Khalid Alsaleh

Multitargeted anti-angiogenic agents and NSCLC: Clinical update and future directions

Increasing understanding of the molecular abnormalities driving cell growth and proliferation has resulted in extensive research into molecularly targeted therapies. Angiogenesis is an appealing target for the treatment of non small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), is already approved for the treatment of NSCLC. Many other anti-angiogenic agents under development form the focus of this review. A variety of agents, including sorafenib, sunitinib, cediranib, axitinib, motesanib, linifinib and brivanib inhibit VEGF in addition to either platelet derived growth factor (PDGF), or fibroblast derived growth factor (FGF). To date, none of these agents in combination with chemotherapy have resulted in improvements in overall survival for patients with advanced NSCLC. Triple angiokinase inhibitors, which inhibit VEGF, PDGF and FGF, have potential to improve the therapeutic outcomes for patients with NSCLC. However, there is a need for identification of appropriate biomarkers to improve patient selection and identify those patients benefiting from anti-angiogenesis therapy.

Role of pemetrexed in advanced non-small-cell lung cancer: meta-analysis of randomized controlled trials, with histology subgroup analysis

PURPOSE Platinum-based regimens represent the standard first-line treatment for non-small-cell lung cancer (nsclc). However, newer data have established a role for pemetrexed in the treatment of this disease. Such data suggest that histology represents a determining factor in the selection of treatment. METHODS We undertook a systematic review of the literature for randomized controlled trials that compared the efficacy of pemetrexed with that of other treatments in advanced nsclc. Data and study quality were assessed according to published guidelines. RESULTS We identified five trials that compared pemetrexed with other treatments or with placebo. Overall survival for patients treated with pemetrexed was superior to that with other treatments: hazard ratio (hr): 0.89; 95% confidence interval (ci): 0.80 to 0.99. The survival benefit was limited to patients with non-squamous histology: hr: 0.82; 95% ci: 0.73 to 0.91. Pemetrexed was inferior to other chemotherapy options in patients with squamous histology: hr: 1.19; 95% ci: 0.99 to 1.43. CONCLUSIONS Compared with other chemotherapy agents, pemetrexed is more effective for the treatment of nsclc in patients with non-squamous histology.

Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention

INTRODUCTION The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The purpose of this study was to estimate the frequency and case-fatality rate of major bleeding and recurrent VTE during secondary prevention of VTE. MATERIALS AND METHODS MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched through September 2014. Two reviewers independently screened citations to identify trials that enrolled patients for secondary prevention of VTE with direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), aspirin or placebo. Two reviewers independently extracted data onto standardized forms. RESULTS Twelve RCTs that enrolled 10,542 patients were included. The rate of major bleeding was 1.6 per 100 patient-years (95% CI, 1.2-2.1), and 0.58 per 100 patient-years (95% CI, 0.24-1.1) on VKAs and DOACs, respectively, with an incidence rate ratio of 0.35 (95% CI, 0.17-0.68, p=0.0023). The case-fatality rates for DOACs and VKAs were not significantly different at 0% (95% CI, 0.0-15.4) and 6.8% (95% CI, 1.4-18.6), respectively. The rate of recurrent VTE was not different between DOACs and VKA, IRR 0.88 (95% CI, 0.15-4.8, p=0.88). Case-fatality rates for recurrent VTE for DOAC and VKAs were 10.8% (95% CI, 4.4-20.9) and 5.6% (95% CI, 1.2-15.4), respectively. Only DOACs showed a significant reduction in the composite outcome of fatal recurrent VTE and fatal bleeding when compared to placebo, IRR 0.40 (95% CI, 0.14-1.0, p=0.03). CONCLUSION Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high.

Case fatality of bleeding and recurrent venous thromboembolism during, initial therapy with direct oral anticoagulants: a systematic review.

INTRODUCTION The frequency and case fatality of venous thromboembolism (VTE) and major bleeding during the initial 3 months of therapy in those treated for symptomatic VTE with either direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA) are important clinically relevant outcomes. We sought to measure it during the initial months of anticoagulation for symptomatic VTE. MATERIAL AND METHODS We searched MEDLINE, EMBASE, and CENTRAL to identify studies that enrolled patients with acute symptomatic VTE treated with DOACs or VKA and reported data on bleeding, VTE recurrence and death. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Single-proportion random-effects models were used to pool estimates. RESULTS Of the 2453 citations retrieved, 5 RCTs that enrolled 24,507 patients were included. The rate of major bleeding was 1.8 (95% CI: 1.3-2.5) and 3.1 (95% CI: 2.4-3.9) per 100 patient-years in DOAC and VKA arms, respectively. The rate of VTE recurrence was 3.7 (95% CI: 2.7-4.7) and 4.1 (95% CI: 3.0-5.4) per 100 patient-years of DOAC and VKA, respectively. The case fatality rate of bleeding was significantly higher in the VKA arms 10.4% (95% CI: 6.6-15.4) compared to DOACs 6.1% (95% CI: 2.7-11.7; p value for difference=0.029) with no statistical difference between the case fatalities for recurrent VTE. The rate of death from either definite major bleeding or definite recurrent VTE was 0.27 (95% CI: 0.16-0.40) and 0.46 (95% CI: 0.32-0.63) per 100 patient-years for DOACs and VKAs respectively, resulting in a number needed to treat of 875 for DOACs to prevent one death. CONCLUSION DOACs are attractive alternatives to VKAs for initial treatment of symptomatic VTE, with lower frequency and case fatality for major bleeding. However, the incremental safety benefit of DOACs over VKAs is small, with large numbers needed to treat.

Routine administration of standardized questionnaires that assess aspects of patients’ quality of life in medical oncology clinics: A systematic review ☆

PURPOSE Increasing interest in the Quality of Life outcomes in cancer patients led to increase implementation of their use in routine clinical practice. The aim of this systemic review is to review the scientific evidence behind recommending the use of quality of life (QoL) scales routinely in outpatient evaluation. METHODS Systematic review for all published randomized controlled trials in English language between January 1, 1990 till December 31, 2012. Out of 487 articles (476 identified by electronic search+11 articles identified by manual search), six trials satisfied the eligibility criteria: (1) the study was a randomized controlled trial (RCT) with randomization of patients or health care providers; (2) the findings of the administered questionnaire or scale (the intervention) were given to health care provider, and compared to standard care with no questionnaire administered (the control); (3) study was conducted in outpatient oncology clinics; and (4) an outcome was measured that related to (i) QoL improvement, (ii) reduction in morbidity, (iii) reduction in stress for the patients, (iv) improvement in communication between patients and health care provider, or (v) improved patient satisfaction. Assessment for the quality of the study was done using the GRADE methodology. RESULTS Serious methodological issues were affecting most of the trials. Overall the evaluation of the quality of the evidence from these identified trials suggests that there is a weak recommendation to use QoL scales in routine oncology practice to improve communication between physicians and patients. CONCLUSION The routine use of such tools in the outpatient settings at improving the patient outcome or satisfaction cannot be recommended based on the available evidence. The potential harm with the excess use of resources needed to implement, collect, store, analyse, and present such data to health care providers should be also considered. Further research and better designed trials is required using recent methodological techniques such as item-response theory based questionnaire and cluster randomization might help to reach an answer to this question.

Frequency, Clinical Pattern and Outcome of Thrombosis in Cancer Patients in Saudi Arabia

OBJECTIVES Thrombotic risk is increased in patients with cancer and there are important implications for those who suffer a venous thromboembolism (VTE). We undertook this study to determine the frequency, clinical patterns, and outcome of VTE in Saudi patients with cancer. METHODS Cancer (solid tumors and lymphoma) patients who developed VTE from January 2004 to January 2009 were studied retrospectively. Demographics and clinical characteristics related to thrombosis and cancer were evaluated. RESULTS A total of 701 patients with cancer were seen during the study period. VTE was diagnosed in 47 (6.7%) patients (median age 52, range 18-80 years). Lower limb DVT was the most common type, seen in 47% patients, followed by PE in 19%, and 19% patients had both DVT and PE. Thrombosis was symptomatic in 72% patients while it was an incidental finding on routine workup in 28% . Cancer and VTE were diagnosed at the same time in 38% of patients, and 47% patients developed VTE during the course of disease after the cancer diagnosis. The majority of VTE post cancer diagnoses occurred during the first year (median 4 months, range 1-14). Additional risk factors for VTE were present in 22 (47%) patients and 14 (30%) of these patients were receiving chemotherapy at the time of thrombosis. Only 5 (10.6%) patients were receiving thrombo-prophylaxis at the time of VTE diagnosis. Most common types of tumors associated with thrombosis were breast cancer, non-Hodgkins lymphoma and lung cancer. The majority of the affected patients (79%) had advanced stage of cancer. After a median follow-up of 13 (range 0.5-60) months, 38 (81%) patients had died. There was no difference in the mortality of patients with symptomatic or asymptomatic thrombosis (82% vs 78.6%). CONCLUSIONS Thrombotic complications can develop in a significant number of patients with cancer, and almost half of the patients have additional risk factors for VTE. Thrombosis is usually associated with advanced disease and can be asymptomatic in more than a quarter of cases. Thromboprophylaxis in cancer patients is under-utilized. Community based studies are needed to accurately define the extent of this problem and to develop effective prophylactic strategies.

Cathepsin B expression in colorectal cancer in a Middle East population: Potential value as a tumor biomarker for late disease stages

Cathepsin B (CTSB), is a cysteine protease belonging to the cathepsin (Clan CA) family. The diagnostic and prognostic significance of increased CTSB in the serum of cancer patients have been evaluated for some tumor types. CTSB serum and protein levels have also been reported previously in colorectal cancer (CRC) with contradictory results. The aim of the present study was to investigate CTSB expression in CRC patients and the association of CTSB expression with various tumor stages in a Middle East population. Serum CTSB levels were evaluated in 70 patients and 20 healthy control subjects using enzyme-linked immunosorbant assay (ELISA) technique. CTSB expression was determined in 100 pairs of CRC tumor and adjacent normal colonic tissue using quantitative PCR for mRNA levels. Detection of CTSB protein expression in tissues was carried out using both immunohistochemistry and western blotting techniques. ELISA analysis showed that in sera obtained from CRC patients, the CTSB concentration was significantly higher in late stage patients with lymph node metastases when compared to early stage patients with values of 2.9 and 0.33 ng/ml, respectively (P=0.001). The majority of tumors studied had detectable CTSB protein expression with significant increased positive staining in tumors cells when compared with matched normal colon subjects (P=0.006). The mRNA expression in early stage CRC compared to late stage CRC was 0.04±0.01 and 0.07±0.02, respectively. Increased mRNA expression was more frequently observed in the advanced cancer stages with lymph node metastases when compared with the control (P=0.002). Mann-Whitney test and paired t-test were used to compare serum CTSB and mRNA levels in early and late tumor stage. A subset of four paired tissue extracts were analyzed by western blotting. The result confirmed a consistent increase in the CTSB protein expression level in tumor tissues compared with that noted in the adjacent normal mucosal cells. These findings indicate that CTSB may be an important prognostic biomarker for late stage CRC and cases with lymph node metastases in the Middle Eastern population. Monitoring serum CTSB in CRC patients may predict and/or diagnose cases with lymph node metastases.

Triple Negative Breast Cancer: A Tale of Two Decades

Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroups. Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. TNBC is subject to intense research activities aiming at dissecting potential pathways, identifying potential molecular signatures and biomarkers in order to properly develop new targeted biologic modifiers. Despite this, there is a lack of approved predictive and prognostic biomarkers, and keeping in view the complexity of TNBC biology, research should be targeted towards identifying multi-factorial signatures rather than single markers. This review aims to summarize the current evidence, ongoing research and discuss future strategies for the treatment of patients with TNBC. In addition we have reviewed the recent advances in detecting predictive and prognostic biomarkers and identifying surrogate markers for early identification of potential responders to the new therapies.

Preoperative transfusion in patients with sickle cell disease to prevent perioperative complications: A systematic review and meta-analysis

Abstract Background Sickle cell disease (SCD) is associated with perioperative vascular (SCD-related) and non-vascular complications. To minimize perioperative complications during elective surgery, either exchange blood transfusion or simple blood transfusion can be used. We systematically reviewed the literature and meta-analyzed randomized and observational trials comparing exchange transfusion to simple transfusion, as well as studies comparing preoperative transfusion to no transfusion to assess the relative risk (RR) and benefit of each strategy in sickle cell patients undergoing surgery. Methods Medline, Embase, and the Cochrane-controlled trial register were searched to identify studies that evaluated exchange transfusion to simple transfusion, as well as studies comparing any form of blood transfusion with no transfusion. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled RR was estimated using a random effects model. Results Three randomized trials and seven observational studies were included. We found there was no difference between exchange transfusion and simple transfusion for perioperative mortality, vascular, or non-vascular perioperative complications. However, transfusion-related complications (RR 2.41, 95% confidence interval (CI): 1.49–3.91) and the amount of blood transfused (mean difference 2.03, 95% CI: 1.23–2.83) were higher in those treated with exchange transfusion versus simple transfusion. Similarly, there was no difference in perioperative mortality, vascular, or non-vascular perioperative complications between those treated with preoperative transfusion strategy and no transfusion strategy. Conclusion Based on the current literature, neither preoperative exchange transfusion nor simple transfusion reduces perioperative complications in patients with SCD who are undergoing surgery; however, available studies were underpowered to detect a treatment effect.

Ergonomic assessment of primary school furniture in United Arab Emirates

BACKGROUND: In many developing countries, anthropometric measures are rarely available and dimensions of school furniture are either based on anthropometric measures from developed countries or are arbitrarily determined. OBJECTIVE: The purpose of this study was to ergonomically assess classroom furniture dimensions in United Arab Emirates as compared to students’ anthropometric measures. METHODS: Relevant anthropometric dimensions of a sample of 200 grade 6 students were measured in two large schools in Dubai and Sharjah. Dimensions of furniture used by these students were also measured and compared to their anthropometric measures. RESULTS: Results show that there was a major mismatch between many anthropometric measures and classroom furniture dimensions. CONCLUSIONS: There is a great discrepancy between furniture dimensions and anthropometrics measures of students. To ensure postural comfort. a new set of furniture dimensions for grade 6 classrooms in is suggested based on anthropometric dimensions of students.