Clinical Utility of a Plasma Protein Classifier for Indeterminate Lung Nodules.

Evaluation of indeterminate pulmonary nodules is a complex challenge. Most are benign but frequently undergo invasive and costly procedures to rule out malignancy. A plasma protein classifier was developed that identifies likely benign nodules that can be triaged to CT surveillance to avoid unnecessary invasive procedures. The clinical utility of this classifier was assessed in a prospective-retrospective analysis of a study enrolling 475 patients with nodules 8-30 mm in diameter who had an invasive procedure to confirm diagnosis at 12 sites. Using this classifier, 32.0 % (CI 19.5-46.7) of surgeries and 31.8 % (CI 20.9-44.4) of invasive procedures (biopsy and/or surgery) on benign nodules could have been avoided. Patients with malignancy triaged to CT surveillance by the classifier would have been 24.0 % (CI 19.2-29.4). This rate is similar to that described in clinical practices (24.5 % CI 16.2-34.4). This study demonstrates the clinical utility of a non-invasive blood test for pulmonary nodules.

Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery.

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond D(max) were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2-1.8 mm (80%-20%) and 1.9-3.8 mm (90%-10%) relative to 10X FFF, which has 1.2-2.2mm and 2.3-5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment.

LC-MS/MS quantitation of esophagus disease blood serum glycoproteins by enrichment with hydrazide chemistry and lectin affinity chromatography.

Changes in glycosylation have been shown to have a profound correlation with development/malignancy in many cancer types. Currently, two major enrichment techniques have been widely applied in glycoproteomics, namely, lectin affinity chromatography (LAC)-based and hydrazide chemistry (HC)-based enrichments. Here we report the LC-MS/MS quantitative analyses of human blood serum glycoproteins and glycopeptides associated with esophageal diseases by LAC- and HC-based enrichment. The separate and complementary qualitative and quantitative data analyses of protein glycosylation were performed using both enrichment techniques. Chemometric and statistical evaluations, PCA plots, or ANOVA test, respectively, were employed to determine and confirm candidate cancer-associated glycoprotein/glycopeptide biomarkers. Out of 139, 59 common glycoproteins (42% overlap) were observed in both enrichment techniques. This overlap is very similar to previously published studies. The quantitation and evaluation of significantly changed glycoproteins/glycopeptides are complementary between LAC and HC enrichments. LC-ESI-MS/MS analyses indicated that 7 glycoproteins enriched by LAC and 11 glycoproteins enriched by HC showed significantly different abundances between disease-free and disease cohorts. Multiple reaction monitoring quantitation resulted in 13 glycopeptides by LAC enrichment and 10 glycosylation sites by HC enrichment to be statistically different among disease cohorts.

Label-free glycopeptide quantification for biomarker discovery in human sera.

Glycan moieties of glycoproteins modulate many biological processes in mammals, such as immune response, inflammation, and cell signaling. Numerous studies show that many human diseases are correlated with quantitative alteration of protein glycosylation. In some cases, these changes can occur for certain types of glycans over specific sites in a glycoprotein rather than on the global abundance of the glycoprotein. Conventional analytical techniques that analyze the abundance of glycans cleaved from glycoproteins cannot reveal these subtle effects. Here we present a novel statistical method to quantify the site-specific glycosylation of glycoproteins in complex samples using label-free mass spectrometric techniques. Abundance variations between sites of a glycoprotein as well as different glycoforms, that is, glycopeptides with different glycans attached to the same site, can be detected using these techniques. We applied our method to an esophageal cancer study based on blood serum samples from cancer patients in an attempt to detect potential biomarkers of site-specific N-linked glycosylation. A few glycoproteins, including vitronectin, showed significantly different site-specific glycosylations within cancer/control samples, indicating that our method is ready to be used for the discovery of glycosylated biomarkers.

A modified frailty index to assess morbidity and mortality after lobectomy.

BACKGROUND: Frailty has yet to be explored as a risk factor for thoracic surgery. We hypothesized that our modified frailty index (mFI) may be a predictor of morbidity and mortality following lobectomy. MATERIALS: National Surgical Quality Improvement Program (NSQIP) participant use files were reviewed (2005-2010). Patients undergoing lobectomy were identified based on Current Procedural Terminology code 32480. We used an mFI with 11 variables, based on mapping the Canadian Study of Health and Aging Frailty Index to the NSQIP comorbidities. Data were analyzed using χ(2) test, independent sample t-test, Jonckheere-Terpstra test, and logistic regression. RESULTS: Of 1940 open lobectomy patients identified, morbidity and mortality uniformly increased as the mFI increased; 14.9% of patients (75/504) with mFI of 0 had at least one complication, compared with 32% of patients (91/284) with mFI of 0.27 (P < 0.001). An mFI of 0 was associated with a mortality rate of 1% (5/504), compared with 5.6% (16/284) for mFI of 0.27 (P < 0001). Failure to wean from the ventilator, reintubation, surgical site infections, pneumonia, and Clavien 4 and above complications occurred in 1.8% (9/504), 2.6% (13/504), 2.2% (11/504), 5.4% (27/504), and 4.2% (21/504), respectively, in patients with an mFI of 0, compared with 7.4% (21/284), 7% (22/284), 3.2% (9/284), 10.9% (31/284), and 14.4% (41/284), respectively, in patients with mFI of 0.27. CONCLUSIONS: This study demonstrates that the mFI may identify patients at higher risk for morbidity and mortality post-lobectomy. With the aging population, preoperative selection is important in minimizing morbidity and mortality and improving risk stratification for informed decision-making.

Esophagectomies for Malignancy Among General and Thoracic Surgeons: A Propensity Score Matched National Surgical Quality Improvement Program Analysis Stratified by Surgical Approach.

Previous studies of esophagectomy outcomes by surgical specialty do not address malignancy or surgical approach. We sought to evaluate these cases using a national database. The National Surgical Quality Improvement Program (NSQIP)-targeted esophagectomy data set was queried for esophagectomies for malignancy and grouped by surgeon specialty: thoracic surgery (TS) or general surgery (GS). 1:1 propensity score matching was performed. Associations of surgical specialty with outcomes of interest (30-day mortality, anastomotic leak, Clavien-Dindo grade ≥ 3, and positive margin rate) were assessed overall and in surgical approach subsets. 1463 patients met inclusion criteria (512 GS and 951 TS). Propensity score matching yielded matched groups of 512, with similar demographics, preoperative stage, and neoadjuvant therapy rates. All outcomes of interest were similar between TS and GS groups, both overall and when stratified by surgical approach. Esophagectomy for malignancy has a similar perioperative safety profile and positive margin rate among general and thoracic surgeons, regardless of surgical approach.

Safety and usability of an endo staple line reinforcement device for pulmonary resections.

Background: Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties, occasionally leading to prolonged air leaks. Staple line reinforcements (SLRs) are widely utilized tools for fortifying the stability and integrity of closures in thoracic surgery, however, materials available and ease of use for both surgeon and scrub nurse have been suboptimal. A novel "click-and-go" device pre-loaded with bioabsorbable buttress material was recently developed, the Echelon Endopath SLR (ESLR, Ethicon, Inc., Cincinnati, OH, USA). This prospective study examines the safety and efficacy of this novel device in lung resections. Methods: Adult surgical candidates undergoing primary pulmonary resection (both open and thoracoscopic) where the ESLR would be used were enrolled. Exclusion included reoperation/revision in same anatomical location, hypersensitivity to polyglactin or related products, and body mass index (BMI) ≥46.0 kg/m2. The primary endpoint assessed the incidence of specific device-related adverse events (AEs): prolonged air leak and empyema. Additional endpoints included number of devices replaced during surgery due to slippage or bunching, and surgeon-reported usability responses. Data was summarized for AEs deemed device-related and usability questionnaire responses. Results: A total of 131 subjects were included in the primary endpoint analysis data set with 120 subjects completing the study (91.6%). The mean age at consent was 62.8±12.0 years and 55.7% were female. The most common primary indication for the procedure was malignancy 61.1%, and primary non-malignant lung disease (non-chronic obstructive pulmonary disease) 12.2%. Common procedures performed were wedge resection (58.0%) and lobectomy (34.4%). There were zero reported device-specific/-related AEs which counted toward the primary endpoint. Responses from a usability questionnaire found all surgeons (100.0%) reported the ease of setup was superior to previous devices utilized. Surgeons expressed greater confidence in the buttress material of the ESLR than that of previous SLR devices (strongly agree 88.9%; slightly agree 11.1%). Most also felt that there was less wastage with the click-and-go ESLR (strongly agree 77.8%, slightly agree 11.1%, neutral 11.1%). Conclusions: The ESLR device demonstrates safe and effective performance in this post-market study of specific thoracic procedures. Furthermore, surgeons found this was easier to use.

N-glycan profiling by microchip electrophoresis to differentiate disease states related to esophageal adenocarcinoma.

We report analysis of N-glycans derived from disease-free individuals and patients with Barrett's esophagus, high-grade dysplasia, and esophageal adenocarcinoma by microchip electrophoresis with laser-induced fluorescence detection. Serum samples in 10 µL aliquots are enzymatically treated to cleave the N-glycans that are subsequently reacted with 8-aminopyrene-1,3,6-trisulfonic acid to add charge and a fluorescent label. Separations at 1250 V/cm and over 22 cm yielded efficiencies up to 700,000 plates for the N-glycans and analysis times under 100 s. Principal component analysis (PCA) and analysis of variance (ANOVA) tests of the peak areas and migration times are used to evaluate N-glycan profiles from native and desialylated samples and determine differences among the four sample groups. With microchip electrophoresis, we are able to distinguish the three patient groups from each other and from disease-free individuals.

Long-term outcomes after robotic-assisted Ivor Lewis esophagectomy.

Robotic assistance has gained acceptance in thoracic procedures, including esophagectomy. There is a paucity of data regarding long-term outcomes for robotic esophagectomy. We previously reported our initial series of robot-assisted Ivor Lewis (RAIL) esophagectomy. We report long-term outcomes to assess the efficacy of the procedure. We performed a retrospective review of 112 consecutive patients who underwent a RAIL. Patient demographics, diagnosis, pathology, operative characteristics, post-operative complications, and long-term outcomes were documented. Descriptive statistical analysis was performed for all the variables. Primary endpoints were mortality and disease-free survival. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Of the 112 patients, 106 had a diagnosis of cancer, with adenocarcinoma the dominant histology (87.5%). Of these 106 patients, 81 (76.4%) received neo-adjuvant chemoradiation. The 30-, 60-, and 90-day mortality was 1 (0.9%), 3 (2.7%), and 4 (3.6%), respectively. There were 9 anastomotic leaks (8%) and 18 (16.1%) patients had a stricture requiring dilation. All-patient OS at 1, 3, and 5 years was 81.4%, 60.5%, and 51.0%, respectively. For cancer patients, the 1-, 3-, and 5-year OS was 81.3%, 59.2%, and 49.4%, respectively, and the DFS was 75.3%, 42.3%, and 44.0%. We have shown that long-term outcomes after RAIL esophagectomy are similar to other non-robotic esophagectomies. Given the potential advantages of robotic assistance, our results are crucial to demonstrate that RAIL does not result in inferior outcomes.

Barrett's esophagus after resection of the gastroesophageal junction: effects of concomitant fundoplication.

BACKGROUND: Barrett's metaplasia has been known to occur after esophagectomy or gastrectomy in which the gastroesophageal junction with its associated lower esophageal sphincter has been resected. It is thought to be secondary to the refluxogenic nature of the operation. The present study was based on the hypothesis that patients who undergo a fundoplication with the resection would have a lower incidence of the development of postoperative Barrett's metaplasia. METHODS: All patients who underwent any type of esophagectomy or proximal gastrectomy in which the gastroesophageal junction was resected and an esophagogastrostomy performed were eligible for the study. Data gathered included age, gender, preoperative diagnosis, operation, postoperative pathology, occurrence and timing of postoperative upper endoscopy, and presence of Barrett's metaplasia on postoperative endoscopy. Statistical analysis was done with Fisher's exact test. RESULTS: Of the 179 patients who underwent resection, 151 had follow-up endoscopy documenting the presence or absence of Barrett's esophagus. Follow-up ranged from 6 months to 10 years. Of the 53 patients without fundoplications, 8 (18%) had Barrett's esophagus on follow-up upper endoscopy. Of the 98 patients with fundoplications, 5 (6%) had Barrett's esophagus (P = 0.04). CONCLUSIONS: The present study suggests that concomitant fundoplication with resection of the gastroesophageal junction may have some protective effect against the development of Barrett's esophagus. A randomized trial will be required to prove this assertion. Also, it is still unclear as to the consequences of the development of post-resection Barrett's esophagus.

A quantitative investigation of fucosylated serum glycoproteins with application to esophageal adenocarcinoma.

Although glycoproteomic studies provide unique opportunities for cancer research, it has been necessary to develop specific methods for analysis of oncologically interesting glycoproteins. We describe a general, multimethodological approach for quantitative glycoproteomic analysis of fucosylated glycoproteins in human blood serum. A total of 136 putative fucosylated glycoproteins were identified with very high confidence in three clinically relevant sample pools (N=5 for each), with a mean CV of 3.1% observed for replicate analyses. Two samples were collected from subjects diagnosed with esophagus disease states, high-grade dysplasia plus esophageal adenocarcinoma, while the third sample was representative of a disease-free condition. Some glycoproteins, observed to be significantly upregulated in esophageal adenocarcinoma, i.e. more than twofold higher than in the disease-free condition, are briefly discussed. Further investigation will be necessary to validate these findings; however, the method itself is demonstrated to be an effective tool for quantitative glycoproteomics of clinical samples.

Targeted serum metabolite profiling of nucleosides in esophageal adenocarcinoma.

Nucleosides are indicators of the whole-body turnover of transfer RNA. Based on the activity of cancer cells these molecules could potentially be used as cancer biomarkers, and several studies have determined that the metabolic levels of nucleosides are significantly altered in cancer patients compared to control groups. Here we report a targeted metabolite investigation of serum nucleosides in esophageal adenocarcinoma specimens. We quantified eight nucleosides using high-performance liquid chromatography/triple quadrupole mass spectrometry (HPLC/TQMS) and determined that the metabolic levels of 1-methyladenosine (p <2.14 × 10(-7)), N(2),N(2)-dimethylguanosine (p <2.78 × 10(-7)), N(2)-methylguanosine (p <2.48 × 10(-6)) and cytidine (p <6.98 × 10(-4)) were significantly elevated while the concentration of uridine (p <3.74 × 10(-3)) was significantly lowered in serum samples from cancer patients compared to those of control group. Our results suggest that nucleosides could potentially serve as useful biomarkers to identify esophageal adenocarcinoma.

Diffusion lung capacity for carbon monoxide (DLCO) is an independent prognostic factor for long-term survival after curative lung resection for cancer.

INTRODUCTION: We examined the early and late prognostic significance of DLCO and forced expiratory volume in 1 sec (FEV1) in patients who underwent surgical resection of lung cancer. METHODS: From 1997 to 2004, 462 patients underwent successful complete resection of their lung cancer and had full pulmonary function testing including DLCO performed. Mean follow-up was over 5 years (64.8 months--range: 0-158 months). RESULTS: Postoperative 90-day mortality was 2.6% (12/462). At last follow-up, of the remaining 450 patients, 182 patients were alive, 130 had died of cancer, and 138 have died of other causes and did not have recurrent cancer. Mean DLCO values were 69.4%, 66.8%, and 53.9%, respectively. Mean FEV1 values were 81.3%, 78.1%, and 71.5%, respectively. Mean DLCOs and FEV1s between patients who died of cancer versus other causes were significantly different (P < 0.0001 and P = 0.0157). When cause-specific survival was analyzed for both DLCO and FEV1 simultaneously, DLCO had a very significant effect on survival from other causes (HR 0.966, P < 0.0001) when adjusted for FEV1. However, when adjusted by DLCO, FEV1 had no significant effect. A DLCO <40% best predicted decreased survival from causes other than cancer within stage I lung cancers (stage IA HR 0.953, P < 0.0001; stage IB HR 0.968, P < 0.0001). CONCLUSIONS: DLCO was found to be a significant prognostic factor for long-term survival after lung cancer surgery. This may serve as a surrogate for competing morbidities with declining values predicting a higher risk of late non-cancer-related death.

Estrogen promotes tumor progression in a genetically defined mouse model of lung adenocarcinoma.

Numerous epidemiological observations point to sex differences in lung cancer etiology and progression. The present study was aimed at understanding the bases of these sex differences. To test the effect of estradiol on tumor progression, we used a mouse model based on conditional Kras expression and concurrent deletion of Tp53 following inhalation of an adenoviral vector expressing Cre recombinase (AdeCre). Ovariectomized females and males were treated with estradiol via a continuous-release capsule. Tumor multiplicity, tumor volume, and histological grade were determined at 10 weeks after AdeCre administration. Cell proliferation was monitored by Ki67 immunohistochemistry at 4 and 10 weeks after AdeCre administration. At 10 weeks, female mice had more than twice the number of tumors evident on the surface of the lungs than male mice; ovariectomy eliminated this sex difference. The estrogen treatment significantly increased tumor number and volume in ovariectomized females and in males. Histological character of the tumors ranged from adenoma to adenocarcinoma. Ovary-intact females exhibited higher grade tumors than ovariectomized females or males. Progression to higher histological grade was stimulated by estrogen in male mice but not in ovariectomized females. At 10 weeks after AdeCre administration, tumor cell Ki67-labeling varied widely, precluding assessment of an estrogen effect; however, at 4 weeks, Ki67 labeling of lung parenchymal cells was increased 3.5-fold by estrogen. In conclusion, estrogen acts as a promoter for lung adenocarcinoma in a genetically defined lung cancer model; estrogen-induced cell proliferation in the oncogene-initiated cells is likely to play a role in this tumor promoter activity.

Is Esophagectomy for Benign Conditions Benign?

BACKGROUND: Outcomes data on esophagectomy performed for benign conditions is scarce. Using the National Surgical Quality Improvement Program database, we sought to analyze outcomes of esophagectomy performed for benign conditions. METHODS: The National Surgical Quality Improvement Program database was queried for all esophagectomies performed from 2005 to 2015. Outcomes for benign conditions were analyzed and compared with outcomes for malignant conditions. RESULTS: Esophagectomy was performed in 7,477 patients during the study period. Of those, 6,762 underwent esophagectomy for malignant conditions and 715 for benign conditions. For patients with benign conditions, reconstruction was performed using gastric conduit in 631 and colon/intestine in 84. The anastomosis was intrathoracic in 420 and cervical in 295. Benign esophagectomies were more likely to be emergent (10.1% vs 0.4%, p < 0.001). In addition, these patients had a longer hospital length of stay (17.2 days vs 14.5 days, p < 0.001) and higher occurrence of Clavien-Dindo grade IV complications (25% vs 20%, p = 0.003). Mortality was similar at 4%. In patients with benign conditions, reconstruction with colon/intestine had higher occurrence of Clavien-Dindo Grade IV complications (37% vs 23%, p = 0.006), surgical wound infections (33% vs 16%, p < 0.001), and death (10% vs 4%, p = 0.017) compared with gastric reconstruction. Site of anastomosis did not affect outcomes. CONCLUSIONS: Benign esophagectomies are associated with significant morbidity. Although the site of the anastomosis does not alter outcomes, use of colon/intestine conduit should be pursued with caution.

Giant Cell Tumor of Bone Presenting as Left Posteromedial Chest Wall Tumor.

Giant cell tumor is a relatively uncommon bone tumor rarely originating from the chest wall. Given its proximity to vital structures in the thoracic cavity, treatment options may be challenging. We report the case of a patient with a giant cell tumor of the posterolateral chest wall with invasion of the thoracic spine treated with neoadjuvant denosumab, followed by surgical resection.

Prospective evaluation of serum amiodarone concentrations when administered via a nasogastric tube into the stomach conduit after transthoracic esophagectomy.

BACKGROUND: Atrial fibrillation occurs in up to 46% of patients following esophagectomy; amiodarone may be used for prophylaxis or treatment in these patients. There are few data regarding drug absorption following esophagectomy. OBJECTIVE: The aim of this study was to determine serum amiodarone concentrations when the drug is administered into the stomach conduit following esophagectomy. METHODS: Patients who underwent noncardiac thoracic surgery were enrolled in this prospective, controlled study. One group of patients underwent esophagectomy, and a second group of patients comprised a control group who underwent pulmonary resection (PR). A continuous IV amiodarone infusion (0.73 mg/min) was initiated at anesthesia induction and continued for 24 hours (total IV dose 1050 mg), followed by 400 mg via a nasogastric tube (in the esophagectomy group) or orally (in the PR group) every 12 hours for 6 days. Blood samples for determination of serum amiodarone concentrations were obtained at completion of the infusion (postoperative day [POD] 1), and before the third (POD 2) and seventh (POD 4) enteral doses. RESULTS: A total of 27 patients were enrolled (esophagectomy group, 13 patients; PR group, 14 patients). Patients in the 2 groups had statistically similar ages (mean [SD], 60 [10] vs 53 [10] years; P = 0.07) and proportions of men (12/13 [92%] vs 8/14 [57%]; P = 0.08). Patients in the 2 groups were statistically similar with respect to race (white, 13/13 [100%] vs 13/14 [93%]) and preoperative weight (mean [SD], 83.3 [11.5] vs 77.7 [18.6] kg). On POD 1, age-adjusted and sex-adjusted serum amiodarone concentrations were not significantly different in the esophagectomy group versus the PR group (mean [SD] 0.65 [0.22] vs 0.84 [0.20] microg/mL). Mean (SD) serum amiodarone concentrations were significantly lower in the esophagectomy group on POD 2 (0.35 [0.27] vs 0.60 [0.18] microg/mL; P = 0.02) and on POD 4 (0.30 [0.34] vs 0.87 [0.16] microg/mL; P < 0.001). Serum amiodarone concentrations were undetectable in 33% and 50% of patients in the esophagectomy group on PODs 2 and 4, respectively, compared with 0% in the PR group (both, P = 0.03). CONCLUSIONS: Serum amiodarone concentrations were significantly lower (and in some cases undetectable) when the drug was administered via a nasogastric tube into the stomach conduit in patients after esophagectomy compared with those concentrations after oral administration in a PR population. Nasogastric administration of amiodarone should probably be avoided for prophylaxis or treatment of postesophagectomy tachyarrhythmias.