Does Surgical Removal of the Thymus Have Deleterious Consequences?

The role of immunosenescence, particularly the natural process of thymic involution during aging, is increasingly acknowledged as a factor contributing to the development of autoimmune diseases and cancer. Recently, a concern has been raised about deleterious consequences of the surgical removal of thymic tissue, including for patients who undergo thymectomy for myasthenia gravis (MG) or resection of a thymoma. This review adopts a multidisciplinary approach to scrutinize the evidence concerning the long-term risks of cancer and autoimmunity postthymectomy. We conclude that for patients with acetylcholine receptor antibody-positive MG and those diagnosed with thymoma, the removal of the thymus offers prominent benefits that well outweigh the potential risks. However, incidental removal of thymic tissue during other thoracic surgeries should be minimized whenever feasible.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

BACKGROUND: The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. PATIENTS AND METHODS: Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. RESULTS: Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. CONCLUSION: We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.

Microscopic Small Airway Abnormalities Identified in Early Idiopathic Pulmonary Fibrosis In Vivo Using Endobronchial Optical Coherence Tomography.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) affects subpleural lung, but is considered to spare small airways. Micro-CT studies demonstrated small airway reduction in end-stage IPF explanted lungs, raising questions about small airway involvement in early-stage disease. Endobronchial optical coherence tomography (EB-OCT) is a volumetric imaging modality that detects microscopic features from subpleural to proximal airways. We use EB-OCT to evaluate small airways in early IPF and control subjects in vivo. METHODS: EB-OCT was performed in 12 IPF and 5 control subjects (matched by age, sex, smoking-history, height, BMI). IPF subjects had early disease with mild restriction (FVC: 83.5% predicted), diagnosed per current guidelines and confirmed by surgical biopsy. EB-OCT volumetric imaging was acquired bronchoscopically in multiple, distinct, bilateral lung locations (total: 97 sites). IPF imaging sites were classified by severity into affected (all criteria for UIP present) and less affected (some but not all criteria for UIP present) sites. Bronchiole count and small airway stereology metrics were measured for each EB-OCT imaging site. RESULTS: Compared to control subjects (mean: 11.2 bronchioles/cm3; SD: 6.2), there was significant bronchiole reduction in IPF subjects (42% loss; mean: 6.5/cm3; SD: 3.4; p=0.0039), including in IPF affected (48% loss; mean: 5.8/cm3; SD: 2.8; p<0.00001) and IPF less affected (33% loss; mean: 7.5/cm3; SD: 4.1; p=0.024) sites. Stereology metrics showed IPF affected small airways were significantly larger and more distorted/irregular than in IPF less affected sites and control subjects. IPF less affected and control airways were statistically indistinguishable for all stereology parameters (p=0.36-1.0). CONCLUSION: EB-OCT demonstrated marked bronchiolar loss in early IPF (between 30 and 50%), even in areas minimally affected by disease, compared to matched controls. These findings support small airway disease as a feature of early IPF, providing novel insight into pathogenesis and potential therapeutic targets.

A Pilot Study Using Machine Learning Algorithms and Wearable Technology for the Early Detection of Postoperative Complications After Cardiothoracic Surgery.

OBJECTIVE: To evaluate whether a machine learning algorithm (i.e. the "NightSignal" algorithm) can be used for the detection of postoperative complications prior to symptom onset after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Methods that enable the early detection of postoperative complications after cardiothoracic surgery are needed. METHODS: This was a prospective observational cohort study conducted from July 2021 to February 2023 at a single academic tertiary care hospital. Patients aged 18 years or older scheduled to undergo cardiothoracic surgery were recruited. Study participants wore a Fitbit watch continuously for at least 1 week preoperatively and up to 90-days postoperatively. The ability of the NightSignal algorithm-which was previously developed for the early detection of Covid-19-to detect postoperative complications was evaluated. The primary outcomes were algorithm sensitivity and specificity for postoperative event detection. RESULTS: A total of 56 patients undergoing cardiothoracic surgery met inclusion criteria, of which 24 (42.9%) underwent thoracic operations and 32 (57.1%) underwent cardiac operations. The median age was 62 (IQR: 51-68) years and 30 (53.6%) patients were female. The NightSignal algorithm detected 17 of the 21 postoperative events a median of 2 (IQR: 1-3) days prior to symptom onset, representing a sensitivity of 81%. The specificity, negative predictive value, and positive predictive value of the algorithm for the detection of postoperative events were 75%, 97%, and 28%, respectively. CONCLUSIONS: Machine learning analysis of biometric data collected from wearable devices has the potential to detect postoperative complications-prior to symptom onset-after cardiothoracic surgery.

Intralesional microbleeding in resected thymic cysts indeterminate on imaging.

Background: The propensity of thymic cysts to mimic solid thymic epithelial tumors (TETs) on computed tomography (CT), on account of attenuation values greater than water and thickened or calcified walls, can lead to non-therapeutic thymectomy. These lesions can fluctuate in volume, CT attenuation, and magnetic resonance imaging (MRI) signal over time. We hypothesized that spontaneous hemorrhage and resorption may contribute to their variable appearance over time. Methods: Completely excised thymic cysts were identified retrospectively over a 20-year period by their pathologic diagnosis. Cysts were excluded if they did not have available presurgical imaging, were not prevascular, were located within or contained an enhancing mass by imaging, or were of non-thymic origin upon microscopic review. Histopathological analysis of all available resected thymic cyst material and radiologic analysis of the cysts on pre-operative imaging were performed. Results: Upon application of exclusion criteria, we identified 18 thymic cysts from the initial 85 mediastinal cystic specimens. Most cysts were unilocular (11/15, 73%), showed turbid-to-semisolid, hemorrhagic fluid (10/12, 83%) and showed histopathological findings suggestive of intralesional microbleeding (14/18, 78%), remodeling (8/18, 44%), pathological wound healing/scarring of the capsule (16/18, 89%), and fat necrosis in the surrounding thymic tissue (12/18, 67%). On CT, 6/17 (35%) cysts demonstrated wall calcification. Sixty-five percent (11/17) had attenuation values ≥20 Hounsfield units (HU). Two of the 4 cysts imaged by MRI were T1-isointense, one was mixed hyper- and isointense, and one T1-hypointense to muscle, with iso- and hyperintensity indicating hemorrhagic or proteinaceous content. Twenty-five percent (1/4) of cyst walls imaged by MRI were T1/T2-hypointense, indicating presence of calcification, hemosiderin, and/or fibrosis. Conclusions: Resected thymic cysts in this cohort often showed features suggestive of intralesional microbleeding, inflammation, and fibrosis, which may explain their appearance and behavior over time on CT and MRI.

B cell-dependent subtypes and treatment-based immune correlates to survival in stage 3 and 4 lung adenocarcinomas.

Lung cancer is the leading cause of cancer-related deaths worldwide. Surgery and chemoradiation are the standard of care in early stages of non-small cell lung cancer (NSCLC), while immunotherapy is the standard of care in late-stage NSCLC. The immune composition of the tumor microenvironment (TME) is recognized as an indicator for responsiveness to immunotherapy, although much remains unknown about its role in responsiveness to surgery or chemoradiation. In this pilot study, we characterized the NSCLC TME using mass cytometry (CyTOF) and bulk RNA sequencing (RNA-Seq) with deconvolution of RNA-Seq being performed by Kassandra, a recently published deconvolution tool. Stratification of patients based on the intratumoral abundance of B cells identified that the B-cell rich patient group had increased expression of CXCL13 and greater abundance of PD1+ CD8 T cells. The presence of B cells and PD1+ CD8 T cells correlated positively with the presence of intratumoral tertiary lymphoid structures (TLS). We then assessed the predictive and prognostic utility of these cell types and TLS within publicly available stage 3 and 4 lung adenocarcinoma (LUAD) RNA-Seq datasets. As previously described by others, pre-treatment expression of intratumoral 12-chemokine TLS gene signature is associated with progression free survival (PFS) in patients who receive treatment with immune checkpoint inhibitors (ICI). Notably and unexpectedly pre-treatment percentages of intratumoral B cells are associated with PFS in patients who receive surgery, chemotherapy, or radiation. Further studies to confirm these findings would allow for more effective patient selection for both ICI and non-ICI treatments.

Evaluation of Release Maneuvers After Airway Reconstruction.

BACKGROUND: Airway release (AR) maneuvers performed during airway resection to reduce anastomotic tension have not been thoroughly studied. METHODS: This study retrospectively analyzed consecutive resections for postintubation stenosis (PITS) and primary tracheal neoplasms (PTNs) at Massachusetts General Hospital (Boston, MA). Anastomotic complications were defined as stenosis, separation, necrosis, granulation tissue, and air leak. Logistic regression modeling was used to identify factors associated with AR and adverse outcome. RESULTS: From 1993 to 2019, 545 patients with PITS (375; 68.8%) and PTNs (170; 31.2%) underwent laryngotracheal, tracheal, or carinal (resections and reconstructions; 5.7% (31 of 545) were reoperations. AR was performed in 11% (60 of 545): in 3.8% of laryngotracheal resections (6 of 157; all laryngeal), in 9.8% of tracheal resections (34 of 347; laryngeal, 12, and hilar, 22), and in 49% of carinal resections (20 of 41; laryngeal, 1, and hilar, 19). Mean resected length was 3.5 cm (range, 1to- 6.3 cm) with AR and 3.0 cm (range, 0.8 to 6.5 cm) without AR (P < .01). Operative mortality was 0.7% (4 of 545); all 4 anastomoses were intact until death. Anastomotic complications were present in 5% of patients who underwent AR (3 of 60) and in 9.3% (45 of 485) of patients who did not. AR was associated with resection length of 4 cm or longer (odds ratio [OR], 6.15; 95% confidence interval [CI], 1.37 to 27.65), PTNs (OR, 7.81; 95% CI, 3.31 to 18.40), younger age (OR, 0.96; 95% CI, 0.94 to 0.98), and lung resection (OR, 6.09; 95% CI, 1.33 to 27.90). Anastomotic complications in patients with tracheal anastomoses were associated with preexisting tracheostomy (OR, 2.68; 95% CI, 1.50 to 4.80), but not release. CONCLUSIONS: Tracheal reconstruction succeeds, even when anastomotic tension requires AR. Because intraoperative assessment may underestimate tension, lowering the threshold for AR seems prudent, particularly in patients with diabetes.

Management and outcomes of esophageal perforation.

BACKGROUND: Esophageal perforation is a morbid condition and remains a therapeutic challenge. We report the outcomes of a large institutional experience with esophageal perforation and identify risk factors for morbidity and mortality. METHODS: A retrospective analysis was conducted on 142 patients who presented with a thoracic or gastroesophageal junction esophageal perforation from 1995 to 2020. Baseline characteristics, operative or interventional strategies, and outcomes were analyzed by etiology of the perforation and management approach. Multivariable cox and logistic regression models were constructed to identify predictors of mortality and morbidity. RESULTS: Overall, 109 (77%) patients underwent operative intervention, including 80 primary reinforced repairs and 21 esophagectomies and 33 (23%) underwent esophageal stenting. Stenting was more common in iatrogenic (27%) and malignant (64%) perforations. Patients who presented with a postemetic or iatrogenic perforation had similar 90-day mortality (16% and 16%) and composite morbidity (51% and 45%), whereas patients who presented with a malignant perforation had a 45% 90-day mortality and 45% composite morbidity. Risk factors for mortality included age >65 years (hazard ratio [HR] 1.89 [1.02-3.26], P = 0.044) and a malignant perforation (HR 4.80 [1.31-17.48], P = 0.017). Risk factors for composite morbidity included pleural contamination (odds ratio [OR] 2.06 [1.39-4.43], P = 0.046) and sepsis (OR 3.26 [1.44-7.36], P = 0.005). Of the 33 patients who underwent stent placement, 67% were successfully managed with stenting alone and 30% required stent repositioning. CONCLUSIONS: Risk factors for morbidity and mortality after esophageal perforation include advanced age, pleural contamination, septic physiology, and malignant perforation. Primary reinforced repair remains a reasonable strategy for patients with an esophageal perforation from a benign etiology.

Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia.

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and DlCO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Extended Pulmonary Resection by Sleeve Lobectomy and Carinal Pneumonectomy: Selection and Technique.

Minimally invasive surgical approaches for extended pulmonary resections are becoming increasingly common as more surgeons gain experience in thoracoscopic and robotic technique. Outcome studies demonstrate improved decreased morbidity as compared with an open surgery.

Programmed Death Ligand 1 and Immune Cell Infiltrates in Solitary Fibrous Tumors of the Pleura.

BACKGROUND: Approximately 10% to 15% of patients with solitary fibrous tumors of the pleura (SFTP) have recurrence after resection. Many are not candidates for reresection and lack effective treatments. We explored the expression of programmed death ligand 1 (PD-L1) as a biomarker for candidacy for treatment with immune checkpoint inhibitors. METHODS: We reviewed the medical records of 52 patients with primary SFTP and 5 with recurrent SFTP. We performed immunohistochemistry on tumor tissue to determine the expression of PD-L1 and infiltration by cluster of differentiation 8 (CD8)-positive immune cells. RESULTS: Any PD-L1 expression was observed in 11 primary SFTP (21.2%). Overall, PD-L1 expression level was less than 1% in 10 patients (19.2%) and greater than 1% in 1 (1.9%). Tumor infiltration by CD8-positive immune cells was absent or rare in 13 patients (25%), less than 5% in 31 (59.6%), and 5% to 25% in 8 (15.4%). There were no associations between PD-L1 expression or immune cell infiltrates and known risk factors for recurrence or a prognostic risk score classification. Time to recurrence was strongly associated with the risk score classification (P < .001), but it was not associated with PD-L1 expression (P = .296) or immune cell infiltrates (P = .619). In recurrent SFTP, PD-L1 was expressed in 4 of 10 tumors (40%; all <1% expression). There was no correlation in PD-L1 expression between primary and recurrent SFTP samples. CONCLUSIONS: A small subset of SFTP express PD-L1 at low levels (<1%) but exhibit colocalization of CD8-positive immune cells suggesting an inducible expression mechanism. The role of PD-L1 merits exploration in the clinical setting in patients with advanced SFTP when alternative treatments or clinical trials are considered.

Pregnancy-associated idiopathic laryngotracheal stenosis: presentation, management and results of surgical treatment.

OBJECTIVES: Idiopathic laryngotracheal stenosis (ILTS) is an uncommon problem arising mostly in women. In some, it arises during or is exacerbated by pregnancy. Experience with management of patients with this rare association is limited. This study seeks to evaluate the management of patients with pregnancy-associated ILTS and compare outcomes to cases not associated with pregnancy. METHODS: Retrospective review of 15 patients undergoing surgical treatment of pregnancy-associated ILTS from 1971 to 2013. Variables of interest and airway outcomes were compared to patients with non-pregnancy-associated ILTS. RESULTS: Pregnancy-associated ILTS was observed in 15/263 (5.7%) patients. Symptoms developed during their first pregnancy. When compared to non-pregnancy patients, these patients were younger (37 vs 47 years; P = 0.0003), had more prior tracheostomies (26.7% vs 10.9%; P = 0.085) and had more preoperative airway dilatations (86.7% vs 57.7%; P = 0.030). All patients completed pregnancy without complications and ultimately underwent laryngotracheal resection. The expression of hormonal receptors in the surgical specimens was similar in both groups (oestrogen receptors: 100% vs 75% and progesterone receptors: 71.4% vs 72.1%, in pregnancy and non-pregnancy patients, respectively). Airway outcomes were good/excellent in 13 (86.7%) patients with pregnancy-associated ILTS and 225 (90.7%) patients without pregnancy association (P = 0.642), and did not change when adjusting for other risk factors. CONCLUSIONS: Pregnancy-associated ILTS is rare. The pathophysiology is unclear, but appearance of symptoms during pregnancy may suggest hormonal factors. To minimize foetal risk, dilatation during pregnancy followed by laryngotracheal resection after delivery is the preferred treatment. Pregnancy association does not seem to affect outcomes with expected satisfactory results in most patients.