tbuckley/cabot-search huggingface dataset:
Trends of stroke-related mortality among patients with cancer in the United States, 1999-2020.
Authors: Roha Saeed Memon, Muhammad Moiz Nasir, Hasan Mushahid, Syed Husain Farhan, Umar Mahmood, Mubashir Mohiuddin, Jawad Ahmed, Rabbia Siddiqi, Muhammad Osama, Syed Ali Farhan, Abdul Ghani Iqbal, Syed Hamza Bin Waqar, Shahid Riaz, Danae M. Hamouda
Journal: Journal of Clinical Oncology (2024)

e24021 Background: Patients with cancer are at an increased risk of stroke and stroke-related mortality via various mechanisms such as hypercoagulability, direct tumor effects, and largely as side effects of treatments. Enhancement of thrombin release from chemotherapy induced release of extracellular vesicles and cell-free DNA, and the use of angiogenesis inhibitors are some of the proposed mechanisms for stroke development in patients with cancer. Despite this, current guidelines lack clarity in identifying patients with cancer as having moderate to high risk of mortality from stroke. Recognizing this complex relationship is pivotal for crafting comprehensive care plans that address the dual challenges of cancer and stroke risks. Hence, our CDC analysis focuses on unraveling mortality trends among patients grappling with both conditions from “1999 to 2020”. Methods: We analyzed national mortality data from the multiple causes of death files in the CDC WONDER database from 1999 to 2020. Age-adjusted mortality rates (AAMRs) per 100,000 people were calculated for the total population, stratified by gender, race, urban/rural metro status, and census region. Annual percent change (APC) was calculated using the Joinpoint regression software. Results: A total of 36,648 stroke-related deaths among patients with cancer occurred between 1999 and 2020. The APC trends are as follows: a major decrease of -6.8 (95% CI: -11.8 to -1.5) from 2002 to 2009, a slight decline of -1.23 (95% CI: -13.8 to 13.2) from 2009 to 2014, a significant decrease of -6.71 (95% CI: -46.2 to 61.7) from 2014 to 2017, and an increase of 2.07 (95% CI: -26.1 to 41.1) from 2017 to 2020. Men consistently showed higher mortality rates compared to women in 1999 (AAMR Men: 1.0 vs Women: 0.63) and 2020 (AAMR Men: 0.94 vs Women: 0.69). Moreover, when stratified by race non-hispanic (NH) Black showed the highest mortality rate, followed by NH Whites, and Hispanics throughout the study period between 1999 (AAMR NH Black: 0.96 vs NH White: 0.75 vs Hispanic: 0.32) and 2020 (AAMR NH Black: 0.85 vs NH White: 0.81 vs Hispanic: 0.53). Rural areas compared to urban areas showed consistently higher mortality rates over the study period. Conclusions: Despite more than a decade-long decline, stroke-related mortality among cancer patients has significantly increased since 2015. Targeted therapy and investigations into the role of social determinants of health may improve care for these patients. Further investigation is warranted to elucidate the mechanisms for the increase in stroke-related mortality among people with cancer, particularly those with the following demographics: Men, Black or African American, and residents of rural areas and Midwestern regions.
Diuretics in pregnancy: Data from the ESC Registry of Pregnancy and Cardiac disease (ROPAC)
Authors: Johanna A. van der Zande, Matthias Greutmann, Daniel Tobler, Karishma P. Ramlakhan, Jerome M. J. Cornette, Magalie Ladouceur, Nicholas Collins, Dawn Adamson, Vijaya P. Paruchuri, Roger Hall, Mark R. Johnson, Jolien W. Roos‐Hesselink
Journal: European Journal of Heart Failure (2024)

Abstract Aims Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in‐utero diuretic exposure. Methods and results The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age &gt;35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2–2.0), other cardiac medication use (OR 5.4, 95% CI 4.2–6.9), signs of heart failure (OR 1.7, 95% CI 1.2–2.2), estimated left ventricular ejection fraction &lt;40% (OR 2.9, 95% CI 2.0–4.2), New York Heart Association class &gt;II (OR 3.4, 95% CI 2.3–5.1), valvular heart disease (OR 6.3, 95% CI 4.7–8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6–5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7–2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0–1.9). Conclusions Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk–benefit ratio on an individual basis to guide clinical decisions.
Candidate molecular alterations associated with potential resistance in <i>KRAS</i> <i>G12D</i> gastrointestinal cancers.
Authors: Khalid Jazieh, Jill Tsai, Sheila R Solomon, Hao Xie
Journal: Journal of Clinical Oncology (2024)

3519 Background: KRAS G12D commonly occurs in pancreatic (PDAC) and colorectal (CRC) cancers. Though developing KRAS G12D inhibitors is pertinent, it is expected that primary and acquired resistance will limit efficacy, similar to those seen with KRAS G12C inhibitors. Here, we assessed the prevalence and outcomes of candidate mutations co-occurring with KRAS G12D in PDAC and CRC using liquid biopsy data. Methods: Patients with advanced CRC and PDAC tested with Guardant360 genomic profiling from 2020 to 2023 (~2500 &amp; 3500 samples) were included. Candidate resistance mutations were determined based on mutations reported following KRAS G12C inhibition. Patients with advanced CRC and PDAC tested with Guardant360 at Mayo Clinic (2016-2023) (1158 &amp; 904 samples) were assessed for overall survival (OS). Patients were divided into three groups: KRAS G12D alone, KRAS G12D with candidate resistance alterations, and KRAS G12D not detected (ND). OS was estimated using Kaplan-Meier method. Cox regression was used for multivariable survival analyses. Results: The Guardant360 database reported KRAS G12D in 16.5% of CRC and 40.2% of PDAC samples. The Table below summarizes the most frequent candidate resistance alterations co-occurring with KRAS G12Dincluding point mutations of KRASand PIK3CAand amplifications of EGFR, KRAS, BRAFand MYC. In the Mayo cohort, 8.9% of CRC and 23.5% of PDAC patients had KRAS G12D. In CRC, those with KRAS G12Dand ≥1 candidate resistance alteration had a significantly lower OS (mOS 18.7m) than KRAS G12D alone (30.9m), and ND (37.3m) ( p=0.004). The presence of concurrent candidate resistance alterations with KRAS G12D remained a poor prognostic factor with HR 2.1 (95% CI: 1.3 – 3.2, p=0.001) after adjusting for age and other patient characteristics. Similarly, in PDAC, those with KRAS G12D and ≥1 resistance mutation had significantly lower OS (mOS 8.1m) than KRAS G12D alone (10.5m) and ND (16.1m) (p&lt;0.0001). In multivariable analyses, both KRAS G12D with candidate resistance alterations (HR 2.1, 95% CI: 1.4-3.3, p&lt;0.001) and G12Dalone (HR 1.6; 1.3–2.0, p&lt;0.001) were poor prognostic factors. Among patients with serial Guardant360, treatment response trended with KRAS G12D variant allele frequency. Conclusions: Circulating tumor DNA testing is a useful tool to reveal candidate molecular alterations linked to potential resistance to KRAS G12D targeting in patients with KRAS G12D gastrointestinal cancers. KRAS G12D with these concurrent molecular alterations is a poor prognostic factor in both PDAC and CRC. [Table: see text]
Fulvestrant and elacestrant utilization on prognostic outcome of patients with HR+ve/HER2-ve MBC.
Authors: Shaheenah S. Dawood, Gema Hernández, Alba Segovia
Journal: Journal of Clinical Oncology (2024)

e13094 Background: OS of pts with HR+ve/HER2-ve MBC has improved with CDK4/6i and endocrine therapy. Fulvestrant (FUL) works post progression on aromatase inhibitors in an endocrine resistant cohort. Ealcestrant (ELA) improves PFS compared to FUL in pts with an ESR1 mutation. This retrospective analysis looks at the trends in use of and associated outcome with FUL and ELA among pts with HR+ve/HER2-ve MBC. Methods: We utilized a federated network of de-identified health data representing approximately 135 million pt lives available through the TriNetX Research Network. We identified 14,387pts with HR+ve/HER2-ve MBC treated with endocrine therapy and CDK4/6i diagnosed between Nov 2018 - Nov 2023. OS was computed using the Kaplan Meier product limit method. Results: Mean age was 66 yrs. 5,736(39.9%) pts received FUL and 143(1%) pts ELA. In 2023 median time to use of FUL was 16m to 18m from metastases and median time to use of ELA decreased with time from 50m to 28m. Among pts who received ELA 65% received CDK4/6i for &gt; 12m, 47% received FUL prior ELA, 7% received FUL after ELA. 5-yr OS of the whole cohort was 56.9%. 5-yr OS among pts who did and did not receive ELA was 85.4% and 60.0% respectively (HR 0.28, 95%CI 0.15-0.49, p&lt;0.0001). 5-yr OS among pts who did and did not receive FUL w/o ELA was 61.5% and 60.9% respectively (HR 0.87, 95% CI 0.81-0.94, p&lt;0.0001). 5-yr OS was 85.4% and 52.4% among pts who received ELA and FUL w/o ELA respectively (HR0.23, 95% CI0.14-0.41, p&lt;0.0001). 5-yr OS was 88.7% and 67.9% among pts who received ELA and FUL w/o ELA respectively for &gt; 3m (HR 0.29, 95% CI 0.05-1.145, p=0.11). Among pts who received CDK4/6i &gt; 12m 5-yr OS was 86.0% and 64.9% among pts who received ELA and FUL w/o ELA respectively (HR 0.36, 95% 0.20-0.67, p = 0.0007). Among pts who received ELA 1-yr OS from the start of ELA was 86.0% and 33.3% among pts who received CDK4/6i&gt;12m and &lt; 12m respectively (p=0.72). Conclusions: To our knowledge this is the first real world data set to show the efficacy of ELA among pts with HR+ve/HER2-ve MBC who had progressed on endocrine therapy and CDK4/6i. Our results show decreasing time to use of ELA with improved outcome compared to FUL especially among pts who received CDK4/6i for &gt; 12m. We continue to collect data among pts who are receiving ELA and expect over 200pts at the time of the presentation.
Blood metabolites–based MCTarg for multi-cancer screening and clinical diagnosis.
Authors: Yan Li, Xinping Xu, Chunyan Zeng, Bei Qing, Li Liu, Guodong Song, Shuqi Yu, Tianqi Shao, Qingyan Wei, He Wen, Junyuan Hu, Wei Zhang, Youxiang Chen, Zhenkun Xia
Journal: Journal of Clinical Oncology (2024)

e15028 Background: Multi-cancer early detection (MCED) tests have emerged as promising tools for reducing cancer-related healthcare costs and mortality. As metabolome is closely linked to the phenotype of bio-individual, metabolomics analysis enables the high throughput investigating of the pathophysiological conditions. Based on metabolomics and machine learning, we developed the Multiple Cancer Target (MCTarg) analysis for multiple cancer screening and diagnosis by a single blood draw. Methods: A total of 1153 individuals (172 healthy participants, 623 patients with lung cancer, gastric cancer, and colorectal cancer, and 358 these organ-related benign disease patients) were enrolled from three independent clinical sites in China. Plasma samples were collected and measured by mass spectrometry (MS)-based platforms (LC-MS polar and lipid). MCTarg was developed with three machine learning modules for three scenarios (community screening for non-healthy individuals, clinical diagnosis for classifying malignant and benign diseases, and tracing tumor of origin). Results: MCTarg exhibited an Area Under the Curve (AUC) of 0.96 with 92.82% sensitivity at 80% specificity to differentiate the non-healthy individuals from healthy controls, and an AUC of 0.86 with 75.41% sensitivity at 79.66% specificity in discriminating multi-cancer from benign diseases. Notably, the classification accuracy for distinguishing between malignant and benign conditions in the colorectal organ was reached 90.74%, with a sensitivity of 83.87% and a specificity of 100%. Furthermore, the overall accuracy for detecting the cancer origin reached 84.78% with an average sensitivity and specificity of 78.08% and 90.7%, respectively. Conclusions: The outstanding results indicated that blood-metabolites-based MCTarg is poised to be a cost-effective, precise, and versatile tool for diagnosing multi-cancer and discriminating tumor of origin. Its potential applications encompass health checkups and supplementary diagnostic scenarios. More deadly cancer types will be extended and the performance of MCTarg will be validated by prospective and population-scale cohorts with longitudinal follow-up.
Concordance between tissue (tumor DNA) and liquid (ctDNA) biopsy next-generation sequencing (NGS) data in detection of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations in breast cancer: A retrospective analysis.
Authors: Neil Vasan, Moumita Chaki, Mona Benrashid, Subir Puri, Smruthy Sivakumar, Ethan Sokol
Journal: Journal of Clinical Oncology (2024)

e15033 Background: In the Phase 3 CAPItello-291 trial (NCT04305496), the addition of capivasertib (a potent, selective pan-AKT inhibitor) to fulvestrant significantly improved progression-free survival in patients with HR+/HER2− advanced breast cancer, especially in those with PIK3CA/AKT1/PTEN-altered tumors identified using tissue biopsy-based FoundationOneCDx. Given the growing utility of circulating tumor DNA (ctDNA) and interest in liquid biopsy-based tests to detect PIK3CA/AKT1/PTEN alterations, we performed a retrospective analytical comparison of FoundationOneCDx and blood-based FoundationOneLiquidCDx NGS data. Methods: We utilized the FoundationCORE database of breast cancer cases profiled during routine clinical care with FoundationOneCDx and/or FoundationOneLiquidCDx (covering the same genomic regions). Analytical comparison of all pathogenic PIK3CA/AKT1/PTEN alterations as well as alterations defined in the CAPItello-291 protocol (CAPItello-291 alterations) was performed in paired data from cases with both tissue and liquid biopsies, sampled within 90 days of each other. Subgroup analysis was conducted based on ctDNA tumor fraction (TF). Data from liquid biopsies were analyzed for co-occurring mutations. Results: CAPItello-291 alterations were detected in 44.9% of 35,730 tissue biopsies and 34.3% of 7056 liquid biopsies profiled from Jan 2017–Jun 2023. In paired NGS data (n=289), the overall positive percent agreement (PPA) for CAPItello-291 alterations across ctDNA TF subgroups was: TF ≥10% (n=99): 92.5%; TF 1–10% (n=66): 97.1%; TF &lt;1% (n=124): 33.9%. The PPA for all PIK3CA/AKT1/PTEN short variants (base substitutions, indels) analyzed was: ctDNA TF ≥10%: PIK3CA, 93.9%; AKT1, 100%; PTEN, 100%, and ctDNA TF 1–10%: PIK3CA, 96.3%; AKT1, 100%; PTEN, 100%. For PTEN biallelic deletions, the PPA was 50% (2/4) in cases with ctDNA TF ≥10%. In liquid biopsies with CAPItello-291 alterations (n=2421), the most frequent co-occurring mutations were in TP53 (49.9%), ESR1 (31.2%), CDH1 (23.7%), NF1 (13.0%), RB1 (12.8%), CHEK2 (12.4%), ATM (11.9%), FGF3 (11.4%), FGF19 (11.0%), and FGF4 (10.5%). Mutations in BRCA1 (2.4%), BRCA2 (4.8%), and PALB2 (1.3%) were also observed. Conclusions: PPA between liquid and tissue biopsy NGS data for the detection of PIK3CA/AKT1/PTEN short variants was high in cases with ctDNA TF ≥1%. Liquid biopsies offer a minimally invasive approach for the detection of some CAPItello-291 alterations. However, limitations posed by ctDNA TF &lt;1% and sample and variant types should be considered. Together, these data can help clinicians make informed decisions regarding suitable diagnostic tests to determine patient eligibility for breast cancer therapies.
Bowel bag sparing in palliative radiotherapy (pRT) of rectal cancer (rCa): Tradeoff between organs at risk (OARs) and use of AI to reduce radiation oncologist (RO) workload.
Authors: Emil Fredén, Johan Knutsson, Rafat Yousif, Albert Siegbahn, Pehr A. Lind
Journal: Journal of Clinical Oncology (2024)

e15615 Background: We retrospectively studied the potential to reduce bowel toxicity after pRT of rCa using a bowel dose (BD) minimization strategy; also its effect on dose to remaining normal tissues (NT) and pelvic bone marrow (PBM). Finally, we studied the use of AI to reduce the RO workload. Methods: 25 consecutive rCa patients (pts) previously treated with pRT were included. Their treatments were planned without consideration to BD. The following OARs were manually segmented retrospectively: Bowel Bag (BB-M) excluding PTV, PBM (PBM-M), and NT defined as the patient contour excluding PTV and BB-M. The AI-Rad Companion software was used to autosegment: Bowel Loops (BL-AI) and PBM (PBM-AI). For the 25 pts, two Pareto optimal treatment plans (5 Gy x 5) were generated with the Monaco treatment planning system. The first plan (Reference) was optimized aiming to limit dose outside the PTV. The second plan (Opt-BB-M) was optimized aiming firstly to limit BB-M dose and secondly to limit NT dose. A third plan (Opt-BL-AI) was generated for the 10 worst-off pts (in terms of BD) aiming instead to limit BL-AI dose. Two volume-at-dose (VD) metrics (V18Gy, V10Gy) were used as endpoints. Endpoint differences (ΔVD-OAR) were tested using one-sided Wilcoxon signed-rank tests. Spearman (rs) and Pearson (r) correlation coefficients were used to study correlation between variables (ΔVD-BB vs. ΔVD-BM, and ΔVD-BB vs. ΔVD-NT). Dice Similarity Coefficient (DCS) was used to compare PBM-M and PBM-AI. Results: After reoptimization, BB-M VD (V18Gy; V10Gy) was lower (p &lt; 0.001; p &lt; 0.001), PBM-M VD was higher (p = 0.002; p &lt; 0.001), and NT VD was higher (p &lt; 0.001; p &lt; 0.001). For BB-M, ΔV18Gy and ΔV10Gy (median, min, max) were (-4, -46, 0) cm 3 and (-33, -254, 0) cm 3 ; for PBM-M: (+2, -4, +56) cm 3 and (+33, -6, +189) cm 3 ; for NT: (+10, -43, +194) cm 3 and (+146, -18, +614) cm 3 . Table 1 presents results for the 10 worst-off pts. Medium/strong correlations were found for ΔV18Gy-BB vs. ΔV18Gy-PBM (rs = -0.72, p &lt; 0.001; r = -0.74, p &lt; 0.001), ΔV10Gy-BB vs. ΔV10Gy-PBM (rs = -0.66, p &lt; 0.001; r = -0.32, p = 0.11), ΔV18Gy-BB vs. ΔV18Gy-NT (rs = -0.74, p &lt; 0.001; r = -0.74, p &lt; 0.001), ΔV10Gy-BB vs. ΔV10Gy-NT (rs = -0.74, p &lt; 0.001; r = -0.51, p = 0.009). The DSC (median, min, max) for PBL was (92%, 87%, 94%). Conclusions: Bowel dose in pRT of rCa can be reduced at the expense of increasing dose to PBM and other NT. AI tools can be used effectively to limit RO workload. [Table: see text]
Relevance of immune tumor microenvironment and its interaction with HABP4 and SERBP1 proteins in bladder cancer.
Authors: Wagner José Fávaro, Gabriela Cardoso de Arruda Camargo, Gabriela Oliveira, Isadora Manzato Roberto, Monaliza Ávila, André Da Silva Santos, Leandro Luiz Lopes de Freitas, Athanase Billis, João Carlos Cardoso Alonso
Journal: Journal of Clinical Oncology (2024)

e15187 Background: This study characterized and compared the immunohistochemical signatures associated with the cytotoxic inflammatory response (IFN-γ, CX3CR1 + CD8 + T cells, iNOS + M1 macrophages), immune checkpoints (PD-L1, CTLA-4), and the presence of immunosuppressive cells (CD163 + M2 macrophages, Foxp3 + regulatory T (Treg) cells) within bladder cancer samples. Furthermore, it aimed to correlate these immune signatures with the functional dynamics of Hyaluronic Acid Binding Protein 4 (HABP4) and Serpin mRNA Binding Protein 1 (SERBP1), proposing a novel perspective on the immunobiology of bladder cancer and its implications for targeted therapeutic strategies. Methods: A total of 30 formalin-fixed, paraffin-embedded bladder samples were obtained from patients aged 34 to 96 years (average 65 years) diagnosed with bladder cancer at the Municipal Hospital of Paulínia, Brazil. The samples were divided into three groups (n = 10 samples per group): Group 1 - Initial Non-Muscle Invasive Bladder Cancer (NMIBC); Group 2 - Bacillus Calmette-Guerin (BCG)-unresponsive NMIBC; and Group 3 - Muscle Invasive Bladder Cancer. Subsequently, the samples were submitted to immunohistochemical analyses. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: Our results demonstrated that total immunoreactivities for IFN-γ, iNOS and CX3CR1 were significantly higher (p &lt; 0.01) in Group 1 compared to Groups 2 and 3. CTLA-4 and PD-L1 immunoreactivities were significantly higher (p &lt; 0.01) in Group 1 compared to Groups 2 and 3. Conversely, immunoreactivities for CD163 and Foxp3 were significantly higher (p &lt; 0.01) in Groups 2 and 3 compared to Group 1. This study marks the first elucidation of HABP4 and SERBP1 immunoreactivities in the context of bladder cancer. We observed that immunoreactivity for SERBP1 was significantly higher (p &lt; 0.01) in Groups 2 and 3 than in Group 1, implicating its overexpression in the facilitation of tumor progression. In a contrasting manner, HABP4 demonstrated significantly greater immunoreactivity (p &lt; 0.01) in Group 1 compared to Groups 2 and 3, indicating a potential inhibitory effect on cellular proliferation. Conclusions: The augmented presence of Foxp3 + Treg cells and CD163 + M2 macrophages, concomitant with SERBP1 overexpression and the decrease of immune checkpoints, likely compromises the therapeutic efficacy of BCG. This immunosuppressive milieu hinders the activation, proliferation, and effector functions of CD8 + T cells, thereby promoting tumor progression. Conversely, a heightened infiltration of CX3CR1 + CD8 + T cells and iNOS + M1 macrophages promotes a cytotoxic microenvironment, rendering it more amenable to immunotherapeutic interventions.