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Cancer Discovery Jul 2024Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte...
Despite its long history of toxicity and limited efficacy, IL2 has re-entered the clinic as a companion to the recently FDA-approved tumor infiltrating lymphocyte therapy. In back-to-back articles, Moynihan and Kaptein introduce a new fusion protein that delivers a biased IL2 mutein to CD8 T cells. See related article by Moynihan et al., p. 1206 (6). See related article by Kaptein et al., p. 1226 (7).
Topics: Humans; Interleukin-2; Neoplasms; CD8-Positive T-Lymphocytes; Lymphocytes, Tumor-Infiltrating
PubMed: 38946323
DOI: 10.1158/2159-8290.CD-24-0558 -
Radiation Oncology Journal Jun 2024To assess risk factors of disease progression after salvage radiation therapy (SRT) with androgen deprivation therapy (ADT) in case of prostate-specific antigen (PSA)...
Analysis of risk factors for disease progression after salvage radiation therapy with androgen deprivation therapy in prostate cancer patients who have prostate-specific antigen persistence after radical prostatectomy.
PURPOSE
To assess risk factors of disease progression after salvage radiation therapy (SRT) with androgen deprivation therapy (ADT) in case of prostate-specific antigen (PSA) persistence after radical prostatectomy (RP).
MATERIALS AND METHODS
We analyzed 57 patients who received SRT with ADT between 2013 and 2019 due to PSA persistence after RP. The endpoint was disease progression defined by biochemical recurrence or clinical recurrence. Age, Pre-RP PSA level, Gleason score, pathologic stage, presence of pelvic lymph node dissection, surgical margins, and PSA at 6-8 weeks after RP were analyzed as predictive factors for disease progression. Kaplan-Meier method and Cox regression models were used for data analysis.
RESULTS
At a median follow-up of 38 months (interquartile range, 26-61), 17 patients had disease progression. Pathologic T stage (pT3b vs. pT3a or lower; hazard ratio [HR] = 9.20; p = 0.035) and PSA level at 6-8 weeks after RP (≥2.04 vs. <2.04 ng/mL; HR = 5.85; p = 0.002) were predictors of disease progression. The 5-year disease progression-free survival rate was 46.7% in pT3b group as compared to 92.9 % in pT3a or lower group, and 18.4% for PSA ≥2.04 ng/mL after RP as compared to 79.2% for PSA <2.04 ng/mL.
CONCLUSION
Pathological T stage (pT3b) and post RP PSA ≥2.04 ng/mL are independent risk factors of disease progression after SRT with ADT in patients with PSA persistence after RP.
PubMed: 38946074
DOI: 10.3857/roj.2023.00962 -
Internal Medicine (Tokyo, Japan) 2024Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The...
Activated CD4 T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy.
Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion. Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022. Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included. Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4CD25CD127 T cells (hereafter referred to as "activated CD4 T cells" ) among the total CD4 T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4 T cells among the total CD4 T cells <0.73 (p=0.01, and p<0.01, respectively). Conclusion These results suggest that the proportion of activated CD4 T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations.
Topics: Humans; Male; Female; Cytokine Release Syndrome; Immunotherapy, Adoptive; Middle Aged; Lymphoma, Large B-Cell, Diffuse; Aged; Retrospective Studies; CD4-Positive T-Lymphocytes; Adult; Treatment Outcome; Receptors, Chimeric Antigen; Prognosis; Receptors, Antigen, T-Cell
PubMed: 38945932
DOI: 10.2169/internalmedicine.2556-23 -
Nihon Yakurigaku Zasshi. Folia... 2024Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular... (Review)
Review
[Pharmacological properties and clinical development overview of pertuzumab (genetical recombination), trastuzumab (genetical recombination) and vorhyaluronidase alfa (genetical recombination) (PHESGO combination for subcutaneous injection MA, IN)].
Pertuzumab and trastuzumab are anti-HER2 humanized monoclonal antibodies with different mechanisms of action. Their combination is expected to suppress intracellular HER2 signaling additively or synergistically. Their combination is widely recommended worldwide and has been established as a standard of care for HER2-positive breast cancer. However, improvement is required because of the prolonged time of intravenous infusion. Vorhyaluronidase alfa (rHuPH20) depolymerizes hyaluronan in the subcutaneous connective tissue. It's reported to increase the permeability and absorption levels of drugs. PHESGO combination for subcutaneous injection MA/IN (PHESGO) is a fixed-dose combination of pertuzumab, trastuzumab, and rHuPH20. A confirmatory phase III study (FeDeriCa) was conducted following a dose-finding phase I study (BO30185). Patients with HER2-positive early breast cancer were randomly assigned to receive either intravenous infusion of pertuzumab and trastuzumab or subcutaneous injection of PHESGO, in combination with chemotherapy, to compare the pharmacokinetics (PK), efficacy and safety. A phase II study (PHranceSCa) was also conducted to assess patients' preference and satisfaction. Based on these results, population PK analysis, and other data, PHESGO obtained marketing approval in Japan in September 2023 with indications for "HER2-positive breast cancer" and "advanced or recurrent HER2-positive colorectal cancer that has progressed following cancer chemotherapy and is not amenable to curative resection". By reducing the administration time, PHESGO is expected to contribute to various needs of patients and improvement of their daily lives. Since drug preparation is not required, it can provide convenience to healthcare professionals, leading to stress reduction of medical resources as well.
Topics: Humans; Trastuzumab; Antibodies, Monoclonal, Humanized; Hyaluronoglucosaminidase; Injections, Subcutaneous; Breast Neoplasms; Drug Combinations; Clinical Trials as Topic; Receptor, ErbB-2; Female; Recombinant Proteins; Cell Adhesion Molecules
PubMed: 38945908
DOI: 10.1254/fpj.24022 -
Muscle-Protective Effect of Carnosine against Dexamethasone-Induced Muscle Atrophy in C2C12 Myotube.Journal of Nutritional Science and... 2024This study investigated the protective effect of carnosine and its components (L-histidine and β-alanine [HA]) against dexamethasone (Dex)-induced muscle atrophy in...
This study investigated the protective effect of carnosine and its components (L-histidine and β-alanine [HA]) against dexamethasone (Dex)-induced muscle atrophy in C2C12 myotubes. Myotubes were treated with Dex (10 μM) to induce muscle atrophy manifested by decreased myotube diameter, low myosin heavy chain content, and increased expression of muscle atrophy-associated ubiquitin ligases (Atrogin-1, MuRF-1, and Cbl-b). Carnosine (20 mM) treatment significantly improved the myotube diameter and MyHC protein expression level in Dex-treated C2C12 myotubes. It also downregulated the expression of Atrogin-1, MuRF-1, and Cbl-b and suppressed the expression of forkhead box O3 (FoxO3a) mediated by Dex. Furthermore, reactive oxygen species production was increased by Dex but was ameliorated by carnosine treatment. However, HA (20 mM), the component of carnosine, treatment was found ineffective in preventing Dex-induced protein damage. Therefore, based on above results it can be suggested that carnosine could be a potential therapeutic agent to prevent Dex-induced muscle atrophy compared to its components HA.
Topics: Carnosine; Dexamethasone; Muscular Atrophy; Muscle Fibers, Skeletal; Animals; Mice; Muscle Proteins; Cell Line; Reactive Oxygen Species; SKP Cullin F-Box Protein Ligases; Ubiquitin-Protein Ligases; Forkhead Box Protein O3; Tripartite Motif Proteins; Myosin Heavy Chains
PubMed: 38945887
DOI: 10.3177/jnsv.70.219 -
Yakugaku Zasshi : Journal of the... 2024Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML...
Venetoclax (VEN) is used in patients with acute myeloid leukemia (AML) and is primarily metabolized by CYP3A4, a major drug-metabolizing enzyme. Patients with AML simultaneously administered VEN and CYP3A4 inhibitors require a more appropriate management of drug-drug interactions (DDIs). Here, we report two cases of patients with AML (54-year-old man and 22-year-old woman) administrated VEN and CYP3A4 inhibitors, such as posaconazole, cyclosporine, or danazol. In the first case, we evaluated the appropriateness of timing for adjusting VEN dosage subsequent to the cessation of posaconazole. Consequently, modifying the VEN dosage in conjunction with the cessation of Posaconazole simultaneously may result in elevated plasma VEN levels. In the second case, plasma VEN concentrations were markedly elevated when co-administered with several CYP3A4 inhibitors. Additionally, in vitro assays were conducted for reverse translational studies to analyze CYP3A4 inhibition. CYP3A4 inhibition by combinatorial administration of cyclosporine A and danazol was demonstrated in vitro, which potentially explains the increasing plasma VEN concentrations observed in clinical settings. Although the acquisition of therapeutic effects is a major priority for patients, frequent therapeutic drug monitoring and dosage adjustments considering DDIs would be important factors in chemotherapy.
Topics: Humans; Sulfonamides; Leukemia, Myeloid, Acute; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Male; Young Adult; Middle Aged; Bridged Bicyclo Compounds, Heterocyclic; Female; Drug Monitoring; Cytochrome P-450 CYP3A; Cyclosporine; Triazoles; Antineoplastic Agents
PubMed: 38945852
DOI: 10.1248/yakushi.24-00018 -
Yakugaku Zasshi : Journal of the... 2024An aqueous solution of 2,3-cis gallate type catechin (-)-epigallocatechin-3-O-gallate (EGCg) and caffeine afforded a precipitate of Creaming-down Phenomenon, which... (Review)
Review
An aqueous solution of 2,3-cis gallate type catechin (-)-epigallocatechin-3-O-gallate (EGCg) and caffeine afforded a precipitate of Creaming-down Phenomenon, which crystallized slowly for about three months to give a colorless block crystal. By X-ray crystallographic analysis, the crystal was determined to be a 2 : 2 complex of EGCg and caffeine, in which caffeine molecules were captured in a hydrophobic space formed with three aromatic A, B, and B' rings of EGCg. It was considered that the solubility of the 2 : 2 complex in water rapidly decreased and the 2 : 2 complex precipitated from aqueous solution. The hydrophobic spaces of EGCg captured a variety of heterocyclic compounds, and the molecular capture abilities of heterocyclic compounds using EGCg from the aqueous solutions were evaluated. Since the C ring of EGCg has two chiral carbon atoms, C and C, the hydrophobic space of EGCg was a chiral space. EGCg captured diketopiperazine cyclo(Pro-Xxx) (Xxx=Phe, Tyr) and pharmaceuticals with a xanthine skeleton, proxyphylline and diprophylline, in the hydrophobic space, and recognized their chirality.
Topics: Catechin; Tea; Caffeine; Hydrophobic and Hydrophilic Interactions; Solubility; Crystallography, X-Ray; Stereoisomerism; Water; Crystallization; Solutions; Heterocyclic Compounds; Xanthines
PubMed: 38945846
DOI: 10.1248/yakushi.24-00086 -
Food Research International (Ottawa,... Aug 2024To improve the color stability of anthocyanins (ACNs) in blueberry fermented beverage, the intermolecular copigmentation between ACNs and 3 different phenolic compounds,...
To improve the color stability of anthocyanins (ACNs) in blueberry fermented beverage, the intermolecular copigmentation between ACNs and 3 different phenolic compounds, including (-)-epigallocatechin gallate (EGCG), ferulic acid (FA), and gallic acid (GA) as copigments, was compared in the model and the real blueberry fermented beverage, respectively. The copigmented ACNs by EGCG presented a high absorbance (0.34 a.u.) and redness (27.09 ± 0.17) in the model blueberry fermented beverage. The copigmentation by the participation of the 3 different phenolic compounds showed all a spontaneous exothermic reaction, and the Gibbs free energy (ΔG°) of the system was lowest (-5.90 kJ/mol) using EGCG as copigment. Furthermore, the molecular docking model verified that binary complexes formed between ACNs and copigments by hydrogen bonds and π-π stacking. There was a high absorbance (1.02 a.u.), percentage polymeric color (PC%, 68.3 %), and good color saturation (C*ab, 43.28) in the real blueberry fermented beverage aged for 90 days, and more malvidin-3-O-glucoside had been preserved in the wine using EGCG as copigment. This finding may guide future industrial production of blueberry fermented beverage with improved color.
Topics: Anthocyanins; Blueberry Plants; Fermentation; Coumaric Acids; Molecular Docking Simulation; Gallic Acid; Phenols; Color; Catechin; Fruit and Vegetable Juices; Fruit
PubMed: 38945622
DOI: 10.1016/j.foodres.2024.114632 -
BMJ Case Reports Jun 2024Extranodal involvement in diffuse large B-cell lymphoma (DLBCL) is defined as disease outside of the lymph nodes and occurs in up to one-third of patients, though...
Extranodal involvement in diffuse large B-cell lymphoma (DLBCL) is defined as disease outside of the lymph nodes and occurs in up to one-third of patients, though multiorgan extranodal involvement is rare. Here, we describe a case of a patient presenting with widely metastatic lesions, including involvement of the lung, parotid gland, breast, pancreas, femur and multiple soft tissue masses, with initial concern for primary breast malignancy. Breast pathology and imaging were consistent with triple-expressor, double-hit stage IV high-grade B-cell lymphoma with extensive extranodal involvement. Extranodal involvement is a poor prognostic factor associated with high rates of treatment failure, and novel therapies targeting CD19 are currently being studied for relapsed and refractory DLBCL. Extranodal disease is a complex entity that can involve virtually any organ system and should be considered for new presentations of malignancy.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Female; Middle Aged; Breast Neoplasms; Lung Neoplasms; Parotid Neoplasms; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome
PubMed: 38945554
DOI: 10.1136/bcr-2023-257416 -
Journal For Immunotherapy of Cancer Jun 2024Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble...
INTRODUCTION
Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.
MATERIALS AND METHODS
This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.
RESULTS
169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).
CONCLUSION
The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
Topics: Humans; Melanoma; Female; Male; Autoantibodies; Middle Aged; Retrospective Studies; Aged; Immune Checkpoint Inhibitors; Seroconversion; Adult; Aged, 80 and over; Programmed Cell Death 1 Receptor
PubMed: 38945553
DOI: 10.1136/jitc-2024-009215