Single-cell sequencing on CD8+ TILs revealed the nature of exhausted T cells recognizing neoantigen and cancer/testis antigen in non-small cell lung cancer.

BACKGROUND: CD8+tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8+ TILs, especially T-cell populations specific for tumor antigens, remain poorly understood. METHODS: High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8+ TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8+ TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells. RESULTS: A total of 6998 CD8+ T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX, PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1. CONCLUSIONS: Our approach focusing on T cells with an exhausted phenotype among CD8+ TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC.

New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis.

BACKGROUND: A better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME. METHODS: Whole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score (tumor proliferation), I-score (antitumor immunity) and S-score (immunosuppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy. RESULTS: The representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in Thi (G5-8) than Tlo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in Thi and was dampened in Thi/Ilo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. Thi/Ilo/Shi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group Tlo/Ihi/Slo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma. CONCLUSION: The TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.

[Thoracoscopic Plication for Congenital Diaphragmatic Eventration in an Adult].

Thoracoscopic plication for congenital diaphragmatic eventration in an adult. Diaphragmatic eventration is known to be abnormal elevation of diaphragm and congenital causes are due to abnormal diaphragm muscle development. Here we report surgical treatment of congenital diaphragmatic eventration. A 45-year-old woman who complained of cough was admitted to our hospital. She had history of cough and was diagnosed as diaphragmatic eventration in childhood. Chest X-ray showed elevated left hemidiaphragm with a bowel gas underneath. Under the diagnosis of congenital eventration of left hemidiaphragm, plication of the left diaphragm by video-assisted thoracoscopic surgery (VATS) was performed. One month after surgery, severe cough disappeared completely.

[Concomitant Cardiac and Pulmonary Operation on an Elderly Patient:Report of a Case].

An 83-year-old woman was admitted because of dyspnea. Transthoracic echocardiography revealed severe aortic valve stenosis with a systolic gradient of 105 mmHg. Coronary angiography showed 75% stenosis at segment 1. Computed tomography( CT) of the chest revealed a mass, of 15 mm in diameter, in the right segment 1 of the lung. She was diagnosed with severe aortic valve stenosis, right coronary artery stenosis, and a lung tumor suspected to be lung cancer. We performed right lobe partial resection, aortic valve replacement and coronary artery bypass grafting through a median sternotomy. The tumor was diagnosed as adenocarcinoma by pathological examination. The postoperative course was uneventful, and she was discharged three weeks after the operation.

Survival benefits of salvage surgery for primary lung cancer based on routine clinical practice.

BACKGROUND: Premeditated induction chemotherapy followed by surgical resection is accepted as safe and effective. Studies on salvage surgery in patients with incompletely cured lung cancer are lacking. This study aimed to demonstrate the safety and efficacy of salvage surgery. METHODS: We conducted a retrospective multi-institutional cohort study on patients who underwent salvage surgery for advanced (stage III and IV) non-small cell lung cancer (NSCLC) between January 2005 and December 2016 at the 14 hospitals of the Chubu Lung Cancer Surgery Study Group. A total of 37 patients were assigned to the salvage surgery group; a lobectomy with mediastinal lymph node dissection was performed. The survival benefit was assessed using the Kaplan-Meier method and the Cox proportional hazard model. RESULTS: Although postoperative complications were observed in 11 patients (29.7%), surgery-related death occurred in only one patient (mortality rate: 2.7%) resulting from respiratory failure caused by interstitial pneumonia exacerbation. Postoperative recurrence was observed in 22 patients (61.1%), the incidence of brain metastasis being high (nine patients: 40.9%). The five-year survival rate from the first day of treatment was 60%. The survival of the postoperative pathological stage (s'-stage) I group was significantly better (five-year survival rate: 80.9%) than that of the other groups (p < 0.05). S'-stage was the most significant factor (p < 0.01) associated with long-term survival. CONCLUSIONS: Salvage surgery is a feasible therapeutic modality for advanced lung cancer. Downstaging to s'-stage I with previous treatment was most important for survival. Complete resection (R0) should be the goal because surgical procedures were tolerated despite intense treatment.

Extensive calcification in adenocarcinoma of the lung: A case report.

Calcification in lung nodules usually indicates a benign lesion. Here, we report the case of a 59-year-old male patient with a well defined 30 mm calcified nodule in his right upper lung lobe and calcified mediastinal lymph nodes. The mass was diagnosed as adenocarcinoma by transbronchial biopsy. He received systemic chemotherapy, followed by lobectomy and mediastinal lymph node dissection. During surgery, the lymph nodes were tightly adherent to the superior vena cava with invasion of the vascular wall. Pathological diagnosis confirmed acinar adenocarcinoma and psammoma bodies (PBs). Immunohistochemical analysis revealed tumor cells positive for parathyroid hormone-related proteins 1 and 2. Calcification of primary lung adenocarcinoma is rare. We report a calcified lesion where the secretion of parathyroid hormone by the tumor may have caused the accumulation of PBs. Calcification of metastatic lymph nodes may increase the risk of adhesion, requiring care during surgery. KEY POINTS: Significant findings of the study Lung adenocarcinoma with extensive calcification in primary and metastatic lymph node lesions is rare and the mechanism involved is poorly understood. Of significance, calcification in our case was related to parathyroid hormone-related proteins 1 and 2 secreted by the tumor. What this study adds This study suggests the potential role of parathyroid hormone-related proteins in lung tumor calcification. The implications for clinicians are that calcified metastatic lymph nodes and tumors might be tightly fused to tissues. Therefore, surgery should be conducted with care.

Three-year Survival Rate after Radiofrequency Ablation for Surgically Resectable Colorectal Lung Metastases: A Prospective Multicenter Study.

Background Although radiofrequency ablation (RFA) is widely performed for the treatment of colorectal cancer (CRC) lung metastases, its efficacy for candidates with surgically resectable disease is unclear. Purpose To evaluate the prognosis after RFA in participants with resectable CRC lung metastases. Materials and Methods For this prospective multicenter study (ClinicalTrials.gov identifier: NCT00776399), participants with five or fewer surgically resectable lung metastases measuring 3 cm or less were included. Participants with CRC and a total of 100 lung metastases measuring 0.4-2.8 cm (mean, 1.0 cm ± 0.5) were chosen and treated with 88 sessions of RFA from January 2008 to April 2014. The primary end point was the 3-year overall survival (OS) rate, with an expected rate of 55%. The local tumor progression rate and safety were evaluated as secondary end points. The OS rates were generated by using the Kaplan-Meier method. Log-rank tests and Cox proportional regression models were used to identify the prognostic factors by means of univariable and multivariable analyses. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. Results Seventy participants with CRC (mean age, 66 years ± 10; 49 men) were evaluated. The 3-year OS rate was 84% (59 of 70 participants; 95% confidence interval [CI]: 76%, 93%). In multivariable analysis, factors associated with worse OS included rectal rather than colon location (hazard ratio [HR] = 7.7; 95% CI: 2.6, 22.6; P < .001), positive carcinoembryonic antigen (HR = 5.8; 95% CI: 2.0, 16.9; P = .001), and absence of previous chemotherapy (HR = 9.8; 95% CI: 2.5, 38.0; P < .001). Local tumor progression was found in six of the 70 participants (9%). A grade 5 adverse event was seen in one of the 88 RFA sessions (1%), and grade 2 adverse events were seen in 18 (20%). Conclusion Lung radiofrequency ablation provided a favorable 3-year overall survival rate of 84% for resectable colorectal lung metastases measuring 3 cm or smaller. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Gemmete in this issue.

[Rapidly Growthing Mediastinal Cystic Teratoma with Suggestive Perforation by Infection in Pregnancy].

The patient was a 34-year-old female and was 32 weeks pregnant. She was admitted to our department because of mediastinal cyst with infection. She complained of chest pain. Chest computed tomography(CT) revealed the rapid growth of anterior mediastinal tumor. The pain increased after 2 days and magnetic resonance imaging (MRI) suggested the rupture of teratoma. After delivery by Caesarean section, we performed abscess drainage, to stabilize the patient's condition and thereafter the resection of mediastinal teratoma with partial resection of right lung was performed. Histological findings showed a mature teratoma.

[Atypical Pulmonary Carcinoid Tumor with Elevated Serum ProGRP;Report of a Case].

We report a case of an atypical pulmonary carcinoid with high serum ProGRP. A 78-year-old man was found to have an abnormal shadow by a chest X-ray. Chest computed tomography (CT) revealed a solitary pulmonary nodule in the right middle lobe, which was homogeneous, well demarcated, and round. The level of serum ProGRP was elevated to 104.6 pg/ml (normal<81 pg/ml). The nodule was suspected to be a pulmonary carcinoid tumor, and a right middle lobectomy with mediastinal lymph node dissection was performed. Histopathological diagnosis was an atypical pulmonary carcinoid. Pro-GRP decreased to be normal level 5 month after operation.

[Mediastinal Bronchial Artery Aneurysm Associated with Bronchiectasis;Report of a Case].

The patient was a 66-year-old man who had treated with bronchiectasis. He was admitted to our hospital because of hemoptysis. A chest plain computed tomography (CT) showed bronchiectasis in the left lower lobe and nodular lesion in the mediastinum. Chest contrast CT revealed a left bronchial artery aneurysm, and hyperplastic left bronchial arteries dilating and winding toward the left lower lobe. We performed selective angiography of the bronchial artery, revealing an aneurysm, and we performed 3 times of bronchial arterial embolization( BAE). He was performed surgery at 7th day following BAE. After postoperative empyema treatment, he was discharged on the 124th postoperative day.

[Successful Primary Endovascular Repair for Aortoesophageal Fistula due to Ruptured Tuberculous Pseudoaneurysm of the Thoracoabdominal Aorta;Report of a Case].

We report a successful case of 50-year-old woman with aortoesophageal fistula due to tuberculous pseudoaneurysm of the thoracoabdominal aorta. We underwent endovascular repair with stent graft. Her clinical course improved without additional surgical repair or postoperative complications. The patient remains well at 3-year follow-up.

[Hemothorax complicated with celiac artery compression syndrome (CACS); report of a case].

We report a case of hemothorax complicated with celiac artery compression syndrome (CACS). A 43-year-old man presented with a sudden onset left back pain. Computed tomography (CT) showed its hemothorax, esophageal artery aneurysm and severe stenosis of the celiac truncus with its anterior compression by median accurate ligament, and a diagnosis of CACS associated with rupture of the aneurysm was made. Emergent transcatheter arterial embolization of the aneurysm resulted in a technical failure, although the patient's condition was stable and performed esophageal artery ligation through video-assisted thoracoscopic surgery on day 5 after onset. After surgery, the patient recovered without significant incidents. A cause of this aneurysmal development was supposed to be a significantly increased esophageal arterial blood flow with its luminal dilation to compensate a decreased celiac blood flow. Segmental arterial mediolysis could not be excluded as another cause.

Adverse events of lung tissue stapling in thoracic surgery.

PURPOSE: The use of staplers for thoracic surgery has been regarded as a safe procedure though sometimes adverse events (AEs) of stapling are experienced. The aim of this study is to analyze AEs of lung tissue stapling. METHODS: A retrospective multi-institutional review was conducted by 27 institutions of the Central Japan Lung Cancer Surgery Study Group. During the research period, lung tissue stapling was performed 10908 times. RESULTS: Total number of AEs related to stapling was 81 (0.74%). Seventy events occurred intraoperatively and 11 events occurred postoperatively. Intraoperative stapling AEs were air leakage (n = 26), laceration of the adjacent lung tissue (n = 23), stapling failure (n = 14), oozing (n = 4), and others (n = 3). The postoperative AEs were prolonged air leakage (n = 9), bleeding from the chest wall (n = 1), and postoperative bleeding (n = 1). Only one case died of acute exacerbation of interstitial pneumonia which was induced after completion lobectomy to cure postoperative bleeding. No relationship was seen between the incidence of AE and cartridge colors or compression types of staplers except the length of cartridges. CONCLUSION: Lung tissue stapling in thoracic surgery was safe. The most frequent cause of AEs was stapler-tissue thickness mismatch. The appropriate selection of the cartridge color may decrease the AE incidence of the lung tissue stapling.

Clinical features of primary lung cancer adjoining pulmonary bulla.

A few investigators have suggested a possible association between lung cancer and a pulmonary bulla. But its correlation is not yet fully understood. Five hundred and forty-five cases with primary lung cancer were studied retrospectively by re-evaluation of their chest computed tomography (CT)-scans. Cancer adjoined a bulla in 19 cases. In these instances, each case's clinical course, pathological findings and surgical results were investigated. All cases were men and were heavy smokers. Three of them were under 50 years of age. Bulla/cancer incidence was 3.5%. Initial symptoms were common respiratory symptoms in five cases (26.3%) and hemosputa and hoarseness in one case (5.3%), respectively. In comparison with the control group, a ratio of squamous cell carcinoma (SCC) and large cell carcinoma was significantly high (P<0.05) and differentiation of the carcinoma was poor (P<0.001). Although the pathological staging and lung function data revealed no statistical difference, the survival curve of bulla/cancer group was significantly worse (P<0.01). Primary lung cancer adjoining pulmonary bulla tends to be poor in prognosis, even if it was small in size. A low-density mass shadow adjoining the bulla should be frequently examined by CT-scans and should proceed to an exploratory thoracotomy if it have increased in size.

[Lung cancer detected by fluorodeoxyglucose-positron emission tomography/computed tomography in the course of Mycobacterium avium infection; report of a case].

The patient was 64-year-old male. Chest computed tomography (CT) scan revealed an 18 mm of nodular lesion in the right upper lobe, in which inflammatory lesions due to the Mycobacterium avium infection was preexisted. On fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT scan, value of standard uptake value (SUV) max was 4.0. This finding may be caused by the inflammatory change but the malignancy was more likely with a concomitant finding of elevated serum carcinoembryonic antigen (CEA). Surgical resection by right upper lobectomy was performed. Postoperative pathology confirmed the existence of adenocarcinoma in the lesions of epithelioid granuloma with giant cells. FDG-PET/CT contributed effectively to detect a malignancy in the inflammatory lesions of Mycobacterium avium infection.

Surgical treatment for chronic lung and thoracic cavity infection.

To avoid the complication of aspiration pneumonia, we attempted a new anterior approach of extrapleural pneumonectomy combined with thoracoplasty in four patients with chronic empyema, a bronchopleural fi stula, and severely destroyed lung. The thoracic cage was exposed by an L-shaped parasternal incision making a muscle-skin flap of the anterior chest. The anterior portions of ribs were removed at fi rst, and exfoliation was started in the mediastinal area. After detaching the lung from the mediastinum, an extrapleural pneumonectomy was completed. The backside ribs were then resected by way of the thoracic cavity. The muscle-skin flap was sutured to close the thoracic cavity completely. The procedure was tolerable for three cases. One patient died from accidental rupture of the descending aorta owing to atherosclerotic degeneration. Of the three successful outcomes, recurrence was observed in one case, although it was recurrence of malignant lymphoma associated with chronic empyema.

[Dor operation for left ventricular aneurysm with sustained ventricular tachycardia].

A 60-year-old woman was admitted to our hospital because of syncope attack due to sustained ventricular tachycardia (VT). She was treated medically after cardiopulmonary resuscitation. Coronary arteriography revealed a 99% stenosis of right coronary artery (posterior descending artery: # 4 PD), a 90% stenosis of left descending artery (# 6) and left akinetic aneurysm was demonstrated. The patient successfully underwent Dor operation with endocardial cryoablation. The postoperative course was uneventful and the recurrence of VT was never recognized clinically.

[Clinicopathologic study of thymic epithelial tumors].

OBJECTIVE: We analyzed clinicopathologic characters and long-term results of 11 thymic epithelial tumors. METHODS: Five cases of thymic carcinoma and 6 cases of thymoma treated in our hospital from September 1991 to June 2002 were retrospectively analyzed. RESULTS: The histological subtypes of thymic carcinoma were basaloid carcinoma in 2 cases, epidermoid non-keratinizing carcinoma in 1 case, undifferentiated carcinoma in 1 case and sarcomatoid carcinoma in 1 case. Four cases underwent chemotherapy and radiotherapy. Three cases underwent midsternal thoracotomy, 1 had total resection and 2 had exploratory thoracotomy due to tumor invasion of the right upper lobe and cardiac sac. Two cases of basaloid carcinoma had been alive more than 10 years since the operation. The histological subtypes of thymoma were 1, 2, 1, 1 and 1 cases with type A, AB, B 1, B 2 and B 3. All cases underwent midsternal thoracotomy, 4 cases had thymothymectomy and 2 cases had extended thymothymectomy. Five cases have been alive since the operation. Strong immunoreactivity for bcl-2 and p 53 expression of epidermoid non-keratinizing carcinoma and undifferentiated carcinoma were seen. ki-67 labeling index of epidermoid non-keratinizing carcinoma and undifferentiated carcinoma and type B 3 thymoma were higher than those of the other carcinomas and thymomas.

Pulmonary sclerosing hemangioma associated with familial adenomatous polyposis.

A 45-year-old woman presented with asymptomatic solid tumor in the lower right lobe of the lung. Histologically, the tumor comprised a monolayer of surface cells and round stromal cells displaying sclerotic areas. Immunohistochemical studies suggested a diagnosis of sclerosing hemangioma. Interestingly, morular lesions were also observed. Analyses of the gastrointestinal (GI) tract showed mild familial adenomatous polyposis (FAP) and numerous fundal gland polyps, indicating attenuated FAP (AFAP). All components of the sclerosing hemangioma displayed aberrant nuclear and cytoplasmic expression of beta-catenin. However, such findings were much weaker in adenomas of the GI tract and were barely observed in fundal gland polyps. These results strongly suggest an association between sclerosing hemangioma and the AFAP. To the best of our knowledge, this is only the second report of lung tumor associated with FAP and is the first describing an association with sclerosing hemangioma. A new category of FAP-associated lung tumors may be indicated.