tbuckley/cabot-search huggingface dataset:
Molecular mechanisms underlying the modulation of T-cell proliferation and cytotoxicity by immobilized CCL21 and ICAM1
Authors: Sofi Yado, Bareket Dassa, Rawan Zoabi, Shlomit Reich-Zeliger, Nir Friedman, Benjamin Geiger
Journal: Journal for ImmunoTherapy of Cancer (2024)

Adoptive cancer immunotherapy, using engineered T-cells, expressing chimeric antigen receptor or autologous tumor infiltrating lymphocytes became, in recent years, a major therapeutic approach for diverse types of cancer. However, despite the transformative potential of adoptive cancer immunotherapy, this field still faces major challenges, manifested by the apparent decline of the cytotoxic capacity of effector CD8+ T cells upon their expansion. To address these challenges, we have developed an ex vivo "synthetic immune niche" (SIN), composed of immobilized CCL21 and ICAM1, which synergistically induce an efficient expansion of antigen-specific CD8+ T cells while retaining, and even enhancing their cytotoxic potency. To explore the molecular mechanisms through which a CCL21+ICAM1-based SIN modulates the interplay between the proliferation and cytotoxic potency of antigen-activated and CD3/CD28-activated effector CD8+ T cells, we performed integrated analysis of specific differentiation markers via flow cytometry, together with gene expression profiling. On day 3, the transcriptomic effect induced by the SIN was largely similar for both dendritic cell (DC)/ovalbumin (OVA)-activated and anti-CD3/CD28-activated cells. Cell proliferation increased and the cells exhibited high killing capacity. On day 4 and on, the proliferation/cytotoxicity phenotypes became radically "activation-specific"; The DC/OVA-activated cells lost their cytotoxic activity, which, in turn, was rescued by the SIN treatment. On longer incubation, the cytotoxic activity further declined, and on day7, could not be rescued by the SIN. SIN stimulation following activation with anti-CD3/CD28 beads induced a major increase in the proliferative phenotype while transiently suppressing their cytotoxicity for 2-3 days and fully regaining their killing activity on day 7. Potential molecular regulatory pathways of the SIN effects were identified, based on transcriptomic and multispectral imaging profiling. These data indicate that cell proliferation and cytotoxicity are negatively correlated, and the interplay between them is differentially regulated by the mode of initial activation. The SIN stimulation greatly enhances the cell expansion, following both activation modes, while displaying high survival and cytotoxic potency at specific time points following stimulation, suggesting that it could effectively reinforce adoptive cancer immunotherapy.
Global, regional, and national trends in metabolic risk factor-associated mortality among the working-age population from 1990-2019: An age-period-cohort analysis of the Global Burden of Disease 2019 study
Authors: Xiao-Lu Lin, Qing-Wei Zhang, Gui-Fen Chen, Shi-Jie Yang, Xiao-Bo Li, Wan-Yin Deng
Journal: Metabolism (2024)
Tumor Promoters and Opportunities for Molecular Cancer Prevention
Authors: William Hill, Clare E. Weeden, Charles Swanton
Journal: Cancer Discovery (2024)

Environmental carcinogens increase cancer incidence via both mutagenic and non-mutagenic mechanisms. There are over 500 known or suspected carcinogens classified by the International Agency for Research on Cancer. Sequencing of both cancerous and histologically non-cancerous tissue has been instrumental in improving our understanding of how environmental carcinogens cause cancer. Understanding how and defining which environmental or lifestyle exposures drive cancer will support cancer prevention. Recent research is revisiting the mechanisms of early tumorigenesis, paving the way for an era of molecular cancer prevention. Significance: Recent data have improved our understanding of how carcinogens cause cancer, which may reveal novel opportunities for molecular cancer prevention.
Exploring “good days” in advanced cancer: Activities, behaviors, and quality of life.
Authors: David Lazris, Svea Cheng, Christianna Bartel, Krina Durica, Jennifer Fedor, Leeann Chen, Yael Schenker, Carissa A. Low
Journal: Journal of Clinical Oncology (2024)

12074 Background: Advancements in cancer treatments have contributed to people living longer with Stage IV cancer. People living with advanced cancer face significant and unique psychological challenges related to dynamic treatment schedules, fluctuating physical symptoms, and uncertainty regarding prognosis. Understanding what constitutes a “good day” may help patients, their family members, and clinicians to recognize and prioritize factors that improve quality of life. The goal of this project was to understand activities and behaviors that characterize a “good day” among people living with advanced cancer. Methods: We enrolled 20 patients with advanced cancer (M 63 years old, range 41-75; 65% female; 65% white and 35% black; mean 1.5 years since Stage IV diagnosis [range 9 days to 7.5 years]). Participants completed semi-structured interviews and two weeks of nightly diaries, using a 1-5 rating scale (1 = very bad, 5 = very good) to rate their daily quality of life and document various activities and experiences. We conducted t-tests to determine differences in “goodness” on days with and without different experiences along with a Pearson correlation between each patients’ mean goodness rating and Patient-Reported Outcomes Measurement Information System (PROMIS) scores. Results: Interviews revealed themes of "good days," including emphasizing control, normalcy, positive impact, and presence. Loss of control, uncertainty, disruptive symptoms, negative healthcare experiences, and unmet goals were more common on “bad days.” Nightly diaries revealed significant correlations between active engagement in social, hobby, club, religious, cooking, reading, and meditation activities and reporting a good day (all p values &lt; .05). Mean diary goodness ratings correlated positively with Ability to Participate in Social Roles/Activities (r(19) = .54, p = .016) and inversely with Anxiety (r(19) =-.63, p = .004) and Depression (r(19) = -.53, p = .020) and was marginally inversely correlated with Fatigue (r(19) = -.44, p = .059) and Pain Interference (r(19) = -.46, p = .050). No significant correlations were observed with Physical Function (r(19) = .15, p = .544), Cognitive Function (r(19) = .36, p = .134), and Sleep Disturbance (r(19) = -.26, p = .286). Conclusions: Preliminary findings suggest that days on which individuals with advanced cancer are able to engage in activities that give them a sense of normalcy, control, self-identity, and connection to others are better than days without these activities. This is further supported by the positive correlation between goodness ratings and the ability to participate in social roles and activities. Understanding the individual’s values, perceived social roles, and priorities may help care teams support people with advanced cancer to optimize their quality of life and functioning and navigate treatment decisions.
When pain management meets harm reduction: Patients with cancer navigate the opioid crisis—2016 to 2020 National Inpatient Sample analysis.
Authors: Himal Kharel, Zeni Kharel, Samikchhya Keshary Bhandari, Nishan Babu Pokhrel, Purva Shah, Aditya Sanjeevi, Aniket Rao, Abdullah Ahmad Orakzai, Basant Eltaher, Tripti Jain, Saad Jamshed
Journal: Journal of Clinical Oncology (2024)

12071 Background: The opioid crisis is a growing public health concern in the United States. In this retrospective study, we aim to look at the trends and predictors of opioid overdose-related mortality in cancer patients. Methods: A retrospective analysis of the National Inpatient Sample database (NIS) from 2016 to 2020 was conducted using International Classification of Diseases-10(ICD-10) codes to identify hospitalizations related to opioid overdose. The 2016-2020 mark was chosen because 2016 is the first NIS year with full implementation of ICD-10 code and there is absence of data after 2020. STATA version SE18.0 was used for statistical analysis. We used multivariate regression analysis to calculate the effects of various demographic and non-demographic variables including age, sex, Charlson Comorbidity Index(CCI), race, median household income, type of insurance, hospital bed size, hospital region, chronic lung disease, neuromuscular disease, and alcohol use disorder on opioid overdose-related mortality. Results: There were 6980 hospitalizations with opioid overdose in cancer patients. Mean age was 62.3 years and 49.9% were females. 97.9% of patients had high CCI. The trend of opioid overdose-related mortality in cancer patients is shown in the table. Unlike increasing opioid overdose related mortality in the general population (which, per CDC, increased by 62.44% from 2016 to 2020), we found that opioid-related admissions and mortality in cancer patients are stable over five years. Significant predictors of mortality (p-value &lt;0.05) included male sex, African-American race, lower-median household income, and chronic lung disease with the odds ratio 1.64, 2.62, 2.13, and 1.69 respectively. Conclusions: The ongoing opioid crisis has led to tighter regulations regarding opioid prescriptions, subsequently creating increasing obstacles for cancer patients to access opioids. This analysis indicates that hospitalizations and deaths related to opioids in cancer patients have remained relatively stable, in contrast to the general population. Therefore, it is crucial to establish distinct regulations for cancer patients compared to the general population to ensure appropriate access to opioids for effective pain management. In addition, this study identified key predictors of mortality from opioid overdose in cancer patients, highlighting the complex interplay of socio-economic factors in medical care. The limitations of this study include multivariate model’s inability to account for all variables, coding errors, and an increased risk of bias due to the retrospective nature of the data. [Table: see text]
Frequency of certain germline polymorphisms among ethnicities and adverse drug reaction risk associated with colorectal cancer therapies.
Authors: Cathryn Jennissen, Jason Walker, Ghada Elnashar, Julie England, Annmarie Hawe, Ellie H. Jhun, Victor Tam, Greyson Twist, Pashtoon Murtaza Kasi, James Michael Kelley
Journal: Journal of Clinical Oncology (2024)

12119 Background: Chemotherapy regimens used to treat colorectal cancer (CRC) often include a combination of a fluoropyrimidine (i.e., fluorouracil or capecitabine), folinic acid, irinotecan, and/or oxaliplatin as first-line therapy in metastatic disease. Adverse drug reactions (ADRs) related to these regimens, such as neutropenia, severe diarrhea, and mucositis, can be severe or even life-threatening. Fluoropyrimidine (FP) and irinotecan-related toxicities in CRC are associated with certain germline polymorphisms in DPYD (*2A, *13, HapB3, and c.2846A&gt;T) and UGT1A1 (*28 allele), respectively. Clinically actionable recommendations are available per the FDA and the Clinical Pharmacogenetics Implementation Consortium (CPIC) for DPYD poor metabolizers (PMs) and intermediate metabolizers (IMs) due to increased risk for FP-induced ADRs. The FDA also provides dosing guidance for UGT1A1PMs in an effort to minimize irinotecan-induced toxicities. The objective of this research was to observe the frequency of DPYDvariants (*2A, *13, HapB3, c.2846A&gt;T, c.557A&gt;G), UGT1A1 variants (*6, *28), and associated phenotypes in various racial and ethnic groups. Methods: A retrospective analysis of 8,640 samples genotyped for DPYD and UGT1A1 was conducted (OneOme, Minneapolis, MN). Phenotype and carrier frequencies were analyzed and stratified by self-reported ethnicity and race. Results: DPYD variants with reduced or no function were observed in 6% of all samples tested where 6% of patients having clinically actionable IM or PM status. UGT1A1 carrier frequency was 56% with 12% of patients with clinically actionable PM status. Conclusions: A significant proportion of patients carry DPYD and/or UGT1A1 variants that result in decreased metabolism of FPs and irinotecan, respectively. In this large sample size, a 6% DPYD risk variant carrier frequency is significantly more than an estimated 2%, as previously reported. The FDA and CPIC provide clinically actionable recommendations for these commonly used colorectal and other gastrointestinal cancer therapies in an effort to avoid severe and even life-threatening toxicities that may be potentiated by these germline variations. [Table: see text]
Patient reported symptoms after cancer diagnosis and the risk of short- and long-term severe mental health events among adolescents and young adults (AYA): A population-based study.
Authors: Sumit Gupta, Qing Li, Rinku Sutradhar, Natalie G. Coburn
Journal: Journal of Clinical Oncology (2024)

12019 Background: AYA with cancer are a vulnerable sub-population at risk of adverse mental health outcomes during and after cancer treatment. Tools to identify AYA at highest risk are required to guide screening and interventions. In a population-based cohort of AYA with cancer, we determined whether self-reported symptoms were associated with subsequent short- and long-term severe mental health events (SMHE). Methods: All Ontario, Canada AYA diagnosed with cancer aged 15-29 between 2010-2018 were identified and linked to healthcare databases, including one capturing self-reported Edmonton Symptom Assessment System (ESAS) scores at cancer-related visits. Scores for depression, anxiety, and poor well-being were categorized as not measured, mild (0-3), moderate (4-6), or severe (7-9). SMHE were defined as emergency room visits or hospitalizations for mental health reasons. First, we used Cox proportional hazard models to determine the association of ESAS scores (time-varying variable) with subsequent SMHE. Second, among 5-year survivors, we determined the association of maximum ESAS score within the first year of diagnosis with long-term SMHE (i.e. starting at 5 years from cancer diagnosis). All analyses were adjusted for patient and disease variables, including mental healthcare use prior to cancer diagnosis. Results: 5,435 AYA met inclusion criteria. Median age at cancer diagnosis was 25 years [interquartile range 22-27]. Hematologic cancers were most common (1,748; 32.2%). Symptom severity was associated with subsequent SMHE risk. For example, AYA reporting severe anxiety were at more than three-fold higher risk of SMHE compared to those reporting mild anxiety [adjusted hazard ratio (aHR) 3.6, 95 th confidence interval (CI) 1.9-6.7; p &lt; 0.001]. Similar risk was seen among AYA reporting severe vs. mild depression (aHR 3.5, 1.7-7.3; p &lt; 0.001). Among 3,518 (64.7%) 5-year survivors, symptom severity also predicted long-term SMHE. For example, starting at 5 years post cancer diagnosis, the subsequent 3-year cumulative incidence of a SMHE among those who reported severe depression at any time during the first year post cancer diagnosis was 10.5% (95CI 6.9-15.9) compared to 2.4% (95CI 1.7-3.3) among those who only reported mild depression (aHR 3.0, 95CI 1.8-4.9; p &lt; 0.0001). Similar results were seen pertaining to severe anxiety and severe impact on well-being. AYA endorsing severe anxiety represented 13.1% of the cohort but accounted for 25.8% of AYA experiencing SMHEs during the first three years of survivorship. Conclusions: Systematic symptom screening in the first year after cancer diagnosis identifies a proportion of AYA at high risk of both short and long-term SMHE who may benefit from targeted screening and interventions. Future work will determine whether interventions during cancer treatment mitigate this risk.
Predictors of cardiotoxicity in patients with early breast cancer treated with doxorubicin and/or trastuzumab: Implications of race/ethnicity and insurance status.
Authors: Shahzaad Khadeem Jahangier, Rubina Qamar
Journal: Journal of Clinical Oncology (2024)

12021 Background: Approximately 4.1 million women in the US are living with breast cancer 1 . Cardiac dysfunction is a significant adverse effect of commonly used breast cancer therapies like doxorubicin (D) and trastuzumab (T). The cardiotoxicity (CTox) associated with these agents manifests as a reduction in left ventricular ejection fraction (LVEF) with or without signs and symptoms of heart failure. Purpose: Identify high-risk populations susceptible to developing CTox, with a focus on identifying individuals who could potentially benefit from the early initiation of empiric cardioprotective therapies. Methods: We investigated the relationship of race/ethnicity, insurance status, treatment regimen and comorbidities including hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), tobacco use, BMI, age, and radiation therapy on the development of CTox from D and/or T. A total of 133 newly diagnosed stage I-III invasive breast cancer patients were enrolled in a prospective clinical trial (2013-2017) and received standard of care D and/or T based systemic therapy. Echocardiogram data was collected every 6 months for two years and then based on clinical need for a total of six years. CTox was defined as a &gt;10% drop in LVEF, and/or LVEF &lt;50%. Results: Our study included a population of 133 patients comprising Black (22%), White (77%), and Hispanic (1.5%) individuals. Among these patients, 32 developed CTox (Black 41%, White 19%, Hispanic 50%). Of all patients, 29% had State insurance while 71% had Private insurance. Prevalence rates for comorbidities were as follows: HTN (41%), HLD (32%), DM (13%), and tobacco use (36%). In a univariate logistic regression model, race/ethnicity, HTN, insurance status, and tobacco use were most strongly associated with Ctox. When controlling for tobacco use and HTN, race/ethnicity was not significantly associated with Ctox. However, direct comparisons of levels of race/ethnicity showed that Black patients were more likely to develop Ctox when compared to White patients (OR 2.60, 95% CI = 1.01-6.65, P = 0.045). HTN patients were also more likely to develop Ctox, when controlling for ethnicity and tobacco use (OR 2.62, 95% CI = 1.10-6.43, P = 0.031). In a separate multivariate analysis, we examined insurance as a surrogate for socioeconomic status. State insurance was associated with an increased risk of developing CTox when controlling for race/ethnicity and HTN (OR 3.73, 95% CI = 1.47-9.58, P = 0.006). Furthermore, in all models, HLD, DM, BMI, age, and radiation field were not found to be significantly associated with increased CTox. Conclusions: In our well characterized population of patients with stage I-III breast cancer, who were prospectively followed and received standard of care systemic therapy, we observed an association between insurance status with increased risk of CTox from treatment regimen.
Impact of palliative care on hospital length of stay and charges in hospitalized patients with cancer at end of life.
Authors: Tien-Chan Hsieh, Guangchen Zou
Journal: Journal of Clinical Oncology (2024)

12072 Background: Early palliative care has been shown to enhance the quality of life and survival for cancer patients. However, the economic implications of using palliative care in hospitalized cancer patients remain inconclusive. While palliative care can prevent aggressive interventions in end-of-life patients, it may also prolong hospitalization. Methods: This retrospective study used four years of National Inpatient Sample data (2016-2019) to explore the association between palliative care and hospital length of stay and charges among cancer patients aged 18 and above, hospitalized for at least 7 days and died. Hospital charges were divided by length of stay to derive the average daily charges. Continuous variables, length of stay and average daily charges, were standardized by subtracting means and dividing by standard deviations. We top-coded length of stay and average daily charges at the 99th percentile. Length of stay was also modeled into categories: 7-13, 14-20, 21-27, and 28+ days. A mixed-effects model with individual hospitals as a random effect was employed to account for potential variations in clinical practices and billing at the institutional level. Results: The study included 59,355 distinct cancer hospitalizations, totaling 296,775 weighted hospitalizations. Palliative care utilization was observed in 54.0%, and Do-not-resuscitate (DNR) status was noted in 57.9%. The observed palliative care use and DNR status were most prevalent in the 7-13 days group (56.6% and 61.3%) and least in the 28+ days group (46.9% and 48.8%). 85.2% didn’t receive cardiopulmonary resuscitation (CPR) and that rate was similar across all length of stay groups. In linear mixed-effects models using standardized length of stay, palliative use was associated with shorter length of stay (adjusted Odds Ratio {aOR} 0.89; confidence interval {CI} 0.88-0.90). After adjustment for covariates, DNR was also associated with shorter hospitalization (aOR: 0.81; CI: 0.80-0.82). Receiving CPR had lower adjusted risk for longer hospitalization (aOR: 0.94; CI: 0.93-0.95). In multivariate model, daily charges were inversely correlated to the length of stay (aOR: 0.92; CI: 0.92-0.92). When using average charges per day as dependent variable, palliative care use was associated with less charges (aOR: 0.83; CI: 0.83-0.84). DNR also showed a lower adjusted odds for hospital charges (aOR: 0.89; CI: 0.88-0.89). Receiving CPR had higher adjusted risk of higher charges (aOR: 1.23; CI: 1.22-1.24). Conclusions: The use of palliative care was associated with a shorter length of stay and lower hospital charges per day among cancer patients who died in the hospital after adjusting for covariates. Many of the 46% who died without palliative care could have benefitted from it. Interventions aimed at promoting palliative care services among inpatient cancer patients nearing the end of life might yield economic benefits.
The predictive role of mammographic breast calcifications in cardiovascular disease among women undergoing breast cancer screening: Insights from a retrospective database analysis of breast cancer screening.
Authors: Usman Ali Akbar, Umer Rizwan, Rida Hussain, Ahmed Muaaz Umer, Andrea Dwiggins, Sabir Hussain, Michael Cheshire
Journal: Journal of Clinical Oncology (2024)

12022 Background: Cancer screenings, particularly mammography, are crucial in early detection and management of breast cancer, the most common cancer among women worldwide. Despite advances, disparities persist in cancer outcomes and cardiovascular health, highlighting the need for an integrative approach to care. Methods: We conducted a retrospective cohort analysis of 22,118 female patients over 40 years of age diagnosed with breast arterial calcification (BAC) on mammography using the TriNetX database. Each patient with BAC was matched to a control based on age, lab values, socioeconomic class, and co-morbidities. None had ASCVD events before screening. Outcomes included acute myocardial infarction, heart failure, cardiomyopathy, and thromboembolic events. Results: Comparing cohorts with and without BAC, we found no significant difference in all-cause mortality (OR: 1.003, P=0.960). However, BAC was associated with increased risks of acute myocardial infarction (OR: 1.281, P=0.003), heart failure (OR: 1.106, P=0.021), cardiomyopathy (OR: 1.437, P&lt;0.001), and DVT/PE (OR: 1.178, P=0.006), particularly DVT (OR: 1.243, P=0.003). Ischemic stroke, CVD, and other cardiovascular conditions showed no significant risk differences, highlighting BAC's predictive value for specific cardiovascular outcomes (Table). Conclusions: Our findings affirm BAC on mammography as a significant predictor of specific cardiovascular conditions, such as acute myocardial infarction and heart failure, highlighting its utility in cardiovascular risk stratification.[Table: see text]