bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term outcomes of a pilot study on highly hypofractionated intensity-modulated radiation therapy over three weeks for localized prostate cancer.
Authors: Nakamura Kiyonao , Ikeda Itaru , Inokuchi Haruo , Aizawa Rihito , Akamatsu Shusuke , Kobayashi Takashi , Mizowaki Takashi 
Published: February 2022

259 Background: A number of reports have been published on both moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancers using 2.4 – 3.4 Gy per fraction over 4 – 6 weeks, and ultrahypofractionation over 1 – 2 weeks using 6 Gy or more per fraction. However, long-term outcomes have sparsely been reported using doses between these two fractionations (3.4 – 6.0 Gy per fraction) over 2 – 3 weeks (high hypofractionation). Therefore, we performed a pilot study of highly hypofractionated IMRT in 15 fractions using 3.6 Gy per fraction over 3 weeks for localized prostate cancer. We now report the long-term outcomes of the study. Methods: Twenty-five patients with low- to intermediate-risk prostate cancer were enrolled in this prospective study from April 2014 to September 2015. Fifty-four Gy in 15 fractions (3.6 Gy per fraction) was delivered over three weeks using IMRT with CBCT-based image guidance without intraprostatic fiducial markers. Based on an estimated alpha/beta ratio for prostate cancer of 1.5 Gy, the EQD2 was 78.7 Gy for the present dose fractionation. Neoadjuvant hormonal therapy (HT) was administered to intermediate-risk patients for 4 – 8 months, but was not mandatory in patients with low-risk disease. Adjuvant HT was not provided for any patient. Biochemical relapse-free survival (BRFS), clinical relapse-free survival (CRFS), overall survival (OS), and the cumulative incidence rate of late toxicities were analyzed using the Kaplan Meier method. Results: Twenty-four patients were treated with highly hypofractionated IMRT, except one case switched to conventionally fractionated IMRT because we could not meet the dose constraint of the small bowel in treatment planning. Among the 24 patients, 17 % had low-risk, and 83% had intermediate-risk disease. Neoadjuvant HT was administered to 23 patients, and the median duration of HT was 5.3 months. The median follow-up period was 77 months (range, 57–87 months). BRFS, CRFS, and OS were 91.7%, 95.8% and 95.8% at 5 years, and 87.5%, 86.3% and 95.8% at 7 years, respectively. No patient died of prostate cancer, but one patient died due to the other cancer. Neither grade ≥2 late gastrointestinal toxicity nor ≥3 late genitourinary toxicity was observed. Grade 2 late genitourinary toxicity did not occur during the first 4 years, but was developed in 5 patients after more than 4-year follow-up. The cumulative incidence rate was 12.9% and 22.8% at 5 and 7 years, respectively. Conclusions: Highly hypofractionated IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer without intraprostatic fiducial markers demonstrates favorable oncological outcomes with no severe complications. This treatment approach could be a possible alternative of moderate hypofractionation, although further studies will be mandatory.
Early initiation of salvage radiotherapy is associated with improved metastasis-free survival in patients with relapsed prostate cancer following prostatectomy.
Authors: Lee Emerson , Singh Tanmay , Han Misop , Deville Curtiland , Halthore Aditya , Greco Stephen C. , Tran Phuoc T. , DeWeese Theodore L. , Song Danny 
Published: February 2022

262 Background: Salvage radiation therapy is a recognized management option for patients who develop biochemical failure following radical prostatectomy. However, given the documented long natural history of biochemically relapsed prostate cancer after prostatectomy, questions remain on the value of early salvage intervention vs initial expectant management, especially with regards to more critical clinical rather than biochemical endpoints. We sought to determine the impact of early salvage radiotherapy (initiated at PSA 0.2 - 0.5 ng/ml) on metastasis-free survival in patients who receive salvage radiotherapy following prostatectomy for clinically localized prostate cancer. Methods: Using tumor registry data, we identified 408 patients who received salvage radiation therapy between 1986 – 2016 at our institution. We analyzed association between survival outcomes and prognostic factors, including pre-treatment and nadir prostate-specific antigen (PSA), interval between prostatectomy and initiation of salvage RT, use of neoadjuvant/concurrent hormonal suppression, and adverse pathologic features, including Gleason score, extraprostatic extension, seminal vesicle invasion, nodal involvement, and margin status. Univariate analyses and multivariable-adjusted Cox proportional hazards models were constructed to assess association between these clinical and pathologic features and duration of biochemical relapse-free survival (bRFS) and metastasis-free survival (MFS). Construction of Kaplan-Meier survival curves stratifies survival by predictive features. Results: Overall, 187 (45.8%) patients received salvage radiotherapy while PSA levels were 0.2 - 0.5 ng/ml (early salvage). One hundred thirty three (32.6%) patients received neoadjuvant/concurrent androgen deprivation therapy (ADT). Median radiation dose was 68.4 Gy and did not differ significantly between treatment subgroups. Independent of pathologic features and use of ADT, early-salvage at lower PSA levels was the most significant predictor of improved bRFS and MFS, HR = 0.52 (95% CI [0.35, 0.79], p = 0.002), and HR = 0.58 (95% CI [0.37, 0.91], p = 0.02), respectively. Seminal vesicle invasion was associated with shorter interval to biochemical failure (HR = 1.79 (95% CI [1.07, 2.98], p = 0.03), but not significant difference in MFS. Conversely, nodal involvement was a significant predictor of worse MFS, with HR = 2.18 (95% CI [1.04, 4.57], p = 0.04). Notably, interval between prostatectomy and initiation of salvage radiation was not a significant prognostic factor for bRFS or MFS. Conclusions: Independent of pathologic features and use of ADT, the initiation of salvage radiation therapy early after biochemical relapse (PSA ≤ 0.5 ng/ml) following prostatectomy is associated with increased metastasis-free as well as biochemical relapse-free survival.
The role of spatial transcriptomic profiling to determine androgen receptor signaling and immune infiltration in prostate cancer
Authors: Patel Parth , Nallandhighal Srinivas , Scoville David , Tran Lynn , Cotta Brittney , Udager Aaron M. , Rao Arvind , Palapattu Ganesh S. , Dadhania Vipulkumar , Pitchiaya Sethu , Salami Simpa 
Published: February 2022

272 Background: Prostate cancer (PCa) in the transition zone (TZ) accounts for approximately 30% of disease and tends to present with higher PSAs with a lower risk of seminal vesicle invasion, extra-capsular extension, and risk of biochemical recurrence compared with peripheral zone (PZ) tumors. The underlying biological mechanism for these differences is poorly understood. Here, we performed spatial transcriptomic profiling to elucidate the molecular differences between TZ and PZ PCa. Methods: We identified three patients who underwent radical prostatectomy for PCa (one each with PZ only, TZ only, and both PZ and TZ tumors) and used the NanoString’s Digital Spatial Profiling (DSP) platform to quantify whole transcriptomic gene expression data (17,128 genes) in multiple regions of interest (ROI) per patient (42 cancer and 8 normal samples). Four morphology markers to facilitate ROI selection in both cancer and normal areas (SYTO13 for nucleus, PanCK for epithelium, SMA for stroma and CD45 for immune cells) were selected. Raw counts for 17,128 genes were imported to R v.4.1.0 for downstream data analyses. Counts were Q3 normalized and scaled (Z-score) to enable plotting of all genes on the same axes. Differential gene expression analysis using a linear model fit by empirical Bayes moderation, gene set enrichment analysis (GSEA) by cancer hallmarks, XCell gene sets for pathway enrichment and immune cell deconvolution using CIBERSORT was performed. Results: There were grade group (GG) 4 (n=10) and 5 (n=10) tumors in PZ and GG 3 (n=10), 4 (n=11) and 5 (n=1) cancers in TZ regions. We observed distinct gene expression profiles between PZ (n = 20) and TZ (n=22) tumors. Interestingly, androgen receptor (AR) signaling was significantly higher in TZ PCa ROIs compared to PZ ROIs in both GSEA (false discovery rate < 5%) and the androgen subcomponent of the genomic prostate score (p<0.001), regardless of grade, epithelial, stromal or immune component of the region. To standardize the comparison, CIBERSORT’s absolute immune signature scores were only computed for GG4 tumors and found to be significantly higher in PZ GG4 tumors compared to TZ GG4 tumors. Notably, CD4+ memory T cells were significantly higher in PZ GG4 regions compared to TZ GG4 tumor regions (p<0.05). Conclusions: Here, we demonstrate distinct gene expression profiles of PZ and TZ PCa. Specifically, we observed higher AR signaling in TZ cancers and higher levels of immune infiltration on PZ cancers. This is in concordance with prior knowledge that TZ tumors may be associated with higher serum PSA and PZ tumors may be associated with inflammation. Further studies are needed to discern the biological and clinical significance of the different molecular features of PZ and TZ PCa.
Longitudinal ctDNA alterations in germline positive CRPC patients.
Authors: Huang Minqi , Jaeger Ellen B. , Caputo Sydney , Fleming William , Light Malcolm , Manogue Charlotte , Sussman Isabelle P. , Lieberman Alex , Lewis Brian E. , Barata Pedro C. , Layton Jodi Lyn , Ledet Elisa M. , Sartor A. Oliver 
Published: February 2022

275 Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing somatic alterations. We report longitudinal ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Patients with both germline testing and ctDNA assessment were included. Germline testing was performed with a multi-gene cancer panel from Invitae (50-83 genes) and somatic alterations in ctDNA were identified by testing with Guardant 360 (70-83 genes). ctDNA alterations were characterized as deletions, frameshift, missense, nonsense, and other mutations. A total of 177 patients in various stages of therapy had both ctDNA and germline DNA tested. Results: From 2015-2021, 177 mCRPC patients were included and had an average of 3 ctDNA tests. 11.3% (20/177) had pathogenic or likely-pathogenic germline mutations. The common pathogenic germline mutations were in BRCA2 (25%; 5/20), ATM (10%; 2/20), and MSH2 (10%; 2/20). In ctDNA, missense mutations were the most prevalent type of gene alteration in germline negative (n = 539/790, 68%) and germline positive (n = 124/218, 57%) followed by frameshift mutations at 22% (n = 48/218) in germline positive and 10% (n = 80/790) in germline negative patients. Germline positive patients were more likely to have somatic frameshift mutations (OR = 2.09, 95% C.I. (1.3792, 3.1618), p = 0.001) and less likely to have missense mutations (OR = 0.61, 95% C.I. (0.4519, 0.8351), p = 0.002). Other alterations including deletions, nonsense, and other mutations were not significantly different. Of the germline positive pts, BRCA2 mutation was associated with the highest number of somatic alterations. Conclusions: Germline positive CRPC patients were more likely to have frameshift mutations and less likely to missense mutations compared to germline negative CRPC patients. Patients with germline mutations in BRCA2 and TP53 had the highest number of somatic alterations detected in ctDNA over the course of ctDNA evaluation.
Clinicopathologic and survival differences between African Americans and Caucasians with renal cell carcinoma.
Authors: Wang Shirley , Cheaib Joseph G. , Patel Sunil H. , Alam Ridwan , Metcalf Meredith , Jing Yuezhuo , Trock Bruce , Allaf Mohamad , Ged Yasser , Pierorazio Phil , Singla Nirmish 
Published: February 2022

296 Background: The incidence of renal cell carcinoma (RCC) has gradually increased over the past decades, particularly among African Americans (AA). Lifestyle and other factors such as high blood pressure and tobacco exposure are associated with its incidence. We aim to compare differences in clinicopathologic characteristics and survival outcomes between AA and Caucasian patients undergoing nephrectomy for RCC. Methods: A retrospective single institutional analysis was performed on AA or Caucasian patients undergoing nephrectomy for RCC between 1996 and 2021. Baseline clinical and pathologic characteristics were compared by race. Survival outcomes, including cancer-specific survival (CSS) and overall survival (OS), were assessed by Kaplan-Meier methods and multivariable Cox regression analysis (MVA). Results: We included 2,439 patients (445 AA, 1987 Caucasians). AA patients were female-predominant compared to Caucasians (54.8% vs. 35.7%, p<0.01). AA patients were more likely to have a history of hypertension (44.0% vs. 40.3%, p<0.001) and diabetes (14.4% vs. 11.4%, p<0.001). Caucasian race was associated with higher pathologic stage (p<0.001), positive nodal status (3.8% vs. 1.1%, p=0.016), and metastatic disease at presentation (3.7% vs. 1.8%, p=0.042). AA had more papillary variant compared to Caucasians (36 v 15.7%, p<0.01). The 5-year CSS across all stages was better for AA vs. Caucasians (93.1% vs. 89.7%, p=0.01), but after adjusting for covariates, race was not significant for CSS on MVA (HR 0.89 (95% CI 0.57-1.38), p=0.8). Similar findings were seen in OS. We performed additional sub-analyses on patients with stage pT1a (n=665) and locally advanced (pT3-4, n=431) clear cell RCC. Among these sub-groups, no significant differences were seen by race. Conclusions: Within our institutional cohort, AA patients with RCC undergoing nephrectomy did not exhibit worse pathologic characteristics at presentation or inferior survival outcomes compared to their Caucasian counterparts. There were notable differences among baseline clinical characteristics and histology by race. Socioeconomic and molecular analyses will help elucidate biological differences and identify socially actionable strategies to improve outcomes among patients with RCC.
Effectiveness of first-line therapy in patients with advanced non-clear renal cell carcinoma (nccRCC).
Authors: Laramee Sophie , Ghosh Sunita , Kollmannsberger Christian K. , Hansen Aaron Richard , Wood Lori , Soulieres Denis , Canil Christina M. , Saleh Ramy , Castonguay Vincent , Bjarnason Georg A. , Basappa Naveen S. , Breau Rodney H. , Heng Daniel Yick Chin , Pouliot Frederic , Kapoor Anil , Lalani Aly-Khan A. 
Published: February 2022

304 Background: Current treatment principles for advanced nccRCC have been largely extrapolated from guidelines for clear cell RCC. Given the emerging randomized data for select nccRCC subtypes, real-world outcomes for these patients are informative particularly in the contemporary checkpoint inhibitor era. Methods: We performed an analysis using the Canadian Kidney Cancer information system (CKCis), a prospective database involving 14 academic centers, on nccRCC patients undergoing first-line systemic therapy between January 2011 – December 2019. Treatment groups were defined as receipt of: vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-TKI), mammalian target of rapamycin inhibitors (mTORi), and PD-1/PD-L1 immune checkpoint inhibitors (ICI, mono- or combination therapy). Primary outcome was 1-yr overall survival (OS) rate. Secondary outcomes were median time to treatment failure ((TTF, months), defined as treatment discontinuation, change or death) and objective response rate (ORR, %). Results: We identified 265 nccRCC patients: 204 (77.0%) received VEGF-TKI, 19 (7.2%) received mTORi and 42 (15.8%) received ICI-based first-line therapy (Table). Overall, median age was 64 years, 75% were male, 84% were classified as IMDC intermediate/poor risk, and 16% underwent prior nephrectomy. Twenty-three percent of patients were enrolled in clinical trials. Patients received primarily sunitinib (81%) or pazopanib (15%) in the VEGF-TKI group (other: 4%), while mTORi-treated patients received temsirolimus (74%) or everolimus (26%). For the ICI-based treatment group, most patients received combination therapy as ipilimumab-nivolumab (71%) or pembrolizumab-axitinib (26%), with 3% receiving ICI monotherapy. 1-yr OS was 65.2% for VEGF-TKI, 57.9% for mTORi and 69.0% for ICI-treated patients. Median TTF was 3.3 for VEGF-TKI, 3.5 for mTORi and 7.1 mos for ICI-treated patients. ORR was 17%, 5%, and 37% respectively for the VEGF-TKI, mTORi and ICI-treated groups. Conclusions: We describe the effectiveness of first-line therapy for patients with nccRCC from a national database. This real-world data suggests an association between first-line ICI-based therapies and improved outcomes, albeit with cabozantinib not available for the indication during this time. Our data supports consensus recommendations for preferred use of ICI-based or VEGF-TKI over mTORi as first-line therapy in nccRCC.[Table: see text]
Real-world experience (RWE) of safety and efficacy of 6-weekly pembrolizumab 400mg (pem6w) plus axitinib (axi) in patients (pts) with advanced renal cell carcinoma (aRCC).
Authors: Ansel Sonam , Ray-Chaudhuri Anirban , Jones Robert J. , Stares Mark , Ding Tze-en , Symeonides Stefan N. , Crearie Christine , Slater Sarah , Cascales Garcia Maria Almudena , Sundaramurthy Aravindhan , Malik Jahangeer , Thomson Nicola , Pringle Marie , Barmack Gillian , Venugopal Balaji 
Published: February 2022

309 Background: The KEYNOTE 426 trial demonstrated pem 200mg plus axi twice daily (bd) is effective in aRCC. Pharmacokinetic modelling of pem 400 mg every six weeks demonstrated similar observed exposures to pem 200 mg every three weeks. In NHS Scotland, pem6w + axi was used during the COVID-19 pandemic to reduce hospital visits and for pts’ convenience. Here, we evaluate the RWE of pem6w + axi in aRCC. Methods: Electronic medical records of pts on pem6w + axi between 1 May 2020 & 1 Jun 2021 in two large cancer centers in Scotland were analyzed retrospectively for pts’ characteristics, treatment related adverse events (TRAE) and efficacy. Results: Total of 93 pts were identified (Table). At data cut off of 8 Sep 2021, with a median follow-up of 7 months (mo) (inter-quartile range (IQR) 5 mo; range 0-15 mo), 73 pts (78%) were alive. Clinician assessed radiological response was evaluable in 87 pts. Overall response rate (ORR) including partial response + complete response was noted in 49 pts (56%) with median time to response of 80 days (d). Clinical benefit rate including pts with ORR and stable disease was seen in 72 pts (83%). At data cut off, 24 pts (26%) had progressed with a median time to progression of 117 d (IQR: 85d). Median overall and progression free survival were not reached and follow-up continues. 81 pts (87%) had any grade and 28 pts (30%) had grade 3/4 TRAE. Immune related AE (irAE) of any grade occurred in 60 pts (65%) and grade 3/4 in 19 pts (20%). Common grade 3/4 irAE were transaminitis (10%), colitis (8%), nephritis (2%) and skin (2%). 28 (30%) and 14 pts (15%) respectively required steroids and hospitalisation for irAE with median hospital stay 6 d (range: 2-43 d). 10 pts suffered a second irAE requiring steroids and 5 pts had a second hospital stay with median hospital stay of 6 d. Any grade AE and grade 3/4 AE related to axi occurred in 67 (72%) and 14 pts (15%) respectively. Axi dose was escalated from 5mg to 7mg bd in 12 pts (13%), reduced to 3mg bd in 35 pts (38%) and 2mg bd in 10 pts (11%). 21pts (23%) on Pem and 15pts (16%) on axi discontinued treatment due to TRAE. Conclusions: Our RWE demonstrates that pem6w + axi appears to have comparable safety profile to pem 200mg + axi reported in Keynote 426 study, with the added benefits of less frequent hospital visits. Further follow up continues for efficacy in this heterogeneous pts population. Pt characteristics, total=93 (%).[Table: see text]
A VA Federal Supply Schedule (VAFSS)–based cost-effectiveness analysis of immunotherapy-tyrosine kinase inhibitor (IO-TKI) regimens and sunitinib in the treatment of metastatic renal cell carcinoma (mRCC).
Authors: Kohli Manish , Cutshall Zachary , Dougherty Maura , Nelson Richard , Yoo Minkyoung 
Published: February 2022

312 Background: Recent FDA approvals for mRCC treatment have resulted in increased effectiveness, drug choices, and costs. We performed a cost effectiveness analysis (CEA) of six recently approved IO-TKI drug combinations and sunitinib. Methods: We used a Markov simulation model from the healthcare sector perspective with a lifetime time horizon. The 7 treatment drug strategies considered in this model included: (1) atezolizumab + bevacizumab (AB), (2) avelumab + axitinib (AA), (3) pembrolizumab + axitinib (PA), (4) nibolumab + ipilimumab(NI), (5) nibolumab + cabozantinib (NC), (6) lenvatinib + pembrolizumab (LP), and (7) sunitinib (S). Input parameters of drug effectiveness and toxicities to construct the model were based on published randomized studies that led to drug approvals. Direct costs for treatment were derived using the VA Federal Supply Schedule (VAFSS). Markov model simulates patient transition between 3 health states at monthly intervals: progression free, progressive disease, and death. The cost-effectiveness outcome in our model were and life-years (LYs), progression-free life-years (PFLYs) gained, and quality-adjusted life-years (QALYs) with utility values based on published literature. Results: The table highlights results of the CEA. The least expensive drug combination was NI ($442,218) while the most expensive was LP ($963,610). AA yielded the most LYs (5.51) and QALYs (5.62) and LP yielded the most PFLYs (1.64) while NL yielded the least LYs (4.35) and PFLYs (1.47) and LP yielded the least QALYs (4.19). AB and S were absolutely dominated strategies yielding less effectiveness and cost more in terms of effectiveness measures. Depending on acceptable willingness-to-pay (WTP) and effectiveness measures, PA or AA were the most cost-effective strategies. Conclusions: Our analyses suggest that based on direct cost acquisition using VA FSS, PA or AA were cost-effective strategies for mRCC with WTP of $20,000 to $200,000 per QALY.[Table: see text]