Khalid Amer

Bio: Khalid Amer is an academic researcher from Southampton General Hospital. The author has contributed to research in topics: Dissection (medical) & VATS lobectomy. The author has an hindex of 10, co-authored 23 publications receiving 263 citations. Previous affiliations of Khalid Amer include University of Southampton.

Early and mid-term outcomes of trans-sternal and video-assisted thoracoscopic surgery for thymoma

Abstract: OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) for thymoma has uncertain safety and effectiveness in comparison with transsternal resection. This feasibility study compared short- and mid-term outcomes for patients undergoing these two procedures, highlights weaknesses in current research and makes recommendations for long-term technological evaluations in this field. METHODS: Consecutive thymoma cases between 2004 and 2010 were identified. Patients were divided into two groups according to surgical approach (Group I trans-sternal; Group II VATS) and comparisons were made between groups. The primary outcome was overall survival. Secondary outcomes included operative morbidity and mortality, hospital stay, recurrence rate and disease-free survival. RESULTS: Thirty-nine patients were included (Group I: n=22 vs Group II: n=17). There were no differences between groups at baseline for all measured covariates. No deaths occurred within 30 days of surgery. More patients in Group I developed complications (Group I: n=10 vs Group II: n=3;P=0.093), while hospital stay was shorter in Group II (Group I: 6.4±4.6 days vs Group II: 4.4±1.8 days; P=0.030). Five-year overall survival (Group I: 93.8±6.1% vs Group II: 83.3±11.2%; P=0.425), 5-year disease-free survival (Group I: 71.0±15.3% vs Group II: 83.3±11.2%; P=0.827) and recurrence rates at final follow-up (Group I: n=2 vs Group II: n=1;P=0.363) were similar between the groups. CONCLUSION: VATS thymectomy for thymoma is feasible, safe and has comparable mid-term oncological outcomes to trans-sternal thymectomy. Future research is required to evaluate long-term oncological outcomes of VATS thymectomy for thymoma in national registries and randomized, controlled trials.

A Novel Lung Explant Model for the Ex Vivo Study of Efficacy and Mechanisms of Anti-Influenza Drugs

Abstract: Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials.

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

Abstract: Background: NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. Methods: The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. Results: There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. Conclusion: Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Video-assisted thoracic surgery systematic mediastinal nodal dissection and stage migration: impact on clinical pathway.

Abstract: OBJECTIVES The aim of this study is to investigate the role of routine systematic mediastinal nodal dissection (SND) performed during video-assisted thoracic surgery (VATS) major pulmonary resections (VMPRs) as a staging strategy for non-small-cell lung cancer (NSCLC), compared with preoperative staging by conventional positron emission tomography (PET) and computed tomography (CT) imaging. METHODS All patients suspected of having early lung cancer (T1-2, N0-1 and M0) were staged preoperatively by CT/PET. During VMPR, all lymph nodes on the right side at stations 2-4, 7, 8, 9, 10 and 11 and on the left stations 4-6, 7, 8, 9, 10, 11 and 3 when indicated were dissected en bloc. Histology was provided on the paraffin-embedded nodes, and patients staged accordingly. Preoperative and postoperative stagings were compared. Stage migration and impact on clinical pathway were noted. Stage IIa and higher were referred for adjuvant chemotherapy. RESULTS Between April 2007 and January 2011, 106 consecutive patients with suspected primary NSCLC proceeded to VMPR+SND. Histology confirmed NSCLC in 96 patients. Forty-five were men and 51 women. Median age was 68.6 (range 42.8-84.7) years. As many as 91 (94.8%) patients underwent lobectomy, three (3.1%) bilobectomy and two (2.1%) pneumonectomy. PET accurately correlated with SND histological diagnosis in 42 (43.8%) patients. The unexpected N2 disease in cN0-1 was 9/86 (10.5%). SND resulted in 25 stage migrations, upstaged 16 (16.6%) and down-staged nine (9.4%) patients. All upstagings were adenocarcinoma. Four (4.2%) PET-negative patients had multi-station N2 disease. SND resulted in changing the clinical pathway for 19 (20%) patients. Fourteen (14.6%) patients upstaged to qualify for chemotherapy, and 5/9 (5.2%) down-staged patients were saved the chemotherapy. There was no morbidity or mortality attributable to this added procedure. CONCLUSIONS SND during VMPR is safe and should be routinely performed even when nodal metastases is considered unlikely. VATS-SND is more accurate than PET in staging the mediastinum for NSCLC. PET sensitivity is significantly reduced in adenocarcinoma and might result in stage migration. Adjuvant multidisciplinary treatment should be based on SND staging.

Video assisted thoracoscopic excision of mediastinal ectopic parathyroid adenomas: a UK regional experience.

Abstract: Background: To report the first series of video-assisted thoracoscopic surgery (VATS) resection of mediastinal ectopic parathyroid adenomas (MEPAs) in the UK. Methods: A case series of seven cases undergoing VATS between 2004 and 2009 to treat single gland hyperparathyroidism. Methylene blue (MB) was used in 5/7 cases immediately before exploration to identify the adenomas. Carbon dioxide (CO 2 ) up to pressures of 10 mmHg was used safely to deflate the lung in two cases. Results: There were five women and two men with a mean age of 53 years (range, 27-72 years). Histopathology confirmed successful resection of the parathyroid adenoma in 6/7 cases. There was one conversion to open thoracotomy due to bleeding from the azygos vein resulting from excessive traction. Despite marked MB uptake, this patient proved to have tuberculoid adenopathy and no parathyroid tissue was identified. Postoperative plasma calcium returned to normal in 6/7 patients and parathyroid hormone (PTH) level in 6/7 patients. The median hospital stay was 2 days and there was no mortality in this series. Conclusions: MEPAs can be safely resected using VATS with minimal surgical morbidity, short drainage time and short hospital stay. CO 2 insufflation and the intraoperative use of MB are safe and help to accurately localise the ectopic adenoma. VATS should be considered as the first-line approach for resection of MEPAs.

Molecular chess? Hallmarks of anti-cancer drug resistance

Abstract: The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results.

Thoracoscopic Lobectomy Has Increasing Benefit in Patients With Poor Pulmonary Function: A Society of Thoracic Surgeons Database Analysis

Abstract: Lung cancer remains the leading cause of cancer-related deaths in the United States of America. Estimated to account for 226,160 new diagnoses of cancer in the year of 2012,1 only 20% to 25% of patients will have resectable disease, with approximately 30,000 pulmonary resections performed per year.2 Several studies have demonstrated the benefit of thoracoscopic lobectomy over lobectomy by thoracotomy. Both single-institution series3,4 and multi-institutional meta-analyses5,6 have demonstrated that thoracoscopic lobectomy is associated with fewer complications and decreased length of stay when compared with thoracotomy. It has also been suggested that thoracoscopy patients may enjoy improved overall survival.5 During the introduction of thoracoscopic lobectomy, patients were selected with early-stage disease and fewer operative risk factors. However, more recent series have documented safety in patients with larger tumors,3,7 patients after induction therapy,8 and benefit in patients who are elderly9–12 and those with poor pulmonary function.13–15 Pulmonary complications are the most common postoperative complication in patients undergoing noncardiac thoracic surgery.16,17 In their study on the outcomes of patients with postoperative respiratory failure after general and vascular surgery, Johnson et al found that respiratory failure predicted further complications such as myocardial infarction, pneumonia, acute renal failure, and deep venous thrombosis.18 In addition, among patients with postoperative respiratory failure, 26% died within 30 days of surgery. Using a national, multi-institutional database, we sought to determine whether a respiratory benefit existed for high-risk patients undergoing thoracoscopic lobectomy over lobectomy by thoracotomy.

Cellular chemosensitivity assays: an overview.

Abstract: Data on cell viability have long been obtained from in vitro cytotoxicity assays Today, there is a focus on markers of cell death, and the MTT cell survival assay is widely used for measuring cytotoxic potential of a compound However, a comprehensive evaluation of cytotoxicity requires additional assays which -measure short and long-term cytotoxicity Assays which measure the cytostatic effects of compounds are not less important, particularly for newer anticancer agents This overview discusses the advantages and disadvantages of different non-clonogenic assays for measuring short and medium-term cytotoxicity It also discusses clonogenic assays, which accurately measure long-term cytostatic effects of drugs and toxic agents For certain compounds and cell types, the advent of high throughput, multiparameter, cytotoxicity assays, and gene expression assays have made it possible to predict cytotoxic potency in vivo

Major intraoperative complications during video-assisted thoracoscopic anatomical lung resections: an intention-to-treat analysis.

Abstract: Objectives A multicentre evaluation of the frequency and nature of major intraoperative complications during video-assisted thoracoscopic (VATS) anatomical resections. Methods Six European centres submitted their series of consecutive anatomical lung resections with the intention to treat by VATS. Conversions to thoracotomy, vascular injuries and major intraoperative complications were studied in relation to surgeons' experience. Major complications included immediate life-threatening complications (i.e. blood loss of more than 2 l), injury to proximal airway or other organs or those leading to unplanned additional anatomical resections. All cases were discussed by a panel and recommendations were drafted. Results A total of 3076 patients were registered. Most resections (90%, n = 2763) were performed for bronchial carcinoma. There were 3 intraoperative deaths, including 1 after conversion for technical reasons. In-hospital mortality was 1.4% (n = 43). Conversion to open thoracotomy was observed in 5.5% (n = 170), of whom 21.8% (n = 37) were for oncological reasons, 29.4% (n = 50) for technical reasons and 48.8% (n = 83) for complications. Vascular injuries were reported in 2.9% (n = 88) patients and led to conversion in 2.2% (n = 70). In 1.5% (n = 46), major intraoperative complications were identified. These consisted of erroneous transection of bronchovascular structures (n = 9); injuries to gastrointestinal organs (n = 5) or proximal airway (n = 6); complications requiring additional unplanned major surgery (n = 9) or immediate life-threatening complications (n = 17). Twenty-three percent of the in-hospital mortalities (n = 10/43) were related to major intraoperative complications. Eight pneumonectomies (five intraoperative and three postoperative at 0.3%) were a consequence of a major complication. Surgeon's experience was related to non-oncological conversions, but not to vascular injuries or major complications in a multivariable logistic regression analysis. Conclusion Major intraoperative complications during VATS anatomical lung resections are infrequent, seem not to be related to surgical experience but have an important impact on patient outcome. Constant awareness and a structured plan of action are of paramount importance to prevent them.

Anticancer drug sensitivity prediction in cell lines from baseline gene expression through recursive feature selection.

Abstract: An enduring challenge in personalized medicine is to select right drug for individual patients. Testing drugs on patients in large clinical trials is one way to assess their efficacy and toxicity, but it is impractical to test hundreds of drugs currently under development. Therefore the preclinical prediction model is highly expected as it enables prediction of drug response to hundreds of cell lines in parallel. Recently, two large-scale pharmacogenomic studies screened multiple anticancer drugs on over 1000 cell lines in an effort to elucidate the response mechanism of anticancer drugs. To this aim, we here used gene expression features and drug sensitivity data in Cancer Cell Line Encyclopedia (CCLE) to build a predictor based on Support Vector Machine (SVM) and a recursive feature selection tool. Robustness of our model was validated by cross-validation and an independent dataset, the Cancer Genome Project (CGP). Our model achieved good cross validation performance for most drugs in the Cancer Cell Line Encyclopedia (≥80 % accuracy for 10 drugs, ≥ 75 % accuracy for 19 drugs). Independent tests on eleven common drugs between CCLE and CGP achieved satisfactory performance for three of them, i.e., AZD6244, Erlotinib and PD-0325901, using expression levels of only twelve, six and seven genes, respectively. These results suggest that drug response could be effectively predicted from genomic features. Our model could be applied to predict drug response for some certain drugs and potentially play a complementary role in personalized medicine.