tbuckley/cabot-search huggingface dataset:
Preclinical development of ATR04-484, an auxotrophic strain of <i>Staphylococcus epidermidis,</i> for the topical treatment of epidermal growth factor receptor (EGFR) inhibitor-induced dermal toxicity.
Authors: Travis M. Whitfill, Sara Mootien, Roger Leger
Journal: Journal of Clinical Oncology (2024)

e24074 Background: Agents targeting the EGFR-mediated signaling pathway are commonly used for the treatment of advanced lung, pancreatic, colorectal, and head and neck cancers. Significant dermal toxicities, which occur in up to 90% of patients treated with EGFR inhibitors (EGFRis) and other therapies inhibiting downstream signaling pathways, may be disruptive to a patient’s quality of life and adherence to therapy. Inhibition of the EGFR pathway may suppress host defenses and lead to opportunistic pathogenic colonization or infection. EGFRi-induced dermal toxicity is associated with elevated levels of Staphylococcus aureus and IL-36γ. ATR04-484 is a topical ointment containing S. epidermidis strain SE484, isolated from a healthy human volunteer that was selected for its ability to inhibit S. aureus and IL-36γ . Methods: Reconstructed human epidermis (RHE) and ex vivo pig skin were used to measure the effect of ATR04-484 on S. aureus in therapeutic and prophylactic settings with S. aureus added prior to or after ATR04-484, respectively. To evaluate the anti-inflammatory effects of ATR04-484, IL-36γ levels were measured on untreated RHE and RHE treated with erlotinib alone or in combination with ATR04-484. 10 4 colony-forming units (CFU) of methicillin-resistant (MRSA) or methicillin-sensitive (MSSA) S. aureus were used. Toxicology was assessed by measuring cell viability in three in vitro toxicology assays: the eye irritant potential was tested on 3D reconstituted human cornea-like epithelium (RhCE), the skin irritant potential of the strain in the ointment was assessed on 3D RHE, and the skin corrosive potential was evaluated on RHE. Results: ATR04-484 comparably inhibited growth of both MRSA and MSSA in therapeutic and prophylactic settings. In a therapeutic setting, ATR04-484 inhibited MRSA growth by 1 log (90%) compared to untreated MRSA in both RHE and pig skin. In a prophylactic setting, ATR04-484 inhibited MRSA growth by approximately 5 logs on RHE and 2 logs on pig skin. Additionally, application of ATR04-484 reduced IL-36γ to a level comparable to untreated RHE. The effect was dose-dependent; application of 10 9 CFU/cm 2 of ATR04-484 showed more potent IL-36γ reduction compared to 10 8 CFU/cm 2 . The three toxicology assays indicate that ATR04-484 does not cause irritation or corrosion. Conclusions: In these preclinical studies, ATR-04-484 showed a promising preclinical profile for the treatment of EGFRi-induced dermal toxicity by significantly reducing S. aureus growth, completely ameliorating IL-36γ levels, and showing no safety concerns.
The metabolic profiles of patients with autologous hematopoietic stem cell transplantation with graft versus host disease.
Authors: Alden J. Dunham, Steven Benyahia, Bhargav Kansara, Lauren Ellis, Gerry Samantha Eichelberger, Jahanzaib Ekram, Mohammed Alomar
Journal: Journal of Clinical Oncology (2024)

e24010 Background: Graft versus host disease (GvHD) is a serious inflammatory complication of hematopoietic stem cell transplant (HSCT) and a leading contributor to morbidity and mortality in HSCT patients. Previous studies have identified increased risk of cardiovascular death in HSCT patients who develop GvHD and characterized echocardiographic changes associated with chronic GvHD. However, details of the metabolic derangements in HSCT patients who develop GvHD remain poorly studied. Methods: This is a retrospective study of patients who underwent HSCT at H. Lee Moffitt Cancer Center and later developed severe chronic GVHD at 1 year. Metabolic data including weight, blood pressure, and lipid profile were recorded at baseline and at 1 year after HSCT. Results: Between January 1, 2010, and December 31, 2020, 1805 patients who received allogeneic HSCT were reviewed. At 1 year, 371 patients (20.5%) had severe GVHD. Compared to baseline, patients had higher total cholesterol (209 vs 183 mg/dL, P &lt; 0.001), high-density lipoprotein (61 vs 47 mg/dL, P &lt; 0.001), and triglycerides (211 vs 163 mg/dL, P &lt; 0.001) at 1 year of follow up. Low-density lipoprotein values were not significantly different (107 vs 102 mg/dL, p = 0.15). Patient weight was significantly less at 1 year (163 vs 183 lbs, p &lt; 0.001). Although blood pressure was not significantly different between baseline and 1 year, more patients were placed on antihypertensive medications at 1 year (50% vs 31%). Conclusions: This study finds that patients who undergo allogeneic HSCT and subsequently develop severe GVHD are at risk for metabolic derangements that may worsen cardiovascular health. We specifically demonstrate an increased need for antihypertensive therapy and elevations in total cholesterol and serum triglycerides. Further research is needed on the impact of these derangements on major adverse cardiac events and the role of cardiovascular risk factor management in these patients.
Harmonization radiomics model to predict immune checkpoint inhibitor-related pneumonitis (CIP) in patients with non-small cell lung cancer (NSCLC).
Authors: Monica Yadav, Jeeyeon Lee, Haseok Kim, Seyoung Lee, Taegyu Um, Salie Lee, Trie Arni Djunadi, Liam IL Young Chung, Jisang Yu, Darren Rodrigues, Nicolo Gennaro, Leeseul Kim, Yuchan Kim, Myungwoo Nam, Ilene Hong, Jessica Jang, Amy Cho, Grace Kang, Yury Velichko, Young Kwang Chae
Journal: Journal of Clinical Oncology (2024)

12142 Background: The increasing use of immunotherapy in advanced non-small cell lung cancer (NSCLC) presents a significant challenge in managing adverse events, particularly checkpoint inhibitor-associated pneumonitis (CIP). This potentially life-threatening complication often necessitates discontinuation of immunotherapy, even in patients experiencing tumor response. Presently, there are no reliable models to predict the onset of CIP. This research utilizes CT radiomics to create an innovative approach for anticipating the risk of CIP in patients with NSCLC. Methods: This IRB-approved, retrospective study analyzed data from 159 stage III-IV NSCLC patients undergoing immunotherapy. We categorized patients into pneumonitis (further subdivided into immunotherapy-induced, radiation-induced, and others) and non-pneumonitis groups. Using LIFEx software, we extracted 3D-radiomic features from both tumors and surrounding 1cm thick peritumoral regions. To address scanner-associated variations, a linear mixed-effect radiomics harmonization model was applied. A Random Forest algorithm was then used to develop a classification model predicting CIP occurrence based on the pre-treatment CT radiomic and clinical data. The dataset was split into training (70%) and test (30%) sets. The accuracy of predictions was evaluated using confusion matrix statistics and bootstrapping with 1,000 iterations for median and 95% confidence interval (CI). The performance metrics included sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the ROC curve (AUC). Results: 159 patients were analyzed, of which only 19 had checkpoint inhibitor-related pneumonitis. Among which, 17 (54.8%) patients had grade 1 pneumonitis, 12 (38.7%) patients had grade 2 pneumonitis, 2 (6.5%) patients had grade 3 pneumonitis, and none had grade 4 or grade 5 pneumonitis. The model achieved a sensitivity of 0.98 (0.97, 0.99), a specificity of 0.08 (0.05, 0.14), a PPV of 0.91 (0.90, 0.91), and an NPV of 0.33 ± 0.23 for predicting CIP. The AUC of 0.59 (0.56, 0.66) indicates that the model may predict checkpoint inhibitor-associated pneumonitis with an accuracy of 59%. Conclusions: The study provides insights into the potential of radiomic analysis coupled with AI algorithms and the use of harmonization model in predicting CIP among NSCLC patients treated with immunotherapy. However, larger studies are needed to validate our findings and the utility of harmonization models in predicting CIP.
Association of childhood trauma with choice of bilateral mastectomy for the treatment of unilateral breast cancer.
Authors: Annemarie D. Jagielo, Catherine Benedict, Nahom Zewde, Eric Neri, Bita Nouriani, David Spiegel
Journal: Journal of Clinical Oncology (2024)

e24096 Background: Patients are increasingly choosing bilateral mastectomy (BMX) for the treatment of primary breast cancer (BC) despite minimal survival benefits and potential for adverse medical and psychosocial consequences. Exposure to childhood trauma is associated with dysregulation of stress response systems, threat perception alterations, increased risk-taking behaviors, and body dissatisfaction. We examined childhood trauma in relation to treatment decision-making in adulthood within a sample of breast cancer patients undergoing either BMX or more conservative BC treatment. Methods: Secondary analyses of a case-control study of the neurobiological and affective determinants of BMX choice were conducted. Cross-sectional data from the baseline survey were analyzed. Participants were recruited via institutional clinic practices, social media, and patient advocacy groups. Patients completed a medical status questionnaire and the Childhood Trauma Questionnaire (CTQ). Chi-square and Mann-Whitney U tests examined differences in treatment decision-making by childhood trauma exposure and type. Results: The sample included 137 patients with unilateral stages 0-III BC (mean age 49.2; SD = 11.2; 76.6% White; 10.9% Hispanic/Latina; 68.6% married). Seven tested positive for a BRCA gene mutation. Patients were divided between BMX (n = 66) and non-BMX (n = 71) treatment groups. On average, patients in the non-BMX group reported higher levels of childhood trauma severity (Median = 7; IQR = 0-12.5) compared to patients in the BMX group (Median = 4; IQR = 0-11.75; Mann Whitney U = 4728; small effect size; SRD = -0.11; p = .26). Patients who reported a major parental upheaval (e.g., divorce, separation) were significantly more likely to pursue non-BMX compared to BMX (small effect size; SRD = -.16; p = .047). Patients who reported any uncategorized major upheaval were more likely to choose non-BMX than BMX (small effect size; SRD = -.14), but group differences did not reach significance (p = .093) . No other statistically significant relationships were observed. Conclusions: Contrary to hypotheses, preliminary results suggest BC patients who were exposed to traumatic events in childhood may be more likely to elect conservative BC surgical treatments. Trauma-related hypervigilance to threats may cause patients to exercise more caution regarding treatment choice. More research exploring the effects of adverse childhood experiences in the BC population is warranted. [Table: see text]
Angiogenesis inhibitors and cardiovascular outcomes in cancer: Real-world, population-based, matched cohort study.
Authors: Arunkumar Krishnan, Diptasree Mukherjee, Saleh A. Alqahtani, Declan Walsh
Journal: Journal of Clinical Oncology (2024)

e24024 Background: Angiogenesis inhibitors (AI) have vascular side effects and are now recognized forcardiovascular adverse events (CVAEs). Clinical trial outcomes can underestimate treatment-related adverse events due to restrictive eligibility criteria, limited sample size, and failure to anticipate specific toxicities. In contrast, observational studies have small sample sizes and insufficient adjustment of confounding covariates. In addition, prospective high-quality evidence in real-world settings is scarce. We evaluated the incidence of CVAEs in real-world populations on AI therapy. Methods: This large retrospective cohort study was conducted using the TriNetX database and included adult patients ( &gt; 18 years) with new cancer diagnoses. We performed 1:1 propensity score matching (PSM) for demographics, BMI, nicotine dependence, comorbidities, cancer type, and medications to similar controls as cancer patients never treated with AIs. The primary outcome was the new incidence of CVAEs-like heart failure (HF), major adverse cardiovascular events (MACE; coronary artery intervention myocardial infarction, or unstable angina), arrhythmia, ischemic heart disease (IHD), venous thromboembolism (VT), and cerebrovascular events (CVE cerebral infarction, carotid intervention, stroke, transient ischemic attack). Sensitivity analysis assessed statistical robustness. Hazard ratios (HR) were calculated to compare the AI therapy association with incident CVAEs. Results: We identified 1,170,667 patients with diagnoses of colorectal, cervical, kidney, liver, nonsmall cell lung, or ovarian cancer between 2010 and 2022. Among these, 59,890 had an AI treatment history, and 110,777 did not, with a median follow-up time of 3.1 years. After PSM, both cohorts (59545 each) were well-matched. In the adjusted analysis, AI therapy was associated with higher risks of MACE (HR, 1.23; 95% CI 1.16 -1.31), HF (HR, 1.16; 95% CI 1.08 - 1.25), and VT (HR 2.07; 95% CI 1.95 - 2.19), IHD (HR 1.23; 95% CI 1.16- 1.31), arrhythmias (HR 1.19; 95% CI 1.12-1.27), CVEs (HR, 1.30; 95% CI 1.21- 1.40) at 1 year of exposure. These outcomes were still significantly higher “increased,” suggesting causation; this is an association at follow-up by increasing the lag exposure. Sensitivity analysis results were consistent, and all statistically significant associations remained unchanged. Conclusions: Angiogenesis inhibitor treatment was associated with a significantly higher risk of CVAEs and various malignancies. The increased risk ranges from approximately 1.16 to 2.07 fold, indicating a substantial elevation in risk. These findings highlight the importance of risk stratification and cardiovascular monitoring during and after AI therapy. There is an unmet need to define strategies for CVAE prevention in this high-risk population.
Progress Toward Tuberculosis Elimination and Tuberculosis Program Performance — National Tuberculosis Indicators Project, 2016–2022
Authors: Rachel Woodruff, Robert Pratt, Maureen Kolasa
Journal: MMWR Surveillance Summaries (2024)

Elimination of tuberculosis (TB) is defined as reducing TB disease incidence in the United States to less than 1 case per million persons per year. In 2022, TB incidence in the United States was 2.5 TB cases per 100,000 persons. CDC's TB program developed a set of national TB indicators to evaluate progress toward TB elimination through monitoring performance of state and city TB program activities. Examining TB indicator data enables state- and city-level TB programs to identify areas for program evaluation and improvement activities. These data also help CDC identify states and cities that might benefit from technical assistance.
The impact of glucagon-like peptide-1 receptor agonists on proteasome inhibitor-associated cardiotoxicity in patients with multiple myeloma.
Authors: Yu-Cheng Chang, Cho Han Chiang, Zhiting Tang, Xin Ya See, Cho Hung Chiang, Kuan-Yu Chi, Yu Chang, Wenli Gao
Journal: Journal of Clinical Oncology (2024)

e24008 Background: Patients with multiple myeloma undergoing proteasome inhibitor therapies face an elevated risk of cardiotoxicity. Existing evidence in the non-cancer population indicates that glucagon-like peptide-1 receptor agonists (GLP1a) can mitigate the risk of cardiovascular events. We hypothesize that GLP1a may reduce the risk of cardiotoxicity in patients with multiple myeloma undergoing proteasome inhibitor therapies. Methods: We conducted a retrospective, propensity score-matched cohort study by utilizing the TriNetX Analytics Network database, which contains de-identified data spanning over 250 million patients. We included adult patients with multiple myeloma and type 2 diabetes mellitus who received proteasome inhibitor therapy. We matched patients treated with GLP1a and those treated with Dipeptidyl Peptidase 4 (DPP4i) in a 1:1 ratio based on predetermined clinical variables. The primary outcome included major adverse cardiovascular events, defined as a composite of heart failure and heart failure hospitalization, myocardial infarction, and ischemic stroke. Other outcomes included individual cardiovascular events, atrial fibrillation/flutter, and all-cause mortality within 3 years of proteasome inhibitor therapy. Results: We matched 183 patients on GLP1a to patients on DPP4i. The prevalence of hypertension, ischemic heart disease, and use of proteasome inhibitors was similar between cohorts. In a Cox proportional hazard analysis, patients who received GLP1a had an approximately 50% lower risk of major adverse cardiovascular events (HR, 0.53 [95% CI: 0.29-0.96]) compared to those who received DPP4i. Furthermore, GLP1a was associated with a reduction in heart failure and heart failure hospitalization, ischemic stroke, and all-cause mortality. The risks of myocardial infarction and atrial fibrillation/flutter were comparable between the two cohorts. Conclusions: GLP1a were associated with a reduction in major adverse cardiovascular events and mortality among patients with multiple myeloma and diabetes mellitus receiving proteasome inhibitors. [Table: see text]
Cardiovascular events in patients receiving immuno-oncology agents, in phase I clinical trials: CAVIO study.
Authors: Paola Zagami, Eleonora Nicolò, Dario Trapani, Luca Boscolo Bielo, Carmine Valenza, Ambra Carnevale Schianca, Gloria Pellizzari, Grazia Castellano, Sara Gandini, Silvano Vignati, Maria Angela Massaro, Chiara Busacca, Antonio Marra, Beatrice Taurelli Salimbeni, Carmen Belli, Ida Minchella, Marzia Adelia Locatelli, Angela Esposito, Carmen Criscitiello, Giuseppe Curigliano
Journal: Journal of Clinical Oncology (2024)

e24009 Background: Among immunoncology agents (IO), immune checkpoint inhibitors are the most used, demonstrating survival benefit across multiple cancer types. Adverse events are often reported with IO; cardiotoxicity is rare, but potentially fatal. CAVIO study evaluated the occurrence of cardiovascular events (CVE) in patients receiving IO in phase I clinical trials (ph1CT). Methods: We retrospectively reviewed clinical and cardiological data of patients consecutively enrolled, from Jan2016 to Dec2021, in ph1CT with IO alone or in combination. Any type and grade of CVE occurred on treatment, related or not to IO, was evaluated. Fisher’s exact tests were used to compare variables. Cox regression and Kaplan Meier methods were used for multivariable analyses and estimating overall survival (OS). Hazard ratio (HR) and 95% confident interval (CI) were calculated. Results: 211 patients were included; median age was 57 years. The most frequent site of primary tumor was breast (25%). 43 of 211 patients experienced ≥1 CVE of any grade (G) during the treatment, of which &lt; 1% G3 and none ³G4. The most frequent ones were hypertension (n = 20, 9%) and thrombosis (n = 15, 7%), only one myocarditis (2%). Table 1 shows the significant differences observed between patients experiencing CVE or not. The occurrence of CVE was not associated with pre-existing cardiovascular risk factors nor with number of prior therapy lines. The median progression free survival (mPFS) and mOS were 2 and 9 months respectively, regardless the CVE occurrence. Patients using anticoagulant at the end of ph1CT showed worse PFS and OS (1.8 and 5.4m) than those who did not (2.5 and 11.1m), similarly was for PS ECOG 1 vs 0. The result was consistent at the multivariate model adjusted for the primary site of tumor, PS ECOG, previous lines of treatment and age, in which PS ECOG 1 and the use of anticoagulant remained statistically significant associated with negative OS (for PSECOG: HR:1.84, 95% CI 1.31-2.57, p &lt; 0.001; for anticoagulant use: HR: 1.72, 95%CI:1.20-2.47, p:0.003). Conclusions: The occurrence of CVE did not change the outcomes of patients treated with IO in ph1RC. Severe CVE were rare, hypertension being the most frequent. Further data are needed on the correlation of anticoagulant use, IO and patients prognosis. [Table: see text]
FOLFOXIRI/bevacizumab (bev) versus doublets/bev as initial therapy of unresectable liver-only, right-sided and/or <i>RAS</i> or <i>BRAF</i> mutated (mut) metastatic colorectal cancer (mCRC): An individual patient data-based pooled analysis of randomized trials.
Authors: Carlotta Antoniotti, Federica Marmorino, Fabian Maximilian Meinert, Francesca Bergamo, Giuseppe Tonini, Daniele Rossini, Beatrice Borelli, Antonio De Rosa, Giacomo Allegrini, Alexander Stein, Roberto Moretto, Monica Ronzoni, Alberto Zaniboni, Marco Maria Germani, Sara Sperotto, Elena Ongaro, Filippo Ghelardi, Gianluca Masi, Hans Schmoll, Chiara Cremolini
Journal: Journal of Clinical Oncology (2024)

e15563 Background: FOLFOXIRI/bev was associated with longer PFS and OS versus doublets/bev independently of the presence of liver-limited disease or not, and the secondary resection of metastatic lesions. Recently, in the CAIRO-5 study patients with liver-limited right-sided and/or RAS or BRAF mutated mCRC experienced no OS difference, but higher ORR, R0 resection rate, and longer PFS with the triplet/bev when compared with doublets/bev. Here we aim at providing an estimation of the efficacy and activity of FOLFOXIRI/bev over doublets/bev in patients with unresectable liver-only, right-sided and/or RAS or BRAF mut mCRC. Methods: We selected pts with liver-only, right-sided and/or RAS or BRAF mut mCRC, and treated with first-line doublets/bev or FOLFOXIRI/bev in four phase II or III randomized controlled trials (RCTs): TRIBE (NCT00719797), TRIBE2 (NCT02339116), CHARTA (NCT01321957), and STEAM (NCT01765582). Patients included in these RCTs were deemed initially unresectable according to a multidisciplinary evaluation and were not selected based on the potential conversion to resectability. We compared FOLFOXIRI/bev with doublets/bev in terms of PFS, OS, ORR, and R0 resection. Results: A total of 300 pts were eligible. The median age was 61 years and most of them had an ECOG performance status of 0 (83%) and synchronous metastases (91%). One hundred and thirty (43%) and 170 (57%) pts received doublets/bev and FOLFOXIRI/bev, respectively. Baseline characteristics were homogeneous between the two treatment groups. Pts receiving FOLFOXIRI/bev showed longer PFS (12.3 vs 10.3 months [mos] HR:0.75, p = 0.019) and a statistically not significant trend for better OS (29.1 vs 23.2 mos, HR:0.85, p = 0.253), than those treated with doublets/bev. FOLFOXIRI/bev was also associated with higher ORR (64% vs 53%, OR:1.54, p = 0.076) and no differences in R0 resection rate (27% vs 24%, OR:1.15, p = 0.696) was reported. No significant interaction was found between treatment effect and the achievement of R0 resection in terms of both PFS (P interaction :0.81) and OS (P interaction :0.53). Conclusions: As compared to doublets/bev, upfront FOLFOXIRI/bev provides a meaningful advantage to pts with initially unresectable, liver-only, right-sided and/or RAS or BRAF mut mCRC, in terms of activity and efficacy, thus corroborating the choice of this regimen as upfront treatment for these pts, regardless of the opportunity to achieve the R0 secondary resection of their liver metastatic lesions.