Raafat Alameddine

Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer.

Despite major advances in cancer therapeutics, the prognosis for lung cancer patients is still poor and the median survival for patients presenting with advanced non-small cell lung cancer (NSCLC) is only 8-10 months. Angiogenesis is an important biological process and a relatively early event during lung cancer pathogenesis. Anti-angiogenic agents are used in treating patients with NSCLC, and their molecular biomarkers are also being assessed to predict response. A better understanding of the biology of angiogenesis in NSCLC may reveal new targets for treating this malignancy. In this article, we review the expression and prognostic impact of the angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in NSCLC.

Methods of overcoming treatment resistance in colorectal cancer

Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.

Crosstalk between HER2 signaling and angiogenesis in breast cancer: molecular basis, clinical applications and challenges.

Purpose of review Angiogenesis is an essential hallmark of cancer. Targeting angiogenesis has proven its efficacy in the modern therapeutic paradigm. HER2 positive breast cancer, in particular, is a challenging disease in which resistance to standard therapy has been attributed to parallel and downstream signaling cascades including angiogenesis. This review explores the molecular mechanisms underlying crosstalk between HER2 signaling and angiogenesis. It highlights the role of angiogenesis in the emerging resistance to anti-HER2 therapy. It surveys the current repertoire of clinical trials involving use of combination of anti-HER2 and antiangiogenic therapies. Finally, it entertains the hopes and challenges posed by this novel therapeutic approach. Recent findings HER2 signaling upregulates angiogenesis at different levels and by different mechanisms. A large number of clinical trials were conducted in attempt to exploit the potential benefit of the combination. Results of early phase trials were promising. However, in the late phase clinical trials, the AVEREL trial did not demonstrate a consistent benefit for bevacizumab in the HER2 positive breast cancer patient population. The BETH trial is ongoing and recruiting patients. Safety issues regarding cardiovascular toxicity of the combination have been already raised. Negative experience of dual EGFR and VEGF targeting in colon cancer cannot be overlooked. Summary Angiogenesis and HER2 signaling are closely related at the molecular level. Appraisal of efficacy of antiangiogenic therapies requires revisit of the current literature as well as following the results of ongoing trials.

From Sprouting Angiogenesis to Erythrocytes Generation by Cancer Stem Cells: Evolving Concepts in Tumor Microcirculation

Angiogenesis is essential for tumor growth and metastasis. Over the last decades, a substantial progress has been achieved in defining different patterns of tumor microcirculation. Sprouting angiogenesis, the oldest model of microcirculation, is the de novo vessel formation from preexisting blood vessels. Vessel splitting and hijacking, also known, respectively, as intussusception and cooption, are alternative models that account for tumor resistance to antiangiogenic therapy. In addition to remodeling the microenvironment, the tumor cell can undergo intrinsic changes and survive hypoxic conditions by acquiring stem cell properties. In line with the concept of pluripotency, tumor cells can form vascular mimicry structures creating their own microcirculation despite a latent vessel growth. The recent identification of the polyploid giant cancer cells and tumor-derived erythrocytes is the most innovative survival mechanism in hypoxia and provides a potential target for more effective therapies.

Postoperative outcomes following pancreaticoduodenectomy: how should age affect clinical practice?

BackgroundPancreaticoduodenectomy is an increasingly common procedure performed for both benign and malignant disease. There are conflicting data regarding the safety of pancreatic resection in older patients. Potentially modifiable perioperative risk factors to improve outcomes in older patients have yet to be determined.MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for 2008 to 2009 was used for this retrospective analysis. Patients undergoing pancreaticoduodenectomy were identified and divided into those above and below the age of 65. Preoperative risk factors and postoperative morbidity and mortality were evaluated.ResultsAmong 2,045 patients included in this analysis, 994 patients were >65 years (48.6%) while 1,051 were (less than or equal to) 65 years (51.4%). Thirty-day mortality was higher in the older age group compared to the younger age group 3.6% vs. 1.9% respectively, P = 0.017, odds ratio 1.94. Older patients had a higher incidence of unplanned intubation, ventilator support >48 h and septic shock compared with younger patients. On multivariate logistic regression, after adjusting for other 30-day postoperative occurrences (significant at the P <0.1 level) only septic shock was independently associated with a higher odds of mortality, unplanned intubation, and ventilator support >48 h in older patients compared with younger patients.ConclusionsThis report from a population-based database is the first to highlight postoperative sepsis as an independent risk factor for mortality and morbidity in older patients undergoing pancreatic resection. Careful perioperative management addressing this issue is essential for patients over the age of 65.

Younger age is an independent predictor of worse prognosis among Lebanese nonmetastatic breast cancer patients: analysis of a prospective cohort

Background Several retrospective studies have reported that younger age at presentation is associated with a worse prognosis for nonmetastatic breast cancer patients. In this study, we prospectively assessed the association between different baseline characteristics (age, tumor characteristics, mode of treatment, etc) and outcomes among newly diagnosed nonmetastatic Lebanese breast cancer patients. Methods We recruited a sample of 123 women newly diagnosed with nonmetastatic breast cancer presenting to American University of Beirut Medical Center. Immunohistochemical, molecular (vitamin D receptor, methylene tetrahydrofolate reductase polymorphisms), and genetic assays were performed. Patient characteristics were compared by age group (<40 and ≥40 years). A Cox regression analysis was performed to evaluate the variables affecting the disease-free survival (DFS). Outcome data were obtained, and DFS was estimated. Results Among the 123 patients, 47 were 40 years of age or younger, and 76 were older than 40 years. Median follow-up duration was 58 months. Nine out of 47 patients <40 years (19.1%) experienced disease relapse in contrast to four out of 76 patients >40 years (5.2%). A wide immunohistochemical panel included Ki-67, cyclin B1, p53, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor, and did not reveal any significant difference in these markers between the two age groups. Older patients had a larger percentage of Luminal A than younger patients. On multivariate analysis including age, stage, grade, and subtype, only age <40 and stage were significantly associated with shorter DFS with hazard ratios of 4 (p=0.03, 95% confidence interval [CI]: 1.1–13.5) and 3 (p=0.03, 95% CI: 0.8–14.9), respectively. The estimated 5-year DFS for patients >40 years was 90%, and for patients <40 years was 37%. Conclusion Being <40 years old was an independent risk factor for recurrence in this cohort of patients.

Cardiac and vascular toxicities of angiogenesis inhibitors: The other side of the coin

Angiogenesis is one of the best-described tumor hallmarks. Targeting angiogenesis is becoming a successful strategy to suppress cancer growth. Vascular endothelial growth factor (VEGF), the fulcrum of angiogenesis, contributes to vascular and cardiac homeostasis. Angiogenesis inhibitors classically associated with vascular side effects are increasingly recognized for cardiac adverse effects as reflected by several meta-analyses. A global approach to these findings is a pressing need, and future strategies involving collaboration among different medical specialties are highly encouraged.

B-type proto-oncogene-mutated tumors of colon cancer: promising therapeutic approaches.

Purpose of review B-type proto-oncogene (BRAF) mutations have been observed in about 10.8% of patients with colorectal cancer (CRC). These patients do not respond to standard therapy with anti-epidermal growth factor receptor kinase (EGFR). Here we review novel BRAF inhibitors that are currently being investigated in these tumors. Recent findings Clinical experience with the BRAF inhibitor vemurafenib in CRC suggests significant differences in response compared with melanoma. Based on preclinical data, resistance to BRAF inhibitors employs alternative signaling pathways that in turn induce cell proliferation and survival. Therapeutic strategies that combine BRAF inhibitors in addition to targeted therapy with anti-EGFR monoclonal antibodies and phosphoinositide 3-kinase pathway inhibitors or standard therapy have yielded promising results in preclinical models and some reported cases. Summary Results from current clinical trials that are exploring novel BRAF inhibitors and others that employ combined therapy are eagerly awaited for the treatment of BRAF-mutated CRC. Video abstract http://links.lww.com/COON/A13.

Effects of Nodal Status and Extent of Surgery on Survival in Triple Negative Breast Cancer

Background : Triple Negative Breast Cancer (TNBC) is one of the most aggressive but least understood subtypes of breast cancer. The roles of nodal status and type of surgery while essential in determining the outcomes of patients with TNBC remain controversial and require more examination. Materials and Methods : Clinical and pathological data were retrieved from 1990 until 2001 by retrospective chart review for patients with breast cancer at the American University of Beirut Medical Center. Out of 1455 patients, 524 had complete histological data, of which 138 (26.3%) were diagnosed with TNBC. Median follow up time of patients with TNBC was 3.34 years (Range 0.55 - 10 years). We used the Kaplan-Meier and Cox proportional hazard models to evaluate prognostic effects and estimate hazard ratios (HR). Results : For the 138 patients with TNBC, median age at presentation was 50.91 years (Range 26 - 81). One-year, 5 and 10-year survivals for node-negative patients (N0) were respectively 98.3 %, 91.1% and 74.5 %, compared to 98.5%, 70.3 % and 42.2% for node-positive patients (N1-N3). Numerical nodal staging did not significantly correlate with survival. On multivariate analysis, higher stage (H.R 3.01) and Breast-Conserving Therapy (BCT) had a significant effect on the survival of TNBC patients (H.R 0.195) Conclusion : Lymph node-positivity predicted poorer survival in patients with TNBC. However, within the group of patients with positive LN, the number of positive lymph nodes did not alter survival nor did the tumor size. BCT including radiation therapy had a better effect on survival when compared to mastectomy.

Perceptions and Attitudes of Cancer Patients and Caregivers Towards Enrollment in Clinical Trials in Lebanon

The rates of participation in oncology clinical trials (CTs) are relatively lower in the Middle East compared to other areas in the world. Many social and cultural factors underlie the patients’ reluctance to participate. To probe the knowledge, attitudes, and perceptions of patients with cancer and their caregivers regarding participation in CTs at our tertiary referral center in Lebanon, we interviewed 210 patients and caregivers visiting the outpatient clinics in the Naef Basile Cancer Institute at the American University of Beirut. A questionnaire was derived from literature and administered in Arabic. The study was approved by the Institutional Review Board (IRB). Two hundred individuals agreed to answer the questionnaire. The majority of participants (90.5%) were Lebanese with the remaining being non-Lebanese Arabs. Eighty-nine participants (45%) were aware of the concepts of CTs. Eighty-two respondents (41%) would participate in phase I CTs. Twenty-nine individuals (14.5%) agree to be enrolled in CTs with the approval of their family members only. One hundred twenty-nine subjects (64.5%) stated that they would refuse enrollment in a CT where they might receive placebo. Eighty-eight (44%) of participants considered that medical records could be reviewed for research without consent while 54% agreed that samples collected during clinical workup could be used for research without the consent of the patient. There are several social and demographic correlates for participation in CTs. Raising awareness and overcoming barriers of misconception are keys to promote participation in CTs in Lebanon.