Surgeon Experience Is Associated With Prolonged Air Leak After Robotic-assisted Pulmonary Lobectomy.

BACKGROUND: Prolonged air leak (PAL) (>5 days) after robotic-assisted pulmonary lobectomy is a significant complication. This study aimed to determine patient- and surgeon-related factors that can predict PAL after robotic lobectomy for lung cancer. METHODS: This study was a retrospective review of a single-center experience of robotic-assisted lobectomy for lung cancer. Perioperative variables, including surgeon case experience, patient demographics, diffusion capacity of lung for carbon monoxide, forced expiratory volume in 1 second, body mass index, and smoking status were evaluated. RESULTS: A total of 305 robotic-assisted lobectomies performed by 4 surgeons met inclusion criteria from June 2016 to February 2019. The 30-day postoperative mortality was 1.2%. PAL developed in 27 of 305 (8.8%) patients. Surgeons' robotic experience was grouped by 10-case increments. When adjusted for age and sex, the odds for PAL decreased by 15% for every 10 robotic lobectomies the surgeons performed (odds ratio [OR], 0.85; 95% CI, 0.74-0.99; P = .0384). Logistic regression models showed a linear transition curve at the 50th case. Female sex (OR, 2.62; 95% CI, 1.03-6.69; P = .0314) and younger age (OR, 0.61; 95% CI, 0.41-0.91; P = .0184) were statistically significant risk factors for PAL. Cumulative sum analysis similarly showed a strong association between experience and PAL. Preoperative diffusing capacity of lung for carbon monoxide, forced expiratory volume in 1 second, body mass index, and smoking status were not statistically significant predictive factors. CONCLUSIONS: These results show that surgeon robotic case experience is associated with the rate of postoperative PAL: as the number of robotic lobectomies increases, the rate of PAL significantly decreases. It is imperative to emphasize that a learning curve exists for this approach that directly affects patient outcomes.

Surgery and invasive diagnostic procedures for benign disease are rare in a large low-dose computed tomography lung cancer screening program.

OBJECTIVE: Lung cancer screening with low-dose chest computed tomography improves survival. However, concerns about overdiagnosis and unnecessary interventions persist. We reviewed our lung cancer screening program to determine the rate of surgery and invasive procedures for nonmalignant disease. METHODS: We reviewed all patients undergoing lung cancer screening from January 2012 to June 2017 with follow-up through January 2019. Patients with suspicious findings (Lung CT Screening Reporting and Data System 4) were referred for further evaluation. RESULTS: Of 3280 patients screened, 345 (10.5%) had Lung CT Screening Reporting and Data System 4 findings. A total of 311 patients had complete follow-up, of whom 93 (29.9%) were diagnosed with lung cancer. Eighty-three patients underwent lung surgery (2.5% of screened patients). Forty patients underwent lobectomy (48.2%), 3 patients (3.6%) underwent bilobectomy, and 40 patients (48.2%) underwent sublobar resection. Fourteen patients underwent surgery for benign disease (0.43% of screened patients). Fifty-four patients, 5 with benign disease, had at least 1 invasive diagnostic procedure but never underwent surgery. The incidence of any invasive intervention for nonmalignant disease was 0.95% (31/3280 patients). There were no postprocedural deaths within 60 days. Twenty-five patients (0.76%) underwent stereotactic body radiation therapy; 19 patients (76%) had presumed lung cancer without pretreatment pathologic confirmation. CONCLUSIONS: Surgical resection for benign disease occurred in 0.43% of patients undergoing lung cancer screening. The combined incidence of any invasive diagnostic or therapeutic intervention, including surgical resection, for benign disease was only 0.95%. Periprocedural complications were rare. These results indicate that concern over unnecessary interventions is overstated and should not hinder adoption of lung cancer screening. A multidisciplinary team approach, including thoracic surgeons, is critical to maintain an appropriate rate of interventions in lung cancer screening.

Pulmonary Adenocarcinomas of Low Malignant Potential: Proposed Criteria to Expand the Spectrum Beyond Adenocarcinoma In Situ and Minimally Invasive Adenocarcinoma.

Lung cancer screening has improved mortality among high-risk smokers but has coincidentally detected a fraction of nonprogressive adenocarcinoma historically classified as bronchoalveolar carcinoma (BAC). In the National Lung Screening Trial (NLST) the majority of BAC-comprising 29% of computed tomography-detected stage I lung adenocarcinoma-were considered overdiagnosis after extended follow-up comparison with the control arm. In the current classification, adenocarcinoma in situ and minimally invasive adenocarcinoma have replaced BAC but together comprise only ∼5% of stage I lung adenocarcinoma. Lepidic and subsets of papillary and acinar adenocarcinoma also infrequently recur. We, therefore, propose criteria for low malignant potential (LMP) adenocarcinoma among nonmucinous adenocarcinoma measuring ≤3 cm in total, exhibiting ≥15% lepidic growth, and lacking nonpredominant high-grade patterns (≥10% cribriform, ≥5% micropapillary, ≥5% solid), >1 mitosis per 2 mm2, angiolymphatic or visceral pleural invasion, spread through air spaces or necrosis. We tested these criteria in a multi-institutional cohort of 328 invasive stage I (eighth edition) and in situ adenocarcinomas and observed 16% LMP and 7% adenocarcinoma in situ/minimally invasive adenocarcinoma which together (23%) approximated the frequency of overdiagnosed stage I BAC in the NLST. The LMP group had 100% disease-specific survival. The proposed LMP criteria, incorporating multiple histologic parameters, may be a clinically useful "low-grade" prognostic group. Validation of these criteria in additional retrospective cohorts and prospective screen-detected cohorts should be considered.

Assessment of Fluorodeoxyglucose F18-Labeled Positron Emission Tomography for Diagnosis of High-Risk Lung Nodules.

Importance: Clinicians rely heavily on fluorodeoxyglucose F18-labeled positron emission tomography (FDG-PET) imaging to evaluate lung nodules suspicious for cancer. We evaluated the performance of FDG-PET for the diagnosis of malignancy in differing populations with varying cancer prevalence. Objective: To determine the performance of FDG-PET/computed tomography (CT) in diagnosing lung malignancy across different populations with varying cancer prevalence. Design, Setting, and Participants: Multicenter retrospective cohort study at 6 academic medical centers and 1 Veterans Affairs facility that comprised a total of 1188 patients with known or suspected lung cancer from 7 different cohorts from 2005 to 2015. Exposures: 18F fluorodeoxyglucose PET/CT imaging. Main Outcome and Measures: Final diagnosis of cancer or benign disease was determined by pathological tissue diagnosis or at least 18 months of stable radiographic follow-up. Results: Most patients were male smokers older than 60 years. Overall cancer prevalence was 81% (range by cohort, 50%-95%). The median nodule size was 22 mm (interquartile range, 15-33 mm). Positron emission tomography/CT sensitivity and specificity were 90.1% (95% CI, 88.1%-91.9%) and 39.8% (95% CI, 33.4%-46.5%), respectively. False-positive PET scans occurred in 136 of 1188 patients. Positive predictive value and negative predictive value were 86.4% (95% CI, 84.2%-88.5%) and 48.7% (95% CI, 41.3%-56.1%), respectively. On logistic regression, larger nodule size and higher population cancer prevalence were both significantly associated with PET accuracy (odds ratio, 1.027; 95% CI, 1.015-1.040 and odds ratio, 1.030; 95% CI, 1.021-1.040, respectively). As the Mayo Clinic model-predicted probability of cancer increased, the sensitivity and positive predictive value of PET/CT imaging increased, whereas the specificity and negative predictive value dropped. Conclusions and Relevance: High false-positive rates were observed across a range of cancer prevalence. Normal PET/CT scans were not found to be reliable indicators of the absence of disease in patients with a high probability of lung cancer. In this population, aggressive tissue acquisition should be prioritized using a comprehensive lung nodule program that emphasizes advanced tissue acquisition techniques such as CT-guided fine-needle aspiration, navigational bronchoscopy, and endobronchial ultrasonography.

Long-Term Patient-Reported Outcomes of Paraesophageal Hernia Repair.

BACKGROUND AND OBJECTIVES: There is a lack of consensus on the optimal repair technique and the definition of good outcomes in paraesophageal hernia (PEH) repair. We reviewed long-term patient-reported outcomes of open and laparoscopic PEH repair to assist with our future surgical consent process. METHODS: This was a retrospective case-control study including all patients with PEH repair performed from 2000 through 2012 at a single center without the use of mesh. We mailed questionnaires to patients to assess reoperation, symptom control, and satisfaction. RESULTS: Chart review identified 217 patients who underwent PEH repair. Nineteen died during the follow-up period. Of the 106 returning the questionnaire, 87 underwent laparoscopic repair, and 19 had open repair, with follow-up of 6.6 (SD 3.9) years and 7.0 (SD 4.1) years, respectively. Reoperation rates were 9.9% and 5.3%, respectively (P = .720). Dysphagia, heartburn, and regurgitation improved in 95.4% of patients after laparoscopic repair and 89.5% after open repair (P = .318). Medication for symptom control was necessary in 54.0% of patients after laparoscopic repair and 26.3% after open repair (P = .029). In each group, 90% stated that they would still choose to have the operation (P = .713). CONCLUSIONS: Long-term patient-specific outcomes showed comparable, encouraging results between open and laparoscopic repair of PEH without mesh reinforcement. However, half of those undergoing laparoscopic repair required the use of medication for symptom control. This study adds to the literature describing long-term patient-specific outcomes and can be useful when counseling patients about PEH repair.

Experience With a CT Screening Program for Individuals at High Risk for Developing Lung Cancer.

PURPOSE: The aim of this study was to compare results of National Comprehensive Cancer Network (NCCN) high-risk group 2 with those of NCCN high-risk group 1 in a clinical CT lung screening program. METHODS: The results of consecutive clinical CT lung screening examinations performed from January 2012 through December 2013 were retrospectively reviewed. All examinations were interpreted by radiologists credentialed in structured CT lung screening reporting, following the NCCN Clinical Practice Guidelines in Oncology: Lung Cancer Screening (version 1.2012). Positive results required a solid nodule ≥4 mm, a ground-glass nodule ≥5 mm, or a mediastinal or hilar lymph node >1 cm, not stable for >2 years. Significant incidental findings and findings suspicious for pulmonary infection were also recorded. RESULTS: A total of 1,760 examinations were performed (464 in group 2, 1,296 in group 1); no clinical follow-up was available in 432 patients (28%). Positive results, clinically significant incidental findings, and suspected pulmonary infection were present in 25%, 6%, and 6% in group 2 and 28.2%, 6.2%, and 6.6% in group 1, respectively. Twenty-three cases of lung cancer were diagnosed (6 in group 2, 17 in group 1), for annualized rates of malignancy of 1.8% in group 2 and 1.6% in group 1. CONCLUSION: NCCN group 2 results were substantively similar to those for group 1 and closely resemble those reported in the National Lung Screening Trial. Similar rates of positivity and lung cancer diagnosis in both groups suggest that thousands of additional lives may be saved each year if screening eligibility is expanded to include this particular high-risk group.

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.

Surgical Outcomes in a Large, Clinical, Low-Dose Computed Tomographic Lung Cancer Screening Program.

BACKGROUND: Lung cancer screening with low-dose computed tomography is proven to reduce lung cancer mortality among high-risk patients. However, critics raise concern over the potential for unnecessary surgical procedures performed for benign disease as a result of screening. We reviewed our outcomes in a large clinical lung cancer screening program to assess the number of surgical procedures done for benign disease, as we believe this is an important quality metric. METHODS: We retrospectively reviewed our surgical outcomes of consecutive patients who underwent low-dose computed tomography lung cancer screening from January 2012 through June 2014 using a prospectively collected database. All patients met the National Comprehensive Cancer Network lung cancer screening guidelines high-risk criteria. RESULTS: There were 1,654 screened patients during the study interval with clinical follow-up at Lahey Hospital & Medical Center. Twenty-five of the 1,654 (1.5%) had surgery. Five of 25 had non-lung cancer diagnoses: 2 hamartomas, 2 necrotizing granulomas, and 1 breast cancer metastasis. The incidence of surgery for non-lung cancer diagnosis was 0.30% (5 of 1,654), and the incidence of surgery for benign disease was 0.24% (4 of 1,654). Twenty of 25 had lung cancer, 18 early stage and 2 late stage. There were no surgery-related deaths, and there was 1 major surgical complication (4%) at 30 days. CONCLUSIONS: The incidence of surgical intervention for non-lung cancer diagnosis was low (0.30%) and is comparable to the rate reported in the National Lung Screening Trial (0.62%). Surgical intervention for benign disease was rare (0.24%) in our experience.

Experience with a CT screening program for individuals at high risk for developing lung cancer.

PURPOSE: The aim of this study was to compare results of National Comprehensive Cancer Network (NCCN) high-risk group 2 with those of NCCN high-risk group 1 in a clinical CT lung screening program. METHODS: The results of consecutive clinical CT lung screening examinations performed from January 2012 through December 2013 were retrospectively reviewed. All examinations were interpreted by radiologists credentialed in structured CT lung screening reporting, following the NCCN Clinical Practice Guidelines in Oncology: Lung Cancer Screening (version 1.2012). Positive results required a solid nodule ≥4 mm, a ground-glass nodule ≥5 mm, or a mediastinal or hilar lymph node >1 cm, not stable for >2 years. Significant incidental findings and findings suspicious for pulmonary infection were also recorded. RESULTS: A total of 1,760 examinations were performed (464 in group 2, 1,296 in group 1); no clinical follow-up was available in 432 patients (28%). Positive results, clinically significant incidental findings, and suspected pulmonary infection were present in 25%, 6%, and 6% in group 2 and 28.2%, 6.2%, and 6.6% in group 1, respectively. Twenty-three cases of lung cancer were diagnosed (6 in group 2, 17 in group 1), for annualized rates of malignancy of 1.8% in group 2 and 1.6% in group 1. CONCLUSION: NCCN group 2 results were substantively similar to those for group 1 and closely resemble those reported in the National Lung Screening Trial. Similar rates of positivity and lung cancer diagnosis in both groups suggest that thousands of additional lives may be saved each year if screening eligibility is expanded to include this particular high-risk group.

Tumor cells are dislodged into the pulmonary vein during lobectomy.

OBJECTIVE: Intraoperative tumor shedding may facilitate tumor dissemination. In earlier studies, shed tumor cells were defined primarily by cytomorphological examination, and normal epithelial cells could not always be distinguished from tumor cells. We sought to accurately identify tumor cells using single-cell sequencing and determine whether these cells were mobilized into the circulation during pulmonary lobectomy. METHODS: Forty-two blood samples collected from the tumor-draining pulmonary vein at the end of lobectomy procedures were analyzed. Arrays of nanowells were used to enumerate and retrieve single EpCAM(+) cells. Targeted sequencing of 10 to 15 cells and nested polymerase chain reaction of single cells detected somatic mutations in shed epithelial cells consistent with patient-matched tumor but not normal tissue. RESULTS: The mean number of EpCAM(+) cells in video-assisted thoracoscopy (VATS) lobectomy (no wedge) specimens (n = 16) was 165 (median, 115; range, 0-509) but sampling cells from 3 patients indicated that only 0% to 38% of the EpCAM(+) cells were tumor cells. The mean number of EpCAM(+) cells in VATS lobectomy (wedge) specimens (n = 12) was 1128 (median, 197; range, 47-9406) and all of the EpCAM(+) cells were normal epithelial cells in 2 patients sampled. The mean number of EpCAM(+) cells in thoracotomy specimens (n = 14) was 238 (median, 22; range, 9-2920) and 0% to 50% of total EpCAM(+) cells were tumor cells based on 4 patients sampled. CONCLUSIONS: Surgery mobilizes tumor cells into the pulmonary vein, along with many normal epithelial cells. EpCAM alone cannot differentiate between normal and tumor cells. On the other hand, single-cell genetic approaches with patient-matched normal and tumor tissues can accurately quantify the number of shed tumor cells.

Purposeful creation of a pneumothorax and chest tube placement to facilitate CT-guided coil localization of lung nodules before video-assisted thoracoscopic surgical wedge resection.

PURPOSE: To evaluate the feasibility and efficacy of pneumothorax creation and chest tube insertion before computed tomography (CT)-guided coil localization of small peripheral lung nodules for video-assisted thoracoscopic surgical (VATS) wedge resection. MATERIALS AND METHODS: From May 2011 to October 2013, 21 consecutive patients (seven men; mean age, 62 y; range, 42-76 y) scheduled for VATS wedge resection required CT-guided coil localization for small, likely nonpalpable peripheral lung lesions at a single institution. Outcomes were evaluated retrospectively for technical success and complications. RESULTS: There were 12 nodules and nine ground-glass opacities. Mean lesion distance from the pleural surface was 15 mm (range, 5-35 mm), and average size was 13 mm (range, 7-30 mm). A pneumothorax was successfully created in all patients with a Veress needle, and a chest tube was inserted. All target lesions were marked successfully, leaving one end of the coil within/beyond the lesion and the other end of the coil in the pleural space. The inserted chest tube was used to insufflate air to widen the pleural space during coil positioning and to aspirate any residual air before transfer of the patient to the operating room holding area. Intraparenchymal hemorrhages smaller than 7 cm in diameter developed in two patients during coil placement. All lesions were successfully resected with VATS. Histologic examinaiton revealed 13 primary adenocarcinomas, four metastases, and four benign lesions. CONCLUSIONS: Pneumothorax creation and chest tube placement before CT-guided coil localization of peripheral lung nodules for VATS wedge resection facilitates the deployment of the peripheral end of the coil in the pleural space and provides effective management of procedure-related pneumothorax until surgery.

Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits.

Ample evidence supports genetic and functional heterogeneity in primary tumors, but it remains unclear whether circulating tumor cells (CTCs) also exhibit the same hierarchical organization. We examined the functional diversity of viable, single CTCs using an array of subnanoliter wells (nanowells). The compartmentalization of single cells by nanowells allowed clonal comparison and mapping of heterogeneity of single cells or preformed clusters of cells. By measuring the short-term viability, invasiveness and secretory profiles of individual CTCs, it was evident that only a rare subset of CTCs possessed malignant traits indicative of metastatic potential in late-stage, progressing metastatic castration-resistant prostate cancer (mCRPC) patients. These CTCs were resistant to anoikis after being in the circulation, were invasive in their epithelial state, or secreted proteases capable of cleaving peptide substrates. Every CTC observed, however, did not exhibit such metastatic potential, suggesting that enumeration of CTCs alone may be insufficient to understand metastasis or stratify patients.

Single cells from human primary colorectal tumors exhibit polyfunctional heterogeneity in secretions of ELR+ CXC chemokines.

Cancer is an inflammatory disease of tissue that is largely influenced by the interactions between multiple cell types, secreted factors, and signal transduction pathways. While single-cell sequencing continues to refine our understanding of the clonotypic heterogeneity within tumors, the complex interplay between genetic variations and non-genetic factors ultimately affects therapeutic outcome. Much has been learned through bulk studies of secreted factors in the tumor microenvironment, but the secretory behavior of single cells has been largely uncharacterized. Here we directly profiled the secretions of ELR+ CXC chemokines from thousands of single colorectal tumor and stromal cells, using an array of subnanoliter wells and a technique called microengraving to characterize both the rates of secretion of several factors at once and the numbers of cells secreting each chemokine. The ELR+ CXC chemokines are highly redundant, pro-angiogenic cytokines that signal via the CXCR1 and CXCR2 receptors, influencing tumor growth and progression. We find that human primary colorectal tumor and stromal cells exhibit polyfunctional heterogeneity in the combinations and magnitudes of secretions for these chemokines. In cell lines, we observe similar variance: phenotypes observed in bulk can be largely absent among the majority of single cells, and discordances exist between secretory states measured and gene expression for these chemokines among single cells. Together, these measures suggest secretory states among tumor cells are complex and can evolve dynamically. Most importantly, this study reveals new insight into the intratumoral phenotypic heterogeneity of human primary tumors.

Determination of 35 cell surface antigen levels in malignant pleural effusions identifies CD24 as a marker of disseminated tumor cells.

Many targets have been identified in solid tumors for antibody therapy but it is less clear what surface antigens may be most commonly expressed on disseminated tumor cells. Using malignant pleural effusions as a source of disseminated tumor cells, we compared a panel of 35 antigens for their cancer specificity, antigen abundance and functional significance. These antigens have been previously implicated in cancer metastasis and fall into four categories: (i) cancer stem cell, (ii) epithelial-mesenchymal transition, (iii) metastatic signature of in vivo selection and (iv) tyrosine kinase receptors. We determined the antigen density of all 35 antigens on the cell surface by flow cytometry, which ranges from 3 × 10(3) -7 × 10(6) copies per cell. Comparison between the malignant and benign pleural effusions enabled us to determine the antigens specific for cancer. We further chose six antigens and examined the correlation between their expression levels and tumor formation in immunocompromised mice. We concluded that CD24 is one of the few antigens that could simultaneously meet all three criteria of an ideal target. It was specifically and abundantly expressed in malignant pleural effusions; CD24(high) tumor cells formed tumors in mice at a faster rate than CD24(low) tumor cells, and shRNA-mediated knockdown of CD24 in HT29 cells confirmed a functional requirement for CD24 in the colonization of the lung. Concomitant consideration of antigen abundance, specificity and functional importance can help identify potentially useful markers for disseminated tumor cells.