deprivation therapy.
Authors: Narayan Vivek , Guerraty Marie , Demissei Biniyam G , Haas Naomi B. , Takvorian Samuel U , Parikh Ravi Bharat , Vaughn David J. , Pryma Daniel A. , Mankoff David A. , Ky Bonnie
Published: March 2021

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Background: Strategies to inform cardiovascular (CV) risk are needed for prostate cancer patients initiating androgen deprivation therapy (ADT). Reduced myocardial blood flow reserve (MBFR) and coronary microvascular dysfunction (CMD) represent functional counterparts of traditional CV risk factors, including hyperlipidemia, insulin-resistance, and the metabolic syndrome. Myocardial perfusion PET stress imaging quantifies MBFR and detects CMD. However, the potential utility of these measures to indicate adverse CV changes in prostate cancer patients receiving ADT is poorly understood. Methods: In this prospective study (NCT03535987), eligible prostate cancer patients were planned for at least 6 months of ADT and curative-intent radiation therapy. All patients had a Framingham 10-year general CV risk score of at least 10% and no prior ADT exposure. Myocardial perfusion PET stress imaging was performed within 3 weeks of ADT initiation and again following 6 months of ADT exposure. MBFR was calculated as the ratio of MBF during stress / MBF during rest, and CMD was defined per established criteria as reduced MBFR (ratio < 2.0) in patients without coronary artery disease. Study outcomes included the change in MBFR following 6 months of ADT exposure and the incidence of reduced MBFR and CMD. McNemar’s test and Wilcoxon signed rank test were used for comparison of paired data. Results: Fifteen patients completed baseline myocardial perfusion PET imaging, of whom 13 completed follow-up imaging at 6 months. At baseline, the median (IQR) Framingham CV risk score was 30.4% (19.6, 35.5). One patient (7.7%) had reduced MBFR at baseline, and 5 additional patients (46.2%) developed newly reduced MBFR (ratio < 2.0) within 6 months of ADT initiation (p = 0.025). While no patients had CMD at baseline, 3 patients (30%) developed incident CMD (p = 0.083). MBFR declined in 69% of patients [median decline -0.32 (IQR -0.51, -0.22)] over 6 months ADT exposure. Conclusions: Myocardial perfusion PET imaging demonstrated a high incidence of reduced MBFR and CMD within 6 months of ADT initiation. These findings support further investigation of myocardial PET imaging, a widely-available clinical tool, as a potential research and clinical strategy to inform CV risk assessment in prostate cancer patients receiving ADT. Clinical trial information: NCT03535987.
Financial toxicity and patient-provider communication about cancer-related cost among prostate cancer patients and survivors.
Authors: Kranzler Elissa C. , Miller Melissa F. , Fortune Erica E. , Geynisman Daniel M. , Bohannon Linda S. , Badt Heather , Zaleta Alexandra Katherine
Published: March 2021

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Background: With early screening and advances in treatment, prostate cancer (PC) patients are living longer and facing increasingly complex therapeutic decisions alongside significant financial burden related to care (e.g., copays, coinsurance, other out-of-pocket (OOP) costs). Conversations with providers about financial concerns can help patients navigate these decisions, thereby promoting delivery of quality care and improving quality of life. We characterized financial toxicity (FT) and patient-provider communication about cancer-related cost among PC patients and survivors. Methods: 107 PC patients and survivors enrolled in Cancer Support Community’s Cancer Experience Registry completed items assessing FT (11-item FACIT-COST measure; range = 0-44, lower scores indicate greater FT). Items include ability to meet monthly expenses, financial stress, and cancer/treatment influence on financial situation. Frequencies and correlations between FT, health care team (HCT) communication, and socio-demographics were examined. Results: Participants were 89% non-Hispanic White, 5% Black, 2% Hispanic; mean age was 68 years (SD = 7.5). Median time since diagnosis was 3 years; 19% reported experiencing symptoms of PC at the time of diagnosis. 21% were ever metastatic, 22% experienced a recurrence, and 48% reported currently receiving treatment. 29% were employed full- or part-time; 52% spent at least $100/month on all OOP PC costs, 30% spent $250 or more, 16% spent $500 or more. Mean FT score was 28 (SD = 11.9). 67% reported members of their HCT did not discuss cost of treatment, 55% did not discuss impact of PC and treatment on work, 77% did not discuss financial distress. While most participants were satisfied with their doctor’s explanation of benefits (89%) and risks/side effects (79%) for each treatment option, only 49% were satisfied with how much their HCT discussed financial costs of each option. Greater patient confidence in communicating with doctor about PC was significantly associated with less FT ( r= .19, p< .05), but experiencing more FT was not correlated with a greater likelihood of HCT discussing cost of treatment ( r= -.05, p= .63) or discussing impact of cancer and treatment on work ( r= .04, p= .67). Conclusions: Results indicate that patients with greater financial toxicity report less confidence in communicating with their doctor about PC, however providers are not frequently or systematically initiating discussions around cost and impact on work even among those experiencing the highest levels of financial burden. Findings underscore the critical value of transparency about health care costs and impact, as well as support for providers in communicating effectively with patients about costs and available resources, to improve patient quality of life and health outcomes.
Visual analogue scales (VAS) as exploratory evaluation of eight dimensions in prostate cancer (PCa) patients aged 60 years and older initiating a gonadotropin-releasing hormone agonist (GnRHa) therapy: Secondary analysis of PRISME study.
Authors: Hennequin Christophe , Mongiat-Artus Pierre , Roupret Morgan , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Rozet Francois
Published: March 2021

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Background: Age, PCa and GnRHa treatment may modify patients health-related quality of life (HRQOL) and clinical parameters routinely evaluated: health status, urinary function, sexual function, memory, mood, motricity, autonomy. Our purpose was to investigate the use of VAS in these 8 domains before and after a 6-month GnRHa therapy, in order to simplify questions and minimize administration burden in future routine practice. Methods: Between March 2018 and February 2020, a prospective, multicenter, non-interventional study was conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with histologically confirmed PCa, initiating a GnRHa therapy. 1000 patients were planned to be included 1:2:1 in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). They reported their levels of satisfaction in the 8 domains at baseline and after a 6-month GnRHa treatment. Each item included a title and a 10 cm-linear analogue scale with descriptive phrases anchored at the ends (0: not satisfied at all; 10: totally satisfied). Significant changes were concluded in case of means 95% CIs not including 0. Correlations between VAS and validated questionnaires on the same dimensions changes were evaluated through Pearson correlation. Results: The final analysis included 652 patients (full analysis set population), enrolled by 138 investigators. Mean (±SD) age was 72.5±6.2 years. 71.6% had at least one comorbidity at baseline and 65.0% were receiving at least one concomitant systemic treatment. Main reasons for GnRHa initiation were high risk in 65.3%, metastatic stage in 18.4%, biochemical recurrence in 13.3%. 36% had received at least one prior treatment for PCa (prostatectomy 57%, radiotherapy 34.5%). Respectively, 47.1%, 58.0% and 17.6% presented at least one urinary symptom, one sexual symptom, or one other clinical symptom at baseline. Baseline mean [CI 95%] scores were: 7.5 [7.3-7.6] in general QOL, 6.8 [6.6-7.0] in general health status, 6.2 [6.0-6.4] in urinary function, 3.4 [3.2-3.6] in sexual function, 7.0 [6.8-7.2] in mood, 7.0 [6.9-7.2] in memory, 7.6 [7.4-7.8] in motricity and 8.0 [7.9-8.2] in autonomy VAS. At follow-up, significant and clinically relevant overall change was observed in sexual (-1.2 [-1.4;-0.9]) VAS. No correlations were found between the changes in VAS and in validated questionnaires. Conclusions: The exploratory use of VAS in the 8 dimensions routinely evaluated in elderly PCa patients treated with GnRHa therapy showed interesting results. No correlations could be shown between evolution in VAS and in validated questionnaire scores. Further explorations on this topic remain to be made. Clinical trial information: NCT03516110.
Efficacy of cabozantinib in advanced MiT family translocation renal cell carcinomas (TRCC).
Authors: Thouvenin Jonathan , Alhalabi Omar , Hirsch Laure , Hasanov Elshad , Barthelemy Philippe , Martini Dylan J. , Campedel Lucas , Amrane Karim , Borchiellini Delphine , Chahoud Jad , Bakouny Ziad , Ravi Praful , Viswanathan Srinivas Raghavan , Bilen Mehmet Asim , Choueiri Toni K. , Tannir Nizar M. , Malouf Gabriel G.
Published: March 2021

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Background: MiT family translocation renal cell carcinomas (TRCC) represent a rare and aggressive subgroup of RCC harboring high expression of c-MET. While response rates of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a TKI that inhibits VEGFR, MET, and AXL) in this subgroup is unclear. Methods: We performed a multicentre, retrospective, international cohort study of patients with TRCC treated with cabozantinib regardless the line of treatment at 7 centers (3 in France and 4 in the US). The main objectives were to estimate response rate according to RECIST criteria, and to analyze progression-free survival (PFS) and overall survival (OS). Results: Among 31 metastatic patients treated in the participating centers, 24 were evaluable for response and were included in this study (21 with TFE3 and 3 with TFEB translocations). Median age at diagnosis was 43.5 years (range, 22–70). Most frequent metastatic sites at diagnosis were lungs (62.5%), retroperitoneal lymph nodes (45.8%) and bone (37.5%). Patient’s IMDC risk group at diagnosis was favourable (20,8%), intermediate (62,5%) and poor (16,7%). Seven (29%) patients received cabozantinib at first line, 9 (37.5%) at second line and 8 (33%) at third line and beyond. The proportion of patients who achieved an objective response was 16.6%, including 1 complete response and 3 partial responses. For 11 (45.8%) patients, stable disease was the best response. With a median follow-up of 14 months (IQR 5-23), median PFS was 8.4 months (range, 1-34+) and median OS was 17 months (range, 2-43). No PFS difference was detected overall or in any subgroup except in patients with bone metastasis which harbored a median PFS of 3.6 months as compared to 9.1 months for those without (p=0.03). Conclusions: This real-world study provides evidence supporting activity of cabozantinib in TRCC, with more durable responses to therapy than those observed with of VEGF receptor-tyrosine kinase inhibitor and immune checkpoint inhibitors. International collaborations and prospective studies are necessary to identifies efficacious therapies for this rare disease that lacks evidence-based treatment options.
TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib.
Authors: Rini Brian I. , Pal Sumanta K. , Escudier Bernard , Atkins Michael B. , Hutson Thomas E. , Porta Camillo , Verzoni Elena , Needle Michael N. , McDermott David F.
Published: March 2021

278

Background: Tivozanib (T) is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for RCC. Axitinib is also a potent and selective VEGF-R inhibitor now commonly part of front-line aRCC treatment. The activity of T after axitinib has not been previously defined. The activity of T after prior therapy types including axitinib is of clinical relevance. Methods: The pivotal TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective of the overall trial was to compare progression free survival (PFS) by blinded independent radiological review. Patients with prior axitinib received as monotherapy in the second or third line setting and other predefined subgroups were reviewed for outcome with T. Results: Patients treated with T after prior axitinib had a PFS of 5.5 months and an ORR of 13% compared to 3.7 months and 8% for patients treated with S. Other subgroups are presented in the table below. Clinical trial information: NCT02627963 . Conclusions: Tivozanib improved PFS vs. sorafenib in patients who have progressed after multiple VEGFR-TKIs, including patients with prior second or third line axitinib treatment. These results suggest differential activity from tivozanib and axitinib despite both being potent and selective VEGF-R inhibitors. [Table: see text]
Oral anticancer agent (OAA) adherence and survival in elderly patients with metastatic renal cell carcinoma (mRCC).
Authors: Dinan Michaela Ann , Wilson Lauren E , Greiner Melissa A. , Spees Lisa , Pritchard Jessica , Zhang Tian , Kaye Deborah , George Daniel J. , Scales Charles D. , Wheeler Stephanie B.
Published: March 2021

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Background: Multiple effective oral anticancer agents (OAAs) are now approved for the treatment of patients with advanced or metastatic renal cell carcinoma (mRCC) based on improvement in overall and progression-free survival in randomized clinical trials. However, real-world adherence and outcomes associated with OAA use in the general mRCC patient population have not been previously investigated. Methods: Retrospective analysis of SEER-Medicare patients with mRCC who received treatment with an OAA between 2007 and 2015. Adherence was assessed as proportion of days covered (PDC) within 3 months of OAA initiation with PDC > 50% categorized as adherent. The impact of initial OAA adherence on overall and disease-specific survival was analyzed landmarked at 3 months after OAA initiation. Results: A total of 905 patients met study criteria, of which 577 (63.8%) were categorized as adherent to initial OAA treatment. Multivariable analysis adjusting for clinical and demographic factors revealed that living within an impoverished neighborhood was associated with a 20% lower likelihood of adherence (OR 0.80, CI 0.68 – 0.93). No association was observed between adherence and race, ethnicity, marital status, or number of comorbidities. In survival analyses OAA adherence was associated with a significant reduction in both overall (HR 0.71, CI 0.58 – 0.87) and RCC-specific mortality (HR 0.68, CI 0.57 – 0.86). Receipt of sunitinib was associated with a significant reduction in overall and disease specific mortality compared with sorafenib. Post-hoc analysis of patients taking pazopanib as their initial OAA (N = 252) demonstrated reduced all-cause mortality if they received the minimum effective dose of 800 mg daily (HR 0.50, CI 0.35 – 0.72) and decreased adherence associated with initial higher out-of-pocket payments (χ2 test, p = 0.003). Conclusions: Socioeconomic factors predict poor adherence to OAA therapy in Medicare beneficiaries with metastatic RCC, which is in turn associated with poor overall and disease-specific survival. Efforts to improve outcomes and mitigate disparities in the general mRCC population should incorporate considerations of OAA adherence and economic factors. Sunitinib and pazopanib appear associated with favorable survival and remain the most commonly used OAAs in this over 65 year old patient population.
Use of 18F-fluciclovine PET/CT (FluPET) for prostate cancer (PC): Initial results from a prospective registry at a tertiary academic center.
Authors: Wong Risa Liang , Cheng Heather H. , Holt Sarah K , Conrad Nathan , Loesch Hannah , Fernandez Sara , Sahoo Rameen , Bauer Zoya , Toulouse Andrea , Grivas Petros , Yezefski Todd , Russell Kenneth J. , Wright Jonathan L. , Schweizer Michael Thomas , Montgomery Robert B. , Lee Jean H , Chen Delphine L. , Zeng Jing , Lin Daniel W. , Yu Evan Y.
Published: March 2021

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Background: FluPET, a next-generation imaging modality approved in 2016 for suspected PC recurrence with elevated PSA after prior therapy, is becoming more widely available; however, practice patterns and impact on outcomes is unknown. We hypothesize FluPET is ordered for a variety of reasons, with findings often leading to changes in treatment plan. Methods: In this prospective registry, providers are surveyed before, 1-2 weeks after, and 1 year after FluPET to assess reasons for obtaining FluPET, projected treatment plan, changes in plan due to FluPET findings, and toxicity potentially attributable to change in treatment plan. Baseline patient characteristics, FluPET results, and longitudinal outcomes are collected. We report early descriptive findings with χ2 and student’s t-test used for univariate analyses. Results: 50 patients enrolled 12/2018-08/2020 had baseline characteristics described in Table; 46 underwent FluPET. Rationale for ordering included initial staging prior to definitive local therapy (6.1%), guidance of salvage local therapy for 1st biochemical recurrence (BCR) (46.9%), guidance of additional salvage after ≥2 local therapies and 2nd BCR (36.7%), and confirmation of equivocal metastatic disease (10.2%). When queried on next steps, providers considered observation (67.3%), androgen deprivation therapy (ADT) (26.5%), ADT + docetaxel or novel anti-androgens (AA) (20.4%), and salvage therapy with surgery, radiation, or cryotherapy (26.5%), often selecting ≥1 option. FluPET found ≥1 PC lesion in 73.9% of cases, ≥1 indeterminate lesion in 8.7%, and no lesions in 17.4%. 45.5% of providers reported changing treatment plan based on FluPET results; 6.8% changed to observation, 20.5% to systemic therapy, 13.6% to local salvage therapy, and 4.5% to a combination of local and systemic therapies. Change in therapy was associated with positive FluPET (54.5% vs. 18.2%, p=0.044), and within those cases, with higher SUVMax (mean 7.7 vs. 5.2, p=0.021) but not number of lesions (p=0.804). Conclusions: FluPET is often obtained to guide salvage therapy after BCR but is also used for initial staging or resolving equivocal findings of metastases. Many providers changed intended treatment based on FluPET findings, especially if positive; de-escalation to observation was rare. [Table: see text]
Impact of PSMA PET/CT on SRT planning: Preliminary results from the randomized phase III trial NCT03582774.
Authors: Calais Jeremie , Armstrong Wesley R , Kishan Amar Upadhyaya , Booker Kiara M , Elashoff David , Fendler Wolfgang Peter , Czernin Johannes , Nickols Nicholas George
Published: March 2021

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Background: The purpose of this trial is to evaluate the success rate of salvage radiation therapy (SRT) for recurrence of prostate cancer (PCa) after radical prostatectomy with and without planning based on prostate specific membrane antigen (PSMA) positron emission tomography (PET). Methods: This is a multicenter, prospective, randomized, controlled, open-label, Phase 3 clinical imaging trial powered for clinical outcome at 5 years. UCLA is the leading central site in which PSMA PET, clinical follow-up and data management are being done. UCSF was a participating site in which PSMA PET imaging can be done. SRT can be performed anywhere, patients are followed remotely by the UCLA investigators. Patients scheduled for SRT for recurrence after primary prostatectomy and with PSA ≥ 0.1ng/ml at time of enrollment were eligible. Patients were randomized to proceed with standard SRT allowing for any conventional imaging aside from PSMA PET/CT (control arm) or undergo a 68Ga-PSMA-11 PET/CT scan prior to SRT planning (investigational arm). The primary endpoint is the success rate of SRT at 5 years in patients who undergo SRT. We report here the preliminary results of a secondary endpoint: the impact of PSMA PET on SRT planning by comparing the pre-randomization RT plans prospectively obtained on surveys before randomization to the actually delivered RT plans obtained after follow-up. Results: Enrollment of the trial was complete. 193 patients were enrolled from 09.06.2018 to 08.17.2020. 7/90 patients (9%) in the control arm dropped-out the study because they underwent a PSMA PET at another institution, while 1/103 (1%) patients of the intervention arm dropped-out due to COVID-19 related complications. After a median follow-up of 13.3 months (last follow-up date 09/01/2020), delivered RT plans were obtained in 60/83 (72%) and 70/102 (69%) of patients of the control and the PSMA arms, respectively. Median PSA at enrollment was 0.32 ng/ml (IQR 0.17-1.35) and 0.22 ng/ml (IQR 0.14-0.50) in the control and PSMA arms, respectively. There was a change between the intended pre-randomization RT plan and the actually delivered RT plan in 17/60 (28%) and 40/70 (57%) of the patients in the control and PSMA arms, respectively (p = 0.002). SRT was aborted in favor of systemic therapy and/or metastasis directed RT for extra-pelvic M1 disease in 2/60 (3%) and 12/70 (17%) of the control and PSMA arms, respectively (p = 0.17). Dose prescription and/or target volume delineation was changed in 2/60 (3%) and 1/70 (26%) in the control and PSMA arms, respectively (p = 0.001). Conclusions: In this prospective randomized phase 3 study, PSMA PET had an impact on the SRT plan in more than half of the patients. Long-term follow-up will show if the impact of PSMA PET on SRT planning translates into improved outcome or not. Clinical trial information: NCT03582774.
Phase II trial of stereotactic ablative radiation (SAbR) for oligometastatic kidney cancer.
Authors: Hannan Raquibul , Christensen Michael , Robles Liliana , Christie Alana , Garant Aurelie , Desai Neil Bipinchandra , Hammers Hans J. , Arafat Waddah , Bowman Isaac Alexander , Cole Suzanne , Courtney Kevin Dale , Woldu Solomon L. , Bagrodia Aditya , Margulis Vitaly , Cadeddu Jeffrey A , Choy Hak , Sher David , Brugarolas James
Published: March 2021

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Background: Stereotactic ablative radiotherapy (SAbR) is a promising treatment option for selected oligometastatic renal cell carcinoma (RCC) patients that can provide longitudinal disease control while preserving quality of life. Retrospective data have shown a local control (LC) rate greater than 90% and longitudinal disease control of over a year without systemic therapy. However, prospective validation of SAbR for oligometastatic RCC is lacking. In this prospective phase II single arm trial, we evaluated the impact of SAbR on freedom from systemic therapy (FFST). Methods: Treatment naïve patients with RCC confirmed by pathology and radiographic evidence of three or fewer extracranial metastases received SAbR with curative intent to all measurable sites of disease. Follow-up included radiographic imaging at three-month intervals to assess disease control. The primary endpoint was FFST defined as time from SAbR to the initiation of systemic therapy. Secondary endpoints included LC, modified progression-free survival (mPFS) (time from first SAbR to progression not amenable to further SAbR), PFS on subsequent systemic therapy, cancer-specific survival (CSS), overall survival (OS), toxicity and health-related quality of life (QOL) indices as measured with EQ-5D-5L and FACT-G. A Wilcoxon signed-rank test was used to evaluate the QOL indices. Results: The trial completed accrual with the enrollment of 23 patients who received SAbR to a total of 38 sites. At a median follow-up of 12 months (interquartile range 1.8-16), 1-year FFST was 87% (95% CI: 56%-96%). The 1-year mPFS was 79% (95% CI:49%-93%), while the median mPFS has not yet been reached. Three patients had disease progression at individual time points of 3.5, 4.0, and 12 months. One of these patients developed brain metastases that were controlled with gamma knife radiosurgery without initiating systemic therapy. The LC, CSS, and OS were 100% (38/38), 100% (23/23), and 95% (22/23), respectively. When compared to baseline, no significant decline in QOL was detected. Three patients experienced treatment-related grade 1 toxicity; no ≥grade 2 toxicities were reported. One patient died of an unrelated cause. Conclusions: SAbR is a safe and effective treatment for oligometastatic RCC that can provide longitudinal disease control and preserve quality of life. These data support further evaluation of SAbR for oligometastatic RCC in a randomized study. Clinical trial information: NCT02956798 .
Association of statins and nivolumab activity in patients with metastatic renal cell carcinoma (mRCC): Results from the phase II nivoren—GETUG AFU 26 trial.
Authors: Colomba Emeline , Flippot Ronan , Dalban Cécile , Negrier Sylvie , Chevreau Christine , Gravis Gwenaelle , Oudard Stephane , Laguerre Brigitte , Barthelemy Philippe , Gross Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Escudier Bernard , Albiges Laurence
Published: March 2021

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Background: Statins are HMG-CoA inhibitors that regulate several mechanisms involved in tumor growth, including mitochondrial metabolism, activation of oncogenic signaling pathways, and immune modulation. Population-based studies showed that statin intake may be negatively associated with RCC onset. The impact of statins on response to immunotherapy in mRCC is unknown. Herein we study the association between statin administration and outcomes in patients with mRCC treated with nivolumab in the NIVOREN-GETUG AFU 26 phase II trial (NCT03013335). Methods: Patients with mRCC who failed previous VEGFR inhibitors were included. We assessed nivolumab activity, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to statin intake at baseline. Toxicity was assessed using CTCAE v4.0. Results: Overall,133 patients were treated with statins at baseline among 702 evaluable for concomitant therapies (19%). Among them, median age was 68 (49-90), 84% were male, 85% had a performance status ≥ 80%, 42% were overweight and 20% obese. Patients treated with statins had mostly good (23%) or intermediate (58%) IMDC risk, 64% had grade 3 or 4 tumors, and nivolumab was given in a third line setting or more in 55%. Median follow-up was 23.9 months (95%CI 23.0-24.5) in the overall cohort. The ORR was 26% in patients treated with statins, PFS 5.0 months (CI95% 3.0 – 5.5), OS 27.9 months (CI95% 19.4-30.3). Outcomes of patients with or without statins did not differ significantly. Similar rates of grade 3-5 TRAE were reported in patients with (20%) or without (18%) statin intake. Conclusions: This is the first study to evaluate statin intake and outcomes with nivolumab in patients with mRCC. Despite numerically higher ORR, statins were not significantly associated with improved outcomes. These data require other analyzes considering other factors such as BMI and other comorbidities. Further studies may help better understand the interplay between immunity and metabolic reprogramming in RCC.