Fighting Fire With Fire: Oncolytic Virotherapy for Thoracic Malignancies.

Thoracic malignancies are associated with high mortality rates. Conventional therapy for many of the patients with thoracic malignancies is obviated by a high incidence of locoregional recurrence and distant metastasis. Fortunately, developments in immunotherapy provide effective strategies for both local and systemic treatments that have rapidly advanced during the last decade. One promising approach to cancer immunotherapy is to use oncolytic viruses, which have the advantages of relatively high tumor specificity, selective replication-mediated oncolysis, enhanced antigen presentation, and potential for delivery of immunogenic payloads such as cytokines, with subsequent elicitation of effective antitumor immunity. Several oncolytic viruses including adenovirus, coxsackievirus B3, herpes virus, measles virus, reovirus, and vaccinia virus have been developed and applied to thoracic cancers in preclinical murine studies and clinical trials. This review discusses the current state of oncolytic virotherapy in lung cancer, esophageal cancer, and metastatic malignant pleural effusions and considers its potential as an emergent therapeutic for these patients.

Medical Product Innovation: A Primer for Early Career Cardiothoracic Surgeons.

Many cardiothoracic surgeons have become less involved in the process of developing therapies and diagnostic tools. There is renewed interest in innovation as a discipline among early career cardiothoracic surgeons and trainees. We describe the role and the essential skillsets that cardiothoracic surgeons must be adopt in order to successfully contribute to medical product innovation.

Comparison of robotic-assisted minimally invasive esophagectomy versus minimally invasive esophagectomy: A propensity-matched study from a single high-volume institution.

OBJECTIVE: Robotic-assisted minimally invasive esophagectomy accounts for a growing proportion of esophagectomies, potentially due to improved technical capabilities simplifying the challenging aspects of standard minimally invasive esophagectomy. However, there is limited evidence directly comparing both operations. The objective is to evaluate the short-term and long-term outcomes of robotic-assisted minimally invasive esophagectomy in comparison with the minimally invasive esophagectomy approach for patients with esophageal cancer over a 7-year period at a high-volume center. The primary end points of this study were overall survival and disease-free survival. Secondary end points included operation-specific morbidity, lymph node yield, readmission status, and in-hospital, 30-day, and 90-day mortality. METHODS: Patients who underwent robotic-assisted minimally invasive esophagectomy or standard minimally invasive esophagectomy over a 7-year period were identified from a prospectively maintained database. Inclusion criteria were patients with stage I to III disease, operations performed past the learning curve, and no evidence of scleroderma or cirrhosis. A 1:3 propensity match (robotic-assisted minimally invasive esophagectomy:minimally invasive esophagectomy) for multiple clinical covariates was performed to identify the final study cohort. Perioperative outcomes were compared between the 2 operations. RESULTS: A total of 734 patients undergoing minimally invasive esophagectomy (n = 630) or robotic-assisted minimally invasive esophagectomy (n = 104) for esophageal cancer were identified. After exclusions and matching, a total cohort of 246 patients undergoing robotic-assisted minimally invasive esophagectomy (n = 65) or minimally invasive esophagectomy (n = 181) were identified. There was no difference in overall survival (P = .69) or disease-free survival (P = .70). There were no significant differences in rates of major morbidity: pneumonia (17% vs 17%, P = .34), chylothorax (8% vs 9%, P = .95), recurrent laryngeal nerve injury (0% vs 1.5%, P = 1), anastomotic leak (5% vs 4%, P = .49), intraoperative complications (9% vs 8%, P = .73), or complete resection rates (99% vs 96%, P = .68). There was no difference in in-hospital (P = .89), 30-day (P = .66) or 90-day mortality (P = .73) between both cohorts. The robotic-assisted minimally invasive esophagectomy cohort yielded a higher median lymph node harvest in comparison with the minimally invasive esophagectomy cohort (32 vs 29, P = .02). CONCLUSIONS: Robotic-assisted minimally invasive esophagectomy may improve lymphadenectomy in patients undergoing esophagectomy for cancer. Minimally invasive esophagectomy and robotic-assisted minimally invasive esophagectomy are otherwise associated with similar mortality, morbidity, and perioperative outcomes. Further prospective study is required to investigate whether improved lymph node resection may translate to improved oncologic outcomes.

Intrapleural interleukin-2-expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease.

OBJECTIVE: The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell-activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus-expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus-expressing interleukin-2 in malignant pleural disease. METHODS: A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus-expressing interleukin-2), systemic anti-programmed cell death-1 antibody, or combination therapy (vaccinia virus-expressing interleukin-2 and anti-programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed. RESULTS: Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8+ T cells (P < .01) and programmed cell death-1 expression on CD8+ tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus-expressing interleukin-2 was superior to systemic vaccinia virus-expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus-expressing interleukin-2 alone or combined treatment with systemic anti-programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αß T-cell receptor diversity (P < .05) compared with systemic anti-programmed cell death-1 monotherapy. CONCLUSIONS: Intrapleural vaccinia virus-expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8+ tumor-infiltrating lymphocytes and αß T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus-expressing interleukin-2 therapy in patients with malignant pleural disease.

Lung Nodule Evaluation Using Robotic-Assisted Bronchoscopy at a Veteran's Affairs Hospital.

The incidence of lung nodules has increased with improved diagnostic imaging and screening protocols. Despite improvements for diagnosing pulmonary nodules with technologies such as electromagnetic navigational bronchoscopy (ENB), several limitations still exist including adequate visualization, localization, and diagnostic yield. Robotic-assisted bronchoscopy with ENB has been introduced as a method to overcome these shortcomings. We describe our initial experience in evaluating lung nodules with robotic assisted bronchoscopy. We retrospectively reviewed data on the first 25 patients that underwent robotic-assisted bronchoscopy and biopsy. We analyzed success with localization, diagnostic yield, and post procedural morbidity. Diagnostic yield was 96% (24/25) with no periprocedural morbidity. The majority of nodules were malignant or atypical (76%) and were located in the right upper lobe. Diameter ranged between 0.8-6.9 cm (median size 1-2 cm). Seventy-five percent of patients underwent subsequent treatment for cancer based on these results, with 25% having continued surveillance. Robotic assisted bronchoscopy is safe and accurate. Studies with larger numbers will allow better understanding of the diagnostic yield and clinical utility of this approach in comparison to other diagnostic tools for lung nodules.

Recommendations for Surveillance and Management of Recurrent Esophageal Cancer Following Endoscopic Therapies.

With advancing endoscopic technology and screening protocols for Barrett disease, more patients are being diagnosed with early-stage esophageal cancer. These early-stage patients may be amendable to endoscopic therapies, such as endomucosal resection and ablation. These therapies may minimize morbidity, but the elevated risk of recurrence cannot be overlooked. This article reports outcomes and recommendations for surveillance and management of recurrent esophageal cancer following endoscopic therapies.

Early Distant Recurrence in Patients With Resected Stage I Lung Cancer: A Case Series of "Blast Metastasis".

BACKGROUND: The standard of care in the management of stage I non-small-cell lung cancer (NSCLC) has been anatomic lung resection with multistation lymph node sampling of ≥ 10 lymph nodes. The 5-year survival for NSCLC has ranged from 73% to 93% (for stage IB and stage IA, respectively) and will be more favorable for patients with fewer comorbidities and those with a higher state of premorbid functioning and who undergo surgical resection. Despite the positive prognosis for operable stage I NSCLC, a subset of patients will develop metastatic disease within as few as 12 months after resection. Using an institutional database, we have presented the data from 68 patients who had developed distant metastatic recurrence after resection of pathologic stage I NSCLC within 1 year after surgery. PATIENTS AND METHODS: A retrospective study was conducted of a prospectively maintained intuitional database. The final cohort included patients with pathologic stage I NSCLC who had undergone anatomic resection but had subsequently presented with multiple sites of distant recurrence within 1 year. The study period extended from 2003 to 2020. Patients with broad local recurrence or recurrence at a single distant site were excluded. Kaplan-Meier analysis was used to estimate the 5-year survival. RESULTS: A total of 2827 patients had undergone surgical resection for stage I NSCLC during the 17-year period and 68 met the criteria for inclusion. Most of the patients (n = 48) were smokers, and the dominant histologic type was adenocarcinoma (n = 37). After recurrence, 22 patients (33%) had undergone chemoradiotherapy and 19 (28%) had received chemotherapy alone. The mean and median overall survival were 23.7 and 14 months, respectively. The 5-year survival from recurrence and surgery were both 13.2%. CONCLUSIONS: Limited data are available on the risk factors for early metastasis after resected stage I NSCLC. The results from our cohort have demonstrated poor survival after recurrence. These data might be the basis for determining a phenotype for patients prone to early widespread metastasis despite seemingly curative surgical resection.

Prognostic Difference of Pleural versus Distant Metastasis after Surgery for Lung Cancer.

BACKGROUND: Pleural metastasis in lung cancer found at diagnosis has a poor prognosis, with 5-11 months' survival. We hypothesized that prognosis might be different for patients who have had curative-intent surgery and subsequent pleural recurrence and that survival might differ based on the location of the first metastasis (distant versus pleural). This may clarify if pleural recurrence is a local event or due to systemic disease. METHODS: A database of 5089 patients who underwent curative-intent surgery for lung cancer was queried, and 85 patients were found who had biopsy-proven pleural metastasis during surveillance. We examined survival based on pattern of metastasis (pleural first versus distant first/simultaneously). RESULTS: Median survival was 34 months (range: 1-171) from the time of surgery and 13 months (range: 0-153) from the time of recurrence. The shortest median survival after recurrence was in patients with adenocarcinoma and pleural metastasis as the first site (6 months). For patients with pleural metastasis as the first site, those with adenocarcinoma had a significantly shorter post-recurrence survival when compared with squamous cell carcinoma (6 vs. 12 months; HR = 0.34) and a significantly shorter survival from the time of surgery when compared with distant metastases first/simultaneously (25 vs. 52 months; HR = 0.49). CONCLUSIONS: Patients who undergo curative-intent surgery for lung adenocarcinoma that have pleural recurrence as the first site have poor survival. This may indicate that pleural recurrence after lung surgery is not likely due to a localized event but rather indicates systemic disease; however, this would require further study.

Delayed Chylothorax during Treatment of Follicular Lymphoma with a Malignant Pleural Effusion.

Chylothorax occurs following dysfunction or disruption of the lymphatic drainage along the thoracic duct. Malignant and traumatic causes account for the majority of these occurrences, with lymphoma accounting for 11-37% of chylothoraces. The clinical course of chylothorax may include dehydration, malnutrition, immunosuppression, electrolyte disturbances, infection, and ultimately death. Management of chylothorax is patient-specific and is based on etiology and surgeon experience. Initially, most chyle leaks are managed with nonoperative strategies, such as gut rest, hyperalimentation, and pleural drainage, and, at times, medium-chained fatty acid diet or octreotide, with hopes to decrease chyle production (Zabeck et al. (2011)). High-output chyle leaks following iatrogenic injury or trauma are commonly managed with thoracic duct ligation. Lymphangiography with or without thoracic duct embolization has become increasingly popular and efficacious with the possible benefit of less morbidity (Cope et al. (2002)). We report a case of a 61-year-old male with delayed chylothorax while having an indwelling pleural catheter for malignant pleural effusion during treatment of follicular lymphoma. Percutaneous thoracic duct embolization was attempted but was unsuccessful. Chemotherapy, fluid management, and nutritional support allowed this to resolve over the course of ninety days from diagnosis. We describe the patient's clinical course and highlight nonoperative management of delayed chylothorax in the setting of follicular lymphoma treatment.

Surgical Techniques for Robotically-Assisted Laparoscopic Paraesophageal Hernia Repair.

The surgical approach to giant paraesophageal hernia repair has evolved considerably, from an open approach to minimally invasive approaches. Laparoscopic and robotic-assisted approaches to giant paraesophageal hernia have been considered safe and are associated with less morbidity and mortality. Limited data exist comparing the efficacy between laparoscopic and robotic-assisted giant paraesophageal hernia repairs, but the benefits of robotic surgery include superior optics and freedom of motion, thus allowing surgeons to accomplish the key points in a successful repair without compromising patient outcomes.

Making cold malignant pleural effusions hot: driving novel immunotherapies.

Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era.

Annuloaortic ectasia in a patient with congenital absence of the left pericardium.

We report a patient with congenital absence of the left pericardium with development of progressive annuloaortic ectasia and aortic insufficiency during a 12-year period. The patient was treated with a Bentall procedure. Pathologic examination of the aorta revealed cystic medial necrosis. The surgical management and a possible association between congenital absence of pericardium and Marfan syndrome are discussed.