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Molecular Therapy. Oncology Jun 2024Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles...
Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety. We recently developed a CAR T cell therapy targeting prostate stem cell antigen (PSCA) for prostate and pancreatic cancers, showing improved preclinical antitumor activity and T cell persistence by optimizing the intracellular co-stimulatory domain. Similar studies were undertaken to optimize HER2-directed CAR T cells with modifications to the intracellular co-stimulatory domain for selective targeting of breast cancer brain metastasis. In the present study, we evaluate various nonsignaling extracellular spacers in these CARs to further improve tumor antigen selectivity. Our findings suggest that length and structure of the extracellular spacer can dictate the ability of CARs to selectively target tumor cells with high antigen density, while sparing cells with low antigen density. This study contributes to CAR construct design considerations and expands our knowledge of tuning solid tumor CAR T cell therapies for improved safety and efficacy.
PubMed: 38939825
DOI: 10.1016/j.omton.2024.200789 -
Clinical & Translational Immunology 2024In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of... (Review)
Review
In recent years, bacteria have gained considerable attention as a promising drug carrier that is critical in improving the effectiveness and reducing the side effects of anti-tumor drugs. Drug carriers can be utilised in various forms, including magnetotactic bacteria, bacterial biohybrids, minicells, bacterial ghosts and bacterial spores. Additionally, functionalised and engineered bacteria obtained through gene engineering and surface modification could provide enhanced capabilities for drug delivery. This review summarises the current studies on bacteria-based drug delivery systems for anti-tumor therapy and discusses the prospects and challenges of bacteria as drug carriers. Furthermore, our findings aim to provide new directions and guidance for the research on bacteria-based drug systems.
PubMed: 38939727
DOI: 10.1002/cti2.1518 -
JACC. Advances Apr 2024Exposure to ionizing radiation is an inherent occupational health hazard in clinical cardiology. Health risks have been reported previously, including predilection to... (Review)
Review
Exposure to ionizing radiation is an inherent occupational health hazard in clinical cardiology. Health risks have been reported previously, including predilection to cancer. In addition, orthopedic injury due to prolonged wearing of heavy protective lead aprons, which are mandatory to reduce radiation risk, have been extensively documented. Cardiology as a specialty has grown with rising volumes of increasingly complex procedures. This includes electrophysiological, coronary, and structural intervention, advanced heart failure/transplant management, and diagnostic imaging. Both the operator as well imaging specialists are exposed to radiation, particularly in structural interventions where interventional cardiologists and structural imagers work closely. Increasingly, women interested in cardiology may deselect the field due to radiation concerns. This expert document highlights the risks of radiation exposure in cardiology, including practical tips within various subspecialty fields such as interventional/structural cardiology, electrophysiology, imaging, advanced heart failure, and pediatric cardiology.
PubMed: 38939686
DOI: 10.1016/j.jacadv.2024.100863 -
JACC. Advances Apr 2024Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models...
BACKGROUND
Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction.
OBJECTIVES
The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes.
METHODS
Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications.
RESULTS
The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%).
CONCLUSIONS
ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.
PubMed: 38939660
DOI: 10.1016/j.jacadv.2024.100852 -
Oncology Letters Aug 2024Tumor lysis syndrome (TLS) is a rare but serious complication in patients with solid tumors. It is characterized by a complex array of metabolic disturbances and...
Tumor lysis syndrome in a patient with advanced lung squamous cell carcinoma undergoing combined therapy with a programmed cell death protein 1 inhibitor and first‑line chemotherapy: A case report.
Tumor lysis syndrome (TLS) is a rare but serious complication in patients with solid tumors. It is characterized by a complex array of metabolic disturbances and clinical symptoms, resulting from the release of cellular contents into the bloodstream after tumor cell lysis. The present study reports the case of a patient with advanced lung squamous cell carcinoma (SCC) who developed TLS following combined treatment with PD-1 inhibitors and first-line chemotherapy. The treatment strategy included intravenous fluid replacement, urine alkalinization, uric acid reduction, renal protection and electrolyte stabilization, leading to the normalization of laboratory values. After one cycle of the combined therapy, the patient achieved a partial response, classified using the Response Evaluation Criteria in Solid Tumours 1.1 criteria. To the best of our knowledge, this is the first reported case of TLS in a patient with advanced lung SCC receiving concurrent PD-1 inhibitor and chemotherapy treatment. Given the increasing use of PD-1 inhibitors, it is essential to remain vigilant about the potential for TLS in solid tumors. Prompt intervention in high-risk patients, ongoing monitoring after treatment, and early detection of TLS are vital to improve patient adherence, ensure continuity of care and enhance outcomes.
PubMed: 38939620
DOI: 10.3892/ol.2024.14513 -
Oncoimmunology 2024The need for reliable biomarkers to predict clinical benefit from anti-PD1 treatment in metastatic melanoma (MM) patients remains unmet. Several parameters have been...
The need for reliable biomarkers to predict clinical benefit from anti-PD1 treatment in metastatic melanoma (MM) patients remains unmet. Several parameters have been considered in the tumor environment or the blood, but none has yet achieved sufficient accuracy for routine clinical practice. Whole blood samples from MM patients receiving second-line anti-PD1 treatment (NCT02626065), collected longitudinally, were analyzed by flow cytometry to assess the immune cell subsets absolute numbers, the expression of immune checkpoints or ligands on T cells and the functionality of innate immune cells and T cells. Clinical response was assessed according to Progression-Free Survival (PFS) status at one-year following initiation of anti-PD1 (responders: PFS > 1 year; non-responders: PFS ≤ 1 year). At baseline, several phenotypic and functional alterations in blood immune cells were observed in MM patients compared to healthy donors, but only the proportion of polyfunctional memory CD4+ T cells was associated with response to anti-PD1. Under treatment, a decreased frequency of HVEM on CD4+ and CD8+ T cells after 3 months of treatment identified responding patients, whereas its receptor BTLA was not modulated. Both reduced proportion of CD69-expressing CD4+ and CD8+ T cells and increased number of polyfunctional blood memory T cells after 3 months of treatment were associated with response to anti-PD1. Of upmost importance, the combination of changes of all these markers accurately discriminated between responding and non-responding patients. These results suggest that drugs targeting HVEM/BTLA pathway may be of interest to improve anti-PD1 efficacy.
Topics: Humans; Melanoma; Male; Receptors, Immunologic; Female; Middle Aged; Aged; Programmed Cell Death 1 Receptor; Receptors, Tumor Necrosis Factor, Member 14; Immune Checkpoint Inhibitors; Adult; Treatment Outcome; CD8-Positive T-Lymphocytes
PubMed: 38939518
DOI: 10.1080/2162402X.2024.2372118 -
Journal of Extracellular Biology Mar 2024Extracellular vesicles (EVs) frequently express human leukocyte antigen class I (HLA-I) molecules. The immunopeptidomes presented on EV HLA-I are being mapped to provide...
Extracellular vesicles (EVs) frequently express human leukocyte antigen class I (HLA-I) molecules. The immunopeptidomes presented on EV HLA-I are being mapped to provide key information on both specific cancer-related peptides, and for larger immunopeptidomic signatures associated with disease. Utilizing HLA-I immunoisolation and mass spectrometry, we characterised the HLA-I immunopeptidome of EVs derived from the melanoma cancer cell line, ESTDAB-026, and the plasma of 12 patients diagnosed with advanced stage melanoma, alongside 11 healthy controls. The EV HLA-I immunopeptidome derived from melanoma cells features T cell epitopes with known immunogenicity and peptides derived from known tumour associated antigens (TAAs). Both T cell epitopes with known immunogenicity and peptides derived from known TAAs were also identifiable in the melanoma patient samples. Patient stratification into two distinct groups with varying immunological profiles was also observed. The data obtained in this study suggests for the first time that the HLA-I immunopeptidome of EVs derived from blood may aid in the detection of important diagnostic or prognostic biomarkers and also provide new immunotherapy targets.
PubMed: 38939414
DOI: 10.1002/jex2.146 -
Frontiers in Oncology 2024Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in...
BACKGROUND
Malignant pleural effusion (MPE) is prevalent among cancer patients, indicating pleural metastasis and predicting poor prognosis. However, accurately identifying MPE in clinical settings is challenging. The aim of this study was to establish an innovative nomogram-derived model based on clinical indicators and serum metal ion levels to identify MPE.
METHODS
From July 2020 to May 2022, 428 patients diagnosed with pleural effusion (PE) were consecutively recruited. Comprehensive demographic details, clinical symptoms, imaging data, pathological information, and laboratory results, including serum metal ion levels, were systematically collected. The nomogram was created by incorporating the most significant predictors identified through LASSO and multivariate logistic regression analysis. The predictors were assigned weighted points based on their respective regression coefficients, allowing for the calculation of a total score that corresponds to the probability of MPE. Internal validation using bootstrapping techniques assessed the nomogram's performance, including calibration, discrimination, and clinical applicability.
RESULTS
Seven key variables were identified using LASSO regression and multiple regression analysis, including dyspnea, fever, X-ray/CT compatible with malignancy, pleural carcinoembryonic antigen(pCEA), serum neuron-specific enolase(sNSE), serum carcinoembryonic antigen(sCEA), and pleural lactate dehydrogenase(pLDH). Internal validation underscored the superior performance of our model (AUC=0.940). Decision curve analysis (DCA) analysis demonstrated substantial net benefit across a probability threshold range > 1%. Additionally, serum calcium and copper levels were significantly higher, while serum zinc levels were significantly lower in MPE patients compared to benign pleural effusion (BPE) patients.
CONCLUSION
This study effectively developed a user-friendly and reliable MPE identification model incorporating seven markers, aiding in the classification of PE subtypes in clinical settings. Furthermore, our study highlights the clinical value of serum metal ions in distinguishing malignant pleural effusion from BPE. This significant advancement provides essential tools for physicians to accurately diagnose and treat patients with MPE.
PubMed: 38939338
DOI: 10.3389/fonc.2024.1431318 -
Cureus May 2024Maxillary osteomyelitis is a rare bone infection and is rarer to come across with the advent of advanced antibiotic therapies. It is often linked to immunocompromised...
Maxillary osteomyelitis is a rare bone infection and is rarer to come across with the advent of advanced antibiotic therapies. It is often linked to immunocompromised conditions, namely diabetes mellitus, cancer, and chronic alcoholism, as they increase the chances of developing osteomyelitis. We present a rare case of maxillary osteomyelitis along with an infraorbital abscess in a 32-year-old male patient with uncontrolled diabetes. The patient complained of dental pain, facial swelling, and visual disturbances. The patient was managed with sequestrectomy along with curettage, incision, and drainage of orbital abscess. The patient responded well to surgery and had no complications post-surgery. As radiographic signs may present late, the authors aim to highlight the significance of thorough clinical examination and good patient history. Prompt radical treatment is necessary to avoid any severe consequences.
PubMed: 38939302
DOI: 10.7759/cureus.61202 -
Cureus May 2024Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, accounting for approximately 25% of childhood cancers. Despite significant advancements in...
Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, accounting for approximately 25% of childhood cancers. Despite significant advancements in treatment protocols, ALL remains a complex disease, often presenting with various complications, including the rare metabolic disturbance of type B lactic acidosis. This case report details the clinical journey of a 14-year-old female with ALL who developed type B lactic acidosis during treatment. The patient presented with intermittent fever, abdominal pain, jaundice, and hepatosplenomegaly, accompanied by severe anemia and thrombocytopenia. Initial management included supportive care and chemotherapy initiation. Despite aggressive interventions, the patient's condition deteriorated, with escalating lactic acidosis and respiratory distress, leading to a critical need for tailored management strategies. This report underscores the importance of early recognition and comprehensive management of type B lactic acidosis in pediatric ALL, highlighting its multifactorial etiology and potentially life-threatening consequences. Enhanced clinical awareness and a multidisciplinary approach are crucial for improving outcomes in such complex cases.
PubMed: 38939285
DOI: 10.7759/cureus.61201