Severe megaloblastic anemia in a patient with advanced lung adenocarcinoma during treatment with erlotinib: a case report and literature review.

BACKGROUND: Erlotinib is a first-generation, tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) used for the treatment patients with NSCLC. Erlotinib is considered as a safe and effective treatment option, with generally good tolerance. Diarrhea and rash are the most common side effects, and more rare side effects appear in long-term real-world applications. Severe erlotinib related megaloblastic anemia is rare and remains unreported. This is the first case report of severe megaloblastic anemia in a patient with advanced lung adenocarcinoma with an EGFR L858R mutation treated with erlotinib. In this report, the clinical manifestations, diagnosis and treatment of erlotinib related severe megaloblastic anemia are described, and the possible pathogenesis and related treatment options are discussed. CASE DESCRIPTION: Herein, we present a 57- year-old non-smoking female diagnosed with metastatic lung adenocarcinoma harboring an EGFR L858R mutation, who had received erlotinib as the first-line therapy. After 44 weeks of treatment, the patient developed severe anemia. Anemia was manifested as megaloblastic anemia with elevated mean corpuscular volume and mean corpuscular hemoglobin. The total vitamin B12 level was below the detection limit of 50.00 pg /mL. Bone marrow smear suggested megaloblastic anemia. Her hematologic parameters were markedly recovered following the withdrawal of erlotinib and vitamin B12 supplement. As a result, the patient was diagnosed with erlotinib-associated megaloblastic anemia. CONCLUSIONS: This is the first case of severe megaloblastic anemia reported with erlotinib. Few of these hematologic adverse effects have been observed in studies on erlotinib, this case report highlights this possibility for long-term erlotinib administration. Close clinical and blood monitoring is recommended for patients receiving long-term TKI therapy.

Black Cohosh Herbal Extract and Hematologic Alterations in B6C3F1/N Mice.

Black cohosh is a readily available dietary supplement currently marketed as a remedy for dysmenorrhea and menopausal symptoms and is one of the top-selling herbal supplements in the United States. Black cohosh extract (BCE) was nominated to the National Toxicology Program (NTP) by the National Cancer Institute and the National Institute of Environmental Health Sciences due to its widespread use and lack of animal toxicity studies. Results of the NTP BCE subchronic mouse toxicity study revealed a dose-dependent, non-regenerative decrease in the erythron with an increase in the mean corpuscular volume (macrocytosis). Howell-Jolly bodies, or micronuclei, were significantly increased. These particular changes indicated an ineffective erythropoiesis consistent with a condition known as megaloblastic anemia. Megaloblastic anemia is due to disruptions in DNA synthesis during hematopoiesis and can be a result of an inherited or drug-induced disorder or a consequence of folate or cobalamin deficiency. Subsequent mouse studies revealed hematological and biochemical changes that were consistent with a functional cobalamin deficiency. This article will review basic mechanisms and laboratory features of megaloblastic anemia. The results of our studies including morphological abnormalities of the erythron and biomarkers of folate and cobalamin deficiencies, as well as hepatic microarray gene changes, are also discussed.

The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2.

A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.

Folate deficiency increases chromosomal damage and mutations in hematopoietic cells in the transgenic mutamouse model.

Folate deficiency causes megaloblastic anemia and neural tube defects, and is also associated with some cancers. In vitro, folate deficiency increases mutation frequency and genome instability, as well as exacerbates the mutagenic potential of known environmental mutagens. Conversely, it remains unclear whether or not elevated folic acid (FA) intakes are beneficial or detrimental to the induction of DNA mutations and by proxy human health. We used the MutaMouse transgenic model to examine the in vivo effects of FA deficient, control, and supplemented diets on somatic DNA mutant frequency (MF) and genome instability in hematopoietic cells. We also examined the interaction between FA intake and exposure to the known mutagen N-ethyl-N-nitrosourea (ENU) on MF. Male mice were fed the experimental diets for 20 weeks from weaning. Half of the mice from each diet group were gavaged with 50 mg/kg body weight ENU after 10 weeks on diet and remained on their respective diet for an additional 10 weeks. Mice fed a FA-deficient diet had a 1.3-fold increase in normochromatic erythrocyte micronucleus (MN) frequency (P = 0.034), and a doubling of bone marrow lacZ MF (P = 0.035), compared to control-fed mice. Mice exposed to ENU showed significantly higher bone marrow lacZ and Pig-a MF, but there was no effect of FA intake on ENU-induced MF. These data indicate that FA deficiency increases mutations and MN formation in highly proliferative somatic cells, but that FA intake does not mitigate ENU-induced mutations. Also, FA intake above adequacy had no beneficial or detrimental effect on mutations or MN formation. Environ. Mol. Mutagen. 59:366-374, 2018. © 2018 Her Majesty the Queen in Right of Canada 2018.

Black cohosh extracts and powders induce micronuclei, a biomarker of genetic damage, in human cells.

Black cohosh extract (BCE) is a widely used dietary supplement marketed to women to alleviate symptoms of gynecological ailments, yet its toxicity has not been well characterized. The National Toxicology Program (NTP) previously reported significant increases in micronucleated erythrocytes in peripheral blood of female Wistar Han rats and B6C3F1/N mice administered 15-1,000 mg BCE/kg/day by gavage for 90 days. These animals also developed a dose-dependent nonregenerative macrocytic anemia characterized by clinical changes consistent with megaloblastic anemia. Both micronuclei (MN) and megaloblastic anemia can arise from disruption of the folate metabolism pathway. The NTP used in vitro approaches to investigate whether the NTP's test lot of BCE, BCEs from various suppliers, and root powders from BC and other cohosh species, were genotoxic in general, and to gain insight into the mechanism of action of BCE genotoxicity. Samples were tested in human TK6 lymphoblastoid cells using the In Vitro MicroFlow® MN assay. The NTP BCE and a BC extract reference material (XRM) were tested in the MultiFlow® DNA Damage assay, which assesses biomarkers of DNA damage, cell division, and cytotoxicity. The NTP BCE and several additional BCEs were tested in bacterial mutagenicity assays. All samples induced MN when cells were grown in physiological levels of folic acid. The NTP BCE and BC XRM produced activity patterns consistent with an aneugenic mode of action. The NTP BCE and five additional BCEs were negative in bacterial mutagenicity tests. These findings show that black cohosh preparations induce chromosomal damage and may pose a safety concern. Environ. Mol. Mutagen. 59:416-426, 2018. © 2018 Published 2018. This article is a US Government work and is in the public domain in the USA.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice.

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Hydroxyurea induced dermatomyositis-like eruption.

Medication-induced dermatomyositis (DM) is rare, but a recent review highlighted hydroxyurea (HU) as the most common inciting agent. To aid diagnosis, HU-induced DM-like eruption (HU DM-LE) forms a distinct dermopathy where the typical cutaneous features of DM are without systemic involvement and co-exist with other HU-induced cutaneous findings such as severe xerosis, atrophy, stomatitis, cutaneous and mucosal ulceration and melanonychia. On cessation of HU the DM-LE clears avoiding unnecessary immunosuppression and demonstrating the importance of consideration of medication aetiology in DM presentations. We present a case report and review of the literature.

Malarial anaemia and nitric oxide induced megaloblastic anaemia: a review on the causes of malarial anaemia.

Direct destruction and ineffective erythropoesis does not adequately explain the cause of anaemia in malaria. It is possible that there are more other mechanisms involved besides the causes described till date in malarial anaemia. The effect of NO on erythropoesis and a major haematological abnormality (microcytic/normocytic/megaloblastic picture) can significantly be observed on repeated exposure. In addition, NO can inhibit the enzyme methionine synthase so functional vit B12 deficiency state may occur which can lead to megaloblastic anaemia. This review will focus on causation of malarial anaemia and nitric oxide induced megaloblastic anaemia.

[Megaloblastic anemia associated with salazosulfapyridine treatment for rheumatoid arthritis].

A 70-year-old man was diagnosed as having rheumatoid arthritis (RA) in 2005. He was treated with 1 g salazosulfapyridine (SASP) daily for two years. Hematological investigations conducted since 2005 demonstrated hemoglobin concentrations of 8 approximately 9 g/dl, which then dropped to 4.9 g/dl on November 21, 2007, following which he was admitted to our hospital. Megaloblastic anemia associated with SASP treatment and anemia of chronic disorders were diagnosed on the basis of folate deficiency and bone marrow examination. This report describes a case of megaloblastic anemia, which developed two years after starting SASP and promptly recovered after its withdrawal and treatment with folic acid and prednisolone. The doses of SASP prescribed for RA in Japan are less than those prescribed abroad. Megaloblastic anemia associated with SASP treatment for RA is not usually detected in Japan. Currently, SASP is widely used and one of the key drugs in the treatment of RA. This case suggests that SASP therapy in RA might result in megaloblastic anemia.

[Drug-induced anemia].

Drug-induced anemia includes many kind of anemias with different mechanisms. Mechanisms of drug-induced anemia are divided into two groups, namely erythrocyte injury in peripheral blood and damage of erythroid progenitor cells or erythroblasts. Hemolytic anemias are included in the former and megaloblastic anemia, ringed sideroblastic anemia and pure red cell aplasia are included in the latter. When the drug induced anemia is suspected, complete blood cell count including reticulocyte count and examination of the blood smear and blood chemistry tests should be done. Also, history of the medication should be precisely taken. As for the treatment of drug-induced anemia, the responsible drug should be stopped immediately and individual therapy will be done if necessary.

The risk of antimalarials in patients with renal failure.

We present here a patient with end stage renal failure who received two weeks antimalarial prophylaxis at full dose leading to life threatening toxicity with severe acute megaloblastic anaemia, symptomatic pancytopenia and exfoliative dermatitis. Prompt recognition and treatment can rapidly reverse these fatal effects but more importantly, education of patients before travel is imperative in preventing such events.

Effect of immunoadsorption on refractory idiopathic focal and segmental glomerulosclerosis.

A case of a young adult with refractory nephrotic syndrome due to focal segmental glomerulosclerosis is reported. Several treatments had been used without success including steroids, cyclophosphamide, cyclosporine A, tacrolimus, and mycophenolate mofetil. Immunoadsorption was performed as a last resort to manage the nephrotic syndrome, which led to a drastic urinary protein reduction. We review the literature supporting immunoadsorption in primary focal segmental glomerulosclerosis.

[Adjuvant chemotherapy with TS-1 for head and neck cancer--side effect of two-week application followed by one-week rest regimen].

Multimodality therapy incorporated with radiotherapy, surgery and chemotherapy are used in the treatment of head and neck cancer in order to improve the local control and survival rate. TS-1, a newly developed oral antitumor agent which could achieve the same therapeutic concentration as that of 5-FU under continuous and intravenous treatment, has been used as adjuvant therapy for carcinomas in recent years. We presented our experience applying a new regimen of TS-1 and its side effects. TS-1 has been applied for head and neck carcinomas since 2001. The oral application of TS-1 has been used in 32 cases of head and neck cancer in our department since 2003, and the agent has been applied in 22 of 32 cases as adjuvant therapy. The primary sites of malignancy included hypopharyngx (7 cases), larynx (6 cases), maxillary sinus (2 cases), oropharynx (2 cases), oral cavity (4 cases), submandibular gland (1 case) and one case in which the primary site was unknown. A regimen of four-week application followed by two-week rest had been used in 6 cases in the first part of this trial. However, a high frequency of blood toxicity was found from the third week, requiring alteration of the protocol. Thus, a new regimen of two-week application followed by one week rest was thereafter used in the other 16 cases. Blood toxicity was found in 66.7% of those cases receiving a four-week application followed by two-week rest regimen. In the 16 cases receiving the two-week application followed by one-week rest regimen, only one case showed grade 2 leucopenia while continuous application for more than eight weeks was possible in 9 cases. Mild macrocytic anemia was found in some of these cases, however none of which required any necessary interruption of the treatment. Side effects other than blood toxicity, such as edema or pigmentation of lower limbs, erythema of skin and diarrhea, were found in the other cases, requiring suspension of the treatment. But the subsequent application was possible after a break or decreasing the dosage. We concluded that the new regimen of two-week application followed by one-week rest is less likely to be interrupted by the side effects and is safer to be used outpatiently, compared with the four-week application followed by two-week rest.