A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs.

Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials.

Combined minimally invasive resection of thoracic neurogenic dumbbell tumors: A European case series.

BACKGROUND: Paraspinal tumors are rare neoplasms arising from neurogenic elements of the posterior mediastinum and surgical resection can be challenging. Here, we demonstrate feasibility and outcomes from the first European case series of combined laminectomy and video-assisted thoracoscopic surgery (VATS) resection of thoracic neurogenic dumbbell tumors. METHODS: A retrospective review of all combined thoracic dumbbell tumor resections performed at our institution between March 2015 to February 2019 was undertaken. Outcomes included operative time, blood loss, length of stay and recurrence rate. Statistical analysis was performed with SPSS statistics (v26). Values are given as mean ± standard deviation and median ± interquartile range. RESULTS: Seven patients were included in the case series and there were no major complications or mortality. Mean tumor size and operative time were 66 (± 35) mm and 171 (± 63) min, respectively. Median blood loss and length of stay were 40 (± 70) ml and four (± 3) days, respectively. One patient required conversion to thoracotomy to remove a tumor of 135 mm in maximal dimension. Histology in all seven cases confirmed schwannoma. There was no disease recurrence at a maximum follow-up of 54 months. CONCLUSIONS: Our experience demonstrates favorable operative times, minimal blood loss and short length of stay when dealing with relatively large tumors compared to previous reports. Thoracotomy may be required for tumors exceeding 90 mm and chest drain removal on the operative day can facilitate early mobility and discharge. We advocate a combined, minimally invasive laminectomy and VATS resection as the gold-standard approach for thoracic neurogenic dumbbell tumors.

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC).

BACKGROUND: NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. METHODS: The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. RESULTS: There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. CONCLUSION: Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Cardiopulmonary bypass to facilitate excision of a giant pleural tumour.

A 55-year-old female developed dyspnoea following an elective hysteroscopy. A chest radiograph demonstrated a tissue density opacity occupying the right hemithorax. A CT scan suggested this was a tumour arising from the postero-lateral chest wall. Surgical resection was attempted; however, mobilisation of the tumour caused significant airway compromise. Cardiopulmonary bypass was used to facilitate oxygenation while the tumour was dissected and removed. Although cardiopulmonary bypass has been used as an adjunct to aid resection of tumours invading major vascular or upper airway structures, in this case CPB was used to aid mobilisation of a giant pleural tumour.

Thoracoscopic approach to congenital diaphragmatic hernias in adults: Southampton approach and review of the literature.

Congenital diaphragmatic hernias (CDH) are likely to present in early postnatal or infancy and are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. Symptomatic adult congenital Bochdalek hernia, on the other hand, is extremely rare with a prevalence of 0.17-6% of all diaphragmatic hernias. They present with recurrent abdominal pain and shortness of breath. Acute presentations could be life threatening especially if there is incarcerated or threatened bowel in the chest. Repair of symptomatic Bochdalek hernia is recommended in the adult population. We present two cases of right and left symptomatic Bochdalek hernias in adults, encountered over 15 years of practice in a tertiary referral centre in the UK. We discuss their presentation and surgical management and review the literature of similar cases treated by video-assisted thoracoscopic surgery (VATS). Thoracic surgeons are increasingly becoming involved in these cases, which used to be the domain of upper gastrointestinal surgeons. A synthetic patch may be required to close the defect, therefore; the thoracic surgeon must be familiar with such techniques. The recent expansion in video format publishing in the internet and social media has revolutionized the way knowledge and how-to-do-it expertise is distributed around the world. It has the advantage of reaching far more viewer than subscription paper-printed format journals and has a rising significance in encouraging thoracic surgeons to do things they were not used to do. Finally; Symptomatic Bochdalek hernia, and possibly Morgagni hernia in the adult population could be safely repaired by VATS with good and lasting results.

VATS Plication of the Diaphragm: A Descriptive Observational 10-Year Southampton Experience.

OBJECTIVE: The aim of the study was to report the safety and efficacy of video-assisted thoracoscopic (VATS) plication of the diaphragm at our institution between 2006 and 2016. METHODS: Adult patients selected on etiology and combination of investigations including plain chest x-ray, computed tomography of chest and abdomen, lung functions in supine and sitting positions, radiological/ultrasonic screening for diaphragmatic movement, and phrenic nerve conduction studies. We incorporated a triportal VATS and Endostitch device for plication, using CO2 insufflation to maximum 12 mm Hg. Bilateral simultaneous plication and high-risk patients were electively admitted to intensive therapy unit postoperatively. RESULTS: Thirty-five patients (24 males) had their diaphragm plicated. The mean age was 56.6 years (range = 23-76 years). The mean body mass index was 32.1 (range = 22.2-45.4). Twenty one were right, 13 left, 2 patients had VATS simultaneous bilateral plication, and 1 had sequential VATS bilateral plication. Paralysis was idiopathic in 17, posttraumatic in 5, postremoval of mediastinal tumor in 4, and postcardiac surgery in 3. All patients presented with lifestyle-limiting dyspnea and orthopnea, three were on nocturnal noninvasive ventilation. Five were diabetic and 16 were smokers. The mean supine forced expiratory volume in the first second was 62.5% of predicted. Twenty two were performed by VATS (63%), three converted to thoracotomy, and 13 were open limited thoracotomy (historic). The mean hospital stay was 4.5 days (range = 1-18, mode 2 days). Intensive therapy unit admission was required in six patients for mechanical ventilation 0 to 3 days. Five patients (14%) had no improvement in symptoms. There were no deaths, no 30-day readmissions, and no long-term neuralgia in this series. CONCLUSIONS: We found minimal access VATS plication of the diaphragm to be feasible and safe, but no firm conclusions should be drawn from our limited resources. We report the feasibility of concomitant bilateral VATS plication of the diaphragm in two adults, and this was not previously reported in the adult population. There is a need for further good quality, prospective studies, and randomized controlled studies evaluating efficacy of VATS diaphragmatic plication.

Recurrent spontaneous esophageal rupture.

Spontaneous esophageal rupture is an uncommon and poorly understood condition. Recurrent rupture is extremely rare, with only one previously reported case in the literature. Here, we present a case series of two patients who had recurrent ruptures, and discuss the principles underlying the management of such cases.

Video assisted thoracoscopic excision of mediastinal ectopic parathyroid adenomas: a UK regional experience.

BACKGROUND: To report the first series of video-assisted thoracoscopic surgery (VATS) resection of mediastinal ectopic parathyroid adenomas (MEPAs) in the UK. METHODS: A case series of seven cases undergoing VATS between 2004 and 2009 to treat single gland hyperparathyroidism. Methylene blue (MB) was used in 5/7 cases immediately before exploration to identify the adenomas. Carbon dioxide (CO2) up to pressures of 10 mmHg was used safely to deflate the lung in two cases. RESULTS: There were five women and two men with a mean age of 53 years (range, 27-72 years). Histopathology confirmed successful resection of the parathyroid adenoma in 6/7 cases. There was one conversion to open thoracotomy due to bleeding from the azygos vein resulting from excessive traction. Despite marked MB uptake, this patient proved to have tuberculoid adenopathy and no parathyroid tissue was identified. Postoperative plasma calcium returned to normal in 6/7 patients and parathyroid hormone (PTH) level in 6/7 patients. The median hospital stay was 2 days and there was no mortality in this series. CONCLUSIONS: MEPAs can be safely resected using VATS with minimal surgical morbidity, short drainage time and short hospital stay. CO2 insufflation and the intraoperative use of MB are safe and help to accurately localise the ectopic adenoma. VATS should be considered as the first-line approach for resection of MEPAs.

Klippel-Trenauney-Weber syndrome associated with hemoptysis.

We report a case of Klippel-Trenaunay-Weber syndrome presenting with hemoptysis.

Pedicled intercostal muscle flap: a simple technique of closing pancreatico-pleural fistula from a thoracic approach.

A simple technique to close a pancreatico-pleural fistula in the course of thoracotomy and decortication for multiloculated empyema complicating acute haemorrhagic pancreatitis is described. Friable diaphragmatic tissue around the fistula made direct closure not a suitable option. The intercostal muscle flap of the thoracotomy space was mobilized on the anterior intercostal artery, tagged around the fistula into healthy diaphragmatic tissue. This simple technique was successful in closing the fistula and helping control the sepsis.

Value of wide-margin wedge resection for solitary pulmonary nodule: a single center experience.

OBJECTIVE: Despite refinements of the diagnostic procedures, often surgery remains the only option to ascertain the histopathological nature of solitary pulmonary nodules (SPN). Aim of the present study was to ascertain the value of wide-margin wedge resection (WMWR) with curative intent in a consecutive cohort of patients afflicted by SPN. METHODS: From January 1995 to January 2002, 129 patients (74 male, mean age 60.5+/-14.4 years) underwent WMWR of a SPN. In-hospital outcome was prospectively collected and retrospectively analyzed. Incidence of malignancy was obtained by histology. Patients found to be afflicted by primary lung cancer (PLC) were sub-grouped according to their preoperative cardiopulmonary status (CPS). In-hospital and mid-term clinical outcome of all the patients is presented. RESULTS: There were 3 (2.3%) in-hospital deaths. Distribution of histology included 61 (47.3%) PLC (41 poor CPS), 20 (15.5%) secondary lung cancer (SLC), and 48 (37.2%) miscellaneous benign lesions. Twenty patients with PLC were fit and underwent completion lobectomy within 2 weeks following WMWR. Hospital length of stay was longer in patients with PLC as compared to patients with SLC (P=0.04). There were 17/61 (27%) recurrences in the PLC group. Of these, 2 occurred in fit patients undergone previous WMWR-lobectomy, and 15 in patients with poor baseline CPS. All these patients were referred for adjuvant therapy. Overall 5-year survival of the PLC group was 66% (61.1% for those with poor CPS and 82.5% for those with good CPR (P=NS). Seven out of 20 (35%) patients with SLC had late recurrent disease, leading to 1 re-operation. The overall 5-year survival in this group was 58.8%. There was only 1 non-related late death in the benign group. CONCLUSIONS: The WMWR resection of a primarily malignant SPN determines a valuable 5-year survival but a relatively high incidence of late recurrence. WMWR is a safe and effective surgical option for patients presenting with poor cardiopulmonary reserve.

Pulmonary sclerosing hemangiomas: new approach in patients with low cancer risk.

Three cases of sclerosing hemangioma managed differently are described. Thoracic surgeons should raise their awareness of this benign slow-growing tumor in the differential diagnosis of solitary pulmonary nodule. Radiographic evidence of expansion of such a lesion is not conclusive for malignancy, and should not affect its biological behavior. Intraoperative frozen-section histology may prevent unnecessary resection of lung tissue. Extracapsular enucleation is the treatment of choice for sclerosing hemangiomas.

Right intraventricular hydatid cyst of the heart.

A 32-year-old woman presented with shortness of breath and palpitations. Echocardiography and contrast-enhanced computed tomography showed a 4 x 5 cm cyst in the apex of the right ventricle. The cyst was excised on cardiopulmonary bypass. The patient made an uneventful recovery. At the one-year follow-up, she was symptom-free and without recurrence. Different clinical aspects of cardiac hydatid cyst and its surgical management are reviewed.

Early and mid-term outcomes of trans-sternal and video-assisted thoracoscopic surgery for thymoma.

OBJECTIVES: Video-assisted thoracoscopic surgery (VATS) for thymoma has uncertain safety and effectiveness in comparison with trans-sternal resection. This feasibility study compared short- and mid-term outcomes for patients undergoing these two procedures, highlights weaknesses in current research and makes recommendations for long-term technological evaluations in this field. METHODS: Consecutive thymoma cases between 2004 and 2010 were identified. Patients were divided into two groups according to surgical approach (Group I trans-sternal; Group II VATS) and comparisons were made between groups. The primary outcome was overall survival. Secondary outcomes included operative morbidity and mortality, hospital stay, recurrence rate and disease-free survival. RESULTS: Thirty-nine patients were included (Group I: n = 22 vs Group II: n = 17). There were no differences between groups at baseline for all measured covariates. No deaths occurred within 30 days of surgery. More patients in Group I developed complications (Group I: n = 10 vs Group II: n = 3; P = 0.093), while hospital stay was shorter in Group II (Group I: 6.4 ± 4.6 days vs Group II: 4.4 ± 1.8 days; P = 0.030). Five-year overall survival (Group I: 93.8 ± 6.1% vs Group II: 83.3 ± 11.2%; P = 0.425), 5-year disease-free survival (Group I: 71.0 ± 15.3% vs Group II: 83.3 ± 11.2%; P = 0.827) and recurrence rates at final follow-up (Group I: n = 2 vs Group II: n = 1; P = 0.363) were similar between the groups. CONCLUSION: VATS thymectomy for thymoma is feasible, safe and has comparable mid-term oncological outcomes to trans-sternal thymectomy. Future research is required to evaluate long-term oncological outcomes of VATS thymectomy for thymoma in national registries and randomized, controlled trials.

Is it safe to include octogenarians at the start of a video-assisted thoracic surgery lobectomy programme?

OBJECTIVE: The study aimed to investigate the safety of including patients ≥ 80 years of age at the start of a video-assisted thoracic surgery major pulmonary resection (VMPR) programme. METHODS: Patients were considered for VMPR if the computed tomography/positron emission tomography (CT/PET) was suggestive of T1-3, N0-1 and M0 lesion. Age was not a criterion for exclusion at the very start of the programme. Data were collected prospectively and comparison made between two groups, (A) <80 years of age and (B) ≥ 80 years, in terms of preoperative risk factors, oncological and functional data, operative results, postoperative complications and survival. RESULTS: Between April 2005 and January 2011, 200 consecutive patients were considered for VMPR. A total of 160 had non-small-cell lung cancer, of whom 136 were in group A, with a median age of 66.5 (range: 42.8-79.4 years) and 24 in group B with a median age of 82 (range: 80-85.5 years). In group B, 13 were men and 11 were women. Rate of conversion to thoracotomy was similar (3 (12.5%) in group B vs 17 (12.5%) in group A, p = 0.65), and so was the mean hospital stay (5.8 ± 3.3 days in group B vs 5.9 ± 4.6 days in group A, p = 0.899). Admission to intensive care unit and atrial fibrillation were significantly higher in octogenarians (six (25%) and six (25%) in group B vs eight (5.9%) and nine (6.6%) in group A, p = 0.008 and p = 0.012, respectively). There was significantly less mean days of air leak in octogenarians (0.06 ± 0.3 days in group B vs 2.8 ± 5.6 days in group A, p = 0.000). Otherwise, there were no age-related differences in relation to morbidity, mortality and the 3-year survival rate. CONCLUSION: Octogenarians undergoing VMPR have a higher incidence of atrial fibrillation and admission to the intensive care unit for cardiopulmonary support but otherwise are no different from younger age groups when it comes to rate of conversion to thoracotomy, hospital stay, morbidity and mortality. Age should not be an excuse to deny the elderly curative VATS resection. In our experience, accepting octogenarians early in the VMPR programme did not compromise the outcome results.

Video-assisted thoracic surgery of major pulmonary resections for lung cancer: the Southampton experience.

OBJECTIVE: Despite proven safety and long-term results of video-assisted thoracic surgery (VATS) lobectomy, the technique is not widely adopted in the UK. We set out to start a VATS lobectomy programme against financial and time constraints to meet cancer waiting times. We present clinical outcomes of patients undergoing VATS major pulmonary resections (VMPRs) with emphasis on postoperative events. METHODS: Patients were deemed suitable for VMPR if on computed tomography (CT)/positron emission tomography (PET); the lesion was suspected to represent lung cancer T1-2, N0-1 and M0. VMPR involved individual hilar structures dissection without rib spreading. Systematic mediastinal nodal dissection was added in the last 64 cases. RESULTS: Between April 2005 and December 2009, 165 patients were considered suitable for first-time VMPR. Seventy were males and 95 were females. Mean age was 67.5 ± 10.1 (range 34.9-85.5 years) years. Nine patients were not suitable after initial videoscopic assessment and 156 proceeded to VMPR: 150 lobectomies, four bilobectomies, one pneumonectomy and one patient with poor lung function who underwent segmentectomy. There were 23 (14.7%) conversions to thoracotomy. The median operative time for VATS lobectomy was 03:20 ± 00:56 (hh:mm). The median length of hospital stay was 4.0 ± 4.0 days (range 1-25 days, mode 3 days). There were no in-hospital deaths and three (1.9%) out-of-hospital <30 days' mortality. Complications included protracted air leak >3 days in 18 (11.5%) cases, intensive care unit (ICU) admission in 18 (11.5%), pneumothorax in 24 (15.4%) respiratory complications in 14 (9%), bronchial complications in six (3.8%) and bleeding requiring exploration in one (0.6%). The median follow-up was 13.6 months (range 0.1-54.4 months). The actuarial survival at 1, 2 and 3 years for all stages was 85.0 ± 3.8%, 82.2 ± 4.2% and 73.5 ± 7.0%, respectively. CONCLUSION: High postoperative events are to be expected when starting a VATS lobectomy programme. Nevertheless, VATS major pulmonary resections are safe and long-term results are not compromised. They should be considered the first choice for T1-2, N0-1 and M0 lung lesions. An aggressive approach to postoperative complications reduced the length of hospital stay to a median of 4 days. Air leak remains the most important cause for prolonged hospital stay.

Video-assisted thoracic surgery systematic mediastinal nodal dissection and stage migration: impact on clinical pathway.

OBJECTIVES: The aim of this study is to investigate the role of routine systematic mediastinal nodal dissection (SND) performed during video-assisted thoracic surgery (VATS) major pulmonary resections (VMPRs) as a staging strategy for non-small-cell lung cancer (NSCLC), compared with preoperative staging by conventional positron emission tomography (PET) and computed tomography (CT) imaging. METHODS: All patients suspected of having early lung cancer (T1-2, N0-1 and M0) were staged preoperatively by CT/PET. During VMPR, all lymph nodes on the right side at stations 2-4, 7, 8, 9, 10 and 11 and on the left stations 4-6, 7, 8, 9, 10, 11 and 3 when indicated were dissected en bloc. Histology was provided on the paraffin-embedded nodes, and patients staged accordingly. Preoperative and postoperative stagings were compared. Stage migration and impact on clinical pathway were noted. Stage IIa and higher were referred for adjuvant chemotherapy. RESULTS: Between April 2007 and January 2011, 106 consecutive patients with suspected primary NSCLC proceeded to VMPR+SND. Histology confirmed NSCLC in 96 patients. Forty-five were men and 51 women. Median age was 68.6 (range 42.8-84.7) years. As many as 91 (94.8%) patients underwent lobectomy, three (3.1%) bilobectomy and two (2.1%) pneumonectomy. PET accurately correlated with SND histological diagnosis in 42 (43.8%) patients. The unexpected N2 disease in cN0-1 was 9/86 (10.5%). SND resulted in 25 stage migrations, upstaged 16 (16.6%) and down-staged nine (9.4%) patients. All upstagings were adenocarcinoma. Four (4.2%) PET-negative patients had multi-station N2 disease. SND resulted in changing the clinical pathway for 19 (20%) patients. Fourteen (14.6%) patients upstaged to qualify for chemotherapy, and 5/9 (5.2%) down-staged patients were saved the chemotherapy. There was no morbidity or mortality attributable to this added procedure. CONCLUSIONS: SND during VMPR is safe and should be routinely performed even when nodal metastases is considered unlikely. VATS-SND is more accurate than PET in staging the mediastinum for NSCLC. PET sensitivity is significantly reduced in adenocarcinoma and might result in stage migration. Adjuvant multidisciplinary treatment should be based on SND staging.

Effective symptomatic relief of hypertrophic pulmonary osteoarthropathy by video-assisted thoracic surgery truncal vagotomy.

Various modalities for the treatment of hypertrophic pulmonary osteoarthropathy (HPOA) associated with lung cancer have been suggested since 1958. Although the etiology remains speculative, unilateral vagotomy on the side of the lung cancer achieves symptomatic relief. We report a case of a 50-year-old woman with disabling HPOA and inoperable lung cancer who experienced effective pain relief and regained full mobility after video-assisted thoracoscopic surgery was used to perform truncal vagotomy. This relatively safe and simple procedure should be considered for terminal lung cancer patients with intractable HPOA.