Naive CD4+ T Cells Carrying a TLR2 Agonist Overcome TGF-ß-Mediated Tumor Immune Evasion.

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4+ T cells that sequester Pam3Cys4 (CD4+ TPam3) become primed for Th1 differentiation. CD4+ TPam3 cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-ß-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection. In contrast, naive OT2 cells without Pam3Cys4 cargo are prone to TGF-ß-dependent inducible regulatory Foxp3+ CD4+ T cell conversion and accelerate tumor growth that is largely unaffected by PD-1/programmed cell death ligand 1 blockade. Ex vivo analysis reveals that CD4+ TPam3 cells are resistant to TGF-ß-mediated gene expression through Akt activation controlled by inputs from the TCR and a TLR2-MyD88-dependent PI3K signaling pathway. These data show that CD4+ TPam3 cells are capable of Th1 differentiation in the presence of TGF-ß, suggesting a novel approach to adoptive cell therapy.

Surgery for T4 lung cancer invading the thoracic aorta: Do we push the limits?

BACKGROUND: Few investigators have described en bloc resection of non-small cell lung cancer (NSCLC) invading the aorta. AIM OF STUDY: Analysis of outcome and prognostic factors for en bloc resections of NSCLC invading the aorta. METHODS: Thirty-five patients (27 males, 8 females; mean age 63 ± 8.6 years) were operated between 1994 and 2015 in four European Centers. HISTOLOGY: 12 (34.3%) squamous cell carcinoma, and 6 (17.1%) undifferentiated/large cell carcinoma. The site of aortic infiltration was the descending thoracic aorta in 24 (68.6%) patients, the aortic arch in 9 (25.7%), and the aortic arch and supraortic trunks in 2 (5.7%). RESULTS: Lung resection consisted of pneumonectomy in 19 (54.3%) patients and lobectomy in 16 (45.7%). Aortic resection management was undertaken by endograft positioning (37.1%), subadventitial dissection (37.1%), cardiopulmonary/aorto-aortic bypass (17.2%), and direct clamping (8.6%). A tubular graft replacement was carried out in five cases, a synthetic patch repair in 6. Mortality was 2.9%, morbidity 37.1%. Patients undergoing pneumonectomy had a significantly higher morbidity rate compared with lobectomy (52% vs 18.7%; P = 0.003), although patients managed with aortic endografting had a lower complication rate. Median overall and disease-free survival rates were 31.3 and 22.2 months, respectively. Gender and site of aortic infiltration were independent prognostic factors. CONCLUSIONS: Resection of NSCLC combined with an infiltrated aorta is a challenging procedure that can be performed with reasonable morbidity and mortality in highly selected patients.

Prognostic Impact of Node-Spreading Pattern in Surgically Treated Small-Cell Lung Cancer: A Multicentric Analysis.

OBJECTIVE: Although surgery in selected small-cell lung cancer (SCLC) patients has been proposed as a part of multimodality therapy, so far, the prognostic impact of node-spreading pattern has not been fully elucidated. To investigate this issue, a retrospective analysis was performed. METHODS: From 01/1996 to 12/2012, clinico-pathological, surgical, and oncological features were retrospectively reviewed in a multicentric cohort of 154 surgically treated SCLC patients. A multivariate Cox proportional hazard model was developed using stepwise regression, in order to identify independent outcome predictors. Overall (OS), cancer-specific (CSS), and Relapse-free survival (RFS) were calculated by Kaplan-Meier method. RESULTS: Overall, median OS, CSS, and RFS were 29 (95 % CI 18-39), 48 (95 % CI 19-78), and 22 (95 % CI 17-27) months, respectively. Lymphadenectomy was performed in 140 (90.9 %) patients (median number of harvested nodes: 11.5). Sixty-seven (47.9 %) pN0-cases experienced the best long-term survival (CSS: 71, RFS: 62 months; p < 0.0001). Among node-positive patients, no prognostic differences were found between pN1 and pN2 involvement (CSS: 22 vs. 15, and RFS: 14 vs. 10 months, respectively; p = 0.99). By splitting node-positive SCLC according to concurrent N1-invasion, N0N2-patients showed a worse CSS compared to those cases with combined N1N2-involvement (N0N2: 8 months vs. N1N2: 22 months; p = 0.04). On the other hand, the number of metastatic stations (p = 0.80) and the specific node-level (p = 0.85) did not affect CSS. At multivariate analysis, pN+ (HR: 3.05, 95 % CI 1.21-7.67, p = 0.02) and ratio between metastatic and resected lymph-nodes (RL, HR: 1.02, 95 % CI 1.00-1.04, p = 0.03) were independent predictors of CSS. Moreover, node-positive patients (HR: 3.60, 95 % CI 1.95-6.63, p < 0.0001) with tumor size ≥5 cm (HR: 1.85, 95 % CI 0.88-3.88, p = 0.10) experienced a worse RFS. CONCLUSIONS: In selected surgically treated SCLC, the long-term survival may be stratified according to the node-spreading pattern.

Transsternal thymectomy.

Thymectomy is a well-established indication for management of myasthenia gravis and it represents the most effective treatment for thymic tumors. The traditional surgical approach is median sternotomy. More recently, different less-invasive surgical approaches for thymectomy have been proposed as an alternative to open surgery. This article discusses the main technical aspects and results of literature.

Reconstruction of the heart and the aorta for radical resection of lung cancer.

INTRODUCTION: We report a single-center experience of resection and reconstruction of the heart and aorta infiltrated by lung cancer in order to prove that involvement of these structures is no longer a condition precluding surgery. METHODS: Twenty-seven patients underwent surgery for lung cancer presenting full-thickness infiltration of the heart (n = 6) or the aorta (n = 18) and/or the supra-aortic branches (subclavian n = 3). Cardiac reconstruction was performed in 6 patients (5 atrium, 1 ventricle), with (n = 4) or without (n = 2) cardiopulmonary bypass, using a patch prosthesis (n = 4) or with deep clamping and direct suture (n = 2). Aortic or supra-aortic trunk reconstruction (n = 21) was performed using a heart-beating crossclamping technique in 14 cases (8 patch, 4 conduit, 2 direct suture), or without crossclamping by placing an endovascular prosthesis before resection in 7 (4 patch, 3 omental flap reconstruction). Neoadjuvant chemotherapy was administered in 13 patients, adjuvant therapy in 24. RESULTS: All resections were complete (R0). Nodal staging of lung cancer was N0 in 14 cases, N1 in 10, N2 in 3. No intraoperative mortality occurred. Major complication rate was 14.8%. Thirty-day and 90-day mortality rate was 3.7%. Median follow-up duration was 22 months. Recurrence rate is 35.4% (9/26: 3 loco-regional, 6 distant). Overall 3- and 5-year survival is 60.9% and 40.6%, respectively. CONCLUSIONS: Cardiac and aortic resection and reconstruction for full-thickness infiltration by lung cancer can be performed safely with or without cardiopulmonary bypass and may allow long-term survival of adequately selected patients.

The influence of propofol, remifentanil and lidocaine on the tone of human bronchial smooth muscle.

BACKGROUND: Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle. MATERIALS AND METHODS: The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA. RESULTS: Propofol (1.3 µg ml(-1)) and lidocaine (1 mg ml(-1)) reduced the baseline tone of bronchial rings (-14.45 ± 4.53% and -33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml(-1) (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (-26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil. CONCLUSION: Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm.

Long-term follow-up after bronchoscopic lung volume reduction in patients with emphysema.

Bronchoscopic lung volume reduction (BLVR) is a novel emphysema therapy. We evaluated long-term outcome in patients with heterogeneous emphysema undergoing BLVR with one-way valves. 40 patients undergoing unilateral BLVR entered our study. Pre-operative mean forced expiratory volume in 1 s (FEV(1)) was 0.88 L · s(-1) (23%), total lung capacity was 7.45 L (121%), intrathoracic gas volume was 6 L (174%), residual volume (RV) was 5.2 L (232%), and the 6-min walk test (6MWT) was 286 m. All patients required supplemental oxygen; the Medical Research Council (MRC) dyspnoea score was 3.9. High-resolution computed tomography (HRCT) results were reviewed to assess the presence of interlobar fissures. 33 patients had a follow-up of >12 months (median 32 months). 37.5% of the patients had visible interlobar fissures. 40% of the patients died during follow-up. Three patients were transplanted and one underwent lung volume reduction surgery. Supplemental oxygen, FEV(1), RV, 6MWT and MRC score showed a statistically significant improvement (p ≤ 0.0001, p = 0.004, p = 0.03, p = 0.003 and p<0.0001, respectively). Patients with visible fissures had a functional advantage. BLVR is feasible and safe. Long-term sustained improvements can be achieved. HRCT-visible interlobar fissures are a favourable prognostic factor.

Pharmacological characterization of adenosine receptors on isolated human bronchi.

Adenosine induces airways obstruction in subjects with asthma, but the receptor subtype responsible remains unknown. The objectives of this study were to determine the pharmacological profile of adenosine receptor subtypes mediating contraction and to investigate the mechanism in normal and passively sensitized human airway tissues. Contraction of bronchial rings isolated from resected lung tissue of patients with lung carcinoma was measured in response to nonselective adenosine receptor agonists, 5-AMP and 5'-(N-Ethylcarboxamido)adenosine, and A(1) receptor agonist, N(6)-cyclopentyladenosine, in the absence and presence of selective adenosine receptor antagonists. Pharmacological antagonists, chemical ablation of airway sensory nerves using capsaicin, and passive sensitization of tissue with serum from subjects with atopy and asthma was used to investigate the mechanism of contraction. Human bronchial tissue contracted in a concentration-dependent manner to adenosine agonists that showed a rank order of activity of A(1) > A(2B) >> A2(A) = A3. The maximum contractile response to N(6)-cyclopentyladenosine (231.0 ± 23.8 mg) was significantly reduced in tissues chemically treated with capsaicin to desensitize sensory nerves (desensitized: 101.6 ± 15.2 mg; P < 0.05). Passive sensitization significantly augmented the contraction induced by adenosine A(1) receptor activation (sensitized: 389.7 ± 52.8 mg versus nonsensitized; P < 0.05), which was linked to the release of leukotrienes, and not histamine (MK571: 25.5 ± 1.7 mg; epinastine 260.0 ± 22.2 mg versus control; P < 0.05). This study provides evidence for a role for adenosine A(1) receptors in eliciting human airway smooth muscle constriction, which, in part, is mediated by the action of capsaicin sensitive sensory nerves.

Surgical management of stage III thymic tumors.

Thymic tumors are classified as stage III when they clearly invade the surrounding structures: pericardium, great vessels (superior vena cava, innominate veins, ascending aorta, and main pulmonary artery), lung parenchyma, phrenic nerves, and chest wall. Surgical treatment with or without induction therapy should always aim to complete resection removing en bloc all the involved structures. Also, extended procedures are justified because only R0 resection allows long-term survival.

Direct Cross-Clamping for Resection of Lung Cancer Invading the Aortic Arch or the Subclavian Artery.

BACKGROUND: Resection of lung cancer infiltrating the aortic arch or the subclavian artery can be accomplished in selected patients with the use of cardiopulmonary bypass (CPB). Direct cross-clamping of the aortic arch and the left subclavian artery without CPB for radical resection of the tumor can be an alternative. This study presents one group's experience with this technique. METHODS: Between October 2016 and May 2019, 9 patients (5 male, 4 female) underwent radical resection of lung cancer infiltrating the aortic arch (n = 5) or the left subclavian artery (n = 4) by direct cross-clamping technique at Sapienza University of Rome, Italy. Seven left upper lobectomies, 1 left pneumonectomy, and 1 left upper sleeve lobectomy were performed. Reconstruction of the aortic arch was performed by direct suturing or polyethylene terephthalate (Dacron) patch, whereas the subclavian artery was reconstructed with a Dacron conduit. Three patients received neoadjuvant chemotherapy. RESULTS: Patients' mean age was 64.7 ± 13.3 years (range, 36 to 78 years). Aortic arch resection was partial in all cases (adventitial in 1 and full thickness in 4); left subclavian artery resection was adventitial in 2 patients and circumferential in 2. All the resections were complete. Prosthetic reconstruction was performed in 4 cases. Mean operative time was 130 ± 25.6 minutes; mean vascular clamping time was 28.2 ± 3.2 minutes. No mortality occurred. The major complication rate was 11.1 %. At a mean follow-up of 17 ± 9 months (range, 5 to 29 months), the recurrence rate was 33.3%. Median survival was 20 months. CONCLUSIONS: Direct cross-clamping as an alternative to CPB for resection of lung cancer infiltrating the aortic arch or the subclavian artery is a feasible, safe, and reliable procedure in selected patients.

Successful Total Tracheal Replacement by Cryopreserved Aortic Allograft in a Patient Post-COVID-19 Infection.

This is the first report to our knowledge of a successful total tracheal replacement in a post-COVID-19 patient by cryopreserved aortic allograft. The graft was anastomosed to the cricoid and carina; a silicon stent was inserted to ensure patency. The patient was extubated on the operative table and was immediately able to breathe, speak, and swallow. No immunosuppression was administered. Three weeks after surgery, the patient was discharged from hospital in excellent health, and was able to resume his normal lifestyle, work, and activity as an amateur cyclist. Two months after surgery, the patient assumes aerosol with saline solution three times per day and no other therapy; routine bronchoscopy to clear secretions is no longer needed.

Surgical approaches for invasive tumors of the anterior mediastinum.

Malignant tumors of the anterior mediastinum frequently appear locally advanced at the time of diagnosis, with invasion of the surrounding organs including major blood vessels, lungs, and pericardium. Surgery can be indicated either with diagnostic intent or for radical resection, usually as a part of a multimodality treatment. Extended operations with complex vascular reconstructions may be required for the complete removal of the mediastinal mass. In this article, surgical approaches and techniques of diagnostic and therapeutic procedures are reported and discussed.

Postoperative strategies to treat permanent air leaks.

Air leakage after pulmonary resections is considered the most prevalent postoperative problem, and it is often the only morbidity identified. Ideally, treatment begins with prevention; the onset of this complication should be anticipated and recognized during surgery, and intraoperative strategies should be attempted to avoid it and reduce the impact on the clinical course. Once an air leak develops, in most of the cases it seals spontaneously within 2 or 3 days of operation. When it persists, it might elicit the onset of other complications and increase costs and length of hospitalization. The postoperative approaches to a prolonged air leak include management of the pleural drainage and residual space, pleurodesis, pneumoperitoneum, endobronchial one-way valve placement, and potential reoperation.

Mediastinal staging: when and how?

Mediastinal staging for lung cancer includes both the assessment of mediastinal lymph nodes status before treatment and the postoperative pathological staging obtained by lymph-node removal performed during surgery. In patients with early stage NSCLC, the aim is to exclude with the highest certainty and the lowest morbidity the presence of mediastinal node involvement. Before treatment, mediastinal staging is based on imaging techniques, endoscopic techniques, and surgical procedures. Final pathological staging is based on lymph-node removal performed with lung resection according with different modalities (sampling, systematic dissection, etc.) and various approaches (thoracotomy, VATS, robotic). Data and indications from literature evidences are reported and discussed.

Surgical treatment of pulmonary sequestration in adults and children: long-term results.

OBJECTIVES: Few experiences comparing paediatric and adult patients treated for pulmonary sequestration (PS) have been reported. Surgical treatment is considered the best choice, but the time of surgery is still controversial. We present our experience in this setting, comparing characteristics, histological results and outcome of paediatric and adult patients undergoing PS resection. METHODS: Between 1998 and 2017, a total of 74 patients underwent lobectomy or sublobar resection for PS. Sixty patients were children (group A: ≤16 years old) and 14 were adults (group B: >16 years old). Preoperative diagnosis was radiological. PS was intralobar (42 cases) and extralobar (32 cases). The operation was a muscle-sparing lateral thoracotomy or video-assisted thoracoscopic surgery. Preoperative characteristics, histological results and short-/long-term results of the 2 groups were retrospectively analysed and compared. RESULTS: Thirty-seven percent of the patients in group A presented with respiratory symptoms and 79% in group B (P = 0.44). Most symptomatic patients were treated with a lobectomy. In group A, 2 patients (3%) had a malignant transformation of the lesion. Patients with a prenatal diagnosis treated after the age of 1 year became more symptomatic than those operated on before the age of 1 year (57% vs 23%; P = 0.08). No differences were found in postoperative complications. Long-term stable remission of respiratory symptoms was obtained in 91% of patients in group A and 100% in group B. Adulthood (P = 0.03) and the association with congenital cystic adenomatoid malformation (P = 0.03) were negative prognostic factors for the development of respiratory symptoms. CONCLUSIONS: Surgical treatment of PS is safe and feasible. Despite the small number of patients included, study results indicated that an early operation during childhood may prevent the subsequent development of respiratory symptoms. Surgical treatment is also recommended to prevent the rare transformation into malignancy.

Chronic Pain After Lung Resection: Risk Factors, Neuropathic Pain, and Quality of Life.

CONTEXT: Chronic postsurgical pain (CPSP) can occur frequently after thoracic surgery. OBJECTIVES: This retrospective study aimed to determine CPSP prevalence, risk factors, neuropathic pain (NP) occurrence, and its impact on quality of life. METHODS: About 200 patients who underwent lung resection via minithoracotomy or thoracoscopy between January 2017 and December 2017 were assessed 4-12 months postoperatively via phone interview for chronic pain by a 0-10 Numeric Rating Scale, for NP using the Douleur Neuropathique 4 test, and for quality of life using a Short Form-36 (SF-36) Health Survey (Italian version). RESULTS: CPSP incidence was 35% (n = 70 of 200; 95% CI 41-28) of which 31.5% (n = 22 of 70; 95% CI 41-21) was with NP. Only 10% of patients with CPSP reported severe chronic pain. According to univariate analysis, CPSP was associated to moderate and severe acute postoperative pain (P < 0.001), open surgery (P = 0.001), and female gender (P = 0.044). According to multivariable analysis, independent risk factors for CPSP development included moderate-to-severe acute postoperative pain occurrence (odds ratio 32.61; 95% CI 13.37-79.54; P < 0.001) and open surgery (odds ratio 6.78; 95% CI, 2.18-21.03; P = 0.001). NP incidence was higher in female patients (16% in women and 6% in men, respectively; P = 0.040). A significant decrease in all SF-36 Health Survey domain scores was recorded for patients with CPSP and NP (P < 0.001). CONCLUSION: More than one of three patients who underwent lung resection could develop CPSP, frequently showing neuropathic component. Female gender reported a higher CPSP and NP incidence. Moderate-to-severe acute postoperative pain occurrence and open surgery seem to be independent risk factors for CPSP. Chronic pain and NP have a negative impact on quality of life, decreasing the SF-36 scores of all domains.

Analysis of pneumothorax recurrence risk factors in 843 patients who underwent videothoracoscopy for primary spontaneous pneumothorax: results of a multicentric study.

OBJECTIVES: Risk factors for pneumothorax recurrence after videothoracoscopy for primary spontaneous pneumothorax are still being debated. The goal of this study was to assess whether the pleurodesis technique and other variables are possibly associated with the postoperative ipsilateral recurrence of pneumothorax. METHODS: We retrospectively collected data of 1178 consecutive ≤40-year-old patients who underwent videothoracoscopy for primary spontaneous pneumothorax in 9 centres between 2007 and 2017. We excluded patients with hybrid pleurodesis and/or incomplete follow-up, leaving for analysis 843 cases [80% men; median age (interquartile range) 22 (18-28) years]. Univariable and multivariable analyses were performed by logistic regression and tested by Cox regression model to assess factors related to ipsilateral pneumothorax recurrence including age, gender, body mass index, smoking habit, cannabis smoking, respiratory comorbidity, dystrophic severity score, surgical indication, videothoracoscopy port number and side, lung resection, pleurodesis technique and postoperative prolonged air leak (>5 days). RESULTS: Blebs/bullae resection was performed in 664 (79%) patients. Pleurodesis was achieved by partial pleurectomy in 228 (27%) cases; by pleural electrocauterization in 176 (21%); by pleural abrasion in 121 (14%); and by talc poudrage in 318 (38%). During a median follow-up period of 70.0 months (95% confidence interval 66.6-73.4), pneumothorax recurred in 79 patients (9.4%); among these, 29 underwent redo surgery; 34, chest drain/talc slurry; and 16, clinicoradiological observation. The only independent risk factor for recurrence was postoperative prolonged air leak (P < 0.001) that was significantly related to blebs/bullae resection (P = 0.03). CONCLUSIONS: In this multicentric series, postoperative ipsilateral pneumothorax recurrence was remarkable and independently related to prolonged postoperative air leak; besides the retrospective study setting, the pleurodesis method did not have an impact on recurrence. To prevent prolonged air leak, blebs/bullae treatment should be accurate and performed only if indicated.

Multimodality treatment of thymic tumors.

Combined modality therapy is gaining acceptance for treating stage 3 and 4A thymic tumors. Also, specific subsets of stage 2 tumors deserve particular attention. Single-center experiences demonstrate that there are some advantages in selected groups of patients. The overall relatively low complete response rate, however, imposes the search for better systemic therapy to optimize results. In fact, although thymic tumors are responsive to different cytotoxic regimens, none has been demonstrated to be the ideal one. New therapies and strategies should be designed and tested in large-scale multicenter prospective trials. Among the others, epidermal growth factor receptor inhibitors have shown some clinical response, because EGFR is overexpressed in thymoma. c-KIT is overexpressed in thymic carcinoma. Although in a recent study a clinical response to imatinib has been reported, results of a prospective study in patients who have thymic carcinoma are pending. Clinical responses have been reported also to other tyrosine kinase inhibitors, such as dasatinib. Other reports have stressed the presence of an up-regulation of COX-2 with a potential separate therapeutic pathway. Other markers, such as the expression of thymidine synthase and dihydropyrimidine dehydrogenase, which predict sensitivity to 5-fluoruracil-based chemotherapy, were not correlated with the clinicopathological characteristics in a series of thymomas. These new therapies should be incorporated in a standardized approach that goes from a careful assessment of histology, staging, and lymph node status, and a constructive and nonempiric cooperation between the oncologist, radiotherapist, pathologist, and thoracic surgeon.

Endobronchial treatment of emphysema with one-way valves.

Numerous endoscopic procedures have recently been studied and progressively introduced in clinical practice to improve mechanics and function in patients who have emphysema. Bronchoscopic lung volume reduction with one-way endobronchial valves facilitates deflation of the most overinflated emphysematous parts of the lung. These valves have been designed to control and redirect airflow by preventing air from entering the target parenchymal area but allowing air and mucus to exit. The preliminary results have shown that this procedure is safe and effective at medium term in a selected group of patients.