tbuckley/cabot-search huggingface dataset:
Anti-PD-1/TGF-βRII bispecific antibody fusion protein LBL-015 in patients with advanced malignant tumors: A phase I, first-in-human, open-label, multicenter, dose-escalation study.
Authors: Qun Li, Wei Zhao, Wei Wang, Po Chen, Zuoxing Niu, Shuqin Ni, Suxia Luo, Junjing Qiao, Mingxi Wang, Yong Li, Yan He, Tao Liu, Tao Li, Shengli Cai, Jin Li
Journal: Journal of Clinical Oncology (2024)

2592 Background: LBL-015 is a bispecific fusion protein which consists of fully anti PD-1 monoclonal antibody and TGF-βRII ectodomain, designed to block PD-1/PD-L1 and TGFβ signal pathway, reversing immune suppression and promoting anti-tumor immunity. Here we report the preliminary safety and efficacy of LBL-015 in patients with advanced solid tumors. Methods: This is a phase Ⅰ, open-label, multicenter, dose-escalation study to evaluate the safety, tolerability, and PK of LBL-015 in patients with advanced solid tumors that progressed after standard therapy. The dose escalation phase consists of 6 dose cohorts of LBL-015 at 0.3, 1.2, 4, 6, 10, and 20 mg/kg (iv Q2W), using an accelerated titration design (first dose) followed by a 3+3 design. The primary endpoints were tolerability and safety. The second objectives were pharmacokinetics, pharmacodynamics, and preliminary efficacy (per RECIST 1.1). Results: As of December 05, 2023, 25 patients [Demography: 11 (44%) male, median age 59 years (range:24, 72), 23 (92%) ECOG score of 1] received LBL-015 treatment. Tumor types included 7 (28%) colorectal cancer, 6 (24%) renal carcinoma (RCC), 2 (8%) gastric carcinoma, 2 (8%) nasopharyngeal carcinoma and 8 (32%) other tumors. 15 (60%) previously received anti-PD(L)-1 treatment. During the study, 2 DLTs (respiratory failure at grade 5 and pulmonary infection at grade 3, respectively) were observed at the dose of 10 and 20 mg/kg, and the MTD was not reached. 25 patients (100%) experienced TEAEs of any grade and 11 patients (44%) at grade ≥3. The most common grade TEAEs (≥20%) were grade 1-2 and included anaemia, AST increased, γ–GT increased, gingival bleeding, pyrexia, LDH increased, proteinuria, ALT increased, weight decreased, asthenia, bilirubin conjugated increased, decreased appetite, hypoalbuminaemia, asthenia. Treatment interruption and permanent discontinuation of LBL-015 due to TEAEs occurred in 3 (12%) and 2 (8%) patients, respectively. Six patients (24%) experienced SAEs. Out of the 20 patients who underwent at least one efficacy evaluation per RECIST, 1 patient with RCC achieved PR at first image assessment which remained partial response for more than 28 weeks, and 4 patients achieved SD. The ORR and DCR were 5%, and 25%, respectively. Conclusions: LBL-015 has demonstrated good safety profiles in patients with advanced solid tumors. The encouraging preliminary efficacy signals indicated additional studies with a focus on TGFβ signaling pathway deregulated or activated tumors such as RCC, pancreatic cancer, etc. should be further explored. Clinical trial information: NCT05107011 .
A Multifunctional Nanostructured Hydrogel as a Platform for Deciphering Niche Interactions of Hematopoietic Stem and Progenitor Cells
Authors: Anita Ludwig‐Husemann, Peter Schertl, Ananya Shrivastava, Udo Geckle, Johanna Hafner, Frank Schaarschmidt, Norbert Willenbacher, Uwe Freudenberg, Carsten Werner, Cornelia Lee‐Thedieck
Journal: Advanced Healthcare Materials (2024)

For over half a century, hematopoietic stem cells (HSCs) have been used for transplantation therapy to treat severe hematologic diseases. Successful outcomes depend on collecting sufficient donor HSCs as well as ensuring efficient engraftment. These processes are influenced by dynamic interactions of HSCs with the bone marrow niche, which can be revealed by artificial niche models. Here, a multifunctional nanostructured hydrogel is presented as a 2D platform to investigate how the interdependencies of cytokine binding and nanopatterned adhesive ligands influence the behavior of human hematopoietic stem and progenitor cells (HSPCs). The results indicate that the degree of HSPC polarization and motility, observed when cultured on gels presenting the chemokine SDF-1α and a nanoscale-defined density of a cellular (IDSP) or extracellular matrix (LDV) α
Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally
Authors: Javier Carmona, Elena Chavarria, Kate Donoghue, Christina von Gertten, Petra Oberrauch, Emma Pailler, Giovanni Scoazec, Ruud Weijer, Judith Balmaña, Irene Brana, Cinzia Brunelli, Suzette Delaloge, Marc Deloger, Pierre Delpy, Ingemar Ernberg, Rebecca C. Fitzgerald, Elena Garralda, Martin Lablans, Janne Lëhtio, Carlos Lopez, Maialen Fernández, Rosalba Miceli, Paolo Nuciforo, Raquel Perez-Lopez, Elena Provenzano, Marjanka K. Schmidt, Cesar Serrano, Neeltje Steeghs, David Tamborero, Valtteri Wirta, Richard D. Baird, Karen Barker, Fabrice Barlesi, Michael Baumann, Jonas Bergh, Filippo de Braud, Karim Fizazi, Stefan Fröhling, Alejandro Piris-Giménez, Kenneth Seamon, Michiel S. Van der Heijden, Wilbert Zwart, Josep Tabernero
Journal: Cancer Discovery (2024)

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.
Prevalence of cannabis related potential medication interactions (PMI) among patients with cancer during treatment.
Authors: Elyssa Kim, Jennifer Cullen, Prateek Mendiratta, Megan Farrell, Shalena Finklea, Lauren Huang, Erika Trapl, Alexandre Chan, Stanton L. Gerson, Richard T. Lee
Journal: Journal of Clinical Oncology (2024)

12073 Background: The utilization of cannabis is increasing among patients with cancer; however, limited information exists about PMI with cannabis during treatment for cancer. Methods: An NCI-funded cross-sectional survey study was conducted at a comprehensive cancer center among patients undergoing anticancer therapy. Subjects completed a survey about utilization of medications including supplements and cannabis – specifically reasons for use and type of cannabis. All patients actively taking any cannabis were identified and included for analysis. Lexicomp and Natural Medicines Comprehensive Database interaction software were used to determine PMIs. Results: A total of 61 patients (19.5%) were identified from 313 participants as actively using a form of cannabis. Subjects had a mean age of 58 (SD±13.3) and mostly self-identified as being White (70%) with one-fifth being Black (21%). The most common types of cancer were lung (18%), breast (15%), lymphoma (12%) and colorectal (12%). The most prevalent modes of cannabis intake were smoking (36%), gummies (33%), and oil/tincture/liquid (16%). The most common reasons for cannabis use included insomnia (46%), pain (41%), and mood (39%). The median number of medications used were 6 (range, 1-16) and supplements (including cannabis) were 3 (range, 1-14). A total of 1157 PMIs and 569 unique PMIs were identified among active cannabis users. The most common PMIs were prescription-supplement interactions (31.7%) and prescription-cannabis interactions (27%). Nearly two-thirds of the PMIs (61%) were labelled as moderate, followed by major interactions (18%). Among these patients, there were 412 cannabis interactions (36% of PMIs) with 124 being unique. Of these cannabis PMIs, 71% were interactions with non-anticancer prescription medications, 17% with over-the-counter medications, and 10% with anticancer agents. Most of the cannabis PMIs were categorized as moderate (87%) and major (12%) severity, and the level of evidence of these PMIs were rated as poor (60%). The most common cannabis-related PMIs were with acetaminophen (9.5%), dexamethasone (8%), and ondansetron (6.3%). The most common chemotherapy PMIs were with paclitaxel (4%) and doxorubicin (2%). Conclusions: This is one of the first studies to assess cannabis-related drug interactions in patients receiving cancer treatment, and results indicates a significant proportion of cannabis users are at risk for moderate to major PMIs including with chemotherapy.[Table: see text]
Patterns of immune-related adverse events (irAEs) in adolescent and young adult (AYA) patients with melanoma receiving immune checkpoint inhibitors (ICIs).
Authors: Jiasen He, Ida John, Faraz Afridi, Mianen Sun, Yinghong Wang, Michael Roth, Jennifer Leigh McQuade
Journal: Journal of Clinical Oncology (2024)

12117 Background: ICIs are increasingly used in AYAs with cancer, however, limited data exists on the frequency and pattern of irAEs in this population and the ability to rechallenge with ICIs after irAEs. Methods: This retrospective study analyzed AYAs aged 15-39 with melanoma who received treatment with ICIs at MD Anderson Cancer Center from 2013 to 2023. Treatment cessation was defined as switching therapies or pausing the original treatment for over 3 months, and rechallenge as resuming immunotherapy post-cessation. Results: A total of 136 pts were included, 80 were male (59%), with median age at 33 years (range, 15-39 years) upon initial ICI exposure. The majority had non-acral cutaneous melanoma (107, 79%) and 83 (63%) had a BRAF V600E/R/K alteration. Ninety-three percent patients had stage III/IV cancer at ICI treatment initiation. Targeted therapy was used in 20 patients (15%) prior to starting ICI and 16 patients (12%) concurrently. Combination immunotherapy was utilized in 43% of cases, while monotherapy in 57%. The initial intent for ICIs was adjuvant in 51% of the cases, palliative in 37% and neoadjuvant in 12%. The incidence of any-grade and grade III/IV irAEs with 1st line ICI therapy was 60% and 21% for the full cohort (with combination of CTLA-4/PD-1 blockers 70% and 33%; with PD-1 blockers monotherapy was 50% and 9%, respectively). Forty-eight AYAs had multi-system irAEs (35%) and 23 were grade III/IV. Thirty-two (24%) patients had their initial ICI stopped due to irAEs with hepatitis (31%, 10/32) and colitis (28%, 9/32) being the most common causes. Eighteen patients (13%) had irAE-related hospitalizations. Specific irAEs are listed in the table. Seventy-two (53%) patients were rechallenged with ICIs. Of these, 51 had previous irAEs and among these, 71% had recurrent irAEs. Seventy-six percent (36/51) experienced irAEs again with 33% (17/51) having the same irAEs. Twenty-six percent of patients (13/51) had grade III/IV irAEs. Conclusions: In AYAs with melanoma who were treated with ICIs, irAE is one of the major reasons for treatment interruption. The incidence of irAEs in AYAs appears somewhat lower than the rates previously reported in registrational trials, though this should be interpreted with caution given retrospective nature of current study. Patients with prior irAEs have a higher risk of recurrent or new irAEs upon rechallenge, however, the majority were low grade without serious negative outcome. [Table: see text]
The impact of glucagon-like peptide 1 agonists on anthracycline or human epidermal growth factor receptor 2 inhibitor-associated cardiotoxicity in patients with breast cancer and diabetes mellitus.
Authors: Cho Han Chiang, Yu-Cheng Chang, Zhiting Tang, Xin Ya See, Kuan-Yu Chi, Yu Chang, Cho Hung Chiang, Azin Ghamari, Lauren Mary Curtis, Tomas G. Neilan
Journal: Journal of Clinical Oncology (2024)

12026 Background: Anthracyclines or human epidermal growth factor receptor 2 (HER-2) inhibitors are associated with the potential for major adverse cardiovascular outcomes (MACE) among patients with breast cancer. Diabetes mellitus (DM) further increases the risk of MACE. Glucagon-like peptide 1 agonists (GLP1a) have been shown to improve MACE in the non-cancer population; however, there are no data testing whether GLP1a reduce the risk for MACE associated with anthracyclines or HER-2 inhibitors. Therefore, we hypothesized that GLP1a may decrease the risk for MACE among patients with breast cancer and DM receiving anthracycline or HER-2 inhibitors. Methods: We performed a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network database, which contains de-identified data from over 120 participating healthcare institutions. We included adult breast cancer patients with type 2 DM who were treated with an anthracycline or HER-2 inhibitor therapy. We matched patients receiving a GLP1a with patients receiving non-GLP1a second-line diabetes medication based on the following variables: age, sex, pre-existing cardiac disease, the use of radiation, metastatic disease, cancer therapy, underlying comorbidities, and use of cardiovascular and diabetes medications. The primary outcome of interest, MACE, was defined as a composite of heart failure, myocardial infarction, and atrial fibrillation/flutter. Secondary outcomes included a composite of heart failure hospitalization and incident heart failure. Safety outcomes included all-cause mortality within 5 years of therapy initiation. Results: We matched 724 patients receiving a GLP1a treatment with patients receiving non-GLP1a treatment. The median age was 60 years for both cohorts. The prevalence of hypertension (81%), metastatic disease (61%), and radiation therapy (42%) was similar between cohorts, as was the use of anthracyclines and HER-2 inhibitors. In Cox proportional hazard analyses, the group receiving GLP1a treatment was associated with a lower risk of MACE (Hazard ratio (HR), 0.59 [95% CI: 0.41-0.86]), and heart failure hospitalization (HR, 0.56 [95% CI: 0.37-0.83]), and all-cause mortality (HR, 0.67 [95% CI: 0.48-0.93]) compared with non-GLP1a. Conclusions: GLP1a were associated with a reduction in major adverse cardiovascular events, incident heart failure and heart failure hospitalization, and all-cause mortality among anthracycline or HER-2 inhibitor-treated patients with breast cancer and DM. [Table: see text]
Development and validation of a deep learning–based cardiovascular disease risk prediction model for long-term breast cancer survivors.
Authors: Sinae Oh, Jae Yong Shim
Journal: Journal of Clinical Oncology (2024)

12023 Background: Previous efforts in predicting cardiotoxicity risk among patients with breast cancer have mostly focused on preventing and monitoring of cardiovascular complications during cancer therapy. We aimed to develop prediction models for the risk of chronic cardiovascular complications in breast cancer survivors during long-term follow-up. Methods: We used the Korean National Health Insurance Service databases between 2005 and 2021, including 5,131 5-year female breast cancer survivors diagnosed in 2006. The study cohort was randomized on a 4:1 ratio into the derivation and validation cohort. The primary outcome was the occurrence of major adverse cardiovascular events (MACEs), a composite of acute myocardial infarction, congestive heart failure, and stroke, at any time before the final follow-up at 10 years. We used the Cox proportional hazards model (CoxPH) with the least absolute shrinkage and selection operator penalty to determine the order of clinical factors based on their absolute coefficient value. We developed a deep learning survival model (DeepSurv) and compared its performance with traditional models such as CoxPH and random survival forest (RSF) using the same dataset. Model performance was assessed by discrimination and calibration. Results: During the 48054.1 person-years of follow-up, 325 (6.3%) patients developed MACE. We identified 18 relevant clinical factors without zero coefficients, including age, hypertension, atrial fibrillation, stroke, diabetes mellitus, myocardial infarction, household income, congestive heart failure, hemoglobin level, systolic blood pressure, peripheral arterial occlusive disease, chronic kidney disease, aromatase inhibitor use, alcohol consumption, cigarette smoking, tamoxifen use, radiotherapy, and total cholesterol level. The CoxPH, RSF, and DeepSurv model yielded time-dependent concordance index values of 0.713, 0.721, and 0.729, respectively, in the validation cohort. all models demonstrated good integrated Brier scores of 0.031 or less. Conclusions: We developed and validated a deep learning survival model that predict MACEs in individual 5-year breast cancer survivors, incorporating both conventional and breast cancer treatment-related cardiovascular risk factors, and demonstrated good calibration and discrimination. These models can assist breast cancer survivors and clinicians in optimally selecting risk-reducing strategies based on individual MACEs risk.
Cancer Rehabilitation: Impact on Breast Cancer Survivors’ Work Ability and Health-Related Quality of Life
Authors: Mackenzi Pergolotti, Kelley C. Wood, Tiffany Kendig, Kim Love, Stacye Mayo
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: Breast cancer survivors (BCSs) report persistent, diminished ability to work, and decreased health-related quality of life (HRQoL). Cancer rehabilitation interventions (physical therapy or occupational therapy [PT/OT]) aim to improve these outcomes, but little is known about their impact in the community. Methods: This retrospective, pre-post, uncontrolled study examined cases of younger BCSs (age &lt;65 years) who attended cancer-specialized PT/OT over a 2-year period. Outcomes and covariates (age, race, US region, payer type, number of visits, length of care [weeks]) were extracted from electronic medical records. Patient-reported outcomes were overall-Work Ability Score (WAS overall ), physical-WAS (WAS physical ), and mental-WAS (WAS mental ) and PROMIS Global Physical Health (GPH), Global Mental Health (GMH), Physical Function (PF), and Ability to Participate in Social Roles and Activities (SRA). We used linear mixed effect models to examine pre- to post-rehabilitation change overall, and separately, while controlling for covariates. Results: PT/OT cases (N PT =758; N OT =140) had a mean [SD] age of 51.39 [8.49] years and attended approximately 12 visits (IQR, 8.0–19.0) over 10.71 weeks (IQR, 6.14–17.00). Overall, work ability outcomes (WAS overall : +1.79; WAS physical : +0.78; WAS mental : +0.47; all P &lt;.001) and HRQoL outcomes improved significantly (GPH: +5.38; GMH: +2.90; PF: +5.17; SRA: +5.83; all P &lt;.001), and average change on each HRQoL outcome exceeded the minimal important change (2 points). Outcome scores were similar at each timepoint for both PT and OT cases (all P &gt;.05) and both groups improved significantly (all P &lt;.01). Conclusions: In this large study of the impact of cancer-specialized, community-based PT and OT, younger BCSs reported significant improvement in ability to work and HRQoL. Although more research is needed, these findings suggest improved access to PT/OT could improve work ability and HRQoL for younger BCSs.
Vitamin B <sub>12</sub> deficiency: NICE guideline summary
Authors: Toby Sands, Aamer Jawed, Emma Stevenson, Maddie Smith, Imran Jawaid
Journal: BMJ (2024)

### What you need to know Vitamin B12 deficiency is associated with a range of symptoms and signs, resulting in substantial variation in patient presentation . While epidemiological data are limited, cross sectional studies from the UK and US suggest a prevalence of 3% in people aged 20-39, increasing with age up to about 20% in people aged 85 and over.12 Complications of vitamin B12 deficiency include visual changes, paraesthesia, and ataxia. In March 2024, the National Institute for Health and Care Excellence (NICE) published new guidance on the diagnosis and management of B12 deficiency.3 This summary aims to raise awareness of the symptoms and signs, assessment, and management of vitamin B12 deficiency, with particular focus on what is most relevant to general practice and primary care. Readers are directed to the full guideline for a comprehensive review of all recommendations. NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline committee's experience and its opinion of what constitutes good practice. Evidence levels for the recommendations are given in italics in square brackets. ### GRADE Working Group grades of evidence
A commentary on “Impact of intravenous dexmedetomidine on postoperative gastrointestinal function recovery: an updated meta-analysis”
Authors: Tao Cai, Jinhu Shi, Xinggui Qin
Journal: International Journal of Surgery (2024)

Department of Warehouse, Jinling Hospital, Medical School of Nanjing University, Nanjing, China, 210000 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 Warehouse, Jinling Hospital, Medical School of Nanjing University, Nanjing, China, 210000. E-mail address: [email protected] (X. Qin). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism
Authors: Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B. Bloch, Takaaki Akaike, Fumito Ichinose
Journal: Journal of Clinical Investigation (2024)

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, we report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome. SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Administration of metronidazole or a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.