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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.

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Aims The rarity of thoracic sarcomas leads to challenges in their diagnosis and evidence-based management. We aim to investigate the management and outcomes of primary thoracic sarcoma patients under the care of our tertiary centre Sarcoma Service over a three-year period. Methods Data of all thoracic sarcoma patients discussed at the tertiary centre multidisciplinary meetings from 2017–2019 were collected from the local electronic database. Results 65 patients met the inclusion criteria. The most common histological subtypes were chondrosarcomas and spindle cell sarcomas. 60% of cases were high-grade sarcomas. 14 out of 19 deaths occurred in patients with high grade sarcomas (p=0.0586). 78.3% of patients underwent surgical resection, with 35.4% undergoing surgical resection as their sole treatment modality. Surgical intervention was associated with a statistically significant improvement in survival (p < 0.0001*). Clear marginal status was associated with better survival outcomes (p = 0.026*). Local recurrence was seen in 15 cases, and 93.3% of these were in high-grade sarcomas. There was no association between recurrence and marginal status. 8 of the 15 cases with recurrence received surgical intervention for the recurrence. 4 of the cases with recurrence passed away within the study time frame. Conclusion Primary resection should remain the gold standard for treatment of thoracic sarcomas due to its significant improvement in survival. Variability between outcomes and overall survival is likely multifactorial – diversity of histological subtypes, predominance of high-grade sarcomas, and a wide range of age at diagnosis. Prospectively maintained databases and cross-centre collaboration would be beneficial for future study in thoracic sarcomas.

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. Summary 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.

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.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.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.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.

Cardiac haemangiomas 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 haemangioma arising from the main PA, which was completely resected with clear margins on the beating heart.

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.

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.

BackgroundThe 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.MethodsWe 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.ResultsBetween 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 (pConclusionsPatients 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.

A 75-year-old man initially presented to the respiratory service in 2012 with severe chronic obstructive pulmonary disease (COPD) defined as Global Initiative for Chronic Obstructive Lung Disease stage 3. Forced expiratory volume in 1 s (FEV1) was 1.1 L (33% predicted) with FEV1/forced vital capacity 32%. He required long-term oxygen therapy at home at 4 L·min−1 and by 2015 nocturnal high-pressure noninvasive ventilation (NIV) was required due to progressive symptomatic hypercapnic respiratory failure including a carbon dioxide tension (PCO2) of 7.9 kPa and bicarbonate of 28.3 mmol·L−1., 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

Unlike most malignant tumours, thymomas rarely have distant metastases, but they are apt to invade neighbouring organs especially vascular structures [1]. Despite the increased complexity of surgical approach, complete resection and vascular reconstruction are recommended for a successful treatment. Here, we described the rare condition of a concomitant thymoma infiltrating an anomalous pulmonary venous drainage, which was successfully treated.

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.