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Abstract High-dose methotrexate (HDMTX) is used in the treatment of a range of adult and childhood cancers. Although HDMTX can provide effective anti-tumor activity with an acceptable safety profile for most patients, delayed methotrexate elimination (DME) develops in a minority of patients receiving HDMTX and may be accompanied by renal dysfunction and potentially life-threatening toxicity. A panel of European physicians with experience in the use of HDMTX as well as of glucarpidase convened to develop a series of consensus statements to provide practical guidance on the prevention and treatment of DME, including the use of glucarpidase. Robust implementation of supportive measures including hyperhydration and urine alkalinization emerged as critical in order to reduce the risk of DME with HDMTX treatment, with leucovorin rescue critical in reducing the risk of DME complications. Early recognition of DME is important to promptly implement appropriate treatment including, intensified hydration, high-dose leucovorin and, when appropriate, glucarpidase.

Background. A significant advancement in the treatment of high-grade aggressive non-Hodgkin’s lymphomas and acute lymphoblastic leukemia is the inclusion of high-dose (1000–5000 mg/m2) methotrexate in the treatment protocol. This approach has significantly increased the long-term survival rate, but it has been associated with toxicity, requiring supportive care. Factors that predict toxicity were identified, including genes involved in the metabolism (MTHFR) or transport (SLCO1B1) of methotrexate. The analysis of methotrexate metabolism has identified additional genes responsible for the elimination of this drug, allowing for more effective prevention and treatment of methotrexate-associated toxicity.Aim. To study the genetic polymorphisms of enzymes involved in the methotrexate metabolism and associated toxicity in the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin’s lymphomas.Materials and methods. Data were analyzed in specialized medical databases such as Pubmed, Scopus, Web of Science, Frontiers, and Google Scholar from 2001 to 2024.Results. The main predictors of high-dose methotrexate-associated toxicity are gene polymorphisms in MTHFR, SLCO1B1, ARID5B.Conclusion. Despite the contradictory data presented in the literature, it is important to consider the detection of polymorphisms during high-dose methotrexate treatment in order to administer timely supportive care and prevent significant toxicity.

We describe the case of a 14-year-old girl with osteosarcoma who was treated with high-dose methotrexate (12 g/m2). Twenty-four hours after the infusion, her plasma methotrexate concentration was elevated at 937 μmol/L (normal

Acute methotrexate (MTX) toxicity is most commonly due to overdose of the drug, which may be due to the patient's noncompliance to doctor's orders or physician's prescription error. Other causes include acute renal failure, concomitant use of other drugs, and genetic susceptibility. MTX toxicity presents with pancytopenia, mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. Treatment involves a polypragmatic approach which includes vigorous hydration, urinary alkalinization, administration of leucovorin, and glucarpidase. Administration of granulocyte colony-stimulating factor should be considered in cases of severe neutropenia. Here, we present two cases of acute MTX toxicity in chronic plaque psoriasis presenting with ulceration of psoriatic lesions and mucosal ulceration successfully treated with leucovorin and pegylated granulocyte colony-stimulating factor (G-CSF). This case report demonstrates that G-CSF might be lifesaving by contributing to rapid reconstitution of leukopoiesis.

Abstract Background Methotrexate is an antifolate antimetabolite that inhibits the activity of dihydrofolate reductase by acting as a false substrate, which leads to defects of DNA synthesis, specifically the inhibition of purine and pyrimidine synthesis. Thus, methotrexate is a powerful agent for treating autoimmune diseases and cancer. In general, methotrexate is thought to be cardioprotective and reports of methotrexate-induced cardiomyopathy are rare. We present a case of methotrexate-induced severe cardiotoxicity diagnosed by exclusion of all other potential causes. Case presentation The patient was a 54-year-old Caucasian man presenting to an outside hospital with a chief complaint of abdominal pain and bloating who reported taking methotrexate up to 20 mg per week for systemic sclerosis. After a transthoracic echocardiogram found a left ventricular ejection fraction of 10% and coronary catheterization demonstrated no significant disease, he was transferred to our hospital for advanced heart failure therapies. His condition deteriorated, and he was eventually placed on veno-arterial extracorporeal membrane oxygenation. Owing to a lack of an identifiable etiology of cardiac failure, toxicology consultation recommended 24 hours of intravenous leucovorin therapy to overcome any residual and potentially cardiotoxic methotrexate still in his system. Over the next 5 days, his cardiac function improved daily, such that on day 5 of extracorporeal membrane oxygenation, he had a left ventricular ejection fraction of 40% and was able to be decannulated. Two days later, his ejection fraction improved to 60% and normal right ventricular function. Initially, his renal function improved while on extracorporeal membrane oxygenation, but over the next week deteriorated such that he required intermittent hemodialysis until hospital discharge. Conclusions After a process of elimination, the most likely cause of this patient’s acute decline and rapid recovery of bi-ventricular function was methotrexate toxicity. Leucovorin may have aided the reversal of methotrexate toxicity.

An elderly male patient, a known case of psoriasis vulgaris, presented with ulcerations in preexisting psoriatic lesions. The patient had fever with chills and severe pain and burning sensations in the lesions. There was a history of intramuscular methotrexate (Mtx) injection 15 mg followed by oral Mtx 7.5 mg once daily from next day for 5 days. Laboratory investigations revealed severe pancytopenia and abnormal renal and liver function tests. A diagnosis of acute Mtx toxicity was made and started treatment with intravenous leucovorin and subcutaneous granulocyte colony-stimulating factor (filgrastim) for 4 days. The patient responded to the treatment with improvement in skin lesions and laboratory parameters. The present case underlines the importance of patient counseling regarding the dosage schedule of the drugs and their adverse effects. The ulceration of preexisting lesions helps in early diagnosis, evaluation, and initiation of specific therapy.

Abstract Splenunculus, or congenital accessory spleen, is a benign anatomical variation, and is rarely of clinical consideration in routine clinical practice. We describe a patient who presented with synchronous herpes simplex 1 viraemia and myelosuppression, with a splenunculus mimicking splenomegaly, and we discuss the implications on clinical practice, investigations, and management.

There are multiple concerns associated with methotrexate (MTX), widely recognized for anti-neoplastic and anti-inflammatory effects in life-threatening disease conditions, i.e., acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, psoriasis, and rheumatoid arthritis, due to long-term side effects and associated toxicity, which limits its valuable potential. MTX acts as an inhibitor of dihydrofolate reductase, leading to suppression of purine and pyrimidine synthesis in high metabolic and turnover cells, targeting cancer and dysregulated immune cells. Due to low discrimination between neoplastic cells and naturally high turnover cells, MTX is prone to inhibiting the division of all fast-dividing cells, causing toxicity in multiple organs. Nutraceutical compounds are plant-based or food-derived compounds, used for their preventive and therapeutic role, ascertained in multiple organ dysfunctions, including cardiovascular disease, ischemic stroke, cancer, and neurodegenerative diseases. Gut microbiota and microbiota-derived metabolites take part in multiple physiological processes, their dysregulation being involved in disease pathogenesis. Modulation of gut microbiota by using nutraceutical compounds represents a promising therapeutic direction to restore intestinal dysfunction associated with MTX treatment. In this review, we address the main organ dysfunctions induced by MTX treatment, and modulations of them by using nutraceutical compounds. Moreover, we revealed the protective mechanisms of nutraceuticals in MTX-induced intestinal dysfunctions by modulation of gut microbiota.

Background: High dose methotrexate (HDMTX) is used for the treatment of pediatric hemato-oncological diseases. HDMTX can induce acute kidney injury in cases of delayed elimination. The use of leucovorin remains the most effective rescue action. Further treatment options are of difficult access in the rare cases where leucovorin fails to prevent renal failure from occurring. Glucarpidase is an effective treatment in cases of methotrexate (MTX) delayed elimination, but cost is high and availability is limited. Charcoal hemoperfusion (CHP) is a very efficient procedure to remove protein-bound drugs, promoting fast MTX elimination, but is rarely considered as a treatment option.Methods: We present three pediatric cases with prolonged exposure to MTX after HDMTX and delayed elimination in which hemoperfusion was performed as rescue treatment for methotrexate intoxication.Results: Charcoal hemoperfusion was performed with positive results and no complications as bridging until glucarpidase was available in two cases and in one case where two doses of glucarpidase led to insufficient reduction of MTX levels.Conclusions: CHP can be considered as a rescue treatment option in MTX intoxication, since it is an effective and safe extracorporeal method for removing MTX, in cases where rescue with leucovorin is insufficient and glucarpidase is not available or while waiting for delivery.

Overdosing is the major cause of acute methotrexate toxicity in psoriasis patients. There are no published data regarding the acute cumulative dose causing acute toxicity, duration to achieve acute cumulative toxic dose and various reasons for wrong dosing of methotrexate in Indian patients. We are presenting a series of seven cases of toxicity due to overdosing of methotrexate in psoriasis. The acute cumulative dose of methotrexate ranging from 35 mg to 150 mg, taken over 3–7 days was responsible for acute toxicity in the psoriasis cases. Lack of counselling regarding the disease course, drug dosing, schedule and awareness about possible outcome of high and daily dose were found to be the causes of overdosing and toxicity in our patients. All cases presented with ulceration, bleeding and pain in skin lesions and five cases had oral mucosal ulceration and genital mucosa was involved in two cases. All cases were given injectable folinic acid. Five cases recovered and two cases expired. Authors postulate counselling about the course of disease, regarding dosing schedule of methotrexate and consequences of methotrexate overdosing is mandatory for all patients of psoriasis in country like India where drug regulation is not strict to prevent methotrexate toxicity and its dreaded consequences.

Methotrexate is the most common disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis. The side effects which are known to occur include pancytopenia, hepatic dysfunction, pulmonary toxicity, and acute renal failure. This is a case report of a patient who presented with florid manifestations of methotrexate toxicity which happened due to mistaken overdosing of methotrexate which had been prescribed to her for rheumatoid arthritis.

Methotrexate (MTX) is an antifolic drug used in the treatment of immune-mediated and neoplastic diseases. Initiation or dosage changes in MTX therapy can cause mucositis and bone marrow suppression. Skin lesions due to acute MTX toxicity are rare, but they serve as a herald for later-onset pancytopenia. Therefore, identification of those cutaneous lesions might help to initiate rescue strategies at an early stage. Here we describe a case with mucocutaneous ulcerations and pancytopenia due to overdosed MTX.

Methotrexate (MTX) is an antimetabolite which competitively inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair, and cellular replication. MTX is a good treatment option for neoplastic, rheumatic and dermatological diseases. However, rarely, may cause side effects, such as agranulocytosis and bone marrow suppression, mucosal tissue inflammation and necrotic changes, liver cell necrosis and hepatic cirrhosis, pulmonary fibrosis, and severe renal dysfunction. Herein, we report a 67-year-old female patient with a history of psoriasis for 15 years and MTX 15 mg/sc/week use for 8 years who was admitted due to the complaints of pancytopenia, mucositis and ulcers on psoriatic plaques despite low-dose MTX use. We present this case to remind that MTX toxicity might occur with low-dose MTX usage and to draw attention to various factors that facilitate the low-dose MTX toxicity, such as age, renal insufficiency, low albumin levels, infections, proton pump inhibitors and non-steroidal anti-inflammatory drugs.

Despite improvements in the prognosis of acute myelogenous leukemia in patients with Down syndrome, the prognosis of acute lymphocytic leukemia (DS-ALL) in these patients is still poorer than that of ALL in the general population. We compared treatment results between 4 patients with DS-ALL and 16 non-Down syndrome patients with ALL (NDS-ALL). Four patients with DS-ALL treated with TCCSG protocols achieved complete remission by the end of the induction phase. During the high-dose methotrexate (HD-MTX) phase, the dosage of MTX was reduced from 3 to 2 g/m2 after the syndrome of inappropriate ADH secretion developed in the first patient. All DS-ALL patients had severe mucositis and a longer period of anorexia than NDS-ALL patients, even after dose reductions, resulting in a longer HD-MTX phase in DS-ALL patients than in NDS-ALL patients. The mean dosages of 6-MP and MTX during the maintenance phase were significantly lower in DS-ALL patients than in NDS-ALL patients (6-MP 22.1 ± 9.9 mg/m2 and MTX 16.1 ± 4.5 mg/m2 vs. 6-MP 43.5 ± 23.1 mg/m2 and MTX 25.2 ± 8.8 mg/m2, respectively). All DS-ALL patients have been in complete remission for a median of 10 years 0 month (range: 8 years 10 months-14 years 1 month) as of January 1, 2017. DS-ALL patients may receive the same treatment protocol as that for NDS-ALL patients with adequate care and few modifications, and this strategy may result in the expansion of treatment protocols suitable for DS-ALL patients in the future.