bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimating the Causal Effect of Filter Ventilation Levels in Cigarettes on Past 30-Day Smoking
Authors: Eaton Anne A , Hatsukami Dorothy K , Stepanov Irina , Shields Peter G , Carroll Dana Mowls 
Published: August 2024

Abstract

Introduction
Cigarettes with higher levels of filter ventilation (FV) are misperceived as less harmful and may be more appealing to consumers. Setting limits on FV has been considered as a policy, but a better understanding of any potential unintended consequences is needed.

Methods
FV (0.2%–61.1%) measured for 114 subbrands was merged with Wave 1 (2012–2013) of the Population Assessment of Tobacco Use and Health (PATH) data, restricted to adults 25+ years of age who smoked daily, and examined by quartiles. Inverse probability of exposure weights were used to estimate the causal effect of FV on past 30-day smoking at subsequent waves while accounting for potential confounders including demographics, menthol, heaviness of smoking, and past quit attempts.

Results
Compared to those in the first (lowest) quartile of FV, those in the second, third, and fourth quartiles had 1.02 (95% confidence interval = 0.57, 1.82), 0.86 (0.42, 1.73), and 1.52 (0.90, 2.56) times the odds of no past 30-day smoking at Wave 2 (approximately 1 year later, p = .163), and 1.28 (0.80, 2.07), 1.11 (0.67, 1.83), and 1.65 (1.01, 1.24) times the odds of no past 30-day smoking at Wave 4 (3 years later, p = .238).

Conclusions
This observational study found no strong evidence of a causal effect of FV on past 30-day smoking at approximately 1 and 3 years follow-up. However, our effect size estimates were not precise and thus an increase in the ability to quit smoking due to higher FV levels cannot be ruled out.

Implications
Setting a maximum limit on FV in cigarettes could address the misperception that highly ventilated cigarettes are less harmful and the link between FV and lung adenocarcinoma. It is important to understand whether such a policy would have unintended consequences on longer-term smoking behavior. We found no strong evidence that FV affects past 30-day smoking 1–3 years later, but could not rule out the possibility that higher FV increases cessation rates. If future studies confirm these epidemiologic findings, this could mean that setting a limit on FV would not lead to reductions in the ability to quit smoking.
11 Tumor evolution of brain-specific tropism in metastatic renal cell carcinoma
Authors: Elias Roy 
Published: August 2024

Abstract

Background
Brain metastases (BMets) pose a clinical challenge in the management of patients (pts) with metastatic renal cell carcinoma (RCC), leading to significant morbidity and mortality. Herein, we sought to comprehensively characterize the molecular landscape of BMets in RCC.

Methods
We performed panel-based DNA (DNAseq) and whole transcriptome (RNAseq) sequencing to analyze BMets, matched non-Brain metastases (nBMets), and matched primary renal tumors (PRT) from pts who underwent surgical resection of BMet(s) from RCC at our institution.

Results
Our cohort consisted of 95 samples from 53 patients (BMets = 54, nBMets = 14, PRT = 27) with clear cell histology in 45 pts (84.9%). DNAseq was available on 85 samples (50 pts). Patient-level mutations revealed recurring mutations in VHL (18 pts, 36%), TP53 (n = 12 pts, 24%), PBRM1 (12 pts, 24%), SETD2 (12 pts, 24%), and BAP1 (4 pts, 8%). Mutations within the MTOR signaling pathway were enriched, with 25 pts (50%) having at least one mutation in PTEN (12 pts, 24%), TSC1 (4 pts, 8%), TSC2 (5 pts, 10%), or MTOR (9 pts, 18%). Copy number analyses revealed frequent deletions in chr14q21 (34 pts, 68%) and chr9p21 (35 pts, 70%) and gains in chr20q13 (n = 31, 62%) and chr7p15 (n = 31, 62%).
At the sample-level, PTEN mutations were more common in BMets (11 pts, 22.9%) vs nBMets (0 pts) and PRTs (3 pts, 12%, p = 0.124), as were deletions in chr13q22 (BMets = 13pts [26.5%], nBMet = 1pts [8.3%], PRT = 1 [4%]; p = 0.036) and gains in chr20q13 (BMets = 30pts [61.2%], nBMet = 4pts [33.3%], PRT = 8 [32%]; p = 0.03). Deletions in chr9p21 were enriched in BMets (32, 65.3%) and nBMets (8, 66.7%) relative to PRTs (7, 28%, p = 0.006), whereas other copy number alterations and somatic mutations exhibited similar proportions across specimen sites.
Differential expression analysis performed on 86 samples (51 pts) identified 806 differentially expressed genes (DEGs) between BMets and PRT (adjusted [adj.] p &lt; 0.05) and 399 DEGs between BMet and nBMets (adj. p &lt; 0.05). Gene set enrichment analysis of MSigDB Hallmark gene sets revealed upregulation of MTORC1 signaling, glycolysis, and MYC targets in BMets comparted to PRT and nBMETs (adj. p &lt;0.0001). In contrast, immune-related gene sets, such as interferon-alpha, interferon-gamma, and tumor necrosis factor-alpha, were enriched in PRT relative to BMets (adj. p &lt;0.0001), but not nBMETs (adj. p &gt; 0.05). CIBERSORT cellular deconvolution analysis comparing BMets with PRT revealed decreased proportions of M1 macrophages (p = 0.0003) and CD8+ T-cells (p = 0.0106), but an increased proportion of M2 macrophages (p = 0.0009).

Conclusions
RCC with brain metastases are characterized by distinct copy number alterations, enrichment of MTOR pathway mutations, MTOR pathway hyperactivation, and an immunosuppressive tumor milieu. These findings may hold therapeutic implications of MTOR pathway inhibition and immune modulators in treating RCC BMets.
Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)
Authors: Serzan Michael 
Published: August 2024

Abstract

Background
First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy.

Methods
ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has &gt; 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR &gt; 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806.

Results
24 Applying genomic analysis to refine unclassified renal cell carcinoma
Authors: Yekeduz Emre , Braun David A , Chehade Razane El Hajj , Eid Marc , Labaki Chris , Machaalani Marc , Nassar Amin , Nawfal Rashad , Saad Eddy , Saliby Renee Maria , Semaan Karl , Sun Maxine , Hirsch Michelle S , Ürün Yüksel , Zarif Talal El , Choueiri Toni K 
Published: August 2024

Abstract

Background
Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets.

Methods
The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate.

Results
Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P&gt;0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q&lt;0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2 (15.8%), TP53 (13.9%), TERT (13.4%), and VHL (11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q&lt;0.001), chRCC (0.7%, Q&lt;0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2 (n=29) than in those with unaltered NF2 (n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q&lt;0.001), followed by VHL and BAP1 (Q&lt;0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%).

Conclusions
uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2 alterations were frequent and correlated with a poorer prognosis.
40 Preclinical evaluation of a novel dendritic cell vaccine for kidney cancer
Authors: Gau David , Taylor Jennifer , Storkus Walter , Roy Partha 
Published: August 2024

Abstract

Background
Dendritic cell (DC)-based vaccines have been previously shown to promote therapeutic T cell responses in both preclinical tumor models and in cancer patients, where extended patient overall survival has been noted in many cases. The goal of the present study is to develop a novel DC-based vaccine as an effective immuno-oncology (IO) agent for the prevention/treatment of kidney cancer. We previously demonstrated that actin-binding protein profilin1 (Pfn1) is overexpressed in tumor-associated vascular endothelial cells (ECs), where it may serve as a prognostic factor in human clear cell renal cancer (ccRCC). We further established a direct causal relationship between EC Pfn1 dysregulation, immune microenvironment alterations, and tumor progression in mouse models of RCC. The current work specifically explores whether Pfn1-targeted DC-based vaccines are effective in preventing orthotopic RCC in mice.

Methods
To generate Pfn1-targeted DC vaccines, we harvested and matured DCs from Balb/C mouse bone marrow-derived precursor cells in cultures containing rmIL4 and rmGM-CSF. DCs loaded with individual Pfn1 synthetic peptides (these sequences were identified using three MHC class I/II peptide-binding algorithms) were injected into syngeneic mice on days 0, 7 and 14. Spleens were harvested from immunized mice on day 21 to isolate CD4+ and CD8+ T cells, with T cells then stimulated with unmanipulated DCs or DCs pulsed with individual immunizing peptides to detect specific T cell activation, as measured by IFN-gamma release quantitated by ELISA. Tissue histology was performed to assess immune-related adverse events (iRAE) in vaccinated mice as a safety index. For cancer studies, Balb/c mice were immunized with DCs loaded with pooled Pfn1 peptides a few days prior to establishing either subcutaneous or orthotopic RCC tumors. Tumor-bearing mice were subjected to an identical booster vaccine prior one week later in advance of euthanasia and study end-point analyses.

Results
Our studies show that vaccination of Balb/c mice with DCs pulsed with Pfn1 peptides elicit specific CD4+ and/or CD8+ T cell responses without promoting irAEs. When applied in the prophylactic setting, DC-Pfn1 peptide vaccines substantially slow the growth of subcutaneous RCC tumors. In support of these findings, we have also developed preliminary data supporting the therapeutic effects of DC/Pfn1-peptide vaccines in a murine orthotopic model of RCC.

Conclusions
In summary, our studies provide first evidence for Pfn1-targeted IO agent in the cancer setting. Given that the survival benefit for dual immune-check point inhibitors (ICI)/anti-angiogenic therapy remains modest and is limited to a small minority of ccRCC patients, Pfn1-targeted vaccines could represent a novel therapeutic agent for improved patient outcomes when applied alone or in combination with in-clinic ICI agents.
DOD CDMRP Funding: yes
47 Generation and Characterization of Ex Vivo Expanded Tumor-Infiltrating Lymphocytes from Renal Cell Carcinoma Tumors for Adoptive Cell Therapy
Authors: Einstein David 
Published: August 2024

Abstract

Background
Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance anti-tumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC.

Methods
Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion.

Results
Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel.
Figure: Assessment of tumor immune microenvironment (TIME) via multiplex immunofluorescence (IF). Cases that failed REP are indicated in red. (A) Representative image at 60x magnification, fluorophore colors as indicated. (B) Density of tumor-infiltrating CD8+ and FoxP3+ cells. (C) Expression of co-inhibitory exhaustion markers as a percentage of total CD8+ cells. (D) Expression of PD-1 in FoxP3+ cells. (E) Comparison of tissue TIME (dots) with TIL product post-REP (open circles) exhaustion profiles as a percentage of total CD8+ cells.

Conclusions
The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion.
50 National trends in the surgical management of renal cell carcinoma in Germany
Authors: Steiner Clara , Fahlenbrach Claus , Gilfrich Christian , Günster Christian , Jeschke Elke , Popken Gralf , Roigas Jan , Gratzke Christian , Stolzenburg Jens-Uwe , Leicht Hanna 
Published: August 2024

Abstract

Background
The incidence of RCC is increasing worldwide. For most patients with localized RCC, surgery remains the preferred treatment option. We aimed to investigate whether international trends towards minimally invasive procedures and nephron-sparing surgery are reflected in Germany.

Methods
Pseudonymized inpatient billing data from the AOK (Allgemeine Ortskrankenkassen), a non-profit oriented health insurance organization in Germany, was used for the conduct of the study. A total of 43,936 RCC cases were identified in which either a partial nephrectomy (PN, n = 20,030) or radical nephrectomy (RN, n = 21,906) was performed between 2012 and 2021. The proportions of different surgical procedures over time, as well as mortality (90 days), transfusion rate, reinterventions, and general postsurgical complications (30 days), were evaluated. Due to the use of pseudonymized data, no ethics vote was required.

Results
During the period of observation, there was a significant shift from RN to PN, with an increase in the proportion of PN among all procedures from 41.0% (1,918/4,684) in 2012 to 57.4% (2,274/3,960) in 2021 (p &lt;0.001). Open surgery decreased for PN and RN but still accounted for the majority of all procedures (2021: 53.2% of PN and 65% of RN). Mortality was higher among patients with RN compared to PN (in hospital: 1.9% vs. 0.6%, 90 days: 4.7% vs. 1.2%). While general complication rates were similar (19.4% after PN versus 20.4% after RN), the reintervention rate was slightly higher after PN at 10.7% than after RN at 7.9%. Transfusion rates decreased significantly in several subgroups, favoring PN and minimally invasive approaches. Open surgical procedures were associated with higher unadjusted complication rates.

Conclusions
Despite shifts in favor of nephron-sparing surgery and minimally invasive surgery during the study period, open surgery remained the dominant surgical option for the treatment of renal cell carcinoma in Germany as of 2021. The adoption of laparoscopic and robotic-assisted techniques appears to reduce overall perioperative morbidity and consequently improve the quality of care in Germany. Further studies are required to examine patient level trends between type of surgical procedure, complication rates, and oncologic outcomes. Optimizing the assessment of the quality of care would enable further improvement of the quality itself.
59 Risk Factors of Immune Related Adverse Events in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors
Authors: Chehade Razane El Hajj , Semaan Karl , Saliby Renee Maria , Saad Eddy , Nawfal Rashad , Machaalani Marc , Eid Marc , Yekeduz Emre , Steiner Clara , Sun Maxine , Kaymakcalan Marina , Choueiri Toni K 
Published: August 2024

Abstract

Background
Immune checkpoint inhibitor (ICI) based combinations have become the standard of care for first-line treatment in patients with metastatic renal cell carcinoma (mRCC). However, ICI can be responsible for immune-related adverse events (irAEs). Herein, we aimed to identify risk factors of immune related adverse events (irAEs) in patients treated with current first line (1L) combination of ICIs (ICI+ICI) or ICI with vascular endothelial growth factor (VEGF) targeted therapy (ICI+VEGF).

Methods
Data was collected retrospectively from patients treated for mRCC at Dana-Farber Cancer Institute, either receiving dual ICI or ICI+VEGF as 1L treatment regimen. Patients were categorized into two groups: those who developed grade ≥ 2 irAEs and those with grade 1 or no AEs. Time to toxicity (TT) was defined as the primary outcome. Univariate Cox regression analysis was initially conducted to identify potential predictive factors associated with irAEs. Subsequently, significant variables related to treatment adverse events were included in a multivariate Cox regression analysis with adjustments for multiple baseline factors.

Results
Among the 158 patients included, 122 (77.2%) were male, and 36 (22.8%) were female. Median age of patients at the treatment start date of therapy was 61 years (Q1-Q3: 62-69). A total of 57 (36.1%) patients developed grade ≥ 2 irAEs. The median follow-up of patients was 25.7 months.
Univariate analysis showed that diabetes, male sex, and ccRCC may indeed influence the development of irAEs with a trend towards significance. However, thrombocytosis could be a protective factor against developing irAEs (p &lt;0.05, Table).
Upon multivariate analysis, only ccRCC remained significant as a risk factor for irAEs compared to other subtypes, with a HR of 2.93 (95% CI:1.05-8.18, p = 0.04) (Table).
Table: Cox regression analysis for assessment of risk factors associated with irAEs

Conclusions
In this real-world study, we investigated potential clinical risk factors at baseline related to irAEs in patients with mRCC undergoing ICI-combination therapy. ccRCC histology was significantly associated with a higher risk of developing irAEs compared to other RCC subtypes. The retrospective design and the number of patients could be potential limitations of our findings.
Ozone Priming Enhanced Low Temperature Tolerance of Wheat (Triticum Aestivum L.) based on Physiological, Biochemical and Transcriptional Analyses
Authors: Dai Bing , Wang Hongyan , Li Weiqiang , Zhang Peng , Liu Tianhao , Li Xiangnan 
Published: August 2024

Abstract
Low temperature significantly inhibits plant growth in wheat (Triticum aestivum L.), prompting the exploration of effective strategies to mitigate low temperature stress. Several priming methods enhance low temperature stress tolerance; however, the role of ozone priming remains unclear in wheat. Here we found ozone priming alleviated low temperature stress in wheat. Transcriptome analysis showed that ozone priming positively modulated the ‘photosynthesis-antenna proteins’ pathway in wheat under low temperature. This was confirmed by the results of ozone-primed plants, which had higher trapped energy flux and electron transport flux per reaction, and less damage to chloroplasts than non-primed plants under low temperature. Ozone priming also mitigated the overstimulation of glutathione metabolism and induced the accumulation of total ascorbic acid and glutathione, as well as maintaining redox homeostasis in wheat under low temperature. Moreover, gene expressions and enzyme activities in glycolysis pathways were upregulated in ozone priming compared with non-priming after the low temperature stress. Furthermore, exogenous antibiotics significantly increased low temperature tolerance, which further proved that the inhibition of ribosome biogenesis by ozone priming was involved in low temperature tolerance in wheat. In conclusion, ozone priming enhanced wheat’s low temperature tolerance through promoting light-harvesting capacity, redox homeostasis and carbohydrate metabolism, as well as inhibiting ribosome biogenesis.