Frequency and mutational spectrum of PIK3CA gene mutations in breast cancer patients: Largest and first report from Lebanon.

The PIK3CA pathway is one of the most frequently altered pathways in human cancers, especially in breast cancer with approximately 40% of HR+/HER2- advanced breast cancer cases exhibiting mutations in the PIK3CA gene. While the mutations can occur across the entire gene, the most common are observed in exon 9 corresponding to the helical domain, and in exon 20 encompassing the kinase domain. This study constitutes the first attempt at determining the frequency and mutational spectrum in Lebanese breast cancer patients. For this purpose, DNA samples from 280 breast cancer patients from across Lebanon were screened for PIK3CA mutations using the Therascreen® PIK3CA RGQ Real-time PCR assay. In line with previous reports, 38.57% of cases were positive for at least one PIK3CA mutation, among which approximately 59% were in exon 9 and 37% in exon 20. However, PIK3CA mutations are breast cancer are heterogeneous whereby 20% of known PIK3CA mutants might not be detected by compact PCR based assays. Thus, the adoption of comprehensive Next Generation Sequencing based panels to decipher the complete clinical, molecular and immunohistochemical profile of breast cancer tumor requires further investigation.

Management of Multiple Myeloma in the Middle East: Unmet Needs, Challenges and Perspective.

Multiple myeloma (MM) is a prevalent hematological malignancy. Resource-constrained settings such as the Middle East are particularly burdened by the increasing trends in MM morbidity and mortality in addition to challenges in the management of MM. It thus becomes necessary to identify and address debatable areas of current practice and gaps in the management of MM in the Middle East. With a special focus on the Lebanese situation, the first-line treatment of the very elderly (> 80 years old) is discussed, in addition to the impact of relapse type (biochemical or clinical relapse) on maintenance therapy, the choice of first relapse therapy in relation to maintenance therapy, and the role of MRD in the MM treatment landscape. The need for realistic management guidelines accounting for local resources and expertise, in addition to the reflection of drug accessibility and cost on clinical practice are recognized.

Prevalence of CYP2C19 polymorphisms in the Lebanese population.

Clopidogrel is one of the most commonly prescribed drugs, as its combination with low-dose aspirin is the recommended oral anti-platelet therapy, to prevent ischaemic events following coronary syndromes or stent placement. Numerous recent studies have shown that polymorphisms in the gene encoding the cytochrome P450 (CYP450) 2C19 enzyme (CYP2C19) contribute to variability in response to clopidogrel; patients with certain common genetic variants of CYP2C19 (2, 3) have a reduced metabolism of clopidogrel and have a higher rate of cardiovascular events or stent thrombosis compared to patients with the CYP2C19 (1) allele. CYP2C19 2 is most common in Caucasians, Africans and Asians while CYP2C19 3 has been found mostly in Asians. Since the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes of CYP2C19 in our population. CYP2C19 (1/2/3) variants were assessed by Polymerase Chain Reaction-Restriction Length Polymorphism (PCR-RFLP) assays in a representative sample of 161 unrelated healthy Lebanese volunteers. The allele frequencies of CYP2C19 2 and 3 were 0.13 and 0.03. Carriers of the CYP2C19 2 or 3 represented 24.2% of the subjects. Our data show no significant difference in the frequency of CYP2C19 allelic variants when compared to Caucasian populations and demonstrate that the application of the recent FDA recommendations would also be beneficial in Lebanon, allowing physicians to identify patients at high risk for atherothrombotic events, and eventually advising them to consider other antiplatelet medications or alternative dosing strategies in poor metabolizers.

A novel genotype c.1228C>G/c.1448C-1498C (L371V/Rec-NciI) in a 3-year-old child with type 1 Gaucher disease.

Gaucher disease (GD) is an autosomal recessive inborn error of metabolism, resulting from a deficiency of the enzyme glucocerebrosidase, causing an accumulation of the glycolipid glucocerebroside within lysosomes of macrophages in the reticuloendothelial system. Three major clinical forms have been assigned and more than 200 gene mutations have been identified. We herein report a Lebanese boy born with a novel combined mutation L371V/Rec-NciI, who presented with moderate-severe type 1 GD. An overview of the clinical and biomarker improvement following enzyme replacement therapy with imiglucerase is described in a follow-up of 30 months. Imiglucerase seems to be efficacious in decreasing the severity of the disease associated with this mutation. However, a high dose may be required to achieve optimal growth, platelet count, and hemoglobin level.

Assessment of Molecular Markers in AML Patients: A Hospital-Based Study in Lebanon.

BACKGROUND: In the past, research has been focused on elucidating the molecular genetics and epigenetic basis of acute myelogenous leukemia (AML). This has led to the change in the classification and management of AML patients. Because no molecular studies regarding AML characterization in Lebanese patients had yet been reported, we decided to determine in our institution the prevalence of the recurrent genetic rearrangements t(8;21), inv(16), t(15;17) and Fms-like (Suzanne McDonough feline sarcoma) tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations. MATERIALS AND METHODS: Fusion gene transcripts from chromosome aberrations were analyzed according to standardized reverse transcription polymerase chain reactions after the report of BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia. FLT3 and NPM1 mutations were screened using home-brew methodologies. RESULTS: We reviewed 144 bone marrow samples from AML patients referred to Saint George Hospital for molecular and cytogenetic studies from September 2006 to July 2014. The male to female patient ratio was 1.34 to 1. We detected the inv(16) in 6 patients [4.2%] (type A, 5 [83%]; type D, 1 [17%]), t(8;21) in 7 patients [4.9%] (e5e2), and t(15;17) in 36 patients [25.0%] (24 [67%] breakpoint cluster region 1 (bcr1), 12 [33%] bcr3). Other chromosomal abnormalities (trisomy 8, complex karyotype, t(6;9),…) were found in 44 patients [31.4%] and 51 [35.5%] cases showed normal karyotype. Among the normal karyotypes, 6 patients [11.8%] were FLT3-positive (4 [67%] internal tandem duplication [ITD], 2 [33%] D835V), 8 [15.7%] had type A NPM1 mutation and 8 [15.7%] type A NPM1 and FLT3/ITD concomitantly. CONCLUSION: Our results, except for the prevalence of acute promyelocytic leukemia, are concordant with those reported in the literature with approximately 35% of the patients cytogenetically normal. Testing patients with normal karyotype for other molecular markers such as CCAAT/enhancer-binding protein alpha mutations, isocitrate dehydrogenase 1/2 mutations, and mixed lineage leukemia rearrangements could therefore provide additional prognostic, predictive, and therapeutic values for AML patients.

A nationwide non-interventional epidemiological data registry on myelodysplastic syndromes in Lebanon.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral blood cytopenias, blood cells dysplasia, and increased risk for progression to acute leukemia.Physicians should be vigilant in diagnosing MDS and should be aware of the contemporary therapies that are always in progress. Most of the data on MDS epidemiology and management comes from developed countries. The incidence and features of MDS in the Arab countries, among them Lebanon, are not known. We undertook a nationwide epidemiological registry study of all newly diagnosed MDS cases through 2010-2011. Patients were referred by 21 hematologists/oncologists practicing in 17 hospitals and medical centers distributed across the entire country. 58 patients (29 males and 29 females) with confirmed MDS were included. The calculated incidence rate of MDS was 0.71 per 100,000 people. The median age at diagnosis was 73 years (range 16-86). The most common complaints on presentation were fatigue (70.7%), weakness (60.3%) and pallor (43.1%). Most patients were diagnosed as refractory anemia with excess blasts (RAEB; 36.2%) and refractory cytopenia with multilineage dysplasia (RCMD; 32.8%). This paper constitutes the first epidemiological report on the incidence and specific subtypes of MDS in Lebanon.

Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population.

BACKGROUND: Polymorphisms in the genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and the vitamin K epoxide reductase (VKORC1) are known to contribute to variability in sensitivity to coumarins. Patients with certain common genetic variants of CYP2C9 (*2 & *3) or a VKORC1 polymorphism (-1639A Allele) require a lower dose of coumarin and are also at higher risk for over-anticoagulation and serious bleeding. In August 2007, the FDA label for warfarin was updated to highlight the benefit of genetic testing to predict warfarin response. AIM: Since the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes of CYP2C9 and VKORC1 in our population and to compare allele frequencies with previous findings from other ethnic groups. MATERIALS AND METHODS: CYP2C9 (*1/*2/*3) and VKORC1 (*A/*G) allelic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism assays in a diversified sample of 161 unrelated healthy Lebanese volunteers. RESULTS: The allele frequencies of CYP2C9 *2 and *3 were 0.112 and 0.096 respectively, whereas VKORC1-1639A was 0.528. Carriers of the CYP2C9 *2 or *3 represented 34.2% of the subjects, whereas those of the VKORC1-1639A represented 73.9%. CONCLUSION: Our data show no significant difference in the frequency of CYP2C9 allelic variants when compared to the Caucasian population, whereas the allelic frequency of VKORC1-1639A was very high. Over 50% of the Lebanese population seem to be carrying more than two independent risk alleles, and is therefore potentially at high risk of over-anticoagulation.

Metastatic prostate adenocarcinoma presenting with pulmonary symptoms: a case report and review of the literature.

INTRODUCTION: Prostate cancer has a high tendency to spread to bone. Pulmonary metastasis and generalized lymphadenopathy commonly develop after pelvic and bone involvement have already occurred. Few patients with prostate cancer present initially with symptomatic metastatic lung lesions and lymphadenopathy without any other concomitant distant dissemination. CASE PRESENTATION: We report a case of a 73-year-old white male who sought medical help for symptoms of cough, hemoptysis, and dyspnea. A chest X-ray was done revealing multiple "cannon ball" infiltrates involving all segments of the lung parenchyma. Fine-needle aspiration cytology under computed tomography guidance of a subpleural lesion revealed adenocarcinomatous cells. Despite the absence of any detectable osseous lesions and with the presence of multiple hilar, mediastinal, para-aortic, and pelvic lymphadenopathy, the patient had a complete work-up in search for the primary adenocarcinoma. His prostate specific antigen was 146 ng/ml and a prostatic biopsy done, revealing an acinar prostatic adenocarcinoma. A tru-cut biopsy of a lung lesion under computed tomography guidance showed a metastatic prostatic adenocarcinoma positive for prostate specific antigen stain. CONCLUSION: This case sheds light on an unusual metastatic pattern of prostatic adenocarcinoma. It also emphasizes the importance of including prostate cancer in the differential diagnosis of men with adenocarcinoma of unknown origin.