bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-PD1 plus oncolytic virus as first-line treatment option for metastatic renal cell carcinomas.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Lee Namhee , Oh Keunhee , Ham Won Sik 
Published: March 2023

675 Background: Although anti-programmed death (PD)1 and anti-cytotoxic T-cell lymphocyte (CTLA)-4 combination therapy is recommended as one of the first line treatment options for metastatic renal cell carcinoma (mRCC), immune checkpoint inhibitor (ICI) combination therapy leads to the increased immune-mediated adverse events (imAEs). Our group has reported the therapeutic potential of oncolytic virus, JX-594 in metastatic murine RCC model. In this study, we explored the effect of JX-594 plus anti-PD1 in comparison to the combination therapy of anti-PD1 and anti-CTLA-4. Methods: Early-stage and advanced-stage highly metastatic orthotopic murine RCC models developed by our group were used. Anti-PD1 with either JX-594 or anti-CTLA-4 were systemically injected through the peritoneum. Immunofluorescence analysis was performed to demonstrate the remodeling of the tumor immune microenvironment (TIME). Results: Both JX-594 plus anti-PD1 and ICI combination therapy significantly reduced primary tumor and metastatic tumor burden in lung and peritoneum compared to cytoreductive nephrectomy plus anti-PD1. For the early-stage and advanced-stage mRCC models, JX-594 plus anti-PD1 significantly decreased the primary tumor sizes and number of lung tumor nodules compared to ICI combination therapy only in the early-stage mRCC model ( P<0.01), but not in advanced-stage mRCC model ( P=0.07). The therapeutic benefit was significantly increased when JX-594 and anti-PD1 was sequentially injected compared to when JX-594 and anti-PD1 was injected simultaneously ( P<0.05). Notable imAEs were observed in 2/16 (12.5%) in ICI combination group, whereas no notable imAEs in JX-594 plus anti-PD1 group. JX-594 plus anti-PD1 induced changes in TIME of both early- and advanced-stage mRCC model. However, tumor-suppressing TIME was more notable in early-stage mRCC model, which increased tumor-infiltrating CD8+ T cells and tumor-suppressing M1 tumor-associated macrophages (TAM), and decreased tumor-promoting myeloid-derived suppressor cells (MDSCs) and M2 TAM. Conclusions: JX-594 plus anti-PD1 effectively reduced primary tumors and metastatic burdens similar to ICI combination therapy. Furthermore, imAEs significantly decreased in JX-594 plus anti-PD1 group, suggesting the potential benefit of JX-594 plus anti-PD1 for reserving ICI induced toxicities, especially by anti-CTLA-4.
Longitudinal detection of circulating tumor DNA in patients with advanced renal cell carcinoma.
Authors: Basu Arnab , Kollipara Revathi , Sudhaman Sumedha , Mahmood Tamara , Pajak Natalia , Carson Carcia , Dutta Punashi , Calhoun Mark , ElNaggar Adam , Liu Minetta C. , Ferguson James , Peyton Charles , Rais-Bahrami Soroush , Tan Alan 
Published: March 2023

715 Background: Treatment response monitoring is key to effective disease management for patients with advanced (RCC) and can potentially improve clinical outcomes. Circulating tumor DNA (ctDNA) has shown promise as a biomarker in the early identification of treatment response in a variety of tumor types. Herein, we evaluated ctDNA-derived molecular residual disease (MRD) detection and dynamics in both clear cell (ccRCC) and non-clear cell (nccRCC) RCC patients treated with standard of care therapy and provide correlations with clinical outcomes. Methods: This was a multi-center retrospective analysis of real-world data obtained from commercial ctDNA testing (Signatera, Natera, Inc.), 41 patients (142 plasma samples) with high-risk resected or metastatic RCC were analyzed for ctDNA. Clinical data were collected on IMDC risk category, pathologic subtype, tumor stage and grade including the presence of sarcomatoid/rhabdoid features. Progression on radiological imaging was based on RECIST 1.1. criteria. Results: Of the 41 patients, 73% (30/41) had ccRCC and the remaining 27% (11/41) were nccRCC. Immunotherapy was administered as a single agent or in combination with other immune checkpoint inhibitor agents/targeted therapy in 78% (32/41) in either frontline or refractory settings. ctDNA detection at any time point was 70% (29/41) and patients were followed-up for a median of 26.4 weeks (range: 0.9-90.6) from the first ctDNA time point. Fourteen patients (34%) experienced disease progression during follow-up and all had ctDNA detected ahead of radiological progression (100% sensitivity) with a median lead time of 13.6 weeks (range: 1-39.7 weeks). Concordance between clinical outcome and ctDNA status (detected or not detected) was observed in 78% (32/41) of the patients, 12% (5/41) showed discordance, and imaging data is pending for 10% (4/41) at the time of analysis. Conclusions: Collectively, our study demonstrates high concordance between MRD status and subsequent clinical outcomes. MRD had 100% sensitivity for predicting subsequent radiographic progression with significant median lead time. MRD may serve as a valuable tool for monitoring patients on immunotherapy-based regimens for RCC.
Baseline circulating soluble factors as predictors of immune-related adverse events (irAEs) in patients (pts) with metastatic clear cell renal carcinoma (mRCC) treated with nivolumab: A translational NIVOREN GETUG-AFU 26 study.
Authors: Carril-Ajuria Lucia , Naigeon Marie , Dalban Cécile , Desnoyer Aude , Rioux-Leclercq Nathalie , Sautès-Fridman Catherine , Meylan Maxime , Vano Yann-Alexandre , Beusenlick Benoit , Chouaib Salem , de Oliveira Caroline , Tantot Florence , Flippot Ronan , Escudier Bernard , Albiges Laurence , Chaput Nathalie 
Published: March 2023

724 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes and irAEs in mRCC pts treated with nivolumab. We previously identified (training-set = 80 pts, validation-set= 233 pts) several soluble factors associated with overall survival (IL-6, IL-8, VEGF, BAFF, and CXCL13) (Carril-Ajuria et al. ASCO. 2022). Our aim was to evaluate the association between baseline levels of circulating soluble factors and the presence of all grade and severe irAEs. Methods: 720 patients treated with nivolumab within the NIVOREN study and with available safety data were included in the study. The association between baseline levels of seven different circulating soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) and the development of all grade and severe irAEs was evaluated in those pts who had previously undergone soluble factors quantification within the translational program. The association between other systemic inflammatory markers (the lung immune prognostic index (LIPI), LDH and the derived neutrophil to lymphocyte ratio (dNLR)) and irAEs was also evaluated. Results: Out of 720 pts, 456 (63%) and 143 (20%) pts presented all grade and severe irAEs respectively. Soluble factors quantification at baseline was available for 353 pts. Baseline characteristics were similar to the overall trial population. Lower levels of circulating IL-6 (cut-off: 8.7 pg/ml) at baseline were significantly associated with a higher risk of all grade irAEs (p=0.025). Lower dNLR levels (<3, p=0.003) at baseline and a good LIPI score (p=0.014) were also associated with a higher risk of all grade AEs. No other significant associations were found between circulating soluble factors and all grade irAEs. No significant associations were found between circulating solubles factors/systemic inflammatory markers and the presence of severe irAEs Conclusions: Using the cut-off values previously identified, we observed that lower baseline levels of circulating IL-6 were associated with an increased risk of all grade irAEs. Good LIPI patients and those with a lower dNLR also presented a higher risk of all grade irAEs. Baseline circulating soluble factors and systemic inflammatory markers failed to demonstrate a significant association with the development of severe irAEs.
Impact of cytoreductive nephrectomy (CRN) on overall survival (OS) in metastatic non–clear cell renal cancer (nccRCC).
Authors: Nelson Ariel Ann , Szabo Aniko , Kilari Deepak 
Published: March 2023

730 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for 25% of kidney cancer diagnoses and encompasses a diverse group of kidney tumors with distinct biology for which treatment in the metastatic setting is evolving. The role of CRN for nccRCC population in the current treatment landscape remains unclear. Methods: We retrospectively identified patients (pts) with nccRCC from The National Cancer Database (NCDB) participant user file (PUF) for Kidney and Renal Pelvis Tumors. Pts with de novo metastatic disease diagnosed between 2006 and 2017, received systemic treatment (trt) with immunotherapy (IO) or non-immunotherapy (NIO) and either underwent or could have undergone a CRN were selected. Demographic and disease characteristics were summarized using descriptive statistics. The cumulative incidence of CRN with death without CRN as a competing risk, was estimated using the Nelson-Aalen estimator. The association of each demographic and disease characteristic on the cumulative incidence of CRN was evaluated using univariate Fine-Gray regression. The effect of CRN on survival was visualized using a Simon-Makuch plot. P values were based on Mantel-Byar test. Cox regression with a time-dependent predictor was used to estimate the change in the hazard of death after CRN. Results: We identified 3644 pts, 72% male, mean age 61 ±13 years. Nearly 40% of pts (n=1453) had sarcomatoid histology, followed by 30% with papillary (n=1075). Most pts, 96% (n=3489) received NIO systemic trt and only 9% were treated with IO (n=319). Nearly half of the study population (45%) underwent CRN (n=1642). Of these, 95% received NIO trt (n=1564) and 9% received IO (n=152). Pts who underwent CRN were younger and less likely to have bone, brain or liver metastases. Minority pts were less likely to undergo CRN. Mean time from dx to surgery was 1.1 ±1.7 months. For all pts, mOS was 9 months (95% CI: 8.6-9.4). OS was improved for pts who underwent CRN vs those who did not (11.3 vs 7.5 months, p<0.0001). In multivariate analysis, cytoreductive nephrectomy was associated with a reduction in the risk of death, HR 0.73 (95% CI: 0.68, 0.80, p<.0001). Conclusions: For pts with de novo metastatic nccRCC, CRN is associated with improved outcomes. Further analysis regarding the effect of treatment regimens on survival outcomes is warranted and planned. Prospective randomized trials in the modern treatment era are needed to further assess the timing and impact of CRN on outcomes in pts with metastatic nccRCC. [Table: see text]
Histopathological upstage, recurrence, and survival in a population-based cohort of surgically treated patients with clinical T1b renal cell carcinoma.
Authors: Lundstam Sven , Karlsson Rosenblad Andreas , Ljungberg Borje 
Published: March 2023

731 Background: T1 renal cell carcinoma (RCC) is considered to have a low malignant potential. Partial nephrectomy (PN) is recommended for nephron sparing whenever technically feasible also for T1b RCC. Despite a favorable prognosis there remains a risk for upstaging and recurrence, and the place for PN in clinical T1b tumors is questionable. Therefore, we have characterized these variables and overall survival (OS) in a real-world population-based cohort of patients with clinical T1b RCC. Methods: Patients without metastases registered in the National Swedish Kidney Cancer Register (99% of RCCs diagnosed in Sweden) 2005-2014 with clinical T1b (> 4-7 cm), surgically treated and with a follow-up of ≥ 5 years were included. Results: There were 2137 patients (1300 males, 837 females) with a mean age of 66 years; 82% had clear cell (ccRCC), 11% papillary (pRCC) and 6% chromophobe (chRCC) RCC. Radical nephrectomy (RN) was performed in 1836 patients and PN in 301 patients. After histopathological examination 435 (20%) were upstaged to pathological (p) T3: 21% of ccRCCs, 13% of pRCC and 20% of chRCCs. Recurrent disease after ≥ 5-years follow-up was diagnosed in 127 (29%) pT3 patients and in 238 (14%) with pT1b, 322 (18%) in ccRCC, 127 (11%) in pRCC and 6(5%) in chRCC. Lung metastases occurred in 52% of patients with recurrencies and 144 (39%) of these had two or more metastatic sites. Patients with pT3RCC had a 67% five-year OS compared to 83% in pT1b patients (Log-rank test, p<0.001). Regardless of other factors, patients treated with PN had a higher 5-year OS of 86% compared to 79% in patients treated with RN (Log-rank test, p=0.006). In multivariable analyses, lower age, female sex, smaller tumors, N0, pRCC and chRCC, and pT1b stage were significantly associated with longer survival. A hazard ratio of 0.93 [95% CI 0.65-1.32] for PN indicated that PN was non-inferior to the treatment with RN in patients with clinical T1bRCC. Conclusions: Clinical T1bRCC is a malignant disease with risk for upstaging and tumor recurrence. Nonetheless, the results indicate that PN is non-inferior to the treatment with RN in clinical T1bRCC and support the recommendation to offer PN also in these patients.
Efficacy of systemic therapy following [177Lu] Lu-PSMA in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kostos Louise Kathleen , Lai William Yu Ching , Lambroglou Peter , Medhurst Elizabeth , Buteau James Patrick , Sandhu Shahneen , Tran Ben , Spain Lavinia Anne , Conduit Ciara , Wallace Roslyn , Alipour Ramin , Akhurst Timothy J. , Kong Grace , Cardin Anthony , Saghebi Javad , Ravi Kumar Aravind , Hofman Michael S , Azad Arun 
Published: March 2023

77 Background: [177Lu]Lu-PSMA (LuPSMA) is currently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Little is known about the efficacy of treatment in pts with subsequent progression after LuPSMA. In this single-centre retrospective analysis, we evaluated efficacy of first subsequent therapy following LuPSMA. Methods: 234 mCRPC pts who received LuPSMA at the Peter MacCallum Cancer Centre from 2015-2022 were analysed. Pts were excluded if they did not receive any subsequent treatment (n=136), if they received the initial course of LuPSMA in combination with another therapy (n=10), or if insufficient follow-up data were available (n=15).Retreatment withLuPSMA was considered a subsequent line of therapy. Data collected included 50% PSA response rate (PSA-RR), PSA-progression free survival (PSA-PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier analysis. Results: Of 73 evaluable pts, 32 were retreated with LuPSMA (median 2 cycles); and 41 commenced a new line of systemic therapy. In the LuPSMA retreatment group, the PSA-RR was 44%, median PSA-PFS was 3.8 months and median OS 14.8 months. In pts who changed to a new line of treatment, cabazitaxel was the most commonly prescribed therapy (n=25), followed by docetaxel (n=7), and single-agent carboplatin (n=4), in addition to carboplatin/etoposide, mitoxantrone, olaparib, capecitabine and a clinical trial (n=1 for each). PSA-RR was 12%, median PSA-PFS was 3.5 months and median OS 6.6 months. Conclusions: This retrospective data demonstrates that retreatment with LuPSMA is associated with benefit, though this is reduced compared to initial treatment. In our cohort of pts who commenced a new line of therapy, most were not suitable for retreatment with LuPSMA, potentially reflecting de-differentiated and more aggressive disease phenotypes. In those not suitable for LuPSMA retreatment, other systemic therapy appears to have limited benefit, highlighting the lack of effective salvage options and raising questions about treatment sequencing. [Table: see text]
Characterization and survival benefit of drugs approved for metastatic prostate cancer.
Authors: Benjamin David Joseph , Rezazadeh Arash 
Published: March 2023

81 Background: The treatment landscape of metastatic prostate cancer (mPC) drastically changed with the approval of chemotherapy (docetaxel) in 2004, and novel hormonal therapy (NHT) abiraterone in 2011. Since then, several other therapies have been approved in the metastatic castrate-sensitive (mCSPC) and -resistant (mCRPC) settings. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for prostate cancer from 2004 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2004 and 2022, there were 14 drug (single or combination) approvals for mPC. Most approvals (81.3%) were granted through regular approval. Average PFS benefit for mCSPC was 4.8 months and average OS benefit for mCSPC was not reached in ongoing trials. Average PFS benefit for mCRPC was 3.7 months (range 1.9-5.4) and average OS benefit for mCRPC was 3.67 months. Conclusions: Despite 14 drug (single or combination) approvals for mPC since 2004, the improvements in average PFS and OS were modest in both castrate-sensitive and -resistant settings. OS data for several NHTs continues to mature, and may alter average OS benefits once median OS is reached. Nonetheless, continued drug development for mPC is warranted. [Table: see text]
Association of intermittent or continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with nonmetastatic prostate cancer.
Authors: Morgans Alicia K. , Ebrahimi Ramin , Bobbili Priyanka J. , Nwokeji Esmond , Gandhi Raj , Desai Raj , Zhang Adina , Ryan Michael , Hanson Sarah , Duh Mei Sheng , Preston Mark A. 
Published: March 2023

83 Background: Evidence on risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) in patients (pts) with nonmetastatic prostate cancer (nmPC) is mixed. This real-world study examined these risks in pts with nmPC receiving iADT or cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with nmPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, and who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment-weighted Cox regression models estimated the adjusted hazard ratio (aHR) of the outcomes. Subgroup analyses examined pts by CVD history. A sensitivity analysis restricted the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 10,655 pts were included; 2095 (20%) received iADT and 8560 (80%) cADT; 63% of iADT pts and 66% of cADT pts had baseline CVD history. Median follow-up was 44 and 48 months and time on ADT (excluding gaps for iADT pts) was 23 and 17 months for the iADT and cADT cohorts, respectively. In adjusted analyses, pts receiving cADT had a lower risk of MACE vs iADT. No difference in risk of endocrine/metabolic events was observed. Results for MACE were similar in pts with prior CVD history; however, there was no difference in risk of MACE in those without CVD history. Sensitivity analysis results for MACESA were similar to the main results. Conclusions: Pts with nmPC receiving cADT had a lower risk of MACE, and no difference in risk of endocrine/metabolic events, compared with iADT. There was no difference in risk of MACE in pts without a prior history of CVD. [Table: see text]
First look at the baseline characteristics of participants in IRONMAN, the international registry for men with advanced prostate cancer.
Authors: Mucci Lorelei A , Vinson Jake , Gerke Travis A. , Hyslop Terry , Howard Lauren , Dreicer Robert , Rathkopf Dana E. , Chi Kim N. , Esteban Emilio , Enting Deborah , Bjartell Anders , Tagawa Scott T. , Nanus David M. , Ong Michael , Barata Pedro C. , Hotte Sebastien J. , Grant Marie , Villanti Paul , Kantoff Philip W. , George Daniel J. 
Published: March 2023

85 Background: Patients with advanced prostate cancer (APC) experience high mortality and increasingly deteriorating quality of life due to the disease itself and the therapies they are treated with. Despite recent advances in the treatment landscape, disparities in outcomes have only worsened. There is an urgent need to identify disparities in treatment patterns and outcomes in advanced disease in diverse populations. The International Registry for Men with Advanced Prostate Cancer (IRONMAN) is uniquely equipped to address these needs. Methods: IRONMAN is a prospective registry initiated in 2017 with a planned accrual of 5000 patients with newly diagnosed metastatic hormone-sensitive (mHSPC) and castration-resistant (CRPC) prostate cancer. As of 10/11/2022, 2890 patients have enrolled from 14 countries at 113 sites, with 2 more countries pending activation. Sites were selected to create a diverse cohort across race/ethnicity, geography and socioeconomic factors. Patients are followed for survival, clinically significant adverse events, changes in cancer treatments, biomarkers, and Patient-Reported Outcome Measures (PROMs). This analysis includes patients with treatment data reported from Baseline through Month 3 as of October 2021 (n=1931, 9 countries). Results: Patients were recruited across the USA (N=799), Australia (146), Canada (282), Spain (238), England (205), and all other countries (261). 61% had mHSPC, and 39% had CRPC at enrollment with little variation in these proportions across countries. Based on self-report, 87% of patients were White, 9% Black, 4% reported other races/ethnicities, and 353 did not report race. In the US, 18% of patients were Black. Globally, 22% of respondents reported current or former military service. The most common first systemic therapy on study was androgen receptor signaling inhibitors (ARSI) +/- ADT in 1039 (54%), ranging between 12% and 66% of patients by country. 19% received chemotherapy +/- ADT and 18% received ADT alone. ARSI use varied by age, race, and metastatic disease site. Conclusions: Our preliminary results highlight our ability to successfully enroll and follow APC patients from 113 sites across 14 countries, with 2890 of 5000 planned patients enrolled. Accrual is greater in de novo mHSPC patients than anticipated. Differences in treatment patterns are already emerging, with more ARSI use in the mHSPC setting in North America than other regions. Our data demonstrates that IRONMAN participating sites are rapidly adopting new treatment recommendations into clinical practice of real-world patients.