Robert E. Merritt

An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage.

Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non–small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

Morbidity and Mortality After Esophagectomy Following Neoadjuvant Chemoradiation

BACKGROUND Neoadjuvant chemoradiation (CRT) is an accepted treatment for locally advanced esophageal carcinoma. A survival benefit has not been definitively established, and there is concern that chemoradiation may increase postoperative morbidity and mortality. METHODS A retrospective review was made of 138 patients treated for esophageal carcinoma between January 1999 and December 2009. Fifty-four patients who underwent CRT followed by esophagectomy were compared with 84 patients who underwent esophagectomy alone. RESULTS The chemoradiation and esophagectomy alone cohorts were well matched on all preoperative variables. There was a higher percentage of Ivor Lewis procedures in the esophagectomy alone cohort (82.0%) compared with the CRT cohort (59.3%; p = 0.006). Thirty-five percent of the CRT group underwent transhiatal esophagectomy. Thirty-day mortality was 6.0% (5 of 84) in the esophagectomy alone cohort compared with 1.9% (1 of 54) in the CRT cohort (p = 0.5). Similarly, mean intensive care unit stay (4.7 versus 6.5 days; p = 0.5), ventilator time (2.4 versus 4.2 days; p = 0.5), and length of stay (13.5 versus 17 days; p = 0.2) did not differ significantly between the groups. The overall major complication rates were similar in the CRT and esophagectomy alone cohorts: 57.4% versus 56% (p = 0.98). Multivariate analysis determined that coronary artery disease (p = 0.01; odds ratio 3.5) and transthoracic esophagectomy (p = 0.05; odds ratio 1.4) were predictive of development of postoperative complications. Only cervical anastomotic location (p = 0.04; odds ratio 3.0) was predictive of anastomotic leak on multivariate analysis. CONCLUSIONS Neoadjuvant chemoradiation does not appear to increase postoperative morbidity or mortality after esophagectomy. Major postoperative complications are associated with the transthoracic approach and preoperative coronary artery disease.

miR-1 Induces Growth Arrest and Apoptosis in Malignant Mesothelioma

BACKGROUND We investigated microRNA expression profiles of malignant pleural mesothelioma (MPM) specimens to identify novel microRNA that are potentially involved in the oncogenic transformation of human pleural cells. METHODS microRNA microarray transcriptional profiling studies of 25 MPM primary tumors were performed. We used normal pleural tissue from an unmatched patient cohort as normal comparators. To confirm microarray data, we used real-time quantitative polymerase chain reaction. Representative cell lines H513 and H2052 were used in functional analyses of miR-1. RESULTS In addition to several novel MPM-associated microRNAs, we observed that the expression level of miR-1 was significantly lower in tumors as compared with normal pleural specimens. Subsequently, pre-miR of miR-1 was introduced into MPM cell lines to overexpress this microRNA. Phenotypic changes of these altered cells were assayed. The cellular proliferation rate was significantly inhibited after overexpression of miR-1. Early and late apoptosis was increased markedly in miR-1-transfected cell lines. Taken together, these data suggested that overexpression of miR-1 induced apoptosis in these MPM cell lines, acting as a tumor suppressor. We confirmed our observations by assessing in the transduced MPM cells cell cycle-related, proapoptotic, and antiapoptotic genes, which all showed coordinated, significant changes characteristic of the apoptotic phenotype. CONCLUSIONS Further investigation and validation of our microRNA database of MPM may elucidate previously unrecognized molecular pathways and/or mechanisms by identifying novel microRNAs that are involved in malignant transformation. Our study has now found miR-1 to be one of these MPM-associated microRNAs, with potential pathogenic and therapeutic significance.

Long-term results of sleeve lobectomy in the management of non-small cell lung carcinoma and low-grade neoplasms.

BACKGROUND The objective of this study was to evaluate the operative mortality, morbidity, and long-term survival of sleeve lobectomy for non-small cell lung cancer and low-grade neoplasms. We evaluated the effects of neoadjuvant therapy on the bronchial anastomotic complication rate and determined whether sleeve lobectomy performed in patients with N1 disease resulted in decreased overall survival. METHODS This study is a retrospective review of 196 patients who underwent sleeve lobectomy. One hundred twenty-five patients had non-small cell lung cancer. There were 117 men (59.7%) and 79 women (40.3%) with a mean age of 54 years. Sixteen patients (13%) received neoadjuvant therapy. Fifty-six patients with N1 disease underwent sleeve lobectomy. RESULTS There were 4 (2.0%) postoperative deaths. The postoperative morbidity rate was 36.7%. Four patients (2.0%) experienced bronchopleural fistulas. Multivariate analysis demonstrated that age older than 70 years (p = 0.02) and the diagnosis of non-small cell lung cancer (p = 0.0002) were risk factors for postoperative complications. Multivariate analysis also demonstrated that neoadjuvant therapy predicted anastomotic complications (p = 0.01). For non-small cell lung cancer patients, the 5-year survival rate was 44%. The 5-year survival rates for patients with pathologic N0 disease and N1 disease were 52.6% versus 39.3%, respectively (p = 0.205). CONCLUSIONS Sleeve lobectomy can be performed with minimal bronchial anastomotic complications and low postoperative mortality. In our study, neoadjuvant therapy for non-small cell lung cancer adversely influenced the rate of anastomotic complications. Performing sleeve lobectomy for patients with N1 disease was not associated with decreased overall survival rates.

Evidence-Based Suggestions for Management of Air Leaks

The management of postoperative alveolar air leaks (AALs) continues to challenge thoracic surgeons. AALs increase length of stay and health care costs, and likely lead to other postoperative complications. Staple line buttresses, topical sealants, pleural tents, pneumoperitoneum, and modifications of traditional chest tube management (ie, reduced suction) have all been proposed to help reduce AAL. However, the cost of some of the commercial products being marketed may outweigh their relative effectiveness, and some of these techniques and products have not been adequately studied to date. This article provides a review of the available evidence-based literature that addresses the efficacy of the options currently available to prevent and manage AALs. Management suggestions based on this literature are presented.

Prophylaxis and Management of Atrial Fibrillation After General Thoracic Surgery

Atrial fibrillation (AF) commonly affects patients after general thoracic surgery. Postoperative AF increases hospital stay and charges. Effective prophylaxis and treatment is the goal. Calcium channel blockers prevent postoperative AF. Beta blockers are a less viable choice. Amiodarone prophylaxis should be avoided in patients with pulmonary dysfunction or who require pneumonectomy. In management of AF, a brief trial of rate-control agents is appropriate; however, chemical cardioversion with rhythm-control agents should be instituted after 24 hours. High-risk patients with history of stroke or transient ischemic attack, or with two or more risk factors for thromboembolism should receive anticoagulation therapy.

Liquid chromatography/mass spectrometry methods for measuring dipeptide abundance in non‐small‐cell lung cancer

RATIONALE Metabolomic profiling is a promising methodology of identifying candidate biomarkers for disease detection and monitoring. Although lung cancer is among the leading causes of cancer-related mortality worldwide, the lung tumor metabolome has not been fully characterized. METHODS We utilized a targeted metabolomic approach to analyze discrete groups of related metabolites. We adopted a dansyl [5-(dimethylamino)-1-naphthalene sulfonamide] derivatization with liquid chromatography/mass spectrometry (LC/MS) to analyze changes of metabolites from paired tumor and normal lung tissues. Identification of dansylated dipeptides was confirmed with synthetic standards. A systematic analysis of retention times was required to reliably identify isobaric dipeptides. We validated our findings in a separate sample cohort. RESULTS We produced a database of the LC retention times and MS/MS spectra of 361 dansyl dipeptides. Interpretation of the spectra is presented. Using this standard data, we identified a total of 279 dipeptides in lung tumor tissue. The abundance of 90 dipeptides was selectively increased in lung tumor tissue compared to normal tissue. In a second set of validation tissues, 12 dipeptides were selectively increased. CONCLUSIONS A systematic evaluation of certain metabolite classes in lung tumors may identify promising disease-specific metabolites. Our database of all possible dipeptides will facilitate ongoing translational applications of metabolomic profiling as it relates to lung cancer.

A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male:

We report a rare synchronous presentation of adrenocortical carcinoma (ACC) and papillary thyroid carcinoma (PTC). A 31-year-old male first presented with a large left adrenal mass that was identified during the workup for refractory hypertension due to hyperaldosteronism. The mass was removed surgically with pathology showing ACC. The patient was then treated with adjuvant radiation therapy and mitotane chemotherapy. Four months post ACC resection, metastatic ACC to the right upper lung and PTC in the left lobe of the thyroid were found in surveillance imaging. He subsequently developed pulmonary, contralateral adrenal and brain metastases from his ACC. Li Fraumeni syndrome and Multiple Endocrine Neoplasia Type I (MEN I) were considered, but testing of both P53 and menin genes showed no mutation. We also performed a review of the literature and found three similar cases, however gene mutation analysis was not performed..

Indications for Surgery in Patients with Localized Pulmonary Infection

Nowadays, antibiotic and antifungal therapy is effective in treating some of the infections that can involve the lung parenchyma in a localized manner, such as bacterial abscess and infection with nonresistant tuberculosis strains. However, other localized pulmonary infections, for example aspergilloma and mucormycosis, are highly resistant to nonsurgical therapy, and in these diseases there are no generally successful options that do not include surgical resection. This article reviews the indications for surgical intervention in the treatment of common infections involving the lung, and also focuses on the general approaches to their management.

Clinical Effectiveness of Negative Pressure Wound Therapy Following Surgical Resection of Sternoclavicular Joint Infection: A Case Report.

Septic arthritis of the sternoclavicular joint (SCJ) is a rare condition accounting for 0.5% of bone and joint infections. The majority of cases require joint resection and advancement flaps to provide coverage to the resulting wound defect. However, in the setting of an infected wound space, surgeons are often inclined to allow wound healing by secondary intention. Negative pressure wound therapy (NPWT) can be an important adjunct to promote and shorten wound healing time following SCJ resection.