Description of an activity-based enzyme biosensor for lung cancer detection.

BACKGROUND: Lung cancer is associated with the greatest cancer mortality as it typically presents with incurable distributed disease. Biomarkers relevant to risk assessment for the detection of lung cancer continue to be a challenge because they are often not detectable during the asymptomatic curable stage of the disease. A solution to population-scale testing for lung cancer will require a combination of performance, scalability, cost-effectiveness, and simplicity. METHODS: One solution is to measure the activity of serum available enzymes that contribute to the transformation process rather than counting biomarkers. Protease enzymes modify the environment during tumor growth and present an attractive target for detection. An activity based sensor platform sensitive to active protease enzymes is presented. A panel of 18 sensors was used to measure 750 sera samples from participants at increased risk for lung cancer with or without the disease. RESULTS: A machine learning approach is applied to generate algorithms that detect 90% of cancer patients overall with a specificity of 82% including 90% sensitivity in Stage I when disease intervention is most effective and detection more challenging. CONCLUSION: This approach is promising as a scalable, clinically useful platform to help detect patients who have lung cancer using a simple blood sample. The performance and cost profile is being pursued in studies as a platform for population wide screening.

Lung cancer is responsible for more deaths worldwide than all other cancers. It is often detected with the appearance of symptoms when treatment is limited and outcomes for the patient are much worse. While imaging chest scans can detect disease, they are poorly used even in the United States where it is an approved screening method. When cancer is present, protease enzymes are responsible for making space and modifying the lung tissue for the growing tumor. This report describes a panel of 18 sensors that release a fluorescent signal when these enzymes are present in a blood sample. The signal acts like a fingerprint of activity that can be used to identify people with lung cancer. This sensor platform can detect patients with curable lung cancer and could provide a platform for screening very large populations of at-risk individuals.

A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma.

BACKGROUND: Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively. METHODS: Patients with locally advanced (T1N1-3M0 or T2-3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging-laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m2 /Leucovorin 400 mg/m2 /5-FU bolus 400 mg/m2 then infusion 2400 mg/m2 for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post-neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4-8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI-related markers PD-L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy. RESULTS: Thirty-seven patients completed the preoperative treatment. Twenty-nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08-0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73-0.98) had ypRR with TRS ≤2. Twenty-six patients finished adjuvant therapy with a median 36.3-month follow-up. Three patients had recurrence/metastatic disease (at 9-, 10-, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD-L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059). CONCLUSIONS: The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long-time survival benefits.

A National Survey of Surgeons Evaluating the Accuracy of Mediastinal Lymph Node Identification.

BACKGROUND: The Commission on Cancer implemented Standard 5.8 in 2021, which requires removal of 3 mediastinal nodes and 1 hilar node with lung cancer resection. We conducted a national survey to assess whether surgeons who treat lung cancer in different clinical settings correctly identify mediastinal lymph node stations. METHODS: Cardiac or thoracic surgeons expressing interest in lung cancer surgery on the Cardiothoracic Surgery Network were asked to complete a 7-question survey assessing their knowledge of lymph node anatomy. General surgeons whose practice includes thoracic surgery were invited through American College of Surgeon's Cancer Research Program. Results were analyzed using Pearson's chi-square test. Multivariable linear regression was used to identify predictors of a higher score on the survey. RESULTS: Of the 280 surgeons that responded, 86.8% were male and 13.2% were female; the median age was 50 years. Of these surgeons, 211 (75.4%) were thoracic, 59 (21.1%) were cardiac, and 10 (3.6%) were general surgeons. Surgeons were most likely to correctly identify lymph node stations 8R and 9R and least likely to correctly identify the midline pretracheal node just superior to the carina (4R). Surgeons whose practice involved a greater percentage of thoracic surgery patients and surgeons who performed a greater number of lobectomies scored higher on the lymph node assessment. CONCLUSION: Knowledge of mediastinal node anatomy among surgeons who perform thoracic surgery is generally high, but varies by clinical setting. Efforts are under way to better educate lung cancer surgeons on nodal anatomy, and to increase adoption of Standard 5.8.

The Key Role of Upper Endoscopy in Diagnosing Gastric Herniation and Volvulus in Acute Gastrointestinal Obstruction.

The diagnosis of gastric volvulus can be a clinical challenge as it is rare, and the symptoms are often nonspecific and intermittent. Upper endoscopy is a minimally invasive intervention that may be repeated more than once to provide key information and ultimately establish such a diagnosis. To emphasize the role of upper endoscopy in surgical cases with recurrent upper gastrointestinal obstructions, we present a case of intermittent gastric volvulus in a patient with a remote history of complex chest wall reconstruction for invasive breast cancer using an omental flap. She presented with substernal chest pain, belching, nausea, and vomiting. Although the initial imaging suggested duodenal obstruction, exploratory laparotomy and intraoperative upper endoscopy did not show any pathology in the stomach or duodenum. Repeat upper endoscopy due to recurrence of obstructive symptoms shortly after the initial exploratory laparotomy revealed a gastric volvulus. This resulted in abnormal duodenal orientation which caused intermittent duodenal obstruction while the pathology was in the stomach. Gastric volvulus may be spontaneously reducible, leading to discordance in findings during the clinical course. This could explain the absence of visible twisting on initial exploratory laparotomy in this patient and the subsequent findings of volvulus on upper endoscopy. Thus, it is important to consider gastric volvulus as a possible cause of symptoms despite initial negative findings as it is a dynamic process and may only be discovered through relook upper endoscopy and imaging.

Exploring the Evolving Scope of Neoadjuvant Immunotherapy in NSCLC.

While lung cancer remains the leading cause of cancer death worldwide, lung cancer mortality has notably decreased in the past decade. Immunotherapy with immune checkpoint inhibitors have played a noteworthy role in contributing to this improved survival, particularly for patients with non-small cell lung cancer (NSCLC). However, until now the benefits have primarily been seen in patients with advanced or metastatic disease. Several recent early phase and ongoing phase III trials have been assessing whether the treatment benefit of immunotherapy in NSCLC can extend to the neoadjuvant setting for resectable diseases. In this comprehensive narrative review, we evaluate the most recent efficacy and safety data from these studies. We also outline questions that will need to be further examined to legitimate neoadjuvant immunotherapy's role in NSCLC treatment, including the best surrogate marker of response, the incorporation of liquid biopsy for disease monitoring, the ability to be combined with other treatment modalities, the need for further adjuvant therapy, and potential future treatment combinations.

Targeting interleukin-1ß and inflammation in lung cancer.

Inflammation is a process that protects organs against various potentially harmful stimuli and enables repair. Dysregulated inflammation, however, damages tissues and leads to disease, including cancer. Cancer-related inflammation is characterized by cytokine production, leukocyte infiltration, angiogenesis, and tissue remodeling-all critical processes in modulating the tumor microenvironment (TME). The TME is known to play a key role in tumor progression, and targeting its immune component to achieve a better anti-tumor response is the basis of immunotherapy. Despite the critical role cytokines play in the TME and tumor progression, there is currently only one therapy approved by the FDA that directly involves cytokine signaling: human recombinant interleukin-2 protein, aldesleukin. The recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial evaluated the use of anti-interleukin-1ß therapy in atherosclerotic disease; however, it also revealed interleukin-1ß (IL-1ß) blockade with canakinumab led to a significantly lower incidence of lung cancer. This has opened a promising new avenue for lung cancer therapy, and strategies using anti-IL-1ß therapy alone or in combination with chemotherapy and/or immune checkpoint blockade are currently being evaluated in several clinical trials.

Consensus for Thoracoscopic Lower Lobectomy: Essential Components and Targets for Simulation.

BACKGROUND: Despite demonstration of its clear benefits relative to open approaches, a video-assisted thoracic surgery technique for pulmonary lobectomy has not been universally adopted. This study aims to overcome potential barriers by establishing the essential components of the operation and determining which steps are most useful for simulation training. METHODS: After randomly selecting experienced thoracic surgeons to participate, an initial list of components to a lower lobectomy was distributed. Feedback was provided by the participants, and modifications were made based on anonymous responses in a Delphi process. Components were declared essential once at least 80% of participants came to an agreement. The steps were then rated based on cognitive and technical difficulty followed by listing the components most appropriate for simulation. RESULTS: After 3 rounds of voting 18 components were identified as essential to performance of a video-assisted thoracic surgery for lower lobectomy. The components deemed the most difficult were isolation and division of the basilar and superior segmental branches of the pulmonary artery, isolation and division of the lower lobe bronchus, and dissection of lymphovascular tissue to expose the target bronchus. The steps determined to be most amenable for simulation were isolation and division of the branches of the pulmonary artery, the lower lobe bronchus, and the inferior pulmonary vein. CONCLUSIONS: Using a Delphi process a list of essential components for a video-assisted thoracic surgery for lower lobectomy was established. Furthermore 3 components were identified as most appropriate for simulation-based training, providing insights for future simulation development.

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

BACKGROUND: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation. METHODS: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation. RESULTS: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein. CONCLUSIONS: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

Liposomal Bupivacaine Enhances the Pain-Control Benefits of Uniportal Thoracoscopic Lobectomy.

BACKGROUND: Liposomal bupivacaine field block is gaining popularity as a critical element of enhanced recovery after surgery protocols in thoracic surgery. Uniportal thoracoscopic surgery has been reported to result in less narcotic consumption compared with traditional video-assisted thoracoscopic surgery. The objective of this study was to evaluate the postoperative narcotic consumption of patients undergoing uniportal thoracoscopic lobectomy with the use of 0.25% bupivacaine vs patients treated with liposomal bupivacaine. METHODS: All consecutive patients undergoing uniportal thoracoscopic lobectomy at an academic medical institution were recorded between October 2015 and February 2018. Narcotic consumption was converted to oral morphine equivalents by using standard formulas. Patients underwent posterior serratus and intercostal nerve blocks with 0.25% bupivacaine or liposomal bupivacaine, transitioning to liposomal bupivacaine in March 2017. Other adjuncts such as gabapentin or cyclooxygenase-2 inhibitors were not administered. RESULTS: Data were reviewed on 32 patients receiving field blocks with 0.25% bupivacaine and on 50 patients receiving liposomal bupivacaine. There was no difference between groups with regard to age, sex, chest tube duration, or length of stay. Patients undergoing field blocks with liposomal bupivacaine consumed less narcotic medication. CONCLUSIONS: The study investigators have previously demonstrated decreased narcotic consumption with the use of uniportal technique over traditional multi-incision thoracoscopic surgery. The use of liposomal bupivacaine for posterior serratus and intercostal field blocks enhanced pain control and decreased narcotic consumption.

Uniportal video-assisted thoracoscopic surgery (VATS) technique is associated with decreased narcotic usage over traditional VATS lobectomy.

BACKGROUND: Uniportal video-assisted thoracoscopic surgery (VATS) is gaining popularity internationally, but remains an uncommon practice in the United States. One proposed benefit is a decrease in narcotic usage and peri-operative pain when compared to traditional multiple incision VATS. The purpose of this study was to determine the post-operative narcotic usage between patients undergoing anatomic lobectomy via traditional VATS as compared to patients undergoing uniportal VATS. METHODS: All consecutive patients undergoing anatomic lobectomy for presumed malignancy by a single surgeon at an academic medical institution were recorded between July 2013 and September 2015. Patients were excluded if they were narcotic dependent prior to the operation, if they had an epidural catheter placed, or if they were under 18 years of age. All narcotics were converted to oral morphine equivalents (OMEq) using standard formulas. RESULTS: Data were collected on 84 patients. There was no difference between groups with regard to age, gender, tumor size, length of stay, or duration of post-operative thoracostomy. The groups had a similar rate of complications including post-operative atrial fibrillation and need for prolonged thoracostomy. Patients undergoing uniportal VATS had significantly lower narcotic usage in the recovery room, and on post-operative days 1 and 2. In addition, the total narcotic usage during their inpatient stay was significantly lower for patients undergoing uniportal VATS. CONCLUSIONS: Uniportal VATS is a safe and effective strategy for the surgical management of benign and malignant lung disease. In patients undergoing anatomic lobectomy, there was an association with significantly less post-operative narcotic usage in patients undergoing uniportal VATS when compared to traditional VATS. This emerging technology may benefit patients by allowing less narcotic usage during their post-operative hospitalization.