tbuckley/cabot-search huggingface dataset:
Trend and burden of cancer related hospitalizations in the US: Insights from a National Inpatient Sample Database analysis.
Authors: Rohit Singh, Karan Jatwani, Akshit Chitkara, Akshee Batra, Nitya Batra, Muni Rubens, Venkataraghavan Ramamoorthy, Veda Rabishanker, Anshul Saxena, Atulya Aman Khosla
Journal: Journal of Clinical Oncology (2024)

1543 Background: Cancer-related hospitalizations constitute one of the primary drivers of cancer-related healthcare expenses. Understanding the burden and characteristics of these hospitalizations is essential to appropriately direct resources, improve outcomes, and avoid unnecessary hospitalizations. Our study sought to evaluate the national trends, reasons, disposition status, length of stay, and associated costs for cancer-related hospitalizations. Methods: We conducted a retrospective analysis of cancer hospitalizations using the 2008-2019 National Inpatient Sample. Cancer-related hospitalizations were identified using validated Clinical Classification Software (CCS) codes 11 to 45. Trends in hospitalization volume, mortality, length of stay, disposition status, and costs were analyzed overall and by cancer type, adjusted according to the US Consumer Price Index. Results: There were 371 million weighted hospitalizations from 2008 to 2019, of which 15.1% (56 million) were cancer related. The most reported cancer types were breast cancer (11.9%), secondary malignancies (11.2%), and prostate cancer (10.3%). The most common reasons for cancer-related hospitalizations were septicemia (4.8%), pneumonia (4.7%), and complications of surgical procedures or medical care (3.1%). Trend analysis showed that the total number of cancer-related hospitalizationsincreased from 12,963 to 16,500 per 100,000 hospitalizations during the study period (relative increase, 27.3%). Mortality rates decreased from 5.1% to 4.0% (relative decrease, 21.6%), while the length of stay decreased from 3.5 to 3.2 days (relative decrease, 8.6%) during the study period. Disposition to home or short-term facilities decreased (relative decrease, 3.1%), while to long-term facilities increased (relative increase, 20.6%) during the same period. Total hospitalization cost increased from $55.5 billion in 2008 to $76.4 billion in 2019 (a relative increase of 37.7%). Conclusions: Our analysis shows that while cancer-related hospitalizations and associated costs increased substantially, mortality rates, and length of stay decreased. These trends reflect rising cancer burden but improvements in hospital cancer care quality and efficiency. Ongoing efforts to optimize cancer treatment, minimize unnecessary hospitalizations, reduce length of stay, and facilitate safe discharges are needed to improve patient outcomes and control costs further. Continued surveillance and health policies should address the rising demand for high-value cancer care.[Table: see text]
Effect of GSDMD-mediated pyroptosis on the myocardial injury induced by PD-1 inhibitor combined with x-ray radiation.
Authors: Wu Bibo, Shengfa Su
Journal: Journal of Clinical Oncology (2024)

e14631 Background: Radiation in combination with programmed cell death 1 (PD-1) antibodies greatly enhanced the anti-tumor activity by reactivating T lymphocytes. Whether it will produce the superposition of toxic side effects and the underlying mechanism remains elusive. Pyroptosis is a novel type of programmed cell death associated with the pathogenesis of many inflammatory diseases. We hypothesized that GSDMD plays a pathogenic role in PD-1 inhibitor combined with radiation-induced myocardial injury (RIMI) and that GSDMD gene knockout (KO) or blockade the caspase-1/GSDMD pathway will alleviate RIMI. Methods: GSDMD-KO mice and their wildtype (WT) C57BL/6J were used to investigate whether PD-1 inhibitor aggravated RIMI through pyroptosis pathway. Myocardial contractile functions, myocardial inflammation and fibrosis, and myocardial injury were assessed. Pyroptosis-related proteins and inflammatory cytokines were evaluated. Flow cytometry was used to detect the level of lymphocyte in myocardium. To further confirm the presence of pyroptosis in cardiomyocyte, double-immunostaining was performed. We verified the effect of radiotherapy combined with PD-1 inhibitor on pyroptosis in cell experiments. Results: Compared with irradiation or anti-PD-1 alone, PD-1 inhibitor could aggravate RIMI, increase the infiltration of CD8+T cells in the myocardium, and aggravate inflammatory reactions. The expressions of pyroptosis-related proteins and inflammatory cytokines were upregulated. Immunofluorescence also indicated that pyroptosis cells were increasing. While GSDMD-KO or caspase-1GSDMD inhibitor, myocardial injury and pyroptosis-related proteins were significantly reduced. Conclusions: We speculate that PD-1 inhibitors activate CD8+T cells and mediate cardiomyocyte pyroptosis. GSDMD-triggered immune-inflammatory response plays a key role in the aggravation of myocardial injury.
Broad-spectrum antibiotic use and risk of early-onset colorectal cancer.
Authors: Chun Chao, Lanfang Xu, Jessica Chubak, Jane C. Figueiredo, Darios Getahun, Kimberly L. Cannavale, Alec Gilfillan, Bechien U Wu
Journal: Journal of Clinical Oncology (2024)

e15653 Background: The incidence of early-onset colorectal cancer (eoCRC) diagnosed under age 50 is rising in the United States, but the underlying causes are largely unknown. Use of broad-spectrum antibiotics can induce intense gut dysbiosis, which is strongly implicated in CRC carcinogenesis. Emerging evidence supports a link between broad-spectrum antibiotic use and CRC. We evaluated the associations between oral broad-spectrum antibiotic use and risk of eoCRC. Methods: We conducted a nested case-control study within Kaiser Permanente Southern California (KPSC). Cases were persons aged 15-49 years with invasive colorectal adenocarcinoma diagnosis between 2009-2021; controls were matched at 10:1 ratio on age, sex at birth, and length of KPSC membership. Those with less than 15 years of prior membership at diagnosis date or controls’ index date were excluded to allow evaluation of exposure up to 15 years prior. We extracted all study data, including use of antibiotics by drug type and days of prescriptions, from KSPC’s electronic medical records. Conditional logistic regression was used to evaluate antibiotic use from three etiologic periods: 10-15, 5-10, and 2-5 years prior to diagnosis/index date, adjusting for potential confounders (narrow-spectrum antibiotics use, clinical and lifestyle risk factors, race/ethnicity, body mass index) with a crude p-value &lt; 0.10. Analyses were conducted overall and separately for colon cancer. Results: A total of 310 cases (mean age at diagnosis 44.5 years, 52% female, 33% non-Hispanic White) and 2,976 controls were included. In the 10-15 years prior to diagnosis/index date, 65% of cases and 62% of controls used broad-spectrum antibiotics. Broad-spectrum antibiotic use was not associated with eoCRC overall [OR = 1.15 (95% CI: 0.88-1.49)]. An increased risk was suggested for &gt; 3 months of cumulative use: OR = 1.07 (0.81-1.42) for ≤1 month; 1.26 (0.87-1.84) for 1-3 months; and 1.59 (0.95-2.65) for &gt; 3 months. The association between exposure and colon adenocarcinoma was: OR = 1.26 (0.91-1.72) for any use; OR = 1.17 (0.83-1.64) for ≤1 month; and OR = 1.50 (0.99-2.27) for &gt; 1 month. No association was observed between broad-spectrum antibiotic use within 5-9.9 years or 2-4.9 years prior to diagnosis and risk of eoCRC overall or for the colon site. Conclusions: Our findings suggest a possible association between cumulative longer-term use of broad-spectrum antibiotics and increased risk of eoCRC. The etiologic window for assessing antibiotic exposure appears to be relevant. Larger studies with long-term follow-up are needed to confirm these findings.
Impact of semaglutide and tirzepatide administration on weight in women with stage I-III breast cancer.
Authors: Neal A. Fischbach, Bin Zhou, Yanhong Deng, Kayla Parsons, Amy Shelton, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2024)

e24140 Background: Weight gain and obesity are significant problems for women receiving adjuvant therapy for breast cancer and obesity is associated with adverse breast cancer outcomes. In addition, obesity is associated with negative impact on overall physical and mental health. The GLP-1 agonists, semaglutide (S) and tirzepatide (T), are effective in achieving weight loss and have been associated with decreased incidence of diabetes, stroke and overall mortality in the non-diabetic as well as diabetic populations. There are limited data on the efficacy and safety of GLP1 agonists in women with breast cancer. Methods: We performed a retrospective analysis of the association of S and T use with weight loss in patients with stage I-III breast cancer diagnosed and treated at the Yale Cancer Center/Yale New Haven Health Network between 2017 and 2022. After institutional review board approval, a database including 7149 patients including 92,989 office visits was constructed. Maximal weight loss after S/T prescription as well as mean weight loss were calculated. S and T treated patient’s stage distribution and rates of recurrence were compared to untreated patients. For patients without metastatic disease, repeated measures regression analysis was utilized to evaluate changes in weight and BMI. Results: Of the 5430 evaluable patients with non-metastatic disease, 70 (1.3%) were prescribed S or T. Mean age was 58 (41-78). 74% received endocrine therapy. Mean pretreatment weight was 95.8 kg and BMI was 35.9 kg/m2. Mean weight loss for S/T treated patients was 3.03 kg (3.9-2.13, p &lt; .0001) corresponding to reduction in BMI of 1.1 kg/m2 (0.7-1.5 p &lt; .0001). We also calculated maximal weight loss after S/T prescription. Mean maximal weight loss was 8.89 kg (6.71-10.98 P &lt; .0001) corresponding to a mean maximal reduction in BMI of 3.2 kg/m2 (2.3-4.2 P &lt; .0001). Rates of local, locoregional, and distant breast cancer recurrence were 1.5%, 0%, 1.5% in the S/T treated patients and 1.3%, 4.7% and 3.3% in the untreated patients. None of these differences were statistically significant. Conclusions: In this retrospective analysis, GLP-1 agonist are associated with clinically meaningful weight loss in overweight and obese women with early breast cancer. Recurrence risk did not appear to be preliminarily impacted by treatment. Additional research is needed on long term safety as well as weight loss maintenance with these drugs in breast cancer survivors.
Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.
Authors: Bei Jiang, Elena Pugacheva, Stell Patadji Santiago, Sijin Wen, Jordan Hill, Michelle Hartzell, Hiba Khan, Laila Sakkal, Maria Hafez
Journal: Journal of Clinical Oncology (2024)

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.
Format-tuning of in vivo-launched bispecific T cell engager enhances efficacy against renal cell carcinoma
Authors: Ryan P O’Connell, Kevin Liaw, Nils Wellhausen, Christopher A Chuckran, Pratik S Bhojnagarwala, Devivasha Bordoloi, Daniel Park, Nicholas Shupin, Daniel Kulp, Carl H June, David Weiner
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Advanced clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer for which long-term survival rates are abysmal, though immunotherapies are showing potential. Not yet clinically vetted are bispecific T cell engagers (BTEs) that activate T cell-mediated cancer killing through intercellular synapsing. Multiple BTE formats exist, however, with limited cross-characterizations to help optimize new drug design. Here, we developed BTEs to treat ccRCC by targeting carbonic anhydrase 9 (CA9) while characterizing the persistent BTE (PBTE) format and comparing it to a new format, the persistent multivalent T cell engager (PMTE). These antibody therapies against ccRCC are developed as both recombinant and synthetic DNA (synDNA) medicines. Methods Antibody formatting effects on binding kinetics were assessed by flow cytometry and intercellular synaptic strength assays while potency was tested using T-cell activation and cytotoxicity assays. Mouse models were used to study antibody plasma and tumor pharmacokinetics, as well as antitumor efficacy as both recombinant and synDNA medicines. Specifically, three models using ccRCC cell line xenografts and human donor T cells in immunodeficient mice were used to support this study. Results Compared with a first-generation BTE, we show that the PBTE reduced avidity, intercellular synaptic strength, cytotoxic potency by as much as 33-fold, and ultimately efficacy against ccRCC tumors in vivo. However, compared with the PBTE, we demonstrate that the PMTE improved cell avidity, restored intercellular synapses, augmented cytotoxic potency by 40-fold, improved tumor distribution pharmacokinetics by 2-fold, and recovered synDNA efficacy in mouse tumor models by 20-fold. All the while, the PMTE displayed a desirable half-life of 4 days in mice compared with the conventional BTE’s 2 hours. Conclusions With impressive efficacy, the CA9-targeted PMTE is a promising new therapy for advanced ccRCC, which can be effectively delivered through synDNA. The highly potent PMTE format itself is a promising new tool for future applications in the multispecific antibody space.
Circadian rhythm analysis using wearable-based accelerometry as a digital biomarker of aging and healthspan
Authors: Jinjoo Shim, Elgar Fleisch, Filipe Barata
Journal: npj Digital Medicine (2024)

Abstract Recognizing the pivotal role of circadian rhythm in the human aging process and its scalability through wearables, we introduce CosinorAge, a digital biomarker of aging developed from wearable-derived circadian rhythmicity from 80,000 midlife and older adults in the UK and US. A one-year increase in CosinorAge corresponded to 8–12% higher all-cause and cause-specific mortality risks and 3–14% increased prospective incidences of age-related diseases. CosinorAge also captured a non-linear decline in resilience and physical functioning, evidenced by an 8–33% reduction in self-rated health and a 3–23% decline in health-related quality of life score, adjusting for covariates and multiple testing. The associations were robust in sensitivity analyses and external validation using an independent cohort from a disparate geographical region using a different wearable device. Moreover, we illustrated a heterogeneous impact of circadian parameters associated with biological aging, with young (&lt;45 years) and fast agers experiencing a substantially delayed acrophase with a 25-minute difference in peak timing compared to slow agers, diminishing to a 7-minute difference in older adults (&gt;65 years). We demonstrated a significant enhancement in the predictive performance when integrating circadian rhythmicity in the estimation of biological aging over physical activity. Our findings underscore CosinorAge’s potential as a scalable, economic, and digital solution for promoting healthy longevity, elucidating the critical and multifaceted circadian rhythmicity in aging processes. Consequently, our research contributes to advancing preventive measures in digital medicine.
Impact of urolithin A supplementation, a mitophagy activator on mitochondrial health of immune cells (MitoIMMUNE): A randomized, double-blind, placebo-controlled trial in healthy adults.
Authors: Dominic Denk, Anurag Singh, Herbert Kasler, Lucia Alcober Boquet, Davide D'Amico, Johanna Gorol, Florian Greten
Journal: Journal of Clinical Oncology (2024)

e14562 Background: Mitochondrial dysfunction and stem cell exhaustion are hallmarks of aging, driving inflammation and limiting immune function. Likewise, cancer is characterized by repression of mitochondrial dynamics in tumor-infiltrating leukocytes that fosters terminal T cell exhaustion. Yet, interventions to reliably improve immune function are still lacking. Urolithin A (UA) is a postbiotic known to improve muscle function in aged adults upon oral intake. We have recently shown that UA induces mitophagy in human CD8+ cells to induce formation of T memory stem cells, while sensitizing murine cancer to immunotherapy. Methods: In this double-blind, prospective, placebo-controlled trial (NCT05735886) we sought to characterize for the first time the effects of UA on the human immune system. Fifty healthy participants aged 45-70 years were randomized (1:1) to an intervention of single-dose (1000mg) UA or placebo per day for a study duration of 28 days. Randomization was performed based on age, gender and BMI. Exclusion criteria were prior medical conditions, BMI &gt;35 kg/m 2 , smoking, and intake of prescription medication or other dietary supplements. The primary end points of the study were changes in peripheral CD3+ cells, as well as alterations in mitochondrial activity in select immune populations of the peripheral blood as assessed by flow cytometry. Results: Intake of UA was safe and well-tolerated in the intervention cohort of 25 participants. After the study period, total peripheral lymphocytes and circulating NK cells were expanded in the UA group. Performing a complete immunophenotyping via spectral flow cytometry, we found that UA elicits immune remodeling characterized by broad changes of immune surface markers and mitochondrial measurements. CD8+ cells of participants in the intervention arm displayed greater mitochondrial mass, while preferably taking on a naive phenotype and expressing more Ki67. In addition, circulating monocytes exhibited a less inflammatory signature. UA intake reduced plasma levels of several proinflammatory cytokines. Conclusions: Collectively, our study constitutes an unprecedented intervention-based assessment of immune aging that globally characterizes the effect of UA on the immune system, proposing validation in future confirmatory studies and potential combination with cancer immunotherapy. Clinical trial information: NCT05735886 .
Immunomodulatory alpha neutrophils: The first-in-class neutrophil progenitor-based allogeneic immuno-cell therapy with cytotoxic and immunomodulatory functionality for the treatment of solid tumours.
Authors: Aoife McGinley, Samuel Florence, Martin James Woodward, Durva Patel, Andrew Willis, Alex Blyth, Alfonso Quintas-Cardama, Oxana Polyakova
Journal: Journal of Clinical Oncology (2024)

e14523 Background: Adoptive cell therapy for the treatment of cancer has largely focused on the administration of autologous engineered αβ T cells. Although successful in some haematological malignancies, the solid tumour microenvironment (TME) poses significant challenges to the efficacy of CAR-T cells, including physical barriers, heterogeneous antigen expression or antigen escape and immunosuppressive mediators. Remodeling the immunosuppressive solid TME is pivotal to the success of immunotherapies. Recent studies have highlighted key roles for neutrophils in tumour control and in facilitating successful responses to cancer immunotherapy, with neutrophil functional heterogeneity within the TME becoming increasingly appreciated. Methods: At LIfT Biosciences we have developed the first-in-class, stem cell-derived immuno-cell therapy with anti-cancer neutrophil properties called Immunomodulatory Alpha Neutrophils (IMANs). IMANs are derived from CD34 + stem cells expanded and differentiated in proprietary media compositions in a simple and scalable GMP-compliant manufacturing process. IMANs are designed to recapitulate those neutrophil states that are both cytotoxic and capable of immunomodulating the solid TME for long-lasting tumour control. Off-the-shelf, allogeneic, innate IMANs have the potential to provide major clinical benefits in the treatment of multiple solid tumours. Results: IMANs multimodal mechanisms of action (MoA) have been demonstrated in different state-of-the-art solid tumour models, including co-culture with patient-derived xenograft organoids (PDX-O) and with 3D ex vivo patient tissues (tumour-on-a-chip). Direct antigen-independent cytotoxicity towards PDX-O from a range of solid tumour indications has been demonstrated. Additionally, and fundamental to IMANs MoA is their ability to migrate to the solid TME and recruit and activate recipients’ anti-tumour immune responses. We have demonstrated IMANs ability to rapidly migrate into the solid TME and promote recruitment of patients’ immune cells leading to enhanced tumour cell death using tumour-on-a-chip technology accompanied by daily live cell imaging. Mechanistically, co-culture with IMANs enhanced expression of co-stimulatory receptors on T and NK cells, such as OX40 and 4-1BB, as well as promoting secretion of TME-modulating factors, such as CXCL10. Furthermore, co-culture with IMANs enhanced secretion of IFN-γ by activated tumour-infiltrating lymphocytes. Conclusions: These cytotoxic and immunomodulatory functions enable IMANs to remodel the TME, leaving the solid tumour more susceptible to host immune responses.