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Cancer Cell Mar 2020Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts....
Here, we show that tumor ADORA1 deletion suppresses cell growth in human melanoma cell lines in vitro and tumor development in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PD-L1 levels, which inactivates cocultured T cells in vitro, compromises anti-tumor immunity in vivo, and reduces anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of ADORA1-deficient or ADORA1 antagonist-treated melanoma and NSCLC immune-competent mouse models. Mechanistically, we identify ATF3 as the factor transcriptionally upregulating PD-L1 expression. Tumor ATF3 deletion improves the effect of ADORA1 antagonist treatment of melanoma and NSCLC xenografts. We observe higher ADORA1, lower ATF3, and lower PD-L1 expression levels in tumor tissues from nonresponders among PD-1 mAb-treated NSCLC patients.
Topics: Activating Transcription Factor 3; Adenosine A1 Receptor Antagonists; Adult; Aged; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cytarabine; Female; Humans; Lomustine; Lung Neoplasms; Male; Melanoma; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Mitoxantrone; Prednisone; Receptor, Adenosine A1; Tumor Escape; Xenograft Model Antitumor Assays
PubMed: 32183950
DOI: 10.1016/j.ccell.2020.02.006 -
Presse Medicale (Paris, France : 1983) Jun 2021Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT.
Topics: Abnormalities, Drug-Induced; Algorithms; Antibodies, Monoclonal, Humanized; Cladribine; Crotonates; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Hematopoietic Stem Cell Transplantation; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Indans; Interferon-beta; Male; Mitoxantrone; Multiple Sclerosis; Natalizumab; Nitriles; Oxadiazoles; Pregnancy; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Toluidines
PubMed: 34033862
DOI: 10.1016/j.lpm.2021.104068 -
The Lancet. Oncology Mar 2023Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the... (Review)
Review
Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
Survivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020.
Topics: Child; Humans; Adolescent; Young Adult; Neoplasms; Survivors; Antibiotics, Antineoplastic; Cardiomyopathies; Mitoxantrone
PubMed: 37052966
DOI: 10.1016/S1470-2045(23)00012-8 -
Blood Feb 2022Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and...
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Etoposide; Female; Glycolipids; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Survival Rate
PubMed: 34543383
DOI: 10.1182/blood.2021010721 -
Veterinary and Comparative Oncology Mar 2022Canine malignant mesothelioma (CMM) is a rare and aggressive tumour associated with a poor prognosis. Limited information is available regarding effective treatment...
Canine malignant mesothelioma (CMM) is a rare and aggressive tumour associated with a poor prognosis. Limited information is available regarding effective treatment options and prognostic factors. The purpose of this retrospective case series was to describe the clinical presentation, treatment and survival in a cohort of dogs with this disease and to investigate possible prognostic factors. Thirty-four dogs were included. Tachypnoea and dyspnoea due to pleural effusion were the most common presenting clinical signs. Twenty-two dogs had a subcutaneous access port placed and 25 dogs were treated with intracavitary and/or intravenous chemotherapy. The main protocols used were single-agent 5-FU (n = 14) and carboplatin single-agent or alternated with mitoxantrone (n = 10). The overall response rate (defined as more than 25% reduction in effusion volume) to chemotherapy treatment was 37% after 3-weeks and 24% after 15-weeks. The median survival time (MST) for all dogs was 195 days (95% CI 53-324). MST was 234 days for dogs receiving chemotherapy and 29 days for dogs not receiving chemotherapy. The 1-year survival rate was 22% for all dogs. Treatment with chemotherapy was the only significant prognostic factor associated with survival (p = .001). Further studies are needed to determine the optimal treatment approach for malignant mesothelioma in dogs. Nevertheless, effusion recurrence should be expected and the prognosis for these patients in the long-term is poor.
Topics: Animals; Carboplatin; Dog Diseases; Dogs; Mesothelioma, Malignant; Retrospective Studies; Treatment Outcome
PubMed: 34647420
DOI: 10.1111/vco.12777 -
Multiple Sclerosis and Related Disorders Aug 2021Today, there are no recommendations on switching disease-modifying treatments (DMTs) in multiple sclerosis (MS).
BACKGROUND
Today, there are no recommendations on switching disease-modifying treatments (DMTs) in multiple sclerosis (MS).
OBJECTIVES
To establish guidelines on switching DMTs MS.
METHODS
A Steering Committee composed of seven MS experts from the French Group for Recommendations in Multiple Sclerosis (France4MS) defined 15 proposals. These proposals were then submitted to a Rating Group, composed of 48 French MS experts, for evaluation. The proposals were classified as 'appropriate', 'inappropriate' or 'uncertain'.
RESULTS
Switching from a first-line therapy to another first-line therapy or a second-line therapy could be done without a washout period. Switching from a second-line therapy to a first-line therapy could be done without a washout period with fingolimod or natalizumab, after 3 months with ocrelizumab or mitoxantrone, and, if disease activity occurs with alemtuzumab or cladribine. The switch from a second-line therapy to another second-line therapy could be done after a washout period of 1 month with fingolimod or natalizumab, after 3 months with ocrelizumab, after 6 months with mitoxantrone, and, if disease activity occurs, with alemtuzumab or cladribine.
CONCLUSION
This expert consensus approach provides physicians with some guidelines on optimizing the benefit/risk ratio when switching DMTs in patients with MS.
Topics: Alemtuzumab; Cladribine; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab
PubMed: 34161898
DOI: 10.1016/j.msard.2021.103076