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BACKGROUND: Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown. METHODS: In a retrospective analysis, we screened 652 patients with CML and identified 22 with prior bariatric surgery, and compared their outcomes to a matched cohort of 44 patients with no prior bariatric surgery. RESULTS: The rate of early molecular response (3-month BCR::ABL1 < 10% International Scale) was lower in the bariatric surgery group compared with the control group (68% vs. 91%; p = .05), with longer median times to achieve complete cytogenetic (6 vs. 3 months; p = .001) or major molecular responses (12 vs. 6 months; p = .001). Bariatric surgery was associated with inferior event-free survival (5-year, 60% vs. 77%; p = .004) and failure-free survival (5-year, 32% vs. 63%; p < .0001). In a multivariate analysis, bariatric surgery was the only independent predictor for the risk of treatment failure (hazard ratio, 9.40; 95% CI, 2.71-32.55; p = .0004) or event-free survival (hazard ratio, 4.24; 95% CI, 1.67-12.23; p = .008). CONCLUSIONS: Bariatric surgery is associated with suboptimal responses that require adapted treatment strategies.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Resultado do Tratamento , Prognóstico , Estudos Retrospectivos , Leucemia Mielogênica Crônica BCR-ABL Positiva/cirurgia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Fusão bcr-ablRESUMO
Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after 1 year has been highlighted as "suboptimal" or "warning" sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long-term outcome. In this analysis, we report the long-term outcome of 131 patients who did not achieve MMR within the first 2 years of TKI therapy. Patients who achieved a major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long-term overall survival (OS) (10-year OS of 88%) and CML-related overall survival (CML-OS) (10-year CML-OS of 95%). The achievement of MCyR within the first 2 years of treatment predicted a better OS (HR = 0.43, p = .03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10-year OS of 55% vs. 10-year CML-OS of 100%). In conclusion, achievement of MCyR within 2 years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Resultado do Tratamento , Proteínas de Fusão bcr-abl/genética , Inibidores de Proteínas Quinases , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genéticaRESUMO
Patients with chronic myeloid leukemia (CML) and T315I mutation generally have a poor prognosis. Their outcome in the post-ponatinib era remains unclear. We reviewed patients with CML in chronic (CP) or accelerated phase (AP) who developed a T315I mutation between March 15, 2004, and July 26, 2022. Patients were divided into CP, AP, or blastic phase (BP) at the time of mutation detection. Overall survival (OS) was defined from the time of mutation detection to the date of death or last follow-up. We identified a total of 107 patients: 54 (51%) in CP, 14 (13%) in AP, and 39 (36%) in BP. One hundred and two patients received subsequent therapy after the T315I mutation was detected. At a median follow-up of 75 months (95% CI, 41-110), the median OS was 49 months (95% CI, 26-73) and the 5-year OS rate was 44%. Patients who were in CML-CP at the time of mutation detection had better survival compared with those in AP or BP, with a median OS of 132, 31, and 6 months, and 5-year OS rates of 70%, 37%, and 10%, respectively (p < .001). Patients with CML-CP treated with ponatinib and/or asciminib had a 5-year OS of 77% compared with 50% in those who received other treatments (chemotherapy, second-generation tyrosine kinase inhibitors, homoharringtonine, and investigational drugs) (p = .14). In summary, patients with CML-CP at the time of T315I mutation detection may have a relatively indolent disease course with a long-term OS of 70%. Treatment with third-generation tyrosine kinase inhibitors seemed to improve survival in patients with CML-CP.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Piridazinas , Humanos , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/genética , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêuticoRESUMO
Recurrence of MRD in AML is associated with imminent relapse unless intervened upon. Change in chemotherapy regimen and/or immediate transplant improve outcomes.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual , Prognóstico , RecidivaRESUMO
Lung adenocarcinoma patients have variable prognosis due to many factors. Detection of epidermal growth factor receptor (EGFR) activating mutations is one of the factors that implies the need for initiating a first-line EGFR tyrosine kinase inhibitor (TKI) treatment. However, T790M resistance mutation emergence during treatment accounts for most EGFR-TKI drug resistance. The traditional sample taken for T790M mutation analysis is tissue biopsy, but its numerous disadvantages have introduced liquid biopsy as a preferred method for testing. We studied the prevalence of T790M mutation among pulmonary adenocarcinoma patients in Lebanese patients based on liquid biopsy testing the circulating tumor DNA (ctDNA). We have reviewed the laboratory charts of 52 patients who developed resistance on treatment and referred to AUBMC for EGFR T790M Liquid Biopsy to analyze the mutational analysis results for EGFR T790M. In total, 82.6% of the tested lung cancer patients were positive for a specific EGFR mutation. Among these patients, a total 26.9% were positive for T790M, which is comparable to the international prevalence of this mutation. However, for those cases who developed resistance with circulating DNA showing an EGFR mutation, 50% were positive for T790M that is also comparable to the international literature. This is the first report from Lebanon to discuss the prevalence of T790M mutation using liquid biopsy among Lebanese population. An important landmark molecular epidemiology study that will be a reference to all oncologists in Lebanon and the region in assessing the potential for targeted therapy options in the country. In addition, the data will be of an asset to the building international literature related to this disease.
Assuntos
Adenocarcinoma de Pulmão/genética , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Líbano , Biópsia Líquida , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Centros de Atenção TerciáriaAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Obesidade/complicações , Obesidade/cirurgiaRESUMO
Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity.
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Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Estudos RetrospectivosRESUMO
The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.
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While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and accelerated phase (40%) CML patients, whereas RUNX1 (20%) was the most common mutation in blast phase. Compared with wild-type ASXL1, CP-CML with mutant ASXL1 was associated with worse event-free survival (EFS) (median of 32.8 vs 88.3 months; P = 0.002) and failure-free survival (median of 13.8 vs 57.8 months; P = 0.04). In a multivariate analysis, ASXL1 mutation was the only independent risk factor associated with worse EFS in chronic phase CML with a hazard ratio of 4.25 (95% CI 1.59-11.35, P = 0.004). In conclusion, mutations in ASXL1 are associated with worse outcomes when detected in chronic phase CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Prognóstico , Estudos Retrospectivos , Crise Blástica , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: In the era of precision medicine, treatment schemes for advanced Colorectal (CRC) disease include monoclonal antibodies which block the epidermal growth factor receptor (EGFR) implicated in tumor proliferation, invasion, migration and neovascularization. Resistance to these agents has been correlated with activating downstream mutations in KRAS, BRAF and NRAS genes, among others, leading to constitutive activation of the EGFR axis bypassing EGFR blockade. The assessment of tumor RASandBRAFmutational status has thus become standard clinical practice. While multiple investigations reported roughly mutations rates of 40% in KRAS, 7% in NRAS and 5-15 % in BRAF, numbers vary across different populations with limited data specifically from the Middle East. METHODS: This is a retrospective observational Laboratory information system (LIS) chart review of all the patients with pathologically confirmed colorectal carcinoma (CRC) or metastatic CRC who underwent KRAS, NRAS and/or BRAF mutational analysis testing at the Molecular Diagnostics Laboratory of the American University of Beirut Medical Center (AUBMC) from January 2012 to December 2018, inclusive. Data retrieved included the results of mutation testing performed for KRAS, NRAS and BRAF genes, the age, gender, and tumor location for each patient. Analysis of the mutations was performed using polymerase chain reaction (PCR) hybridization StripAssay® (ViennaLab, Vienna, Austria). RESULTS: 130 (47.6%) out of 273 histologically confirmed CRC cases, had positive KRAS mutations, namely in codons 12 (82%), 13 (17%), 146 (1.5%), 117 (0.75%), or 61 (0.75%). Two patients had two concomitant mutations: 12 + 12 (different mutations) and 12 + 146. Of 203 CRC cases tested for NRAS mutations, 16 (7.8%) were found to be positive for a mutation in codon 12 (37.5%), 61 (37.5%), or 13 (12.5%). Two patients had two concomitant mutations: 12 + 13 and 59 + 61. Of 172 CRC cases tested for BRAF mutations, 2 (1.2 %) were positive for the V600E -. CONCLUSION: This retrospective study is the first to report the frequencies of KRAS, NRAS and BRAF gene mutations in a Lebanese CRC cohort diagnosed and managed at a tertiary care center. The frequencies of the studied somatic gene mutations were similar to previously reported cohorts in other populations however the rate of BRAF mutation was lower in this cohort than expected.
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Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Códon , Estudos de Coortes , Neoplasias Colorretais/patologia , Receptores ErbB/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Estudos RetrospectivosRESUMO
Introduction: Reports of multisystem inflammatory syndrome in children (MIS-C), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, have been increasing worldwide, with an incidence varying significantly across studies based on the definition used for the diagnosis. At our tertiary medical center in Lebanon, we encountered several cases that presented a diagnostic challenge because they mimicked MIS-C but did not meet the US Centers for Disease Control and Prevention (CDC) definition. We decided to review these cases and describe their features in comparison with cases that met the CDC criteria of MIS-C and those that had an alternative diagnosis. Methods: This is a retrospective chart review of subjects aged <19 years old admitted to the American University of Beirut Medical Center (AUBMC) between March 1, 2020, and May 31, 2021, with suspected or confirmed MIS-C, following documented COVID-19 infection, with sufficient or insufficient criteria for diagnosis. Subjects were classified into 3 groups: "MIS-C", "Near MIS-C" and "Alternative Diagnosis". Results: A total number of 29 subjects were included in our cohort. Fever was present in all subjects. In the MIS-C group, evidence for cardiovascular system involvement was the most common feature followed by the mucocutaneous and gastrointestinal systems. In the "Near MIS-C" and "Alternative Diagnosis" group, gastrointestinal symptoms were the most common with only one patient with cardiac abnormalities and none with coagulopathy. Subjects with typical MIS-C presentation had higher inflammatory markers when compared to subjects in the other groups. Almost all the subjects had positive IgG for SARS-CoV-2. Of the 29 subjects, the Royal College of Paediatrics and Child Health (RCPCH) case definition would have identified all suspected cases without an alternative diagnosis as MIS-C, whereas the World Health Organization (WHO) and the CDC definitions would have excluded 6 and 10 subjects, respectively. Conclusion: MIS-C presents a diagnostic challenge due to the nonspecific symptoms, lack of pathognomonic findings, and potentially fatal complications. More research is needed to fully understand its pathogenesis, clinical presentation spectrum, and diagnostic criteria. Based on our experience, we favor the hypothesis that MIS-C has a continuum of severity that necessitates revisiting and unifying the current definitions.
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The regular administration of intrathecal chemotherapy has significantly reduced the risk of central nervous system leukemia in patients with acute lymphoblastic leukemia. We report the case of 28-year-old man who developed intrathecal methotrexate induced myelopathy; a rare but serious side effect of intrathecal chemotherapy. In the light of absent effective treatment strategies, description of the case, along with reviewing similar cases published in the literature will help shed a light on the possible pathophysiologic mechanisms behind this injury. To this date, there are no specific clinical, biochemical and imaging signs that would allow timely detection of intrathecal methotrexate induced myelopathy. This in turn is causing delayed treatment of this injury, resulting in significant morbidity and mortality.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Doenças da Medula Espinal , Adulto , Humanos , Masculino , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doenças da Medula Espinal/induzido quimicamenteRESUMO
Soft tissue sarcomas remain one of the rarest malignancies with numerous subtypes that go undiagnosed. The PDGFRα antagonist Olaratumab (Lartruvo) was withdrawn from the market due to disappointing findings in the phase III studies. We share our experience with this medication in a tertiary care center in the Middle East and North Africa region. Monitor the effect of Olaratumab on sarcomas when it was used prior to its withdrawal, and compare our findings with the literature. We performed a retrospective analysis of adult patients with advanced-/metastatic soft tissue sarcomas treated with at least two cycles of Olaratumab at a tertiary care center in Lebanon during the period from January 1, 2017 to December 31, 2018. Fifteen patients were included in the study. The mean age was 49 with a range of 26-75 years. The median duration of the use of Olaratumab was 21.3 months with a range of 7.3-37 months. The average number of number of cycles received per patient was four. Five patients were deceased. Median PFS was 7.87 months (95% CI 5.28-10.45), and mean OS was 12.26 months (95% CI 8.47-16.05) Median OS was 9.8 months (95% CI 6.07-13.53). Olaratumab has been withdrawn from the market, and it is currently being investigated as part of the phase II ANNOUNCE 2 trial. Our experience from a tertiary care center shows results similar to those reported in the literature. The immunogenicity and heterogeneity of soft tissue sarcomas pose a challenge to the treatment of soft tissue sarcomas, but they also allow a wide array of possible management solutions.