The DNA methylation landscape of small cell lung cancer suggests a differentiation defect of neuroendocrine cells.

Small cell lung cancer (SCLC) is a disease characterized by aggressive clinical behavior and lack of effective therapy. Owing to its tendency for early dissemination, only a third of patients have limited-stage disease at the time of diagnosis. SCLC is thought to derive from pulmonary neuroendocrine cells. Although several molecular abnormalities in SCLC have been described, there are relatively few studies on epigenetic alterations in this type of tumor. Here, we have used methylation profiling with the methylated-CpG island recovery assay in combination with microarrays and conducted the first genome-scale analysis of methylation changes that occur in primary SCLC and SCLC cell lines. Among the hundreds of tumor-specifically methylated genes discovered, we identified 73 gene targets that are methylated in >77% of primary SCLC tumors, most of which have never been linked to aberrant methylation in tumors. These methylated targets have potential for biomarker development for early detection and therapeutic management of SCLC. SCLC cell lines had a greater number of hypermethylated genes than primary tumors. Gene ontology analysis indicated a significant enrichment of methylated genes functioning as transcription factors and in processes of neuronal differentiation. Motif analysis of tumor-specific methylated regions identified enrichment of binding sites for several neural cell fate-specifying transcription factors including NEUROD1, HAND1, ZNF423 and REST. We hypothesize that two potential mechanisms, loss of cell fate-determining transcription factors by methylation of their promoters and functional inactivation of their corresponding genomic-binding sites by DNA methylation, can promote a differentiation defect of neuroendocrine cells thus enhancing the ability of tumor progenitor cells to transition toward SCLC.

The first series of completely robotic esophagectomies with three-field lymphadenectomy: initial experience.

BACKGROUND: This study investigated the use of robotics to perform extended esophageal resection in a series of patients. METHODS: A total of 14 patients with a median age of 64 years underwent esophagectomy using the da Vinci robot. At presentation, there were 12 cases of cancer, staged at T2N1 (n = 2), T3N0 (n = 2), T3N1 (n = 6), T4N1 (n = 1), and M1a (n = 1); 2 cases of high-grade dysplasia; 8 cases of adenocarcinoma; and 4 cases of squamous cell cancer; as well as 2 middle third, 9 lower third, and one gastroesophageal junction tumor. Nine patients had undergone preoperative chemoradiotherapy, and six had undergone prior abdominal surgery. The patients were categorized into three chronological groups according to the procedure performed. Group 1 consisted of the first three patients in the series, whose surgery was thoracic only (robotically assisted esophagectomy). Group 2, the next three patients, had robotically assisted thoracic esophagectomy plus thoracic duct ligation using a laparoscopic gastric conduit. Group 3, the last eight patients, underwent completely robotic esophagectomy. RESULTS: For Group 3, the total operating room time was 11.1 +/- 0.8 h (range, 11.3-13.2 h), with a console time of 5.0 +/- 0.5 h (range, 4.8-5.8 h). The estimated blood loss was 400 +/- 300 ml (range, 200-950 ml). One patient in group 1 had a thoracic duct leak. In groups 2 and 3, thoracic duct ligation resulted in no further leaks. Other postoperative complications included severe pneumonia (1 case), atrial fibrillation (5 cases), cervical anastomotic leak (2 cases), wound infection (1 case), and bilateral vocal cord paresis requiring tracheostomy (1 case). In seven of the cases, no intensive care unit time was required. There was one death from pneumonia 72 days after the procedure. The rate of disease-free survival was 87%. CONCLUSION: The robotic approach facilitates an extended three-field esophagolymphadenectomy even after induction therapy and abdominal surgery. Larger scale trials are needed to define the role of this technique.

Evaluation of various corrections to the standardized uptake value for diagnosis of pulmonary malignancy.

OBJECTIVE: Standard uptake values (SUVs) are widely used for quantifying the uptake of 18F-fluorodeoxyglucose (18F-FDG) in tumours. The objective of this study was to evaluate the accuracy of SUVs for malignancy in lung nodules/masses and to analyse the effects of tumour size, blood glucose levels and different body weight corrections on SUV. METHODS: One hundred and twenty-seven patients with suspicious lung lesions imaged with 18F-FDG positron emission tomography (PET) were studied retrospectively. Pathology results were used to establish lesion diagnosis in all cases. SUVs based on maximum pixel values were obtained by placing regions of interest around the focus of abnormal 18F-FDG uptake in the lungs. The SUVs were calculated using the following normalizations: body weight (BW), lean body weight (LBW), scaled body surface area (BSA), blood glucose level (Glu) and tumour size (Tsize). Receivers operating characteristic (ROC) curves were generated to compare the accuracy of different methods of SUV calculation. RESULTS: The areas under the ROC curves for SUV(BW), SUV(BW+Glu), SUV(LBW), SUV(LBW+Glu), SUV(BSA), SUV(BSA+Glu) and SUV(BW+Tsize) were 0.915, 0.912, 0.911, 0.912, 0.916, 0.909 and 0.864, respectively. CONCLUSION: The accuracy of SUV analysis for malignancy in lung nodules/masses is not improved by correction for blood glucose or tumour size or by normalizing for body surface area or lean body weight instead of body weight.

Complete video-assisted resection of trilobar mucormycosis.

A case of trilobar pulmonary mucormycosis in a diabetic patient with severe obstructive pulmonary disease, successfully treated with systemic antifungal therapy and complete video-assisted thoracic surgery (VATS) resection, is presented. The VATS approach permitted accurate diagnosis and definitive therapy using lung-sparing techniques in a minimally invasive manner.

The incidence of right upper-lobe collapse when comparing a right-sided double-lumen tube versus a modified left double-lumen tube for left-sided thoracic surgery.

UNLABELLED: Lung deflation for left-sided thoracic surgery can be accomplished by using either a left- or right-sided double-lumen endotracheal tube (L-DLT or R-DLT). Anatomic variability of the right mainstem bronchus and the possibility of right upper-lobe obstruction have discouraged the routine use of R-DLT. There are, however, situations in which it is preferable to avoid manipulation/intubation of the left main bronchus, requiring placement of a R-DLT. We compared the modified L-DLT with the R-DLT to determine whether R-DLTs can be used during left-sided thoracic surgery without an increased risk of right upper-lobe collapse. Forty patients requiring left lung deflation were randomly assigned to one of two groups. Twenty patients received a modified L-DLT BronchoCath((R)) (Mallinckrodt Medical Inc., St. Louis, MO), and 20 received a R-DLT BronchoCath((R)). The following variables were studied: 1) time required to position each tube until satisfactory placement was achieved; 2) number of times fiberoptic bronchoscopy was required to readjust tube position; 3) number of malpositions after initial tube placement; 4) time required for left lung collapse; 5) incidence of right upper-lobe collapse from an intraoperative chest radiograph obtained in a lateral decubitus position; 6) overall surgical exposure; and 7) tube acquisition cost. Median time required for initial tube placement was greater in the R-DLT group (3.4 min) versus the L-DLT (2.1 min); P = 0.04. Overall tube cost was also larger for the R-DLT group (US $1819.40) versus the L-DLT group (US $1107.75). The incidence of malpositions, (five versus two), need for fiberoptic bronchoscopy, time for adequacy of left lung collapse, and incidence of intraoperative right upper-lobe collapse (0) did not significantly differ between R-DLT and L-DLT groups. We conclude that R-DLTs can be used for left-sided thoracic surgery without an increased risk of right upper-lobe collapse. Our data suggest that R-DLTs may be more prone to intraoperative dislodgment/malposition than L-DLTs; however, in all cases, correction of malposition was easily achieved. IMPLICATIONS: In this study, right-sided double-lumen tubes (R-DLTs) were compared with modified left-sided double-lumen tubes in patients requiring one-lung ventilation for left-sided thoracic surgery. The incidence of right upper-lobe collapse was assessed intraoperatively by a chest radiograph which showed no collapse of the right upper lobe in all patients who received R-DLTs or left-sided double-lumen tubes. Therefore, we conclude that R-DLTs present no increased risk of complications for left-sided thoracic surgery and should not be abandoned.

Autonomous decision-making: a data mining approach.

The researchers and practitioners of today create models, algorithms, functions, and other constructs defined in abstract spaces. The research of the future will likely be data driven. Symbolic and numeric data that are becoming available in large volumes will define the need for new data analysis techniques and tools. Data mining is an emerging area of computational intelligence that offers new theories, techniques, and tools for analysis of large data sets. In this paper, a novel approach for autonomous decision-making is developed based on the rough set theory of data mining. The approach has been tested on a medical data set for patients with lung abnormalities referred to as solitary pulmonary nodules (SPNs). The two independent algorithms developed in this paper either generate an accurate diagnosis or make no decision. The methodolgy discussed in the paper depart from the developments in data mining as well as current medical literature, thus creating a variable approach for autonomous decision-making.

PET, CT, and MRI with Combidex for mediastinal staging in non-small cell lung carcinoma.

BACKGROUND: To determine the relative utility of positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging with Combidex (MRI-C) in the non-invasive staging of non-small cell lung cancer (NSCLC) mediastinal lymph nodes (MLN), we compared the three tests' individual performance with surgical mediastinal sampling. In contrast to prior studies, cytology was not used. METHODS: The MLN were evaluated using PET and CT in 64 NSCLC patients. MRI-C was performed in 9 of these patients. MLN with a PET standard uptake value greater than or equal to 2.5, or greater than 1 cm in the short axis by CT or lack of MRI-C signal change were considered positive for metastatic disease. All MLN were sampled and subjected to standard pathologic analysis. PET, CT, and MRI-C scans were interpreted blinded to the histopathological results. Sensitivity, specificity, and accuracy for each scan type to appropriately stage MLN was determined using pathologic results as the standard. RESULTS: Thirty patients had stage I disease, 8 stage II, 9 stage IIIA, 7 stage IIIB, and 10 stage IV. Two-hundred-and-thirty MLN were sampled. Sixteen patients had metastatic mediastinal disease. Compared to the pathological results, PET, CT, and MRI-C had a sensitivity, specificity, and accuracy of 70%, 86%, 84%; 65%, 79%, 76%; 86%, 82%, and 83%, respectively. PET and MRI-C were statistically more accurate than CT (p<0.001). In cases where PET and CT did not identify MLN involvement with NSCLC, 8% (2/25) were pathologically positive. CONCLUSIONS: PET and MRI-C are statistically more accurate than CT. However, the differences are small and may not be clinically relevant. No technique was sensitive or specific enough to change the current recommendation to perform mediastinoscopy for MLN staging in NSCLC.

Multicenter clinical trial of ultrasmall superparamagnetic iron oxide in the evaluation of mediastinal lymph nodes in patients with primary lung carcinoma.

The purpose of this study was to evaluate the clinical efficacy of ultrasmall superparamagnetic iron oxide particles as a magnetic resonance (MR) contrast agent in differentiating metastatic from benign lymph nodes. Eighteen patients with primary lung malignancy and suspected regional lymph node metastases underwent MR imaging before and after Combidex(R) infusion in a multi-institutional study. All MR sequences were interpreted by one or more board-certified radiologists experienced in imaging thoracic malignancy. Each patient was evaluated for the number and location of lymph nodes, homogeneity of nodal signal, and possible change of MR signal post contrast. All patients underwent resection or sampling of the MR-identified lymph node(s) 1-35 day(s) post contrast MR imaging. In all, 27 lymph nodes or nodal groups were available for histopathologic correlation. Combidex had a sensitivity of 92% and a specificity of 80% in identifying pathologically confirmed metastatic mediastinal lymph nodes. Based on our preliminary data, Combidex MR imaging may provide additional functional information useful in the staging of mediastinal lymph nodes.

Gastroduodenal artery-duodenal fistula: a complication of continuous floxuridine (FUDR) infusion into the gastroduodenal artery.

This case report describes a patient who for 31 months has received regional intrahepatic chemotherapy from a continuous infusion pump and who developed a gastroduodenal artery-duodenal fistula, a previously unreported complication of regional infusion therapy. The patient presented with signs and symptoms of upper gastrointestinal bleeding. The clinical evaluation and management are described. An angiogram was performed through the auxillary septum to identify the source of bleeding. The possible etiologic factors in this case are discussed. We believe that this complication will continue to be rare, but health care providers should be aware of its presentation and its preferred method of evaluation and management.

Restoration and maintenance of intravenous insulin infusion in the vapor-pressure powered implantable infusion device.

Of the reasons to discontinue continuous implantable insulin pump therapy, flow rate reduction is the most common, occurring in 27 of 42 pumps in the University of Minnesota series. Thrombosis at the catheter tip appears to be a major reason for flow reduction. Six different procedures to restore flow in pumps were performed. Two of the procedures involve the infusion of an alkaline solution through the device, replacing the insulin/glycerol solution normally infused; the other four procedures are surgical ones involving manipulation of the catheter. In restoring flow the non-operative procedures achieved a success rate of 50%, having taken as long as 3 months to restore flow, and having allowed up to 1 year of further insulin pump therapy; flow in all the pumps so treated eventually decreased again. The operative procedures were nearly 100% successful, restored flow immediately, and allowed longer periods of adequate flow, but flow rate did again decrease. When flow rate reduction occurs further flow improvement procedures may be attempted without difficulty and are well tolerated. In implantable pumps the biocompatibility of the blood-catheter tip interface needs to be improved to deal with the recurrent problems of insulin infusion device flow rate decrease.