bluuebunny/crossref_metadata_2025 huggingface dataset:
Provider referral patterns following nephrectomy in high-risk locoregional renal cell carcinoma.
Authors: Dzimitrowicz Hannah Elizabeth , Esterberg Elizabeth , Miles LaStella , Zanotti Giovanni , Borham Azah , Harrison Michael Roger
Published: February 2020

636

Background: It is unclear whether post-nephrectomy patients with renal cell carcinoma (RCC) in real-world practice settings are typically assessed for recurrence risk post-operatively and whether patients at high risk of recurrence are seen by providers who can evaluate candidacy for adjuvant systemic therapy (AST), clinical trials, or alternative surveillance schedules. Methods: We identified all patients with locoregional RCC who underwent nephrectomy within Duke University Health System between April 1, 2015 and March 31, 2019 via an institutional database. Medical records were reviewed to identify patient characteristics, post-nephrectomy treatment and referrals, and follow up. Patients with tumor stage 3 or higher and tumor grade 2 or higher, regional lymph-node metastasis, or both, were classified as high risk of recurrence. Results: Of 500 patients with locoregional RCC who underwent nephrectomy, 111 (22.2%) had high risk of recurrence (Table). 15 patients with high risk disease (13.5%) were referred to a medical oncologist for discussion of AST. Fourteen of the 15 referrals took place in 2018 or later. 7 of 29 (24.1%) high risk patients were referred for discussion of AST in 2018 and 7 of 9 (77.8%) in 2019. All referrals were made by urologists to medical oncologists. Two patients received AST – one as part of a clinical trial and one node-positive patient received standard-of-care sunitinib. In the cohort of high-risk patients, follow up data was available for 83 patients with median follow up time of 1.16 years; 31 patients (37.4%) developed recurrent disease. Conclusions: Within a single large academic institution, despite increasing numbers of patients with locoregional RCC at high risk of recurrence being referred to medical oncologists after nephrectomy, few patients received AST. These findings highlight the need for continued efforts at identifying effective AST and referring patients most likely to benefit.[Table: see text]
Tumor protein expression of BRCA1 and development of lethal prostate cancer.
Authors: Ceraolo Carl , Gerke Travis A. , Zareba Piotr , Pettersson Andreas , Stopsack Konrad H. , Chowdhury Dipanjan , Ebot Ericka M. , Flavin Richard , Finn Stephen P. , Kantoff Philip W. , Stampfer Meir J. , Loda Massimo , Fiorentino Michelangelo , Mucci Lorelei A.
Published: February 2020

65

Background: DNA repair genes including BRCA1 are commonly altered in metastatic prostate tumors. However, mutations and copy number aberrations in these genes are rare in primary tumors. Instead, preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. Methods: We undertook a prospective study of tumor BRCA1 protein expression and lethal prostate cancer among men with clinically localized prostate cancer in the Health Professionals Follow-up Study. We performed immunohistochemical staining for BRCA1 on tumor tissue microarrays using a validated antibody and scored expression as positive or negative. We also assessed tumor proliferation by immunostaining for Ki67, angiogenesis by immunostaining for CD34, and apoptosis using a TUNEL assay. Proportional hazards regression was used to evaluate the association between BRCA1 protein expression and development of lethal prostate cancer (metastasis or cancer-specific death). Results: Ten percent of tumors (60 of 589) stained positive for the BRCA1 protein. BRCA1-positive tumors were characterized by higher Gleason scores, a higher proliferative index, and a higher apoptotic index. During a median follow-up of 14.3 years, 18 men (34%) in the BRCA1-positive group and 74 men (14%) in the BRCA1-negative group developed lethal prostate cancer. There was a strong positive association between BRCA1 protein expression and lethal prostate cancer in both unadjusted analyses (HR 2.71, 95% CI 1.73–4.26) and after adjusting for clinical factors (HR 2.00, 95% CI 1.26–3.18). The positive association with BRCA1 protein expression was also independent of proliferation index. Conclusions: Primary prostate tumors expressing the BRCA1 protein have a highly proliferative phenotype and are more likely to progress to lethal disease, independent of its higher proliferative index. Assessing tumor protein expression of BRCA1 may help elucidate the Janus-faced role of DNA repair pathways in prostate cancer progression.[Table: see text]
Does presence of bone metastases portend worsened prognosis in metastatic renal cell carcinoma? Analysis of the REMARCC (Registry of MetAstatic RCC) database.
Authors: Bradshaw Aaron , Mir Maria Carmen , Autorino Ricardo , Minervini Andrea , Kriegmair Maximilian , Maurer Tobias , Porpiglia Francesco , Van Bruwaene Siska , Linares Espinos Estefania , Hevia Vital , Musquera Mireia , Rousel Eduard , Pavan Nicola , Antonelli Alessandro , Zhang Shudong , Meagher Margaret , Rubio Jose , Albersen Maarten , Furlan Maria , Derweesh Ithaar
Published: February 2020

655

Background: The presence of brain metastases and bone metastases are generally understood to herald worsened prognosis following nephrectomy in patients with renal cell carcinoma (RCC). However, we sought to determine the effect of bone metastases on outcomes when already present at the time of cytoreductive radical nephrectomy (RN). Methods: Multicenter retrospective analysis of mRCC patients from the REgistry of MetAstatic RCC) REMARCC. Demographics, clinical variables, and outcomes were collected. Patients were stratified into low, medium, and high-risk groups based on Motzer Criteria, and analysis of impact of bone metastases was conducted within each group utilizing Kaplan-Meier analysis (KMA). Multivariable analysis (MVA) was utilized to identify predictors for outcomes. Primary outcome was progression-free survival (PFS) and secondary outcome was overall survival (OS). Results: A total of 447 patients (low- n=30, intermediate- n=208, and high-risk mRCC n=123, median follow-up 14.3 months) were included in the analysis. 124 patients had bone metastases and 323 had mRCC but no bone metastases. No significant demographic differences were noted between groups. KMA (Figure) showed no difference in median PFS for bone metastases vs. non bone metastases groups (6.1 vs. 6.4 months, p=0.973). KMA showed no difference in median OS (25.5 vs. 26.5 months, p=0.958). Similarly, stratification of patients into different Motzer risk categories did not demonstrate difference between bone vs. none bone mRCC for PFS and OS. MVA for PFS demonstrated increasing Motzer risk category (low risk referent vs. intermediate OR 1.89, p=0.006, high risk OR 3.24, p<0.001) as independent predictors. MVA for OS revealed increasing Motzer risk category (low ref, vs. intermediate OR 1.88, p=0.033, high risk 5.17, p<0.001) as being predictive. In neither analysis was presence of bone metastases significant (PFS p=0.690, OS p=0.268). Conclusions: Presence of bone metastases does not independently predict survival or oncologic outcomes in mRCC. While further validation is needed, the prognostic significance of bone metastases may be less than previously thought.
Treatment-free survival after discontinuation of immuno-checkpoint therapy, and outcome of subsequent molecular targeted therapy: Retrospective study of Japanese metastatic renal cell carcinoma patients (after I-O study).
Authors: Tomita Yoshihiko , Kimura Go , Fukasawa Satoshi , Sugiyama Yutaka , Numakura Kazuyuki , Yamana Kazutoshi , Naito Sei , Kabu Koki , Tajima Yohei , Oya Mototsugu
Published: February 2020

677

Background: Guidelines for treatment of metastatic renal cell carcinoma (mRCC) recommend nivolumab monotherapy (NIVO) for treated mRCC, and nivolumab + ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor risk mRCC patients. Though molecular targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their impact is still unclear. Methods: Japanese mRCC patients treated with TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator assessed ORR of the first TT after NIVO, and after NIVO+IPI. Secondary endpoints included treatment-free survival (TFS) after discontinuation of NIVO and NIVO+IPI, and progression-free survival (PFS) and safety of the first subsequent TT after NIVO and NIVO+IPI. Results: Twenty-six patients of CheckMate 025 and 19 patients of CheckMate 214 from 20 centers in Japan were analyzed. Median TFS after ICI discontinuation was 1.0m and 2.5m for CheckMate 025 and CheckMate 214 patients, respectively. Median follow-up period from the start of TT after ICI discontinuation to date of analysis or death was 22.1m for CheckMate 025, and 20.3m for CheckMate 214 patients. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most treated therapy for both CheckMate 025 (53.8%) and CheckMate 214 (47.4%) patients. ORR of TT after NIVO and NIVO+IPI was 26.9% and 31.6%, and median PFS was 8.9m and 16.3m, respectively. During the treatment of first TT after NIVO and NIVO+IPI, 98% percent experienced treated-related adverse events, 51% experienced grade 3-4, but no treatment related death. Conclusions: TTs have favorable antitumor activity for mRCC after NIVO and NIVO+IPI, possibly by changing the mode of action. Safety signals of TTs after ICI were similar to the previous reports. These results indicate sequential TTs after ICI may contribute for durable survival benefit.
Evaluation of brain metastasis in JAVELIN Renal 101: Efficacy of avelumab + axitinib (A+Ax) versus sunitinib (S).
Authors: Jonasch Eric , Hasanov Elshad , Motzer Robert J. , Hariharan Subramanian , Choueiri Toni K. , Huang Bo , Haanen John B. A. G. , Albiges Laurence , Venugopal Balaji , Schmidinger Manuela , Larkin James M. G. , Grimm Marc-Oliver , Negrier Sylvie , Wang Jing , Mariani Mariangela , Chudnovsky Aleksander , di Pietro Alessandra , Rini Brian I.
Published: February 2020

687

Background: Patients (pts) with brain metastasis from renal cell carcinoma (RCC) have poor prognosis and are often excluded from randomized registrational trials. The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) for A+Ax vs S in pts with advanced RCC (Motzer NEJM 2019). The activity of A+Ax in pts with brain metastasis enrolled in JAVELIN Renal 101 is presented. Methods: PFS was compared between treatment arms for the subgroup of pts randomized in JAVELIN Renal 101 with brain metastases at enrollment (pts with brain disease site prior to randomization by blinded independent central review [BICR] or by investigator assessment). PFS time was summarized per BICR assessment by treatment arm using the Kaplan-Meier method. The Cox proportional hazards model was fitted to compute the hazard ratio (HR) and the corresponding CI. In addition, time to brain metastasis was assessed for pts without brain metastasis by BICR at enrollment after treating death as a competing risk. Results: Of all randomized pts (A+Ax arm, N=442; S, N=444), 23 in each arm (5.2%) had asymptomatic brain metastasis at enrollment; of these, pts assigned to A+Ax had a PFS of 4.9 mo (95% CI: 1.6, 5.7) vs 2.8 mo (95% CI: 2.3, 5.6) for pts assigned to S (HR: 0.90; 95% CI: 0.43, 1.88). Among pts without brain metastasis at enrollment, 8 pts on the A+Ax arm and 10 on the S arm developed brain metastasis during the trial, based on BICR assessment; 17/18 occurred ≤12 mo from randomization. The cumulative incidence rate of brain metastasis at 18 mo was 2% (95% CI: 0.6, 3.3) for the A+Ax arm and 3% (95% CI: 1.1, 4.8) for the S arm. Conclusions: In this post hoc exploratory analysis of JAVELIN Renal 101, the observed PFS among pts with brain metastasis at enrollment was similar between the two arms, with HR and median PFS numerically favoring A+Ax. Pts on the S arm had a numerically higher incidence of new brain metastases on trial. Outcomes are poor in pts with advanced RCC and brain metastasis; more effective treatments are needed. Clinical trial information: NCT02684006.
Using high-resolution magic angle spinning magnetic resonance spectroscopy to characterize the metabolomic profile of fat-poor angiomyolipoma and renal cell carcinoma.
Authors: Huynh Melissa Jessica , Gusev Andrew , Palmas Francesco , Vandergrift Lindsey , Wu Chin-Lee , Cheng Leo , Feldman Adam S.
Published: February 2020

711

Background: Fat-poor angiomyolipoma (AML) can be difficult to differentiate from renal cell carcinoma (RCC) radiographically and may lead to biopsy or unnecessary intervention. In vivoplatforms with the ability to identify tumor histology based on metabolic profiles may avoid unnecessary procedures & their complications. The metabolomics of AML have not been characterized, & research into this area may provide targetable molecules for large AMLs. In this study, we investigate the metabolomic profile of AMLs compared to clear cell RCC (ccRCC) using high resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS). Methods: Tissue samples were obtained from radical or partial nephrectomy specimens that were fresh frozen & stored at -80ºC. Tissue HRMAS MRS was performed by a Bruker AVANCE spectrometer. Metabolomic profiles of RCC & adjacent benign renal tissue were compared, and false discovery rates (FDR) accounted for multiple testing. Regions of interest (ROI) with FDR <0.05 were considered potential predictors of ccRCC rather than AML. The Wilcoxon rank sum test was used to compare median MRS relative intensities for candidate predictors. Logistic regression was used to determine odds ratios for risk of malignancy based on abundance of each metabolite. Results: There were 16 ccRCC samples & 7 AML specimens. Candidate predictors of malignancy rather than AML based on FDR p-values include histidine, phenylalanine, phosphocholine, serine, alanine, glutamate, glutathione, glycerophosphocholine, & glutamine. While an abundance of these metabolites is associated with higher risk of malignancy, the odds ratio was particularly high in the 3.5-3.49 ppm spectral region (OR 2.99x106, 95% CI 3.27, 2.73x1012, p=0.033)in ccRCC samples. Conclusions: HRMAS MRS identified metabolites that may help differentiate fat-poor AML from ccRCC. In particular, metabolites in the 3.5-3.49 ppm spectral region increased the risk of harboring RCC. Our findings may contribute to future in vivostudies to help identify which patients require intervention for malignancy & which may be observed for benign AML without requiring biopsy.
Selective modulation of immune transcripts in extracellular vesicles from plasma of renal cell carcinoma patients receiving nivolumab.
Authors: Verzoni Elena , Shahaj Eriomina , Frigerio Simona , Cova Agata , Squarcina Paola , Pesce Samantha , Vergani Elisabetta , Vallacchi Viviana , Lalli Luca , Pietrantonio Filippo , Di Nicola Massimo A. , Procopio Giuseppe , De Braud Filippo G. , Mennitto Alessia , Claps Melanie , Sepe Pierangela , Rodolfo Monica , Rivoltini Licia , Huber Veronica
Published: February 2020

719

Background: Patients (pts) displaying a full-fledged immune response show high levels of circulating extracellular vesicles (EVs) containing immune transcripts that might be transferred to neighboring cells to amplify immune responses, as in autoimmunity and transplantation. We hypothesized EV immune transcripts could reflect immune activation in cancer pts receiving immunotherapy with immune checkpoint inhibitors (ICI). These RNA-containing EVs may surrogate immune functionality and represent a plasma transcriptional signature of adaptive immunity that can be readily detected by liquid biopsy. Methods: Blood samples from metastatic renal cell cancer pts,treated with ICI nivolumab (n=8) or tyrosine kinase inhibitor cabozantinib (n=9) were collected at baseline, week 4 and 12. EV-RNA was isolated from plasma with membrane affinity spin columns and evaluated for CD274(PD-L1), IFNG, PDCD1 (PD-1), CD3 and GZMB (granzyme B) transcripts by qRT-PCR. Results: All pts showed a statistically significant increase of CD3, IFNG, GZMB, PD-1 and PD-L1 immune transcripts in plasma EVs, evidenced at 4 and 12 weeks of therapy. Treatment subgroup analysis revealed an upregulation of CD3, IFNG, GZMB and PD-1 transcripts only in plasma EVs of patients receiving nivolumab that was more evident in those showing clinical benefit (4/8), while PD-L1 increased significantly during cabozantinib treatment. Upon comparing transcripts with soluble proteins, PD-L1 displayed similar kinetics, while PD-1 increased only as transcript but not as protein, given its potential sequestration by the anti-PD-1 antibody. This effect was detectable only in nivolumab but not in cabozantinib treated pts. Conclusions: Monitoring immune transcripts carried by plasma EVs holds promise as potential tool to assess the entity of the ongoing immune activation during immunotherapy. Plasma EVs may be exploited as indicators of immune response and help to predict clinical efficacy at early on-treatment time points. This approach based on plasma EVs might represent a starting point for the development of a novel strategy to study immune responses in clinical setting.
NF2 mutation-driven renal cell carcinomas (RCC): A comprehensive genomic profiling (CGP) study.
Authors: Yakirevich Evgeny , Perrino Carmen , Necchi Andrea , Grivas Petros , Bratslavsky Gennady , Shapiro Oleg , Jacob Joseph , Sokol Ethan , Vergilio Jo-Anne , Killian Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Chung Jon , Alexander Brian Michael , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S.
Published: February 2020

726

Background: NF2 genomic alterations (GA) have been associated with aggressive behavior in RCC. Methods: FFPE tissues from 1,386 clear cell (ccRCC), 307 papillary (pRCC), 72 chromophobe (chRCC), 145 sarcomatoid (sRCC), 54 collecting duct (cdRCC),37 medullary (medRCC) and 134 unclassified (nosRCC) underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and MSI was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 140 (7%) RCC featured NF2 GA which were predominantly short variant (SV) mutations. Gender and age were similar with male preponderance in all histologic subtypes. NF2 GA frequency was highest in cdRCC (20%) and sRCC (19%) and lowest in ccRCC (3%). The medRCC at 5% NF2 GA and chRCC at 0% NF2 GA were not further evaluated. VHL and PBRM1 GA were significantly more frequent in NF2 altered ccRCC than all other RCC (P < 0.001). Other mTOR pathway GA were uncommon. Potentially targetable kinase GA in NF2-mutated RCC included BRAF (2% of ccRCC), EGFR (3% of pRCC), ERBB3 (4% of sRCC) and PIK3CA (9% of cdRCC). No NF2 mutated RCC featured MSI -high status and both TMB and PD-L1 expression levels were extremely low in all subsets with exception of high PD-L1 staining in sRCC tumors. Conclusions: cdRCC, sRCC, pRCC and nosRCC are enriched in NF2 GA. Low PBRM1 GA, TMB and MSI- high predict resistance to immunotherapy in NF2 mutated RCC although the high PD-L1 expression in sRCC is noteworthy.[Table: see text]
Validation of the lung immune prognostic index (LIPI) in patients with metastatic renal cell carcinoma treated with nivolumab in the GETUG-AFU 26 NIVOREN trial.
Authors: Lavaud Pernelle , Dalban Cécile , Negrier Sylvie , Chevreau Christine , Gravis Gwenaelle , Oudard Stephane , Laguerre Brigitte , Barthelemy Philippe , Borchiellini Delphine , Gross Goupil Marine , Geoffrois Lionnel , Rolland Frederic , Thiery-Vuillemin Antoine , Joly Florence , Ladoire Sylvain , Tantot Florence , Mezquita Laura , Escudier Bernard , Albiges Laurence
Published: February 2020

735

Background: The Lung Immune Prognostic Index (LIPI) is a prognostic score combining pretreatment dNLR (neutrophils/ (leucocytes-neutrophils) and LDH correlated to immune checkpoint inhibitors (ICI) benefit in several advanced cancers. We aimed to correlate LIPI score with Nivolumab (N) benefit in metastatic clear cell renal cell carcinoma (mccRCC) patients. Methods: We investigated the LIPI score in the GETUG-AFU 26 NIVOREN phase II trial assessing the activity and safety of N after failure of upfront VEGF-targeted therapies. A dNLR ≥ 3 and LDH ≥ upper superior limit were analyzed for the LIPI, and patients were stratified into 3 groups (good (GG), intermediate (IG) and poor (PG)) (Mezquita et al, JAMA Oncol 2018). The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR). Results: Overall, 619 pts were included. Median age was 64 years old, 22.1% pts had received more than 2 previous lines and IMDC risk groups were 18.3%, 56.5% and 25.0% for good/intermediate and poor risk respectively. Median (m) follow up was 23.7 months (mo). The mPFS with N was 4.0 mo and mOS was not reach. LIPI classified 364 pts (58.8%) as GG, 216 pts (34.9%) as IG and 39 pts (6.3%) as PG. The PFS and OS results are summarized in the Table. In multivariate analysis, LIPI score remains an independent prognostic factor after adjustment for sex, age, ECOG PS and IMDC. ORR did not seem to be influenced by the LIPI groups. Conclusions: We report for the first time that LIPI score is associated with PFS and OS in patients treated with N for mccRCC. LIPI score appears as an independent prognostic factor even after adjustment for established risk factors. External validation in a VEGF-targeted therapy cohort is ongoing and will contribute to evaluate the predictive value of LIPI in mccRCC.[Table: see text]
Cognitive status of prostate cancer (PCa) patients aged 60 years and older initiating gonadotropin-releasing hormone agonist (GnRHa) therapy, by age group.
Authors: Rozet Francois , Hennequin Christophe , Roupret Morgan , Pello Leprince Ringuet Nathalie , Houchard Aude , Mongiat Artus Pierre
Published: February 2020

74

Background: Age is a risk factor for both PCa and cognitive impairment. Moreover, androgen deprivation therapy (ADT) is suspected to alter cognition, but little is known about the cognitive status of men starting ADT. Our purpose was to analyze cognitive status in 3 groups of age ([60-70[, [70-75[ and ≥ 75 years). Methods: Initiated in March 2018, a prospective, multicenter, longitudinal, non-interventional study is conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with histologically confirmed PCa, candidate for GnRHa therapy. Patients were included (1:2:1) in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). Cognitive status was evaluated through Mini Mental State Evaluation (MMSE) questionnaire (scores 0-30), and through a visual analog scale (VAS) measuring satisfaction of patients with memory (score 0-10 cm). Significant differences (*) were concluded in case of non-overlapping of the means 95% CIs. Results: 528 patients were included in the pre-planned interim analysis of baseline results. Mean (±SD) age was 72.9±6.5years. There were 145, 207 and 176 patients, in the [60-70[, [70-75[ and ≥75y age groups, respectively. 93.8% of patients had a Karnofsky score ≥ 80%; 73.4% had at least one comorbidity at baseline and 67.9% were receiving at least one concomitant systemic treatment. Reason for GnRHa initiation was high risk localized or locally advanced tumor (57.6%), metastatic stage (19.8%), biochemical recurrence after local treatment (14.7%). Mean [95% CI] MMSE score was significantly* lower in the ≥75y age group (26.1 [25.5-26.8]) than in the [60-70[ (27.6 [27.0-28.1]) and [70-75[ (27.5 [27.1-28.0]) age groups. Cognitive impairment (MMSE < 26) concerned 18.2%, 17.6% and 32.0% of patients, respectively. Similarly, memory VAS mean score was significantly* lower in the ≥75y age group (6.4 [6.0-6.8]) than in the [70-75[ age group (7.2 [6.9-7.5]). Conclusions: Analysis of the cognitive status of 3 age groups at initiation of GnRHa therapy showed a higher rate of cognitive impairment in the eldest group. Clinical trial information: NCT03516110.
Circulating tumor DNA (ctDNA) to detect neuroendocrine prostate cancer genomic and DNA methylation changes.
Authors: Beltran Himisha , Romanel Alessandro , Conteduca Vincenza , Casiraghi Nicola , Sigouros Michael , Franceschini Gian Marco , Fedrizzi Tarcisio , Ku sheng-Yu , Alonso Alicia , Mosquera Juan Miguel , Dann Emma , Sboner Andrea , Xiang Jenny , Elemento Olivier , Nanus David M. , Tagawa Scott T. , Benelli Matteo , Demichelis Francesca
Published: February 2020

8

Background: Loss of androgen receptor signaling dependence occurs in approximately 20% of treatment resistant prostate cancers, and this may manifest as transformation to castration resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE relies on a metastatic tumor biopsy, which is invasive for patients. Here we study ctDNA as an approach to identify CRPC-NE-associated genomic and epigenomic changes. We also use this as a tool to understand tumor heterogeneity and clonal dynamics that occurs during CRPC-NE progression. Methods: 64 patients with metastatic prostate cancer (10 hormone naive, 35 castration resistant adenocarcinoma (CRPC-Adeno), 17 CRPC-NE) were prospectively enrolled for matched metastatic biopsy and blood collection. Twenty-four had multiple time-points, for total of 69 plasma and 98 metastatic tissues. Whole exome sequencing (WES) and whole genome bisulfite sequencing(of subset) of ctDNA,germline DNA, and metastatic biopsies were performed. Results: Overall there was high concordance of alterations between ctDNA and patient-matched metastasis, though this was highest in CRPC-NE. There was also less heterogeneity across patients with CRPC-NE. Alteration frequencies were consistent with published tissue-based studies with AR alterations enriched in CRPC-Adeno and TP53and RB1loss enriched in CRPC-NE ctDNA. The prognostic significance of these alterations differed based on histologic subtype. Allele-specific copy number analysis and serial sampling allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was reflective of methylation patterns in biopsies and detected CRPC-NE-associated epigenetic changes.A targeted set combining genomic ( TP53, RB1, CYLD, AR) and epigenomic(20 differential DNA methylation sites) was capable of identifying patients with CRPC-NE. Conclusions: WES and whole genome methylation of ctDNA is feasible, concordant with biopsy tissues, and identifies the spectrum and frequency of CRPC-NE genomic and epigenomic changes. A targeted panel extended and validated in larger cohorts could potentially improve the detection of CRPC-NE using non-invasive ctDNA profiling.
Phase II trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer.
Authors: Gross Mitchell E. , Agus David B. , Dorff Tanya B. , Pinski Jacek K. , Quinn David I. , Castellanos Olga O. , Gilmore Patrick O. , Shih Jean
Published: February 2020

94

Background: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. Methods: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by: PSA ≥ 0.4 ng/ml (post-prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. Results: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥ 30% and ≥ 50% were observed in 25% (n=5/20) and 10% (n=2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥ 30% and ≥ 50% of 24% (n=4/17) and 6% (n=1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2= 35%), hypertension (grade ≥ 2 =30%), and edema (grade 1=25%, grade 2=10%). There was 1 episode of grade 4 hypertension (cycle 4) and 2 episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. Conclusions: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate sensitive prostate cancer. Most treatment related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer. Clinical trial information: NCT02217709.
A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641).
Authors: Chi Kim N. , Rathkopf Dana E. , Attard Gerhardt , Smith Matthew Raymond , Efstathiou Eleni , Olmos David , Small Eric Jay , Lee Ji Youl , Sieber Paul R. , Dunshee Curtis , Ricci Deborah S. , Simon Jason S. , Zhao Xin , Kothari Nishi , Cheng Shinta , Sandhu Shahneen Kaur
Published: February 2020

TPS257

Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor abiraterone acetate. (1) The addition of a PARPi to abiraterone acetate plus prednisone (AAP) showed improved radiographic progression-free survival (rPFS) vs AAP alone in patients with mCRPC regardless of DNA repair gene defect (DRD) status. (2) Interim results from a phase 1 study support safety and tolerability of niraparib 200 mg combined with AAP in patients with mCRPC. (3) The objective of this Phase 3 study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Methods: This ongoing multicenter MAGNITUDE study will open in 300 sites across 28 countries and will enroll patients with mCRPC who have not received treatment in the metastatic castrate resistant setting other than ongoing androgen deprivation therapy [ADT] and ≤4 months of AAP. The DRD positive cohort (Cohort 1, n=400) will comprise patients whose tumors have DRD, as determined by a previously validated plasma or tissue assay. The cohort without DRD (Cohort 2, n=600) will enroll patients whose tumors are not found to have DRD. Enrollment began in February 2019. The primary objective of the study is to compare radiographic progression-free survival (rPFS) as assessed by blinded independent central radiology review for patients treated with niraparib and AAP versus placebo and AAP. To test superiority of the combination vs AAP, sample sizes were estimated to provide 92% power to detect HR≤0.65 rPFS in the DRD positive cohort and 94% power to detect HR≤0.67 in rPFS in the cohort without DRD, both at a 2-tailed level of significance of 0.05. The main secondary objectives are time to symptomatic progression, time to cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic profiles will be evaluated.1) Rajendra N, et al. Cancer Res 2019;79 (13 Suppl): Abstract nr 2134. 2) Clarke N, et al. Lancet Oncol. 2018;(7):975-986. 3) Saad, et al. Ann Oncol, 2018;29 (suppl 8), mdy284.043, https://doi.org/10.1093/annonc/mdy284.043 ). Clinical trial information: NCT03748641.
VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sartor A. Oliver , Morris Michael J. , Messman Richard , Krause Bernd J.
Published: February 2020

TPS259

Background: The novel therapeutic drug 177Lu-PSMA-617 is a prostate-specific membrane antigen (PSMA) targeting agent that is used to deliver radionuclide therapy for the treatment of patients with mCRPC. Based on preclinical data that demonstrated high PSMA binding affinity and internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development. Preliminary clinical data indicates that 177Lu-PSMA-617 may demonstrate clinical benefit in patients with mCRPC in a setting where patients had no clear standard of care. VISION (NCT03511664) is a phase 3 study designed to assess the efficacy of 177Lu-PSMA-617 in patients with PSMA-positive mCRPC. Methods: Patients were randomized 2:1 to receive best standard of care with or without 177Lu-PSMA-617. Eligibility criteria were: PSMA expressing tumor assessed by PSMA positron emission tomography imaging; prior exposure to a taxane and a novel androgen axis inhibitor (NAAI). The primary objective of this study is to compare the two alternative endpoints of progression-free survival (rPFS) and overall survival (OS). Stratification factors include lactate dehydrogenase, liver metastasis, ECOG PS, and use of an NAAI at time of randomization. On active treatment, median OS is assumed to be 13.7 months with a hazard ratio (HR) of 0.7306, and rPFS is assumed to be 6 months with an HR of 0.67. Enrollment began in June 2018 and the target of 814 patients has been reached. Clinical trial information: NCT03511664.
A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Einstein David Johnson , Choudhury Atish Dipankar , Saylor Philip James , Werner Lillian , Erlander Mark G. , Ridinger Maya , Bubley Glenn
Published: February 2020

TPS266

Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and progression, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient and reversible hematologic effects. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A safety lead-in phase has been completed at one dosing schedule (24 mg/m2 on days 1-5 of a 21-day cycle) and is ongoing at a second dosing schedule (18 mg/m2 on days 1-5 of a 14-day cycle). Expansion phases are ongoing on both arms. In addition, a more continuous dosing schedule has been proposed (12 mg/m2 on days 1-14 of a 21-day cycle). With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if <2 of the first 13 patients achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) and other genomic alterations in circulating tumor cells and circulating tumor DNA that may be associated with response to treatment. Clinical trial information: NCT03414034.
Phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) and nivolumab (Nivo) in patients (pts) with nonmetastatic, PSA-recurrent prostate cancer (PCa).
Authors: Emamekhoo Hamid , Kyriakopoulos Christos , Liu Glenn , McNeel Douglas G.
Published: February 2020

TPS273

Background: Radical prostatectomy (RP) and radiation therapy (RT) are the gold standard, curative intent treatment for pts with presumed organ-confined PCa. However, about one third of these pts will have progressive or metastatic disease at 10 years (yr). Pts with PSA recurrence without radiographic evidence of metastatic (m) PCa (stage M0) will ultimately develop radiographically apparent mPCa within a median of 8 yr. Pts with rapid PSA doubling time (DT) have a markedly shorter time to mPCa and death. Utilizing an immunotherapeutic approach could utilize the sensitivity and specificity of the immune system to treat microscopic disease and potentially avoid or postpone androgen deprivation therapy (ADT) and its unwanted side effects. Methods: In this single arm, two-stage phase II trial, a total of 21-41 PCa pts with PSA only progression (4 rising PSA with final PSA ≥ 2 ng/mL) after initial RP for presumed organ-confined disease who have no radiographic evidence of mPCa in conventional imaging (CT and bone scan) will be enrolled. Pts with small cell or other variant PCa, or history of ADT other than concurrent with RT are excluded. All pts will be treated with pTVG-HP 100 μg intradermally (id) and Nivo 240 mg IV every (Q) 2 weeks (w) x6, and then pTVG-HP 100 μg id and Nivo 480 mg IV Q4w x9 beginning w12 on study. Pts with PSA on w4 > PSA on day 1 will additionally receive rhGM-CSF 208 μg id, as a vaccine adjuvant, Q2w x4 beginning w4 on study. Pts will be treated until progression or up to a total of 1 yr. Response will be monitored by CT and bone scan Q6 months or as clinically indicated. Primary endpoints are safety and tolerability of this combination and PSA complete response rate (PSA < 0.2 ng/mL). Key secondary endpoints are 2-yr metastasis-free survival, median radiographic progression-free survival, PSA response rate (≤50% of baseline), and changes in PSA DT. Elicited antigen-specific T-cell and/or IgG response and its correlation with PSA response will be explored. Bone mets not detected by conventional imaging and their association with response will be evaluated by Quantitative Total Bone Imaging (QTBI) by NaF PET/CT. Updated enrollment will be presented. Clinical trial information: NCT03600350.
Phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK).
Authors: Lalani Aly-Khan A. , Swaminath Anand , Pond Gregory Russell , Kapoor Anil , Chu William , Bramson Jonathan L. , Surette Michael G. , Levine Mark Norman , Hotte Sebastien J.
Published: February 2020

TPS761

Background: Randomized data from the interferon era demonstrated modest survival benefits of cytoreductive nephrectomy (CN) in patients with advanced renal cell carcinoma (aRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN especially in IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in aRCC now includes first-line combination immunotherapy. Data from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and objective response rate with ipilimumab and nivolumab (I/N) compared to sunitinib. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an ‘abscopal effect’, leading to enhanced systemic anti-tumour immune response. We hypothesize that SBRT to the primary kidney mass in aRCC patients will enhance the efficacy of I/N compared to standard of care I/N alone. Methods: This phase II trial randomizes untreated aRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven aRCC (any histology), IMDC intermediate/poor risk disease, and who decline or are unsuitable for CN. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include blood immune signatures and stool microbiome. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Clinical trial information: NCT04090710.
Twice as High Diet-Induced Thermogenesis After Breakfast vs Dinner On High-Calorie as Well as Low-Calorie Meals
Authors: Richter Juliane , Herzog Nina , Janka Simon , Baumann Thalke , Kistenmacher Alina , Oltmanns Kerstin M
Published: February 2020

Background

The question of whether there is daytime time variation in diet-induced thermogenesis (DIT) has not been clearly answered. Moreover, it is unclear whether a potential diurnal variation in DIT is preserved during hypocaloric nutrition.

Objective

We hypothesized that DIT varies depending on the time of day and explored whether this physiological regulation is preserved after low-calorie compared with high-calorie intake.

Design

Under blinded conditions, 16 normal-weight men twice underwent a 3-day in-laboratory, randomized, crossover study. Volunteers consumed a predetermined low-calorie breakfast (11% of individual daily kilocalorie requirement) and high-calorie dinner (69%) in one condition and vice versa in the other. DIT was measured by indirect calorimetry, parameters of glucose metabolism were determined, and hunger and appetite for sweets were rated on a scale.

Results

Identical calorie consumption led to a 2.5-times higher DIT increase in the morning than in the evening after high-calorie and low-calorie meals (P < .001). The food-induced increase of blood glucose and insulin concentrations was diminished after breakfast compared with dinner (P < .001). Low-calorie breakfast increased feelings of hunger (P < .001), specifically appetite for sweets (P = .007), in the course of the day.

Conclusions

DIT is clearly higher in the morning than in the evening, irrespective of the consumed calorie amount; that is, this physiological rhythmicity is preserved during hypocaloric nutrition. Extensive breakfasting should therefore be preferred over large dinner meals to prevent obesity and high blood glucose peaks even under conditions of a hypocaloric diet.
PIWI–piRNA pathway-mediated transposable element repression in Hydra somatic stem cells
Authors: Teefy Bryan B. , Siebert Stefan , Cazet Jack F. , Lin Haifan , Juliano Celina E.
Published: February 2020

Transposable elements (TEs) can damage genomes, thus organisms use a variety of mechanisms to repress TE expression. The PIWI–piRNA pathway is a small RNA pathway that represses TE expression in the germline of animals. Here we explore the function of the pathway in the somatic stem cells of Hydra, a long-lived freshwater cnidarian. Hydra have three stem cell populations, all of which express PIWI proteins; endodermal and ectodermal epithelial stem cells (ESCs) are somatic, whereas the interstitial stem cells have germline competence. To study somatic function of the pathway, we isolated piRNAs from Hydra that lack the interstitial lineage and found that these somatic piRNAs map predominantly to TE transcripts and display the conserved sequence signatures typical of germline piRNAs. Three lines of evidence suggest that the PIWI–piRNA pathway represses TEs in Hydra ESCs. First, epithelial knockdown of the Hydra piwi gene hywi resulted in up-regulation of TE expression. Second, degradome sequencing revealed evidence of PIWI-mediated cleavage of TE RNAs in epithelial cells using the ping-pong mechanism. Finally, we demonstrated a direct association between Hywi protein and TE transcripts in epithelial cells using RNA immunoprecipitation. Altogether, our data reveal that the PIWI–piRNA pathway represses TE expression in the somatic cell lineages of Hydra, which we propose contributes to the extreme longevity of the organism. Furthermore, our results, in combination with others, suggest that somatic TE repression is an ancestral function of the PIWI–piRNA pathway.
Health-related Quality of Life of Nurses Working in Tertiary Care Hospital of Karachi
Authors: Ali Amjad , Rasheed Abdur , Naz Subia
Published: February 2020

Objective: The aim of this study was to assess nurses’ health-related quality of life.

Methods: This cross-sectional analytical study was accomplished among 154 nurses. Data were collected from two tertiary care hospitals of Karachi. Consent was taken prior to data collection from every participant. Questionnaire Short Form Health Survey-26 (SF-26) and Patients Health Questionnaire-9(PHQ-9) were used as a study tool. Data were analyzed through SPSS version 21.

Results: ANOVA and T-test confirmed that energy/fatigue domain differed significantly with level of education, duty shift and monthly income with p-values 0.025, 0.001 and 0.006 respectively. It was observed that mean scores of physical functioning, role limitation due to physical health and pain domains differ significantly between depressive and non-depressive participants, with p-values 0.045, 0.01 and 0.005 respectively.

Conclusions: Health related quality of life differs in comparison of physical health domain with depressive and non-depressive nurses. Only energy/fatigue domain was significantly associated with level of education, duty shift and monthly income of nurses.

doi: https://doi.org/10.12669/pjms.36.3.1267

How to cite this:Ali A, Rasheed A, Naz S. Health-related Quality of Life of Nurses Working in Tertiary Care Hospital of Karachi. Pak J Med Sci. 2020;36(3):490-495. doi: https://doi.org/10.12669/pjms.36.3.1267

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.