Early Video-assisted Thoracoscopic Surgery or Intrapleural Enzyme Therapy in Pleural Infection: A Feasibility Randomized Controlled Trial. The Third Multicenter Intrapleural Sepsis Trial-MIST-3.

Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery-versus-nonsurgery trial as well as the key outcome measures that are important to identify relevant patient-centered outcomes in a subsequent RCT. Methods: The MIST-3 (third Multicenter Intrapleural Sepsis Trial) was a prospective multicenter RCT involving eight U.K. centers combining on-site and off-site surgical services. The study enrolled all patients with a confirmed diagnosis of pleural infection and randomized those with ongoing pleural sepsis after an initial period (as long as 24 h) of standard care to one of three treatment arms: continued standard care, early IET, or a surgical opinion with regard to early VATS. The primary outcome was feasibility based on >50% of eligible patients being successfully randomized, >95% of randomized participants retained to discharge, and >80% of randomized participants retained to 2 weeks of follow-up. The analysis was performed per intention to treat. Measurements and Main Results: Of 97 eligible patients, 60 (62%) were randomized, with 100% retained to discharge and 84% retained to 2 weeks. Baseline demographic, clinical, and microbiological characteristics of the patients were similar across groups. Median times to intervention were 1.0 and 3.5 days in the IET and surgery groups, respectively (P = 0.02). Despite the difference in time to intervention, length of stay (from randomization to discharge) was similar in both intervention arms (7 d) compared with standard care (10 d) (P = 0.70). There were no significant intergroup differences in 2-month readmission and further intervention, although the study was not adequately powered for this outcome. Compared with VATS, IET demonstrated a larger improvement in mean EuroQol five-dimension health utility index (five-level edition) from baseline (0.35) to 2 months (0.83) (P = 0.023). One serious adverse event was reported in the VATS arm. Conclusions: This is the first multicenter RCT of early IET versus early surgery in pleural infection. Despite the logistical challenges posed by the coronavirus disease (COVID-19) pandemic, the study met its predefined feasibility criteria, demonstrated potential shortening of length of stay with early surgery, and signals toward earlier resolution of pain and a shortened recovery with IET. The study findings suggest that a definitive phase III study is feasible but highlights important considerations and significant modifications to the design that would be required to adequately assess optimal initial management in pleural infection.The trial was registered on ISRCTN (number 18,192,121).

The Musculoskeletal Manifestations of Marfan Syndrome: Diagnosis, Impact, and Management.

PURPOSE OF REVIEW: Marfan syndrome (MFS) is an autosomal dominant heritable disorder of fibrillin-1 (FBN1) with predominantly ocular, cardiovascular, and musculoskeletal manifestations that has a population prevalence of approximately 1 in 5-10,000 (Chiu et al. Mayo Clin Proc. 89(1):34-42, 146, Dietz 3, Loeys et al. J Med Genet. 47(7):476-85, 4). RECENT FINDINGS: The vascular complications of MFS still pose the greatest threat, but effective management options, such as regular cardiac monitoring and elective surgical intervention, have reduced the risk of life-threatening cardiovascular events, such as aortic dissection. Although cardiovascular morbidity and mortality remains high, these improvements in cardiovascular management have extended the life expectancy of those with MFS by perhaps 30-50 years from an estimated mean of 32 years in 1972 (Dietz 3, Gott et al. Eur J Cardio-thoracic Surg. 10(3):149-58, 147, Murdoch et al. N Engl J Med. 286(15):804-8, 148). The musculoskeletal manifestations of MFS, which to date have received less attention, can also have a significant impact on the quality of life and are likely to become more important as the age of the Marfan syndrome population increases (Hasan et al. Int J Clin Pract. 61(8):1308-1320, 127). In addition, musculoskeletal manifestations are often critically important in the diagnosis of MFS. Here, we review the main clinically relevant and diagnostically useful musculoskeletal features of MFS, which together contribute to the "systemic features score" (referred to hereafter as systemic score), part of the revised Ghent nosology for MFS. We discuss current treatment strategies and highlight the need for a multidisciplinary approach to diagnosis and management. Finally, we review new pharmacological approaches that may be disease modifying and could help to improve the outcome for individuals with this syndrome.

Complete resection of pulmonary artery hemangioma on the beating heart.

Cardiac hemangiomas are rare entities and very few cases have been reported where they originate from the main arteries of the heart. We present a case of hemangioma arising from the main pulmonary artery, which was completely resected with clear margins on the beating heart.

Should all patients receive extended thromboprophylaxis after resection of primary lung cancer?

OBJECTIVE: The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and venous thromboembolism in patients undergoing early-stage lung cancer resection and the impact of change from short duration to extended thromboprophylaxis. METHODS: We reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer following a change in protocol from inpatient-only to extended thromboprophylaxis to 28 days. Propensity-score matching of control (routine inpatient pharmacologic thromboprophylaxis) and treatment group (extended pharmacologic thromboprophylaxis) was performed. Adjustment for covariates based on the Caprini risk assessment model was undertaken. Thromboembolic outcomes were compared between the 2 groups. RESULTS: Seven hundred fifty consecutive patients underwent resection of primary lung cancer at Oxford University Hospitals NHS Foundation Trust between January 2013 and December 2018. Six hundred patients were included for analysis and propensity-score matching resulted in 253 matched pairs. Extended prophylaxis was associated with a significant reduction in pulmonary emboli (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01). One patient (0.4%) developed a bleeding complication within the treatment cohort. Multivariable logistic regression model demonstrated that extended thromboprophylaxis was independently associated with a reduction in postoperative pulmonary emboli. CONCLUSIONS: Patients undergoing lung cancer resection surgery are at moderate-to-high risk of postoperative thromboembolic disease. Extended dalteparin for 28 days is safe and is associated with reduced incidence of pulmonary embolus in patients undergoing resection of early-stage primary lung cancer.

Optimal resection rate for lung cancer in the UK: how high should we go?

BACKGROUND: The optimal resection rate for institutions managing early-stage primary lung cancer is not known. Whether the prognosis of patients who do not proceed to operation is determined by their comorbidities for which they were deemed at prohibitively high-operative risk, or disease progression, is uncertain. We investigated the outcomes of patients with early-stage lung cancer who were considered for surgical management. METHODS: We reviewed the outcomes of consecutive patients who were considered for resection of early-stage primary lung cancer at Oxford University Hospitals National Health Service Foundation Trust between 2012 and 2017. RESULTS: Between 29 November 2012 and 31 March 2017, 467 consecutive patients underwent resection with curative intent for primary lung cancer (operative group), while 81 patients were deemed resectable but either inoperable or did not wish to proceed to operation (non-operative group). Reason for not proceeding to resection was cardiovascular in 16 patients (19.8%), respiratory in 21 (25.9%), cardiorespiratory in 11 (13.6%), performance status in 8 (9.9%) and patient choice in 25 (30.9%) patients. Sixty-six patients (81.5%) received an alternative radical treatment. Median follow-up was 169 weeks (IQR 119-246 weeks) in the operative group and 118 weeks (IQR 74-167 weeks) in the non-operative group. Median survival of patients with early-stage lung cancer who did not proceed to operation was 2.5 years; median survival of patients undergoing lung cancer resection was undefined (p<0.0001). Lung cancer was documented as directly or indirectly leading to or contributing to death in 40 patients (76.9%). In 11 patients, the cause of death was due to comorbidities (21.2%). CONCLUSIONS: Patients turned down for operation in a high-resection rate UK unit have limited survival due to lung cancer progression. We conclude that 'optimal' resection rates may not have been reached in the UK even in high-resection rate centres.

Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. RESULTS: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. CONCLUSIONS: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Secondary pneumothorax in end-stage lung disease complicated by noninvasive ventilation and a persistent air leak.

Pneumothorax is a well-recognised complication of end-stage COPD, but the management is often complex and may be complicated by other sequelae of advanced respiratory disease including the requirement for NIV http://ow.ly/vkoJ30mB4nZ.

Late presentation of congenital H-type tracheoesophageal fistula in an immunocompromised patient.

Congenital tracheoesophageal fistulas without esophageal atresia - H-type tracheoesophageal fistula - accounts for approximately 4% of esophageal malformations. This term refers to a connection at an oblique course between the posterior wall of the trachea and the anterior wall of the esophagus, presenting as an 'H' form. Typically, the diagnosis is made before the third year of life; however, some reports have been made of late presentation in adults who present chronic cough and frequent respiratory infections. Traditionally, surgery has been considered as the best treatment, depending on the level of the fistula. We present the case of an immunocompromised patient who was diagnosed as having a congenital tracheoesophageal fistula of the upper third of the trachea.