Biospecimen Repositories in Low- and Middle-Income Countries: Insights From an American University of Beirut and Memorial Sloan Kettering Collaboration.

PURPOSE: Biobanking helps source tissue and blood for studying cancer genomics. Access to biorepository resources in low- and middle-income countries is lacking. Memorial Sloan Kettering Cancer Center (MSK) and the American University of Beirut (AUB) established a joint tissue biorepository at AUB in Beirut, Lebanon. The undertaking encountered key challenges that were unanticipated. MATERIALS AND METHODS: Patients age 18 years or older were eligible for enrollment at AUB. After consent, biospecimens were obtained at the time of routine diagnostic and/or therapeutic interventions. Both normal and abnormal tissue and solid and/or liquid specimens were collected from varied body sites. Early on, declining consent was frequently observed, and this was highlighted for investigation to understand potential participants reasoning. RESULTS: Of 850 patients approached, 704 (70.8%) elected to consent and 293 (29.5%) declined participation. The number of declined consents led to an amendment permitting the documentation of reasons for same. Of 100 potential participants who declined to consent and to whom outreach was undertaken, 63% indicated lack of research awareness and 27% deferral to their primary physician or family member. A financial gain for AUB was cited as concern by 5%, cultural boundaries in 4%, and 1% expressed concern about confidentiality. Of the patients who elected to consent, 682 biospecimens were procured. CONCLUSION: The AUB-MSK biospecimen repository has provided a unique resource for interrogation. Patient participation rate was high, and analyses of those who elected not to consent (29%) provide important insights into educational need and the local and cultural awareness and norms.

Antitumor efficacy of arsenic/interferon in preclinical models of chronic myeloid leukemia resistant to tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard treatment for chronic myeloid leukemia (CML). Despite their clinical success, TKIs are faced with challenges such as treatment resistance, which may be driven by kinase domain mutations, and frequent disease relapse upon the cessation of treatment. The combination of arsenic trioxide (ATO) and interferon-α (IFN) was previously demonstrated to inhibit proliferation and induce apoptosis in CML cell lines, prolong the survival of primary wild-type CML mice, and dramatically decrease the activity of leukemia-initiating cells (LICs). METHODS: The ATO/IFN combination was tested in vitro on imatinib (IMN)-resistant K562-R and Ar230-R cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays were used to evaluate proliferation and apoptosis, respectively. The acridine orange assay was used to assess autophagy, and quantitative reverse transcription-polymerase chain reaction was used to assess the involvement of the hedgehog (Hh) pathway. In vivo, a retroviral transduction/transplantation T315I BCR-ABL CML mouse model was used to assay the effect of the treatment on survival, tumor burden (histopathology and blood counts), and LIC activity (secondary transplantation). RESULTS: In vitro, ATO/IFN synergized to inhibit proliferation and induce apoptosis of IMN-resistant cells with variant modes of resistance. Furthermore, the preclinical effects of ATO/IFN were associated with induction of autophagy along with inhibition of the Hh pathway. Most remarkably, ATO/IFN significantly prolonged the survival of primary T315I-CML mice and displayed a dramatic impairment of disease engraftment in secondary mice, which reflected decreased LIC activity. CONCLUSIONS: Collectively, the ATO/IFN strategy has been demonstrated to have the potential to lead to durable remissions in TKI-resistant CML preclinical models and to overcome various TKI-specific mechanisms of resistance.

Second primary malignancy after radical prostatectomy in a cohort from the Middle East.

BACKGROUND: Data from the Middle East regarding second primary malignancy (SPM) after radical prostatectomy are limited. Our objective was to estimate the overall risk of developing second primary malignancy (SPM) among Middle Eastern men with prostate cancer who underwent surgical extirpation of their prostate. MATERIALS AND METHODS: We conducted a retrospective study of 406 patients who underwent radical prostatectomy in a tertiary centre and who had no evidence of previous malignancy from 1998 to 2012. Standardized incidence ratios (SIRs) and 95% confidence interval (CI) were calculated to analyze the risk of SPM in our population compared with the general population. Cox-regression models were also conducted to correlate the clinicopathological factors with the development of SPM. RESULTS: After 14 years of follow-up, the incidence rate of SPM was 100.9 per 1,000 person-years. The most frequent SPMs were bladder cancer (n = 11, 27%) followed by hematological malignancies (n = 9, 22%) and lung cancer (n = 7, 17%). The overall risk for men with prostate cancer to develop SPM is lower than the men in the general population (standardized incidence ratios = 0.19; 95% CI: 0.14-0.25). A multivariate analysis failed to correlate any of the clinicopathological factors with the development of SPM. CONCLUSION: Patients with prostate cancer who underwent surgical expiration of their prostate are at lower risk of developing SPM compared with the general population.

microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Comparative Analysis.

Breast cancer (BC) has a higher incidence in young Lebanese woman as compared to the West. We assessed the microRNA (miRNA) microarray profile of tissues derived from Lebanese patients with early BC and performed mRNA-miRNA integration analysis. 173 miRNAs were significantly dysregulated in 45 BC versus 17 normal adjacent breast tissues, including 74 with a fold change more than two of which 17 were never reported before in cancer. Integration analysis of mRNA-miRNA microarray data revealed a potential role of 51 dysregulated miRNA regulating 719 tumor suppressive or oncogenic mRNA associated with increased proliferation and decreased migration and invasion. We then performed a comparative miRNA microarray profile analysis of BC tissue between these 45 Lebanese and 197 matched American BC patients. Notably, Lebanese BC patients had 21 exclusively dysregulated miRNA (e.g. miR-31, 362-3p, and 663) and 4 miRNA with different expression manner compared to American patients (e.g. miR-1288-star and 324-3p). Some of these differences could reflect variation in patient age at diagnosis or ethnic variation affecting miRNA epigenetic regulation or sequence of miRNA precursors. Our data provide a basis for genetic/epigenetic investigations to explore the role of miRNA in early stage BC in young women, including ethnic specific differences.

BRAF and NRAS Mutations in Papillary Thyroid Carcinoma and Concordance in BRAF Mutations Between Primary and Corresponding Lymph Node Metastases.

Concordance between mutations in the primary papillary thyroid carcinoma (PTC) and the paired x lymph node metastasis may elucidate the potential role of molecular targeted therapy in advanced stages. BRAF and NRAS mutations in primary PTC (n = 253) with corresponding metastatic lymph node (n = 46) were analyzed utilizing StripAssays (ViennaLab Diagnostics). Statistical analysis was performed using (SPSS, Inc.), version 24.0 with a p-value of <0.05, and concordance via kappa agreement. BRAF mutation frequency in conventional PTC (cPTC): 56.8%, papillary thyroid microcarcinoma (PTMC): 36.5%, PTMC-FV: 2.7% and PTC-FV: 4.1%. NRAS mutation frequency in PTC-FV: 28.6%, PTMC: 28.6%, PTMC-FV: 23.8%, and cPTC: 19.0%. BRAF mutation correlation with older age in cPTC (42.6 versus 33.6) years (p < 0.001) was the only significant clinicopathologic parameter. BRAF mutations were concordant in the primary and its corresponding lymph node deposits in PTC with a kappa of 0.77 (p-value < 0.0001). BRAF mutations are predominant in cPTC and PTMC while NRAS mutations in PTC-FV. BRAF mutation is conserved in metastatic lymph node deposits, thus BRAF is an early mutational pathogenetic driver. Therefore, targeted therapy is potential in recurrent and advanced stage disease.

Phosphorus Supplementation Mitigated Food Intake and Growth of Rats Fed a Low-Protein Diet.

Background: Low protein intake is associated with various negative health outcomes at any life stage. When diets do not contain sufficient protein, phosphorus availability is compromised because proteins are the major sources of phosphorus. However, whether mineral phosphorus supplementation mitigates this problem is unknown, to our knowledge. Objective: Our goal was to determine the impact of dietary phosphorus supplementation on food intake, weight gain, energy efficiency, body composition, blood metabolites, and liver histology in rats fed a low-protein diet for 9 wk. Methods: Forty-nine 6-wk-old male Sprague-Dawley rats were randomly allocated to 5 groups and consumed 5 isocaloric diets ad libitum that varied only in protein (egg white) and phosphorus concentrations for 9 wk. The control group received a 20% protein diet with 0.3% P (NP-0.3P). The 4 other groups were fed a low-protein (10%) diet with a phosphorus concentration of 0.015%, 0.056%, 0.1%, or 0.3% (LP-0.3P). The rats' weight, body and liver composition, and plasma biomarkers were then assessed. Results: The addition of phosphorus to the low-protein diet significantly increased food intake, weight gain, and energy efficiency, which were similar among the groups that received 0.3% P (LP-0.3P and NP-0.3P) regardless of dietary protein content. In addition, phosphorus supplementation of low-protein diets reduced plasma urea nitrogen and increased total body protein content (defatted). Changes in food intake and efficiency, body weight and composition, and plasma urea concentration were highly pronounced at a dietary phosphorus content <0.1%, which may represent a critical threshold. Conclusions: The addition of phosphorus to low-protein diets improved growth measures in rats, mainly as a result of enhanced energy efficiency. A dietary phosphorus concentration of 0.3% mitigated detrimental effects of low-protein diets on growth parameters.

Gene expression profiling of breast cancer in Lebanese women.

Breast cancer is commonest cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. Molecular alterations in breast cancer are complex and involve cross-talk between multiple signaling pathways. The aim of this study is to extract a unique mRNA fingerprint of breast cancer in Lebanese women using microarray technologies. Gene-expression profiles of 94 fresh breast tissue samples (84 cancerous/10 non-tumor adjacent samples) were analyzed using GeneChip Human Genome U133 Plus 2.0 arrays. Quantitative real-time PCR was employed to validate candidate genes. Differentially expressed genes between breast cancer and non-tumor tissues were screened. Significant differences in gene expression were established for COL11A1/COL10A1/MMP1/COL6A6/DLK1/S100P/CXCL11/SOX11/LEP/ADIPOQ/OXTR/FOSL1/ACSBG1 and C21orf37. Pathways/diseases representing these genes were retrieved and linked using PANTHER®/Pathway Studio®. Many of the deregulated genes are associated with extracellular matrix, inflammation, angiogenesis, metastasis, differentiation, cell proliferation and tumorigenesis. Characteristics of breast cancers in Lebanese were compared to those of women from Western populations to explain why breast cancer is more aggressive and presents a decade earlier in Lebanese victims. Delineating molecular mechanisms of breast cancer in Lebanese women led to key genes which could serve as potential biomarkers and/or novel drug targets for breast cancer.

Undifferentiated Nasopharyngeal Carcinoma Mimicking Hodgkin Lymphoma With CD30 Expression.

The presence of CD30-expressing Hodgkin-like cells with a background of inflammation and eosinophils in a young adolescent is usually diagnostic of classical Hodgkin lymphoma. Herein we present the case of a 12-year-old boy presenting with enlarged cervical lymph node characterized by the presence of Hodgkin-like cells expressing CD30 and EBV-LMP1 with a Hodgkin-like background. The Hodgkin-like cells were negative for CD15, CD20, CD45, and Pax-5. The tumor cells, however, expressed several cytokeratins, confirming the diagnosis of an undifferentiated carcinoma nasopharyngeal type. This case highlights the importance of possessing a high index of suspicion when encountering lymph nodes with Hodgkin-like cells and a Hodgkin-like background, even with CD30 expression, as the differential can include undifferentiated carcinoma nasopharyngeal type.

Activating BRAF Mutations Detected in Mixed Hürthle Cell Carcinoma and Multifocal Papillary Carcinoma of the Thyroid Gland: Report of an Unusual Case and Review of the Literature.

Despite the increase in the incidence of thyroid carcinomas, the occurrence of collision tumors in the thyroid remains a rare event. We present the case of a 69-year-old female who presented to the emergency department with a chief complaint of painful neck swelling. Imaging revealed a large right hemithyroid mass and a left hemithyroid nodule. Fine needle aspiration of the lesions and subsequent total thyroidectomy revealed a Hürthle cell carcinoma in the right lobe and bilateral multicentric papillary carcinoma foci, including 2 foci with a classical pattern and 1 encapsulated follicular variant in the isthmus. BRAF gene mutation analysis revealed V600E gene mutation in the classical variants of papillary carcinoma and in the Hürthle cell carcinoma. The focus of follicular variant of papillary carcinoma in the isthmus and a sample from normal thyroid tissue did not harbor BRAF mutations. This case is remarkable in being an unusual report of a follicular Hürthle cell carcinoma harboring the BRAF V600E mutation and occurring in collision with multifocal papillary carcinoma. Documentation of such cases is important as it helps better understand the pathogenesis, clinical behavior, and radiologic findings of such rare lesions and to determine the optimal treatment modalities.

Programmed Death-Ligand 1 Expression in Muscle-Invasive Bladder Cancer Cystectomy Specimens and Lymph Node Metastasis: A Reliable Treatment Selection Biomarker?

BACKGROUND: The programmed death-1 (PD-1) pathway negatively regulates T-cell activation and has an important role in regulating antitumor host immunity. Monoclonal antibodies directed against PD-1 or the PD-1 ligand (PD-L1) have shown activity in several tumor types with preliminary data suggesting a relationship between PD-L1 expression and response. The aim of this study was to establish the frequency of PD-L1 expression in muscle-invasive bladder cancer and associated lymph node metastasis using immunohistochemistry and to investigate the feasibility of using PD-L1 expression as a biomarker to select patients for PD-1-directed therapy. PATIENTS AND METHODS: Cases of radical cystectomy for muscle-invasive bladder cancer with no exposure to previous chemotherapy were identified and representative slides from archived paraffin-embedded blocks stained with anti-PD-L1 antibody (5H1 clone) were identified. PD-L1 positivity was defined by a 5% expression threshold. RESULTS: Fifty-two radical cystectomy specimens were reviewed. PD-L1 was overexpressed in the tumor cells of 5/52 (9.6%) of cystectomy specimens in this cohort with 17/52 (32.7%) of cases showing PD-L1 overexpression in tumor-infiltrating immune cells. Discordance was observed between PD-L1 expression in lymph node metastasis and the primary tumor. CONCLUSION: Standard assays for PD-L1 expression have yet to be established. The observation of discordance between PD-L1 expression in metastatic sites and primary tumors suggests that prospective biomarker studies should aim to acquire material immediately before treatment initiation rather than archived tissue from resected specimens that might not reflect the current immune-active microenvironment.

p53 Restoration in Induction and Maintenance of Senescence: Differential Effects in Premalignant and Malignant Tumor Cells.

The restoration of p53 has been suggested as a therapeutic approach in tumors. However, the timing of p53 restoration in relation to its efficacy during tumor progression still is unclear. We now show that the restoration of p53 in murine premalignant proliferating pineal lesions resulted in cellular senescence, while p53 restoration in invasive pineal tumors did not. The effectiveness of p53 restoration was not dependent on p19(Arf) expression but showed an inverse correlation with Mdm2 expression. In tumor cells, p53 restoration became effective when paired with either DNA-damaging therapy or with nutlin, an inhibitor of p53-Mdm2 interaction. Interestingly, the inactivation of p53 after senescence resulted in reentry into the cell cycle and rapid tumor progression. The evaluation of a panel of human supratentorial primitive neuroectodermal tumors (sPNET) showed low activity of the p53 pathway. Together, these data suggest that the restoration of the p53 pathway has different effects in premalignant versus invasive pineal tumors, and that p53 activation needs to be continually sustained, as reversion from senescence occurs rapidly with aggressive tumor growth when p53 is lost again. Finally, p53 restoration approaches may be worth exploring in sPNET, where the p53 gene is intact but the pathway is inactive in the majority of examined tumors.

Mesothelial Cells Within Vascular Transformation of Mediastinal Lymph Node Sinuses: An Unusual Benign Collision Mimicking Colliding Malignancies.

Vascular transformation of lymph node sinuses represents a rare benign entity mimicking malignant counterparts such as nodal Kaposi sarcoma. The presence of mildly atypical benign mesothelial cells within nodal sinuses raises the possibility of metastatic malignancy. Herein, a rare case of vascular transformation of lymph node sinuses with reactive sinusoidal mesothelial cells is outlined as a unique benign pathology and a potential mimicker of a malignant collision tumor.

Association between CLN3 (Neuronal Ceroid Lipofuscinosis, CLN3 Type) Gene Expression and Clinical Characteristics of Breast Cancer Patients.

Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines. Here, we determine CLN3 expression in non-tumor vs. tumor samples from fresh and formalin-fixed/paraffin-embedded (FFPE) breast tissue and analyze the association between CLN3 overexpression and different clinicopathological characteristics of breast cancer patients. Additionally, gene expression of 28 enzymes involved in sphingolipid metabolism was determined. CLN3 mRNA is overexpressed in tumor vs. non-tumor breast tissue from FFPE and fresh samples, as well as in mouse MCF7 breast cancer compared to MCF10A normal cells. Of the clinicopathological characteristics of tumor grade, age, menopause status, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), only absence of HER2 expression correlated with CLN3 overexpression. Sphingolipid genes for ceramide synthases 2 and 6 (CerS2; CerS6), delta(4)-desaturase sphingolipid 2 (DEGS2), and acidic sphingomyelinase (SMPD1) displayed higher expression levels in breast cancer vs. control tissue, whereas ceramide galactosyltransferase (UGT8) was underexpressed in breast cancer samples. CLN3 may be a novel molecular target for cancer drug discovery with the goal of modulation of ceramide pathways.

Liver resection for metastatic colorectal leiomyosarcoma: a single center experience.

BACKGROUND: Leiomyosarcoma arising in the colorectum is a rare malignancy of the smooth muscles accounting for less than 1% of gastrointestinal tumors. Surgery remains the most accepted modality for the treatment of this entity however management of liver metastases remains controversial. METHODS & RESULTS: From 1998 to 2009, five patients diagnosed with primary leiomyosarcoma of colorectal origin with metastatic liver disease, underwent liver resections at the American University of Beirut Medical Center. The median overall survival was 47 months (range, 7-135 months). CONCLUSIONS: Leiomyosarcoma of colorectal origin with liver metastasis is a very rare entity. Long-term survival can be achieved after surgical resection and should be considered for all patients.

Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy.

INTRODUCTION: Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1α is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1α as aTNBC-specific marker. METHODS: 62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1α, HIF-1ß, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1α and VEGF transcripts was performed on 54 cases (18 from each subtype). RESULTS: HIF-1α protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; χ2 test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1α protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1α protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; χ2 test), while MVD was comparable among all groups (p = 0.928; χ2 test). VEGFR3 was highest in TNBC expressing HIF-1α. HIF-1ß protein was expressed in 32.0% of HIF-1α(+), and in (44.3%) of HIF-1α(-) breast cancer cases (p = 0.033; χ2 test). Moreover, HIF-1α expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; χ2 test). CONCLUSIONS: A proportion of TNBC express HIF-1α but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1α targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or refractory disease.

Cervical ganglioneuroma in collision with a metastatic undifferentiated carcinoma.

Cervical ganglioneuromas are extremely rare with approximately six case reports. The current report highlights a unique collision tumor between a cervical ganglioneuroma and a metastatic undifferentiated carcinoma arising from a primary gingival mass. A 53-year-old male presented with a 2 cm left gingival mass that was excised and treated with systemic chemotherapy. Consequently, 9 months later, he developed a 3.2 cm left submandibular mass followed by recurrence of the left gingival mass. From the clinicopathologic perspective, this had to be separated from the differentials: ganglioneuroblastoma or metastatic involvement of a lymph node from primary gingival undifferentiated carcinoma.

ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.

The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.

miRNA as potential biomarkers of breast cancer in the Lebanese population and in young women: a pilot study.

Relative to western populations, the percentage of women diagnosed with breast cancer at a young age in Lebanon is high. While the younger age of the Lebanese population compared to the West certainly contributes to this difference, potential genetic, reproductive and/or biological factors likely play an important role. The objective of this study is to investigate the contribution of miRNAs in this setting through the analysis of the expression of five reported dysregulated miRNAs, miR-148b, miR-10b, miR-21, miR-221, and miR-155 in 20 normal and 57 cancerous breast tissues from Lebanese breast cancer patients. After finding their relative expression by quantitative reverse transcription real time PCR, the results were analyzed with respect to the patients' clinical and histopathology presentations. Compared to normal breast tissues, significant upregulation of miR-155, miR-21 and miR-148b, notable downregulation of miR-10b and non-significant expression of miR-221 were observed in tumor tissues. Moreover, miR-10b was significantly underexpressed in estrogen/progesterone receptor (ER/PR) negative tumors relative to ER/PR positive tumor tissues. miR-155 was also significantly overexpressed in postmenopausal patients and in those of age at diagnosis greater than 40 years old as well as in PR negative or in human epidermal growth factor 2 (Her2) positive tissues. This study is the first one to report miRNA expression patterns in Lebanese breast cancer patients. We found that differential miRNA expression in breast cancer could be variable between Lebanese and Western populations. miR-10b was positively correlated with the ER and PR status and miR-155 could be a noteworthy biomarker for the menopausal state, age at diagnosis, PR and Her2 status. Hence, miRNA can be used as biomarkers for early breast cancer detection.

Epidermal growth factor receptor and KRAS mutations in lung adenocarcinoma: a retrospective study of the Lebanese population.

Molecular genetic analysis of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) mutations in lung adenocarcinoma has become an integral part of lung cancer diagnosis and treatment; however, their prevalence varies with ethnicity. Little is know concerning their prevalence in Arab populations. In the present study, mutational analysis for EGFR and KRAS was performed on two cohorts of the Lebanese population. Lung adenocarcinoma cases (106) underwent mutational analysis for KRAS in exon 2, codon 12 and 13 and exon 3 codon 61 by reverse hybridization using the KRAS 12/13/61 StripAssay®. Subsequently, cases with no KRAS mutations underwent EGFR mutational analysis using the EGFR RGQ polymerase chain reaction (PCR) kits for real­time PCR on the Rotor­Gene Q 5-plex HRM. KRAS mutations were detected in 37.7% of 106 lung adenocarcinomas; 85% had a G>T substitution in codon 12 and 13 of exon 2, and 8.5% had EGFR mutations with exon 19 deletions (88.9%) and one case with L858R substitution in exon 21. EGFR mutations were significantly correlated with females, non-smokers and well differentiation of the tumor. This is the first study in an Arab population that reports the prevalence of both EGFR and KRAS gene mutations in lung adenocarcinoma using very sensitive mutational analysis techniques. Therefore, EGFR reflex testing should be implemented in the management of lung adenocarcinomas, while KRAS testing must await the identification of effective targeted therapy.

Preclinical efficacy of the synthetic retinoid ST1926 for treating adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1-positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.