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Nutrients Aug 2022Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely...
Myelosuppression is a common and intractable side effect of cancer therapies including radiotherapy and chemotherapy, while the underlying mechanism remains incompletely understood. Here, using a mouse model of radiotherapy-induced myelosuppression, we show that inorganic phosphate (Pi) metabolism is acutely inhibited in hematopoietic stem cells (HSCs) during irradiation-induced myelosuppression, and closely correlated with the severity and prognosis of myelosuppression. Mechanistically, the acute Pi metabolic inhibition in HSCs results from extrinsic Pi loss in the bone marrow niche and the intrinsic transcriptional suppression of soluble carrier family 20 member 1 (SLC20A1)-mediated Pi uptake by p53. Meanwhile, Pi metabolic inhibition blunts irradiation-induced Akt hyperactivation in HSCs, thereby weakening its ability to counteract p53-mediated Pi metabolic inhibition and the apoptosis of HSCs and consequently contributing to myelosuppression progression. Conversely, the modulation of the Pi metabolism in HSCs via a high Pi diet or renal Klotho deficiency protects against irradiation-induced myelosuppression. These findings reveal that Pi metabolism and HSC survival are causally linked by the Akt/p53-SLC20A1 axis during myelosuppression and provide valuable insights into the pathogenesis and management of myelosuppression.
Topics: Bone Marrow; Hematopoietic Stem Cells; Phosphates; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53
PubMed: 36014901
DOI: 10.3390/nu14163395 -
Cureus Dec 2022High-dose methotrexate (MTX, 5 g/week) is typically used for the treatment of different malignancies and may be associated with serious side effects, such as acute...
High-dose methotrexate (MTX, 5 g/week) is typically used for the treatment of different malignancies and may be associated with serious side effects, such as acute kidney injury, myelosuppression, and hepatotoxicity. On the other hand, low-dose MTX (10-25 mg/week) is considered to be a safe and effective treatment for autoimmune arthropathies. Toxicity due to low-dose MTX is rare but can present with serious complications, such as pancytopenia. In this report, we present the case of an 82-year-old woman who presented with low-dose, MTX-induced severe pancytopenia and was treated with leucovorin rescue therapy with granulocyte colony-stimulating factor (G-CSF) therapy.
PubMed: 36654616
DOI: 10.7759/cureus.32494 -
Infection and Drug Resistance 2022Linezolid is classed as oxazolidinone antibiotics which can be used to treat severe infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired...
BACKGROUND
Linezolid is classed as oxazolidinone antibiotics which can be used to treat severe infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired pneumonia caused by Staphylococcus aureus, complicated skin, and uncomplicated skin structure infections (SSSIs) caused by methicillin-susceptible S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by Streptococcus pneumoniae. However, many studies have suggested it can also cause thrombocytopenia and pancytopenia.
PATIENTS AND METHODS
We report on three patients with linezolid-pancytopenia. Patients in cases 1 and 2 were diagnosed with heart failure with preserved ejection fraction (HFpEF) and were both administered with dapagliflozin, one of the sodium-dependent glucose transporters 2 inhibitors (SHLT-2i).
RESULTS
Two patients were diagnosed with type 2 diabetes, pneumonia, and hyponatremia. Severe myelosuppression occurred in both patients, with a severe decrease in leukocytes and platelets and a moderate decrease in hemoglobin, who eventually passed away despite the discontinuation of linezolid and adopting appropriate treatment measures. The patient in case 3 was diagnosed with pneumonia, type 2 diabetes, and sequelae of cerebral thrombosis. After twelve days of treatment, the patient developed moderate thrombocytopenia and anemia. She recovered without any additional treatment after the discontinuation of linezolid.
CONCLUSION
In this case series, two patients with irreversible myelosuppression were treated with both linezolid and SGLT-2i, and one diabetic patient with single linezolid use presented with reversible pancytopenia, suggesting that SGLT-2i may exacerbate myelosuppression of linezolid. Linezolid should be used with caution in infectious patients with a history of SGLT-2i. We will conduct relevant animal experiments to clarify the interaction between the two drugs.
PubMed: 36158232
DOI: 10.2147/IDR.S375694 -
Drugs 2006Wegener's granulomatosis (WG) is the most common pulmonary granulomatous vasculitis and was a uniformly fatal disease prior to the identification of efficacious... (Review)
Review
Wegener's granulomatosis (WG) is the most common pulmonary granulomatous vasculitis and was a uniformly fatal disease prior to the identification of efficacious pharmacological regimens. The pathogenesis of WG remains elusive but proteinase 3-specific anti-neutrophil cytoplasmic antibodies may be involved. Histologically, WG is defined by the triad of small vessel necrotising vasculitis, 'geographic' necrosis and granulomatous inflammation. Organ involvement characteristically includes the upper and lower respiratory tracts and kidney, but virtually any organ can be involved. The severity of the disease varies, ranging from asymptomatic disease to fulminant, fatal vasculitis. Similarly, the degree of organ involvement is highly variable; WG may be limited to a single organ (typically the lungs or upper respiratory tract), or may be systemic. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids, which induces complete remission in the majority of patients, is considered standard therapy. Since approximately 50% of patients experience a relapse following discontinuation of therapy, alternative regimens designed to maintain remissions after using cyclophosphamide and corticosteroids are usually necessary. This 'induction maintenance' approach to treatment has emerged as a central premise in planning therapy for patients with WG.A number of trials have evaluated the efficacy of less toxic immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil) and antibacterials (i.e. cotrimoxazole [trimethoprim/sulfamethoxazole]) for treating patients with WG, resulting in the identification of effective alternative regimens to induce or maintain remissions in certain sub-populations of patients. Given the efficacy of methotrexate (for early systemic WG) and cotrimoxazole (in WG limited solely to the upper airways) to induce remissions, and the relatively decreased associated morbidity compared with cyclophosphamide, these alternative regimens are preferred in appropriate patients. Similarly, therapeutic options to maintain disease remission that are less toxic than cyclophosphamide should be offered following induction of remission unless a specific contraindication exists. By following this premise, the development of cyclophosphamide-induced morbidities (e.g. haemorrhagic cystitis, uroepithelial cancers and prolonged myelosuppression) may be minimised. Recent investigation has focussed on other immunomodulatory agents (tumour necrosis factor-alpha inhibitors [infliximab and etanercept] and anti-CD20 antibodies [rituximab]) for treating patients with WG. However, the current data are conflicting and difficult to interpret. As a result, these newer agents cannot be recommended for routine use until vigorous clinical study confirms their efficacy.
Topics: Anti-Inflammatory Agents; Granulomatosis with Polyangiitis; Humans
PubMed: 16827598
DOI: 10.2165/00003495-200666090-00004 -
Frontiers in Pharmacology 2020Patients with advanced cancer often undergo myelosuppression after receiving chemotherapy. However, severe myelosuppression results in treatment delay, and some can even...
Patients with advanced cancer often undergo myelosuppression after receiving chemotherapy. However, severe myelosuppression results in treatment delay, and some can even be life-threatening. At present, cancer patients undergoing chemotherapy urgently need effective intervention strategies to prevent myelosuppression. Fortunately, ginsenoside Rg3 has shown promise as an anti-myelosuppression agent. Therefore, this study was conducted to evaluate the effectiveness of ginsenoside Rg3 in preventing chemotherapy-induced myelosuppression in cancer patients. The PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu (VIP), and Wanfang databases were searched in this study. A total of 18 trials which reported on 2,222 subjects were identified. All trials concerning the use of ginsenoside Rg3 for the prevention of chemotherapy-induced myelosuppression (the decline of leukocyte, hemoglobin, platelet, and neutrophil counts) were randomized-controlled trials. Dichotomous data were expressed as odds ratio (OR) with their respective 95% confidence intervals (CI). The Cochrane evidence-based medicine systematic evaluation was used to evaluate the methodological quality of the included trials. The Review Manager 5.3 and Stata 12.0 software were used to perform the statistical analyses. The trial sequential analysis (TSA) was used to evaluate information size and prevention benefits. The results revealed obvious ginsenoside Rg3-induced improvement in the leukocyte (OR, 0.46; 95% CI, 0.37-0.55), hemoglobin (OR, 0.64; 95% CI, 0.53-0.77), platelet (OR, 0.60; 95% CI, 0.48-0.75) and neutrophil (OR, 0.62; 95% CI, 0.43-0.90) counts at toxic grades I-IV, and leukocyte (OR, 0.39; 95% CI, 0.28-0.54) counts at toxic grades III-IV. The sensitivity analysis revealed that the results were robust. The Egger's test indicated that there was no publication bias in the results. Overall, this study suggested that ginsenoside Rg3 is beneficial for alleviating the chemotherapy-induced decrease in leukocyte, hemoglobin, platelet, and neutrophil counts. However, the confirmation of the ginsenoside Rg3 can be recommended for myelosuppression patients was limited due to poor methodological quality. Thus, more rigorously designed randomized-controlled trials (RCTs) are required to assess the efficacy of ginsenoside Rg3 for myelosuppression.
PubMed: 32477128
DOI: 10.3389/fphar.2020.00649 -
Frontiers in Immunology 2022Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause,... (Review)
Review
Autoimmune diseases are usually associated with environmental triggers and genetic predisposition. However, a few number of autoimmune diseases has a monogenic cause, mostly in children. These diseases may be the expression, isolated or associated with other symptoms, of an underlying inborn error of immunity (IEI). Autoimmune cytopenias (AICs), including immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), autoimmune neutropenia (AN), and Evans' syndrome (ES) are common presentations of immunological diseases in the pediatric age, with at least 65% of cases of ES genetically determined. Autoimmune cytopenias in IEI have often a more severe, chronic, and relapsing course. Treatment refractoriness also characterizes autoimmune cytopenia with a monogenic cause, such as IEI. The mechanisms underlying autoimmune cytopenias in IEI include cellular or humoral autoimmunity, immune dysregulation in cases of hemophagocytosis or lymphoproliferation with or without splenic sequestration, bone marrow failure, myelodysplasia, or secondary myelosuppression. Genetic characterization of autoimmune cytopenias is of fundamental importance as an early diagnosis improves the outcome and allows the setting up of a targeted therapy, such as CTLA-4 IgG fusion protein (Abatacept), small molecule inhibitors (JAK-inhibitors), or gene therapy. Currently, gene therapy represents one of the most attractive targeted therapeutic approaches to treat selected inborn errors of immunity. Even in the absence of specific targeted therapies, however, whole exome genetic testing (WES) for children with chronic multilineage cytopenias should be considered as an early diagnostic tool for disease diagnosis and genetic counseling.
Topics: Anemia, Hemolytic, Autoimmune; Autoimmunity; Child; Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia
PubMed: 35464467
DOI: 10.3389/fimmu.2022.846660 -
Frontiers in Immunology 2022To investigate the Th1/Th2 cytokine profile in patients with lymphoma during the myelosuppression stage of infection. 52 patients with gram-negative bacterial infection...
To investigate the Th1/Th2 cytokine profile in patients with lymphoma during the myelosuppression stage of infection. 52 patients with gram-negative bacterial infection (G- group), 49 patients with gram-positive bacterial infection (G+ group), 51 uninfected patients with lymphoma (uninfected group) and 20 healthy controls (healthy group) were enrolled in this study. We evaluated the quantification of Th1/Th2 cytokines with flow cytometry bead assay (CBA) in the sera to explore a rapid diagnostic method to determine the type of infection and anti-infective effect. The levels of procalcitonin (PCT) were also detected simultaneously. The four groups did not differ with regard to IL-2 and IL-4 (P>0.05). The IFN-γ and TNF-α levels of patients with lymphoma were higher than those of healthy controls (P<0.05). There was significantly upregulated IL-6 and IL-10 expression in the G- group (P<0.001). A similar trend was reflected in the IL-6 of the G+ group, which was significantly increased (P<0.001). However, no significant upregulation was observed for IL-10 in the G+ group. According to the different degrees of increased IL-6 and IL-10 levels, We proposed to use the G- Bacterial Infection Cytokine Profile (G- BICP) and the G+ Bacterial Infection Cytokine Profile (G+ BICP) for the first time to differentiate between Gram-negative and Gram-positive (G-/G+) bacterial infection in adults with lymphoma in the myelosuppression stage after chemotherapy. The IL-6, IL-10 and PCT in the G- group and the IL-6, PCT in the G+ group were significantly decreased at day 4 and day 8 compared with those at day 1. IL-6 and IL-10 are closely associated with the severity and treatment efficacy in adults with lymphomas who develop infections after chemotherapy and can help distinguish between G- and G+ bacterial infections at an early stage.
Topics: Adult; Cytokines; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Interleukin-10; Interleukin-6; Lymphoma; Procalcitonin
PubMed: 35432366
DOI: 10.3389/fimmu.2022.856039 -
Brazilian Journal of Otorhinolaryngology 2007Increasing the intensity of radiation therapy and chemotherapy in the management of cancer has increased the incidence of adverse effects, especially oral mucositis. (Review)
Review
UNLABELLED
Increasing the intensity of radiation therapy and chemotherapy in the management of cancer has increased the incidence of adverse effects, especially oral mucositis.
AIM AND METHODS
a bibliographical review was conducted on the definition of oral mucositis, its clinical findings, the incidence, its etiology, the pathophysiology, associated morbidity, prevention and treatment.
RESULTS
current studies define oral mucositis as a very frequent and painful inflammation with ulcers on the oral mucosa that are covered by a pseudo membrane. The incidence and severity of lesions are influenced by patient and treatment variables. Oral mucositis is a result of two major mechanisms: direct toxicity on the mucosa and myelosuppression due to the treatment. Its pathophysiology is composed of four interdependent phases: an initial inflammatory/vascular phase; an epithelial phase; an ulcerative/bacteriological phase; and a healing phase. It is considered a potential source of life-threatening infection and often is a dose-limiting factor in anticancer therapy. Some interventions have been shown to be potentially effective to prevent and treat oral mucositis. Further intensive research through well-structured clinical trials to obtain the best scientific evidence over the standard therapy of oral mucositis is necessary to attain ideal parameters for radiotherapy and chemotherapy.
Topics: Antineoplastic Agents; Humans; Mouth Mucosa; Neoplasms; Radiotherapy; Stomatitis
PubMed: 17923929
DOI: 10.1016/s1808-8694(15)30110-5 -
Frontiers in Oncology 2020An essential component of acute lymphoblastic leukemia (ALL) therapy is the prolonged maintenance phase with daily 6-mercaptopurine (6-MP) as the cornerstone. While 6-MP... (Review)
Review
An essential component of acute lymphoblastic leukemia (ALL) therapy is the prolonged maintenance phase with daily 6-mercaptopurine (6-MP) as the cornerstone. While 6-MP is generally well-tolerated, some patients suffer from significant side effects such as gastrointestinal (GI) toxicity, including hepatitis, hypoglycemia, nausea, and pancreatitis, which can substantially limit the tolerated dose of 6-MP. These toxicities are thought to result from skewed metabolism of 6-MP leading to an accumulation of the 6-methylmercaptopurine (6-MMP) metabolite. Here, we describe current knowledge behind the use of allopurinol to modify 6-MP metabolism and improve tolerance to therapy. This method has been successfully used in adults with inflammatory bowel disease refractory to purine therapy and has been modified for use in children with GI toxicities related to 6-MP in maintenance therapy for ALL. Use of allopurinol for 6-MP related toxicities should be reserved for patients in which an alternative cause of signs or symptoms has been excluded and for whom non-pharmacologic measures have failed. When allopurinol is used, simultaneous dose reduction of 6-MP is required to avoid severe myelosuppression and related side effects, though overall combination therapy appears to be well-tolerated and effective when instituted appropriately.
PubMed: 32766146
DOI: 10.3389/fonc.2020.01129 -
The Oncologist 2004Imatinib mesylate (Gleevec), Glivec, formerly STI571; Novartis Pharma AG; Basel, Switzerland) is a rationally-designed, molecularly-specific oral anticancer agent that... (Review)
Review
Imatinib mesylate (Gleevec), Glivec, formerly STI571; Novartis Pharma AG; Basel, Switzerland) is a rationally-designed, molecularly-specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer. It has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant gastrointestinal stromal tumors. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low. Adverse effects most commonly include mild-to-moderate edema, nausea and vomiting, diarrhea, muscle cramps, and cutaneous reactions. Hepatic transaminase level elevations and myelosuppression occur less frequently and resolve with interruption of imatinib therapy. In general, the incidence and severity of adverse effects tend to correlate with imatinib dose and, in chronic myeloid leukemia patients, the phase of disease; but, patient age and other factors are also associated with some types of reactions. With prompt and appropriate intervention, adverse effects in imatinib-treated patients have proven to be manageable across the spectrum of severity, and they seldom require permanent cessation of therapy. Dose reduction is not usually necessary, and reduction to subtherapeutic levels is not recommended.
Topics: Antineoplastic Agents; Benzamides; Bone Marrow; Chemical and Drug Induced Liver Injury; Drug Eruptions; Edema; Enzyme Inhibitors; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Muscle Cramp; Piperazines; Pyrimidines
PubMed: 15169982
DOI: 10.1634/theoncologist.9-3-271