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This study aimed to investigate azole resistance mechanisms in Aspergillus flavus, which involve cyp51A and cyp51B genes. Real-time Reverse Transcriptase qPCR method was applied to determine the overexpression of cyp51A and cyp51B genes for 34 A. flavus isolates. PCR sequencing of these two genes was used to detect the presence of gene mutations. Susceptibility test found sensitivity to voriconazole (VOR) in all strains. 14.7% and 8.8% of isolates were resistant to itraconazole (IT) and posaconazole (POS), respectively, with a cross-resistance in 5.8%. For the double resistant isolates (IT/POS), the expression of cyp51A was up to 17-fold higher. PCR sequencing showed the presence of 2 mutations in cyp51A: a synonymous point mutation (P61P) in eight isolates, which did not affect the structure of CYP51A protein, and another non synonymous mutation (G206L) for only the TN-33 strain (cross IT/POS resistance) causing an amino acid change in the protein sequence. However, we noted in cyp51B the presence of the only non-synonymous mutation (L177G) causing a change in amino acids in the protein sequence for the TN-31 strain, which exhibits IT/POS cross-resistance. A short single intron of 67 bp was identified in the cyp51A gene, whereas three short introns of 54, 53, and 160 bp were identified in the cyp51B gene. According to the models provided by PatchDock software, the presence of non-synonymous mutations did not affect the interaction of CYP51A and CYP51B proteins with antifungals. In our study, the overexpression of the cyp51A and cyp51B genes is the primary mechanism responsible for resistance in A. flavus collection. Nevertheless, other resistance mechanisms can be involved.

Introduction: Imatinib is a first-line selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia. Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the mechanism of imatinib-induced hepatotoxicity has rarely been investigated. Case report: We report a 51-year-old man, suffering from acute toxic hepatitis after 5 months of imatinib treatment for chronic myeloid leukemia. Management and outcome: The outcome was favorable after discontinuation of treatment with normalization of biological liver function after 12 weeks. The treatment was switched to nilotinib without any incidents. Discussion: Regular liver function test monitoring is recommended during imatinib treatment. In fact of acute hepatic toxicity, treatment with imatinib should be stopped in the case of cytolysis more than five times the upper limit of normal. [ABSTRACT FROM AUTHOR]

Objective Biclonal gammopathies (BGs) are rare situations characterized by the production of 2 monoclonal proteins. There are no available data on BGs in North Africa. We aimed to estimate the prevalence of BGs in our population and describe their clinical and laboratory features. Methods We conducted a 31-year retrospective study including patients with persistent double monoclonal bands based on the results of immunofixation/immunoelectrophoresis. Results A total of 35 patients with available clinical data (sex ratio, M/F = 1.53; mean age, 70 ± 10.87 years [range, 45–90 years]) were included. The main associated conditions were multiple myeloma (MM) (40%), BG of undetermined significance (BGUS) (34%), and lymphoproliferative diseases (23%). Only one-third of the patients had 2 monoclonal spikes on serum protein electrophoresis. The most common paraprotein combinations were immunoglobulin (Ig)G-IgG (25%) and IgG-IgA (23%) with different light chains in one-half of the cases. The mean follow-up was 25.6 months (median, 12 months). No BGUS evolved into a malignant disease. Conclusion BGs are rare in clinical laboratory routine but must be accurately identified by the pathologist. Our cohort is characterized by a high prevalence of BGUS compared with MM. [ABSTRACT FROM AUTHOR]

Introduction: Tyrosine kinase inhibitor had changed the prognosis of chronic myeloid leukemia (CML) and the overall survival had reached 95%. Unfortunately, adverse events (AEs) remain an obstacle to following successful treatment in CML impairing the quality of life and sometimes endangering the lives of patients. To this end, we show this clinical case to discuss strategies to deal with rare AEs in a way to preserve the patient's life and to maintain not only a good response to treatment but also confidence and compliance of the patient. Case report: We report the case of a 57-year-old woman diagnosed with CML at the chronic phase who developed rare life-threatening hepatotoxicity (major cytolysis and prothrombin time fall) secondary to Nilotinib used as second-line treatment. This complication settled despite an optimal molecular response. Management and outcome: We discuss below the follow-up and management in our center and according to the literature with more sophisticated pharmacological methods. Discussion: Although we used to monitor disease molecular response to treatment, we need solutions and manuscripts for monitoring drug dose parameters to avoid unusual dangerous effects risking the patient life. We conclude that monitoring the disease as well as the treatment pharmacokinetics is mandatory to better carry on CML patients. [ABSTRACT FROM AUTHOR]

Aim: This study was carried out to assess the minimal residual disease in Tunisian patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors in routine clinical practice, to recognize potentially eligible carrier for treatment discontinuation, based on a molecular response (MR). Patients and Methods: A retrospective study was carried out in the Hospital University of Sfax, south of Tunisia from January 2016 to October 2020, including all CML patients in the chronic phase at diagnosis, treated with TKI (tyrosine kinase inhibitors) for a minimum duration of 6 months. Quantitative assessment of the BCR-ABL transcript was performed using the Cepheid Xpert BCR-ABL ultra-assay. Molecular response and outcome were evaluated, according to the European Leukemia Net guidelines. Results: A total of 162 CML patients were carried out. The median age was 50 years, the sex ratio M/F was 1.62. The rate of cumulative EMR; MMR and DMR was 80.8%; 73.8% and 55.9% respectively. According to the ELN criteria, 141 CML patients were evaluable. Optimal, suboptimal response and failure were noted in 81 (57.4%), 33(23.4%), and 27(19.1%) patients, respectively. Overall survival (OS) and progression-free survival (PFS) were 96.3% and 85%. Risk factors for an event (death/progression) were lack of EMR, MMR, and DMR (P < 0.05). Among 149 patients with sustained DMR; 14 (8.6%) CML patients have discontinued TKI therapy. Conclusion: Despite the limit of our study (duration and size), the available real-life molecular responses with TKI therapy should be considered to identify potentially CML patients eligible for discontinuation of TKI therapy. [ABSTRACT FROM AUTHOR]

Introduction: Non-Hodgkin lymphoma induced by imatinib, as a tyrosine kinase inhibitor, is a rare complication. Case report: A 54-year-old female with a history of chronic myeloid leukemia (CML) was treated with imatinib as first-line therapy. The patient achieved a profound molecular response with treatment-free remission after five years but lost major molecular responses. A second deep molecular remission was again achieved. Nine years after imatinib therapy, the patient developed odynophagia and rhinorrhea. Physical examination revealed enlarged tonsils with a tumor-like appearance without palpable lymph nodes. Immunohistochemical examination of the tonsils revealed a large B-cell lymphoma. According to Naranjo's algorithm, the causality relationship with the drug is possible with a score of 3. Management and outcome: Imatinib was discontinued. The lymphoma was treated with rituximab and chemotherapy. Discussion: Non-Hodgkin's lymphoma is a rare side effect of tyrosine kinase inhibitors and highlights the importance of follow-up CML patients. [ABSTRACT FROM AUTHOR]

Introduction: Functional variants of the Methylenetetrahydrofolate reductase (MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods: Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results: The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity's score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion: Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker. [ABSTRACT FROM AUTHOR]