tbuckley/cabot-search huggingface dataset:
Anlotinib combined with sintilimab as first-line treatment in patients with advanced non-clear cell renal cell carcinoma (nccRR): Preliminary results from an exploratory prospective multicentre clinical study.
Authors: Pei Dong, Wensu Wei, Lijuan Jiang, Zhiling Zhang, Deling Wang, Yulu Peng, Tingxuan Huang, Xi Zhong, Shengjie Guo, Hui Han, Xiuyu Cai, Fangjian Zhou
Journal: Journal of Clinical Oncology (2024)

4544 Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for approximately 25% of all kidney cancers, however, the effect of systemic chemotherapy is limited. We report the first results of a single-arm, phase 2 study (NCT05220267) evaluating the efficacy and safety of anlotinib (a multi-target tyrosine kinase inhibitor) combined with sintilimab (a monoclonal antibody against programmed cell death protein 1) as first-line treatment in patients with advanced nccRCC. Methods: Patients with histologically confirmed advanced nccRCC and measurable disease per RECIST v1.1 who had not previously received systemic therapy were received anlotinib (12 mg qd, d1-14, repeated every 21 days) plus sintilimab (200 mg IV Q3W) till disease progression or intolerant toxicity. The primary endpoint is progression-free survival (PFS); secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From April 2022 to December 2023, 43 patients were enrolled with a median age of 43 years (range: 18-79), 10 (23.3%) had papillary histology, 10 (23.3%) had FH-RCC histology, 8 (18.6%) had TFE3-RCC histology and 15 (34.9%) were unclassified. Among these participants, 34 patients were evaluable. 62.8% were IMDC intermediate- or poor-risk, 74.4% had prior nephrectomy and 100% had synchronous metastatic disease. ORR and DCR were 52.9%(95%CI 0.35-0.70)and 94.1%(95%CI 0.80-0.99), respectively.≥1 and &lt;1 Combined Positive Score of PD-L1 expression were observed in 50.0% (17/34) and 32.4% (11/34) patients respectively, and the ORR was 52.9% (95%CI: 0.278-0.770) and 45.5% (95%CI: 0.167-0.766) in the two groups. The median time of the first response was 3.7 months (range, 3.3-9.5). As of January 7, 2024, median follow-up time was 8.5m (95%CI 4.8-12.3). The median PFS was 15.1m (95%CI 13.2-15.9). Treatment-related grade 3/4 adverse events were observed in 20.9% (9/43) of the patients, encompassed hyponatremia (3 patients, 7%), proteinuria (1 patients, 2%), anemia (1 patients, 2%), Hand-foot syndrome (4 patients, 9.1%). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: Our results showed promising efficacy and acceptable toxicity of anlotinib plus sintilimab for patients with advanced nccRCC. Complete results are awaited in 2024 after follow-up completion of the entire cohort. Clinical trial information: NCT05220267 .
Analyzing disparities in socioeconomic factors, clinical characteristics, and outcomes in bladder cancer: Insights from the National Cancer Database (NCDB).
Authors: Faran Polani, Min Woo Hwang, Eun-mi Yu, Hongkun Wang, Jeanny B. Aragon-Ching
Journal: Journal of Clinical Oncology (2024)

4572 Background: Social determinants of health can influence mortality in bladder cancer. We sought to understand the trends and survival differences for urothelial cancer (UC) and non-urothelial cancer (nUC) based on demographic, socioeconomic, clinical, and treatment from the NCDB. Methods: Using the NCDB database with patient-level data extraction from 2004 to 2020, we sought to identify the socioeconomic differences, clinical characteristics and examine survival trends for both UC and nUC bladder cancer. Results: Majority of UC patients (pts) were M (555107, 75.6%) and 178733 were F; nUC pts had 14296 M and 8835 F, median age was 72 years. 669,669 (or 91.3%) of UC pts were White (W), 5.4% (39444) were Black (B) and nUC pts had 19771 (85.5%) W and 2492 (10.8%) B. 41.2% of UC pts were treated at a Comprehensive Community Cancer Program (CCCP) followed by 28.3% at an academic/research program (ARP) with 20.7% at an integrated network cancer program (INCP) compared to nUC pts at 37.5%, 34.3% and 19.2%, respectively. Most UC pts (65.6%) had Medicare followed by 26.9% with private insurance and 3.2% with Medicaid. Distribution of stage at diagnosis for UC pts were: Stage 0 at 36.9%, Stage I at 16.3%, Stage II &amp; III at 11.8% and Stage IV at 3.6%. While most (51.74%) of F UC pts had stage I, only 12.81% of F nUC had stage I. Majority had Charlson-Deyo Score (CDS) of 0 at 512237 (69.8%). Median Overall survival (mOS) in UC for M was 89.26 months (mos) (CI 88.8-89.76) and for F it was 94.88 mos (CI 93.83-95.93), Log-rank p=0.0011; worse for B = 73.03 mos (CI 71.03 – 74.84) vs W = 90.38 mos (CI 89.95-90.81), Log-rank p&lt;0.0001; mOS was highest for ARP at 96.46 mos (CI 95.54-97.45); CDS of 0 at 108.29 mos (CI 107.66-108.85); private insurance at 185.79 mos (CI 183.98-188.16); mOS for nUC was better for M at 15.64 (CI, 15.05 -16.28) vs F at 12.68 (CI, 12.02, 13.31), Log-rank p&lt;0.001. mOS for metastatic involvement for bone: UC: 5.03 (CI, 4.8, 5.39) vs nUC: 5.42 (4.4, 6.34), Log-rank p=0.2007; brain: U: 3.61 (CI 2.99, 4.3) vs nUC: 5.06 (2.5, 7.13); Log-rank p=0.5765; lung: U: 5.09 (CI, 4.76, 5.39) vs nUC: 4.8 (3.68, 5.78); Log-rank p=0.2163; liver: U: 3.32 (CI,3.06, 3.61) vs nUC: 5.42 (CI, 4.11, 6.44); Log-rank p=0.0009; LN: U: 7.1 (CI, 6.6, 7.56) vs nUC: 6.34 (5.36, 6.9); Logrank p=0.0007; Treatment using surgery, radiation, chemotherapy and immunotherapy all showed improvement in U vs nUC (all Log-rank p&lt;0.0001). Conclusions: Women had better survival than men in UC but not in nUC. Factors including lower stages, Whites, private insurance, better CDS scores, treatment at academic/research facility, and lymph node metastases all showed improved survival. These data highlight the importance of bridging the gap between socioeconomic differences to improve outcomes for UC and nUC pts.
Age and other criteria influencing nontreatment of patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC): Results of a physician survey in five European countries (Eu5).
Authors: Shilpa Gupta, Thomas Powles, Mairead Kearney, Laura Panattoni, Natalie Land, Thomas Flottemesch, Patrick Sullivan, Melissa Kirker, Murtuza Bharmal, Silke Guenther, Nuno Costa, Enrique Grande
Journal: Journal of Clinical Oncology (2024)

4570 Background: Real-world studies have shown that a majority of pts with la/mUC do not receive first-line (1L) systemic therapy (tx), despite guideline recommendations. This cross-sectional study assessed the criteria that Eu5 physicians consider when making decisions about 1L tx for pts with la/mUC. Methods: A quantitative online survey of Eu5 physicians was performed in Aug-Sep 2022. Respondents answered questions related to demographics, practice patterns, and criteria considered in 1L decision-making. Descriptive statistics were used to analyze demographics and responses. Logistic regression was used to analyze physician characteristics associated with reporting no age threshold vs any age threshold when defining platinum ineligibility. Results: 503 physicians (69% oncologists and 31% urologists) completed the quota-based survey. Most respondents had been in practice for &gt;10 years (69%) and treated 5-19 pts with la/mUC per month (58%) in public teaching hospitals (40%), public nonteaching hospitals (24%), and private hospitals (20%). Physicians estimated that they do not prescribe 1L tx for ≈25% of their pts. The majority of physicians selected advanced age (62.0%) and poor performance status (PS; 54.7%) as their top reasons for not prescribing 1L tx, followed by pt refusal (45.9%) and poor renal function (43.1%). Most physicians (78.1%) reported having an age threshold above which they recommend against 1L systemic tx (mean, 74.7 years old [Table]). After adjusting for baseline characteristics, physicians were more likely to have an age threshold if they were from Italy vs Germany (odds ratio [OR] 0.22 [95% CI 0.06-0.73]), practiced in a public nonteaching hospital (OR 0.28 [95% CI 0.10-0.73]) or public/private office settings (OR 0.14 [95% CI 0.03-0.57]) vs private hospital, and if they treated &lt;20 pts/month (2-10 pts: OR 0.36 [95% CI, 0.17-0.74]; 11-19 pts: OR 0.25 [95% CI 0.09-0.62]). Conclusions: 1L systemic tx rates self-reported by Eu5 physicians were higher than those previously published. Many physicians reported having an age threshold for not offering systemic tx, which was relatively low compared with the senior age profile of the la/mUC population. Physicians who reported an explicit age threshold may be inappropriately excluding pts from tx; this could be a driver for systemic tx underutilization in la/mUC. [Table: see text]
Associations of dietary fructose with survival of patients (pts) with metastatic cancer of the urothelium (UC) and renal cell carcinoma (RCC) on immune checkpoint blockade (ICB).
Authors: Anas Badri, Brendan John Guercio, Neha Ratna, David Gavrilov, Nicholina Metzker, Cihan Duzgol, Min Yuen Teo, Ashley M. Regazzi, Lauren Supplice, Samuel A Funt, David H Aggen, Martin H Voss, Marie Isabel Carlo, Neil J. Shah, Robert J. Motzer, Dean F. Bajorin, Jonathan E. Rosenberg, Chung-Han Lee, Ritesh R Kotecha, Gopa Iyer
Journal: Journal of Clinical Oncology (2024)

4571 Background: The gut microbiome is a modifiable determinant of ICB efficacy. Dietary fiber is associated with longer progression-free survival (PFS) on ICB in melanoma and UC, putatively via effects on the gut microbiome. Other dietary factors may also impact ICB efficacy. Fructose promotes adverse health effects and induces ICB resistance in pre-clinical models via upregulation of the antiapoptotic enzyme heme oxygenase-1. Thus, we set out to explore effects of fructose intake on ICB efficacy. Methods: In a retrospective analysis of a prospectively collected cohort, we leveraged dietary data collected with the validated Harvard Willett Food Frequency Questionnaire from pts with advanced UC and RCC initiating ICB at Memorial Sloan Kettering to assess for associations between baseline dietary fructose and PFS and overall survival (OS). Tumor mutational burden (TMB) was estimated via MSK-IMPACT. Associations of fructose with clinical outcomes were evaluated using univariate (UV) and multivariable (MV) Cox proportional hazards regression. Fructose was normalized via log transformation and treated as a continuous variable. MV models adjusted for fiber intake and prior ICB exposure. UC models adjusted for TMB and Bellmunt risk score and RCC models for histology and IMDC score. Results: From 2/2021-6/2022, 88 eligible pts enrolled. Median follow-up was 10.2 and 17.0 months among pts with UC (n = 40) and RCC (n = 48), respectively; 32 RCC pts (67%) were IMDC intermediate/poor risk and 21 UC pts (52%) had visceral metastases. High fructose and fiber intake correlated (rho 0.66). Among UC pts, higher fructose was associated with shorter PFS after adjusting for covariables (Table). In the MV model, high fiber was associated with longer PFS (HR 0.2, 95% CI 0.07-0.62, p = .004). Among RCC pts, fructose was not associated with PFS. Fructose was associated with OS in the RCC UV model, but this association was not statistically significant in the MV model (Table). In an exploratory model for PFS pooling all pts, a test for interaction between fructose intake and disease type (UC vs RCC) showed p = .01. Conclusions: Dietary fructose is associated with shorter PFS in UC pts treated with ICB, but not RCC pts. Discrepant results between UC and RCC require further study and may be attributable to differences in therapy or cancer biology. Our findings provide insights into potentially beneficial dietary interventions. Efforts to characterize effects of fructose on the gut microbiome are ongoing. [Table: see text]
Rewinding the ratchet: rare recombination locally rescues neo-W degeneration and generates plateaus of sex-chromosome divergence
Authors: Thomas Decroly, Roger Vila, Konrad Lohse, Alexander Mackintosh
Journal: Molecular Biology and Evolution (2024)

Natural selection is less efficient in the absence of recombination. As a result, nonrecombining sequences, such as sex chromosomes, tend to degenerate over time. Although the outcomes of recombination arrest are typically observed after many millions of generations, recent neo-sex chromosomes can give insight into the early stages of this process. Here, we investigate the evolution of neo-sex chromosomes in the Spanish marbled white butterfly, Melanargia ines, where a Z-autosome fusion has turned the homologous autosome into a nonrecombining neo-W chromosome. We show that these neo-sex chromosomes are likely limited to the Iberian population of M. ines, and that they arose around the time when this population split from North-African populations, around 1.5 million years ago. Recombination arrest of the neo-W chromosome has led to an excess of premature stop-codons and frame-shift mutations, and reduced gene expression compared to the neo-Z chromosome. Surprisingly, we identified two regions of ∼1 Mb at one end of the neo-W that are both less diverged from the neo-Z and less degraded than the rest of the chromosome, suggesting a history of rare but repeated genetic exchange between the two neo-sex chromosomes. These plateaus of neo-sex chromosome divergence suggest that neo-W degradation can be locally reversed by rare recombination between neo-W and neo-Z chromosomes.
Effect of Apixaban on Clinical Outcomes in Outpatients With COVID-19: The APOLLO Randomized Clinical Trial
Authors: Pedro Gabriel Melo de Barros e Silva, Ariane Vieira Scarlatelli Macedo, Bruna Bronhara, Lucas Petri Damiani, Lilian Mazza Barbosa, Nathália Rodrigues Lopes, Mayra Akimi Suiama, Murillo O. Antunes, Mariana Raquel Gonçalves, Otávio Celso Eluf Gebara, Priscilla de Aquino Martins, Mariana Galvão Ribeiro, João Batista de Moura Xavier de Moraes, Valéria Cristina Resende Aguiar, Alexandre B. Cavalcanti, Regis G. Rosa, Otavio Berwanger, Viviane C. Veiga, Luciano C.P. Azevedo, Eduardo Ramacciotti, Christopher B. Granger, John H. Alexander, Alvaro Avezum, Renato D. Lopes
Journal: Circulation (2024)
Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice
Authors: Diana De Oliveira-Gomes, Parag H. Joshi, Eric D. Peterson, Anand Rohatgi, Amit Khera, Ann Marie Navar
Journal: Circulation (2024)

Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.
Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation
Authors: Zezhong Mou, Yiling Chen, Jinzhong Hu, Yun Hu, Lujia Zou, Xinan Chen, Shenghua Liu, Qiuping Yin, Jian Gong, Shuchen Li, Shanhua Mao, Chenyang Xu, Haowen Jiang
Journal: Acta Pharmaceutica Sinica B (2024)

Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.
Direct factor Xa inhibitors and the risk of cancer and cancer mortality: A Danish population-based cohort study
Authors: Floris Bosch, Erzsébet Horváth-Puhó, Suzanne C. Cannegieter, Nick van Es, Henrik T. Sørensen
Journal: PLoS Medicine (2024)

Background Preclinical animal studies have suggested that myeloid cell–synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. Methods and findings This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. Conclusions In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort.
The ACROBAT 2022 challenge: Automatic registration of breast cancer tissue
Authors: Philippe Weitz, Masi Valkonen, Leslie Solorzano, Circe Carr, Kimmo Kartasalo, Constance Boissin, Sonja Koivukoski, Aino Kuusela, Dusan Rasic, Yanbo Feng, Sandra Sinius Pouplier, Abhinav Sharma, Kajsa Ledesma Eriksson, Stephanie Robertson, Christian Marzahl, Chandler D Gatenbee, Alexander R A Anderson, Marek Wodzinski, Artur Jurgas, Niccolò Marini, Manfredo Atzori, Henning Müller, Daniel Budelmann, Nick Weiss, Stefan Heldmann, Johannes Lotz, Jelmer M Wolterink, Bruno De Santi, Abhijeet Patil, Amit Sethi, Satoshi Kondo, Satoshi Kasai, Kousuke Hirasawa, Mahtab Farrokh, Neeraj Kumar, Russell Greiner, Leena Latonen, Anne-Vibeke Laenkholm, Johan Hartman, Pekka Ruusuvuori, Mattias Rantalainen
Journal: Medical Image Analysis (2024)

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results provide a comparison of the performance of current WSI registration methods and guide researchers in selecting and developing methods.
Heat-related risk at Paris 2024: a proposal for classification and review of International Federations policies
Authors: David Bandiera, Sebastien Racinais, Frédéric Garrandes, Paolo Emilio Adami, Stéphane Bermon, Yannis P Pitsiladis, Antonio Tessitore
Journal: British Journal of Sports Medicine (2024)

Several International Federations (IFs) employ specific policies to protect athletes’ health from the danger of heat. Most policies rely on the measurement of thermal indices such as the Wet Bulb Globe Temperature (WBGT) to estimate the risk of heat-related illness. This review summarises the policies implemented by the 32 IFs of the 45 sports included in the Paris 2024 Olympic Games. It provides details into the venue type, measured parameters, used thermal indices, measurement procedures, mitigation strategies and specifies whether the policy is a recommendation or a requirement. Additionally, a categorisation of sports’ heat stress risk is proposed. Among the 15 sports identified as high, very high or extreme risk, one did not have a heat policy, three did not specify any parameter measurement, one relied on water temperature, two on air temperature and relative humidity, seven on WBGT (six measured on-site and one estimated) and one on the Heat Stress Index. However, indices currently used in sports have been developed for soldiers or workers and may not adequately reflect the thermal strain endured by athletes. Notably, they do not account for the athletes’ high metabolic heat production and their level of acclimation. It is, therefore, worthwhile listing the relevance of the thermal indices used by IFs to quantify the risk of heat stress, and in the near future, develop an index adapted to the specific needs of athletes.