tbuckley/cabot-search huggingface dataset:
Effect of sodium-glucose cotransporter 2 inhibitor dapagliflozin on ejection fraction reduction, myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity.
Authors: Vincenzo Quagliariello, Maria Laura Canale, Irma Bisceglia, Alessandro Inno, Francesca Bruzzese, Giuseppe Palma, Antonio Luciano, Martina Iovine, Ilaria Giacobbe, Fabrizio Maurea, Vienna Giordano, Francesca Izzo, Matteo Barbato, Raffaele Arianna, Massimiliano Berretta, Nicola Maurea
Journal: Journal of Clinical Oncology (2024)

e24013 Background: Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in cancer patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exerts multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease and heart failure with reduced and preserved ejection fraction. We hypothesized that the SGLT2i Dapagliflozin administered before and during doxorubicin therapy, could improve cardiac function and reduce pro-inflammatory pathways in preclinical models. Methods: Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO (2.17 mg/kg), DAPA (10 mg/kg) or DOXO combined to DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, hs-CRP and pro-inflammatory chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. After treatments, immunohistochemical staining of myocardial and renal p65/NF-kB was performed. Results: DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in DOXO-DAPA group compared to DOXO mice. Systemic levels of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in DOXO group; contrary, their expression were reduced in DAPA-DOXO group. Troponin-T, BNP and NT-pro-BNP were strongly reduced in DOXO-DAPA group, revealing cardioprotective properties of SGLT2-i. Mice treated with DOXO and DAPA exhibited reduced myocardial and renal NF-kB expression. Conclusions: The overall picture of the study encourages the use of DAPA in primary prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Managing complications in patellar fracture surgery: tension band wiring challenges and innovations-Correspondence
Authors: Jie Peng, Mi Zou, Zhiqiang Qiu, Chen Li, Liang Hao
Journal: International Journal of Surgery (2024)

aDepartment of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, China bThe Second Clinical Medical College, Jiangxi Medical College, Nanchang University, 330006 Nanchang, China cDepartment of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China Jie Peng, Mi Zou These authors have contributed equally to this work Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author Address: Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, China. E-mail address: [email protected] (L. Hao). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
Tumor-derived ILT3 inhibition to reshape the immunosuppressive microenvironment and potentiate the PD-L1 blockade immunotherapy in lung adenocarcinoma.
Authors: Leirong Wang, Yanxin Sun, Juan Li, Aiqin Gao, Shuyun Wang, Xuebing Fu, Xiufen Wang, Yuping Sun
Journal: Journal of Clinical Oncology (2024)

e14647 Background: The low response of immune checkpoint inhibitors against PD-1/PD-L1 in cancer patients calls for further development of new immune targets. Immunoglobulin-like transcript (ILT)3 and its ligand ApoE have been demonstrated to be highly expressed in a variety of malignant tumor cells and involved in tumor biological behaviors, including invasion and angiogenesis. ILT3 targeting drugs are undergoing increasing preclinical and clinical trials. However, the role of tumor-derived ILT3 in immune regulation is unclear. The aim of this study was to investigate the immunomodulatory effect of tumor-derived ILT3 and its immunotherapy therapeutic efficacy that combination with PD-L1 blockade in NSCLC. Methods: The correlations between ILT3/ApoE expression and prognosis of NSCLC patients were analyzed basing on public databases. Multiplex immunofluorescence was performed to analyze the correlations between tumor-derived ILT3/ApoE expression and intratumoral immune cells infiltration in human adenocarcinoma tissues. The impact of ILT3 and ApoE on tumor-associated macrophage (TAM) recruitment and polarization were evaluated by transwell migration assay, flow cytometry, and RT-PCR, while their direct impact on T cell survival and cytotoxicity was detected by flow cytometry. Using lung cancer xenograft murine models, we further confirmed the pro-tumoural activity of tumor-derived gp49B and analyzed its correlations with immune cells in vivo. Tumor immunotherapy models targeting at gp49B and/or PD-L1 were established in C57BL/6 mice inoculated with LLC cells. Gp49b inhibition was implemented by infection of specific knockdown lentivirus and PD-L1 was blocked using mouse neutralizing antibodies. Flow cytometry was performed to detect the frequency and phenotype of macrophages and T cells in the tumors, spleen, and blood of the mice. Results: Patients with high expression of ILT3 had significantly worse prognosis in LUAD, but not in LUSC. In vitro assays demonstrated that tumor-derived ILT3/ApoE promoted recruitment and M2-like polarization of TAMs and directly inhibited the proliferation and cytotoxicity of T cells, which had been further confirmed in vivo models. Moreover, ILT3 (gp49B) inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immunosuppressive TME; the combined inhibition of gp49B and PD-L1 showed the most dramatic tumor retraction in LLC xenograft models. Conclusions: Tumor-derived ILT3 overexpression suppressed anti-tumor immunity by recruiting M2-like TAMs and directly impairing T cell activities, while ILT3 inhibition counteracted above immunosuppression and potentiated the efficacy of PD-L1 blockade in LUAD. Our study verified that ILT3 may be a promising novel immunotherapeutic target for LUAD patients.
Preclinical studies of an innovative 5T4-ADC ACR246 with the potential to better treat 5T4-positive solid tumors.
Authors: Zhenwei Miao, Yunsheng Huang, Deliang Li, Xiaobei Wang, Guorong Sheng, Feng Wang, Kai Wu, Xiuying Huang, Li Yang, Yaowu Li, Shanhui Weng, Naresh kumar Manchukonda, Yao LU
Journal: Journal of Clinical Oncology (2024)

e15005 Background: 5T4 oncofetal antigen shows limited expression in normal adult tissues but highly expressed by many different cancers. It drives spread of cancer cells through epithelial mesenchymal transition (EMT), potentiation of CXCL12/CXCR4 chemotaxis and favoring non-canonical Wnt pathway, leading to poor prognosis of cancer patients. Besides, 5T4 has a highly efficient endocytosis ability which enables it to be an ideal target for the development of ADC drugs. A handful of 5T4-targeted ADCs have been evaluated in early phase clinical trials for several years showing only preliminary anti-tumor activity. However, uncertainty of their safety profiles has also raised concerns due to high toxic payloads, MMAF and duocarmycin, being used. Thus, additional approaches to this target with the potential of improved efficacy and reduced toxicity are needed urgently. ACR246, an innovative 5T4-targeted ADC consisting of specific humanized monoclonal antibody site-specifically conjugated with a cell penetrating and moderate toxic payload (DNA topoisomerase I inhibitor, D2102) that has a robust bystander effect through a stable and cleavable linker, with a drug-to-antibody ratio (DAR) of 8, was designed to improve the safety and efficacy in treating tumor patients. Methods: The pharmacologic profiles of ACR246 were assessed in vitro and in vivo including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, in 5T4-positive cell lines, cell-derived xenograft (CDX) models and cynomolgus monkeys. Results: ACR246 bound specifically to 5T4 and was internalized into tumor cells followed by D2102 release, which induced DNA damage, cell cycle arrest and apoptosis in 5T4 positive tumor cells in vitro. In vivo low systemic exposure and tumor-specific accumulation of D2102 rendered ACR246 superior efficacy and safety property. Accordingly, ACR246 exhibited robust in vivo anti-tumor activity across various types of 5T4 positive CDX models in a dose-dependent manner, with DNA damage induced by the accumulated D2102 in tumor tissue. GLP toxicity studies indicated that ACR246 was well tolerated in cynomolgus monkeys. The estimated therapeutic index was 24. Conclusions: The overall preclinical profile marks ACR246 has the potential to become the best in class (BIC) 5T4-ADC, showing more favorable benefit-risk ratio in clinic.
Orthorexia nervosa in breast cancer survivors: The role of disease characteristics and psychological aspects (GOIRC 02-2019).
Authors: Elena Barbieri, Luca Moscetti, Angela Toss, Laura Cortesi, Riccardo Cuoghi Costantini, Alessia Molinaro, Silvia Ferrari, Massimo Dominici
Journal: Journal of Clinical Oncology (2024)

e24092 Background: Orthorexia Nervosa (ON), although not yet considered as a full-blown psychopathological disorder, is defined as altered thoughts and behaviours related to healthy eating and its prevalence is increasing in general population. Surviving cancer is a condition that may affect patients behaviour and mental status leading to beliefs that may affect everyday life to avoid cancer recurrence. Among these, eating behaviour is mostly represented in cancer survivors. The aim of the present study is to evaluate the prevalence and characteristics of ON among breast cancer (BC) survivors. Methods: This observational study enrols adult patients attending the outpatient clinic at the Oncology Division of Modena University Hospital. Patients with a BC diagnosis that have concluded the surgical, radiotherapy and chemo and/or targeted therapy treatment phase were considered eligible. Ongoing hormonal adjuvant therapy was permitted. Socio-demographic, clinical variables (stage, year of diagnosis, hormone receptor status, HER2 status, proliferation index, treatment) were collected on an anonymized database. Moreover, three psychometric measurements were administered to patients: the Hospital Anxiety-Depression Scale (HADS), the Personality Inventory for DSM-5 Brief Form (PID-5-BIF) and the ORTO-R, a 6-item self-administered tool that is the most used scale to measure ON. Results: Data were collected from 137 patients. Mean age was 62.4 years and (± 10.3) and the mean BMI was 26.3 (± 5.2). Sixty-six percent of patients were diagnosed with stage I disease, 28% with stage II and 6% with stage III disease. Thirty percent of patients received adjuvant chemotherapy, 89% hormonal therapy and 15.5% anti-HER2 targeted therapy. The ORTO-R mean score was 12.2 ± 3.8. The prevalence of psychiatric symptoms at the HADS was 36.5%. The ORTO-R score was found to correlate negatively to age of patients (the older, the less the score at ORTO-R, p = 0.001) and positively to 3 of the constructs of personality at the PID-5-BF, disinhibition, psychoticism and negative affect. Interestingly, ORTO-R was poorly associated to cancer variables, such as stage, hormone receptors, treatments, phenotype (luminal, HER2 positive, triple negative), lifestyle and psychiatric symptomatology. Conclusions: Eating behaviours among cancer patients may be influenced by psychological aspects and need to be addressed during follow-up. Further investigations are needed to evaluate correlation with BC specific characteristics.[Table: see text]
Navigating disparities: Insights from a colorectal cancer screening program in federally qualified community healthcare centers.
Authors: Robby Amin, Christopher Turner, Brenda Santellano, Lorriane A. Odhiambo, Sable Fleming, Samah Ibrahim, Katreena Mitchell, Cynthia Merchant, Douglas Patten, Koosh Desai, James Hotz, Lynn M. Durham, Sheryl G. A. Gabram, Jorge E. Cortes, KM Monirul Islam
Journal: Journal of Clinical Oncology (2024)

1537 Background: Colorectal cancer (CRC) is the second leading cause of cancer deaths in Georgia. Despite evidence for the effectiveness of CRC screening, disparities in access are prevalent in underserved populations. Georgia’s Federally Qualified Health Centers (FQHCs) struggle with low screening rates (42.8%), partly due to Georgia’s lack of Medicaid expansion, poor access to health services in rural areas, and deficiencies in coordinated strategies. The Georgia Colorectal Cancer Control Program (GCRCCP) was funded by the Centers for Disease Control and Prevention to implement evidence-based interventions (EBIs) in qualifying FQHCs across South Georgia. Here, we assess the program's impact on clinic-level screening rates (SR). Methods: Fourteen clinics with 12,159 CRC-eligible patients (ages 50-75) were enrolled from East Georgia Healthcare Center (EGHC) and Albany Area Primary Health Center (AAPHC). FQHC clinics had to have a SR below 60% to participate in the program. In addition to the EBIs (provider assessment and feedback, provider reminders, patient reminders, reducing structural barriers), the GCRCCP integrated provider education using the ECHO Model and navigation through a nationally recognized, evidence-based patient navigation program. We compared baseline (2020 and 2021) and follow-up data (2022) to determine the average change in SR over time, overall, and by demographic sub-groups. Results: The overall change in SR for the 14 clinics was +6.7%, from a baseline average of 45.3% to 52% in 2022. The average change in SR for EGHC clinics (n=9) was +11.5% (from 32.2 to 43.7%). Women had a higher SR (44.9%) than men (41.8%), but both realized an increase in SR, +10.5% and +9.1%. Non-Hispanic Black Americans (NHBA) experienced a higher increase in SR, +13.7% (from 37.2 to 50.9%) than their Non-Hispanic White (NHW) counterparts (+7.5% (from 29.8 to 37.3%)). The uninsured vs. insured followed a similar pattern (+15.3% (from 17.8 to 33.1%)) vs. +2.1 (from 45.9 to 48%). The average change in SR for AAPHC clinics (n=5) was +1.8% (from 58.4 to 60.2%). There was a decline in SR for men, -8.6% (from 64 to 55.4%), and an increase for women, +3.8% (from 58.2 to 62%). NHBA had a decrease in SR, -0.8% (from 61.2 to 61%), while NHW Americans had an increase in SR, +0.2% (from 53.8 to 54.2%). The uninsured and insured groups realized minimal increases of +0.6% (from 46 to 46.6%) and +0.8% (from 62 to 62.8%), respectively. Conclusions: The implementation of EBIs and patient navigation show varied potential to reduce disparities in accessing CRC screening in underserved populations. FQHC clinics that sustain implementation activities and workflow processes can benefit communities long-term and improve health equity.
Preclinical analysis of the efficacy of near-infrared photoimmunotherapy and anti-PD-1 antibody combination therapy for treating CD73-positive lung cancer.
Authors: Ryohei Chiba, Kohei Nakajima, Kanako C Hatanaka, Hideki Ujiie, Masato Aragaki, Takuma Kobayashi, Teppei Konishi, Ichiro Kinoshita, Yutaka Hatanaka, Mikako Ogawa, Tatsuya Kato
Journal: Journal of Clinical Oncology (2024)

e14521 Background: The CD73/adenosine pathway, which converts extracellular ATP to adenosine, is emerging as a promising target for immunotherapy in various cancers. In the tumor microenvironment, hypoxia triggers upregulation of adenosine-activating molecules, including CD73, a membrane-anchored enzyme expressed on cancer cells. CD73 induces the expression of PD-1 and CTLA4, and all of this leads to immunosuppression. Therefore, we focused utilizing near-infrared photoimmunotherapy (NIR-PIT) to kill CD73-expressing cells and alleviate immunosuppression. NIR-PIT is an innovative cancer treatment approach which involves irradiating NIR light after the administrated antibody-photosensitizer conjugate binds to the target cells. Methods: In vitro, anti-CD73 antibody-IR700 conjugate was prepared and added to the CMT167 and LLC cell lines, which were irradiated with NIR light under a microscope. In vivo, a mouse model was established using the CMT167 cell line. The mice were divided into 6 groups: 1) NIR-PIT group against CD73; 2) anti-PD-1 antibody group; 3) combined treatment group of 1) and 2); 4) control group; 5) anti-CD73 antibody-IR700 conjugate group; and 6) near-infrared light irradiation group. Tumor volume and survival rate were compared among these groups. Additionally, after 2 weeks of treatment, tumors in the four groups 1) to 4) above were pathologically evaluated using two different AI-equipped software programs. Results: Microscope observation revealed that NIR-PIT induced immunogenic cell death of CD73-positive mouse lung cancer cell lines in vitro. In vivo, the effect of NIR-PIT on this mouse model was also demonstrated. Although previous studies have shown the efficacy of treatment with anti-CD73 antibodies, the present study compared the CD73-IR700 conjugate group to the NIR-PIT to CD73 group, and the latter group showed better therapeutic outcomes. Additionally, the combined treatment group displayed the highest anti-tumor efficacy in terms of survival and tumor volume. Pathological evaluation of the tumor interior showed a significant increase in tumor-infiltrating lymphocytes compared to the other groups. Additionally, the percentage of tumor cells was significantly reduced, while the percentage of stroma, including fibrous tissue, was significantly increased. In line with other studies that have already reported the additive effect of combination therapy with anti-CD73 antibodies and immune checkpoint inhibitors, the present study showed that the combination therapy resulted in further activation of immune cells and enhanced the therapeutic effect. Conclusions: CD73 represents a promising target for NIR-PIT, with potential for enhanced effectiveness when used in combination with immune checkpoint inhibitors.
Immune related adverse events in patients with breast cancer and autoimmune disease treated with immunotherapy.
Authors: Neelima Vidula, Jennifer Hutchinson, Abigail McLaren, Lianne Ryan, Andrzej Niemierko, Aditya Bardia
Journal: Journal of Clinical Oncology (2024)

1103 Background: Pembrolizumab is approved for early and advanced triple negative breast cancer (TNBC), and atezolizumab was approved for advanced TNBC. Toxicity of immunotherapy (IO) and immune related adverse events (irAEs) in patients with breast cancer with an underlying autoimmune disease are not well understood as autoimmune disease is often an exclusion criterion in immunotherapy trials. Understanding real-world IO toxicity and irAEs in patients with breast cancer and autoimmune disease may inform clinical decision making. Methods: We studied IO toxicity and irAEs in patients with early and metastatic breast cancer, and underlying autoimmune disease vs. those without autoimmune disease (at IO start) who received IO at an academic institution. A retrospective review was conducted to identify IO toxicity and irAEs (CTCAE v 5.0). Cohorts were compared with Pearson’s chi-squared test (categorical variables) and Wilcoxon rank-sum test (continuous variables), with p&lt;0.05 for statistical significance. Results: Cohorts had 23 patients with breast cancer and ≥1 autoimmune disease (AD) prior to receipt of IO (thyroid: 48%, rheumatologic: 26%, gastrointestinal: 13%, dermatologic: 9%), and 106 patients with breast cancer but without autoimmune disease (non-AD). Median age at IO start was 63 (interquartile range [IQR] 54-69) in AD vs. 50 in non-AD (IQR 39-59). Stage I-III/IV distribution was 39%/61% for AD and 67%/33% in non-AD. IO was mainly pembrolizumab (AD: 87%; non-AD: 85%) vs. atezolizumab. Table depicts characteristics of IO toxicity. A significantly higher overall rate of irAEs was seen in AD (96%) vs. non-AD (59%) [p&lt;0.001]. Significantly greater immune related transaminitis was observed in AD (52%) vs. non-AD (24%) [p=0.006]. Immune related hypothyroidism (AD: 30% vs. non-AD: 15%, p=0.08), nephritis (AD: 9% vs. non-AD 2%, p=0.08), and hyperthyroidism (AD: 9% vs. non-AD: 3%, p=0.19) had numerically higher rates in AD, but these findings did not achieve statistical significance. Flare of the baseline AD with IO was observed in 6/23 (26%) patients, and 50% of flares occurred within 1 month of starting IO (range 1-5 months). Management of irAEs was similar in AD vs. non-AD, and rates of full resolution of irAEs were similar (AD: 55%; non-AD: 61%, p=0.65). Late onset irAEs (&gt; 3 months after IO discontinuation) were rare (AD: 12%; non-AD: 4%, p=0.21). Conclusions: A higher overall rate of irAEs was observed in patients with underlying autoimmune disease, including greater immune related transaminitis and flare of the underlying autoimmune disease, suggesting the need for close monitoring of irAEs in this population. [Table: see text]