Nizar Bitar

Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia

BackgroundMicroRNAs (miRNAs) are small (19-22-nt) single-stranded noncoding RNA molecules whose deregulation of expression can contribute to human disease including the multistep processes of carcinogenesis in human. Circulating miRNAs are emerging biomarkers in many diseases and cancers such as type 2 diabetes, pulmonary disease, colorectal cancer, and gastric cancer among others; however, defining a plasma miRNA signature in acute myeloblastic leukemia (AML) that could serve as a biomarker for diagnosis or in the follow-up has not been done yet.MethodsTaqMan miRNA microarray was performed to identify deregulated miRNAs in the plasma of AML patients. Quantitative real-time RT-PCR was used to validate the results. Receiver-operator characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of the highly and significantly identified deregulated miRNA(s) as potential candidate biomarker(s).ResultsThe plasma expression level of let-7d, miR-150, miR-339, and miR-342 was down-regulated whilst that of let-7b, and miR-523 was up-regulated in the AML group at diagnosis compared to healthy controls. ROC curve analyses revealed an AUC (the areas under the ROC curve) of 0.835 (95% CI: 0.7119– 0.9581; P<0.0001) and 0.8125 (95% CI: 0.6796–0.9454; P=0.0005) for miR-150, and miR-342 respectively. Combined ROC analyses using these 2 miRNAs revealed an elevated AUC of 0.86 (95% CI: 0.7819–0.94; P<0.0001) indicating the additive effect in the diagnostic value of these 2 miRNAs. QRT-PCR results showed that the expression level of these two miRs in complete remission AML patients resembled that of healthy controls.ConclusionsOur findings indicated that plasma miR-150 and miR-342 are novel important promising biomarkers in the diagnosis of AML. These novel and promising markers warrant validation in larger prospective studies.

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long‐term disease control.

Adult T-cell leukemia/lymphoma in the Middle East: first report of two cases from Lebanon.

BACKGROUND: Adult T‐cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disorder caused by human T‐cell leukemia virus type I (HTLV‐I). HTLV‐I is endemic in southern Japan, the Caribbean, Central and South America, certain areas of Africa, and the southeastern United States. In the Middle East, North East Iran, particularly the region of Mashhad, has been recognized as an endemic region.

A clinical phase II study of cisplatinum and vinorelbine (PVn) in advanced breast carcinoma (ABC).

Objectives:The effectiveness of cisplatinum and vinorelbine (PVn) as a salvage regimen in patients with metastatic breast cancer was reported in previous studies. This report is a pilot study assessing the antitumor efficacy and safety of this regimen as first line therapy for advanced breast cancer patients. Methods:Thirty-five patients were enrolled: 22 with metastatic breast carcinoma and 13 with locally advanced breast carcinoma (stage III). A total of 4 cycles of PVn were planned. After the 4th cycle, patients with metastatic breast cancer received vinorelbine biweekly until disease progression or for a total of 12 cycles, whereas those with locally advanced breast cancer who showed complete or partial response underwent curative surgery. Results:The overall response rate of our whole population was 74.29%. For the metastatic breast cancer group, the overall response rate was 64%, with a median survival of 19 months (range 2–36). For the locally advanced breast cancer group, the overall response rate was 92.3% with a median time to disease progression of 26 months (range 25–27). Toxicity was acceptable, and no treatment-related mortality was encountered. Conclusions:PVn is effective as first line treatment of advanced breast cancer with overall response rate of 64% in metastatic breast cancer and 92.3% in locally advanced breast cancer, and acceptable toxicity.

A clinical phase II study of a non-anthracycline sequential combination of cisplatin-vinorelbine followed by docetaxel as first-line treatment in metastatic breast cancer.

Background: We tested a sequential combination regimen using cisplatin and vinorelbine (PVn) followed by docetaxel as first-line chemotherapy in a phase II clinical trial in metastatic breast cancer (MBC). Patients and Methods: Thirty-five patients were enrolled. Cisplatin 80 mg/m2 was given on day 1 and vinorelbine 30 mg/m2 on days 1 and 8 every 3 weeks for 4 cycles. Responding patients received docetaxel 75 mg/m2 every 21 days for a maximum of 4 cycles. Three patients were excluded from analysis because of death unrelated to treatment. Results: After a median follow-up of 14 months, 32 patients completed the study. The overall response rate was 53.1%. Complete remission was seen in 5 patients (15.6%), partial response in 12 (37.5%), stable disease in 6 (18.75%), and progressive disease in 9 patients (28.1%). Median time to disease progression was 8 months (range 1–24). At 24 months, 12 (37.5%) patients were alive. A total of 183 cycles were administered. Febrile neutropenia was observed in 4 patients (2.2%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and grade III vomiting in 31/183 cycles (16.9%). Discussion: PVn is a feasible non-anthracycline option as first-line chemotherapy in patients with metastatic breast cancer and has acceptable toxicity. The sequential addition of 4 cycles of docetaxel following 4 cycles of PVn did not improve the overall response rate and results.

Prevalence of EGFR and ALK Mutations in Lung Adenocarcinomas in the Levant Area - a Prospective Analysis

Background: A significant percentage of lung adenocarcinomas have a driver mutation. To date, there has been no assessment of the prevalence of such mutations in a Middle Eastern population. The present multicenter prospective study of formalin fixed paraffin embedded (FFPE) tissues from patients diagnosed with lung adenocarcinoma was performed to assess the prevalence of EGFR and ALK mutations in the Levant. Methods: Patients of Middle Eastern origin with lung adenocarcinomas at 10 sites in Lebanon, Jordan and Iraq were prospectively enrolled. Tumors were tested for EGFR by PCR and for EML4-ALK translocation by fluorescence in situ hybridization (FISH). Results: A total of 210 patients were enrolled, 139 (66.2%) males and 71 females (33.8%), with a mean age of 63.4 years. EGFR testing of 205 (97.6%) demonstrated the wild type in 173 (84.4%) and mutated forms in 32 (15.6%). Some 46.9% of EGFR positive patients were non-smokers and 62.5% were females as opposed to 22.4% and 33.8%, respectively, in the general population. As for the EML4-ALK translocation, testing in 157 (74.8%) cases gave negative results in 154 (98.1%), only 3 being positive (1.9%), 2 being females and 2 non-smokers. Conclusion: Our study established a 15.6% EGFR mutation rate in lung adenocarcinomas with ALK translocation mutations in only 1.9%, as compared to a 15-20% and 5%, respectively, in the Western literature.

A clinical phase II study of cisplatin and vinorelbine followed by docetaxel as first-line treatment in metastatic breast cancer (MBC)

822 Background: Based on our encouraging positive experience with Cisplatin and Vinorelbine combination (PVn) in first and second line for (MBC). Material and Methods: From August 2002 to August 2004, 35 patients (pts) with MBC were recruited of whom 32 were evaluable for response. Median age was 48 years (range: 22–76). 17 (51.5%) pts were premenopausal. 26 (78.8%) of pts had 2 or more sites of metastasis. No previous therapy was allowed except as adjuvant. 11 (33%) pts were chemo naive and 22 (67%) pts underwent previous surgery for breast cancer and received adjuvant anthracycline chemotherapy regimen. 20 (60.6%) pts received locoregional radiotherapy, and 12 (37.5%) pts received hormonal therapy. Chemotherapy consisted of cisplatin 80 mg/m2 given on day 1 of a three week-cycle and vinorelbine 30 mg/m2 on days 1 and 8 for a total of 4 cycles with evaluation every 2 cycles. After the 4th cycle responding pts received docetaxel 75 mg/m2 on day 1 every 21 days for a maximum of 4 cycles. Evaluation of meas...