CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory.

Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundant in tumor tissues. Here, hypothesizing that tumor Tregs would clonally expand after they are activated by tumor-associated antigens to suppress antitumor immune responses, we performed single-cell analysis on tumor Tregs to characterize them by T cell receptor clonotype and gene-expression profiles. We found that multiclonal Tregs present in tumor tissues predominantly expressed the chemokine receptor CCR8. In mice and humans, CCR8+ Tregs constituted 30 to 80% of tumor Tregs in various cancers and less than 10% of Tregs in other tissues, whereas most tumor-infiltrating conventional T cells (Tconvs) were CCR8- CCR8+ tumor Tregs were highly differentiated and functionally stable. Administration of cell-depleting anti-CCR8 monoclonal antibodies (mAbs) indeed selectively eliminated multiclonal tumor Tregs, leading to cure of established tumors in mice. The treatment resulted in the expansion of CD8+ effector Tconvs, including tumor antigen-specific ones, that were more activated and less exhausted than those induced by PD-1 immune checkpoint blockade. Anti-CCR8 mAb treatment also evoked strong secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that elimination of tumor-reactive multiclonal Tregs was sufficient to induce memory-type tumor-specific effector Tconvs. Despite induction of such potent tumor immunity, anti-CCR8 mAb treatment elicited minimal autoimmunity in mice, contrasting with systemic Treg depletion, which eradicated tumors but induced severe autoimmune disease. Thus, specific removal of clonally expanding Tregs in tumor tissues for a limited period by cell-depleting anti-CCR8 mAb treatment can generate potent tumor immunity with long-lasting memory and without deleterious autoimmunity.

Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

In situ analysis of CCR8+ regulatory T cells in lung cancer: suppression of GzmB+ CD8+ T cells and prognostic marker implications.

BACKGROUND: CCR8-expressing regulatory T cells (Tregs) are selectively localized within tumors and have gained attention as potent suppressors of anti-tumor immunity. This study focused on CCR8+ Tregs and their interaction with CD8+ T cells in the tumor microenvironment of human lung cancer. We evaluated their spatial distribution impact on CD8+ T cell effector function, specifically granzyme B (GzmB) expression, and clinical outcomes. METHODS: A total of 81 patients with lung squamous cell carcinoma (LSCC) who underwent radical surgical resection without preoperative treatment were enrolled. Histological analyses were performed, utilizing an automated image analysis system for double-stained immunohistochemistry assays of CCR8/Foxp3 and GzmB/CD8. We investigated the association of CCR8+ Tregs and GzmB+ CD8+ T cells in tumor tissues and further evaluated the prognostic impact of their distribution profiles. RESULTS: Histological evaluation using the region of interest (ROI) protocol showed that GzmB expression levels in CD8+ T cells were decreased in areas with high infiltration of CCR8+ Tregs, suggesting a suppressive effect of CCR8+ Tregs on T cell cytotoxicity in the local tumor microenvironment. Analysis of the association with clinical outcomes showed that patients with more CCR8+ Tregs and lower GzmB expression, represented by a low GzmB/CCR8 ratio, had worse progression-free survival. CONCLUSIONS: Our data suggest that local CCR8+ Treg accumulation is associated with reduced CD8+ T cell cytotoxic activity and poor prognosis in LSCC patients, highlighting the biological role and clinical significance of CCR8+ Tregs in the tumor microenvironment. The GzmB/CCR8 ratio may be a useful prognostic factor for future clinical applications in LSCC.

Progressive changes in the protein expression profile of alveolar septa in early-stage lung adenocarcinoma.

BACKGROUND: Adenocarcinomas show a stepwise progression from atypical adenomatous hyperplasia (AAH) through adenocarcinoma in situ (AIS) to invasive adenocarcinoma (IA). Immunoglobulin superfamily containing leucine-rich repeat (ISLR) is a marker of tumor-restraining cancer-associated fibroblasts (CAFs), which are distinct from conventional, strongly α-smooth muscle actin (αSMA)-positive CAFs. Fibroblast activation protein (FAP) has been focused on as a potential therapeutic and diagnostic target of CAFs. METHODS: We investigated the changes in protein expression during adenocarcinoma progression in the pre-existing alveolar septa by assessing ISLR, αSMA, and FAP expression in normal lung, AAH, AIS, and IA. Fourteen AAH, seventeen AIS, and twenty IA lesions were identified and randomly sampled. Immunohistochemical analysis was performed to evaluate cancer-associated changes and FAP expression in the pre-existing alveolar structures. RESULTS: Normal alveolar septa expressed ISLR. The ISLR level in the alveolar septa decreased in AAH and AIS tissues when compared with that in normal lung tissue. The αSMA-positive area gradually increased from the adjacent lung tissue (13.3% ± 15%) to AIS (87.7% ± 14%), through AAH (70.2% ± 21%). Moreover, the FAP-positive area gradually increased from AAH (1.69% ± 1.4%) to IA (11.8% ± 7.1%), through AIS (6.11% ± 5.3%). Protein expression changes are a feature of CAFs in the pre-existing alveolar septa that begin in AAH. These changes gradually progressed from AAH to IA through AIS. CONCLUSIONS: FAP-positive fibroblasts may contribute to tumor stroma formation in early-stage lung adenocarcinoma, and this could influence the development of therapeutic strategies targeting FAP-positive CAFs for disrupting extracellular matrix formation.

Native lung surgery after single lung transplantation: clinical characteristics and outcomes.

PURPOSE: Single lung transplantation (SLT) is a viable option for patients with end-stage pulmonary parenchymal and vascular diseases. However, various diseases can occur in native lungs after SLT. METHODS: Between January 2000 and December 2021, 35 patients underwent cadaveric SLT and survived for more than 30 days in our hospital. Among these 35 patients, 10 required surgery for diseases that developed in their native lungs. The clinical characteristics of these 10 patients and the outcomes of native lung surgery (NLS) were investigated. RESULTS: Among these ten patients, the indications for lung transplantation were chronic obstructive pulmonary disease and idiopathic interstitial pneumonia in three patients each, and lymphangioleiomyomatosis and collagen vascular disease-related interstitial pneumoniain two patients each. The causes of NLS included pneumothorax (n = 4), primary lung cancer (n = 2), native lung hyperinflation (n = 2), and pulmonary aspergilloma (n = 2). The surgical procedures were pneumonectomy (n = 7), lobectomy (n = 2), and alveolar-pleural fistula repair (n = 1). Only one postoperative complication, empyema, was treated with antibiotics. The 5-year overall survival rates after transplantation with and without NLS were 70.0% and 80.0%, respectively, and did not differ to a statistically extent (p = 0.56). CONCLUSION: NLS is an effective treatment option for diseases that develop in the native lungs after SLT.

Surgical resection of advanced intrathoracic tumors through a combination of the hemiclamshell and transmanubrial approaches.

PURPOSE: The hemiclamshell (HCS) approach provides a comprehensive view of the anterior mediastinum, whereas the transmanubrial osteomuscular sparing approach (TMA) allows sufficient exposure of the cervico-thoracic transition. We assessed the effectiveness and the outcomes of the combined HCS plus TMA approach to resect thoracic malignant tumors. METHODS: We reviewed five patients with thoracic malignant tumors invading the thoracic outlet who underwent surgery using an HCS and TMA approach between 2018 and 2021. RESULTS: The preoperative diagnosis was myxofibrosarcoma, lung cancer, thymic cancer, thymoma, and neurofibromatosis type1 in one patient each, respectively. Cardiovascular reconstruction was done on the aortic arch in two patients, on the descending aorta in one, and on the superior vena cava in one, combined with resection of the vagus nerve in three patients, of the phrenic nerve in two, and of vertebra in one, with overlap in some cases. The TMA was added because all patients required dissection of the periphery of the subclavian artery, and two had tumor extension to the neck. Macroscopic complete resection was achieved in four patients. There was no postoperative mortality. CONCLUSION: The combination of the HCS and TMA approaches at the same operation provides a comprehensive view of the mediastinum, lung, and cervico-thoracic transition and allows safe access to the thoracic great vessels and subclavian vessels.

Clinical outcomes of left upper segmentectomy vs. lobectomy for early non-small-cell lung cancer: a nationwide database study in Japan.

PURPOSE: Given that left upper lobe and right upper and middle lobes share a similar anatomy, segmentectomy, such as upper division and lingulectomy, should yield identical oncological clearance to left upper lobectomy. We compared the prognosis of segmentectomy with that of lobectomy for early stage non-small-cell lung cancer (NSCLC) in the left upper lobe. METHODS: We retrospectively examined 2115 patients who underwent segmentectomy or lobectomy for c-stage I (TNM 8th edition) NSCLC in the left upper lobe in 2010. We compared the oncological outcomes of segmentectomy (n = 483) and lobectomy (n = 483) using a propensity score matching analysis. RESULTS: The 5-year recurrence-free and overall survival rates in the segmentectomy and lobectomy groups were comparable, irrespective of c-stage IA or IB. Subset analyses according to radiological tumor findings showed that segmentectomy yielded oncological outcomes comparable to those of lobectomy for non-pure solid tumors. In cases where the solid tumor exceeded 20 mm, segmentectomy showed a recurrence-free survival inferior to that of lobectomy (p = 0.028), despite an equivalent overall survival (p = 0.38). CONCLUSION: Segmentectomy may be an acceptable alternative to lobectomy with regard to the overall survival of patients with c-stage I NSCLC in the left upper lobe.

Effect of revised organ transplant law in Japan on lung transplantation.

PURPOSE: To investigate how revision of the organ transplant law in Japan affected lung transplantation in this country. METHODS: Lung transplant candidates registered between January, 2000 and December, 2009 were designated as the pre-revision group (n = 396) and those registered between January, 2011 and December, 2020, as the post-revision group (n = 1326). Both groups were analyzed retrospectively using data collected by the Japanese Society of Lung and Heart-Lung Transplantation. RESULTS: The number of patients who underwent brain-dead donor lung transplantation (BDLT) increased significantly after the law amendment (32.2 vs. 13.8%, p < 0.01). The median waiting time for BDLT was significantly reduced (708 days vs. 1163 days, p < 0.01) and the mortality rate while waiting for BDLT improved significantly after the law amendment (33.1 vs. 42.6%, p < 0.01). In the post-revision group, 18 pediatric patients underwent BDLT. The 5-year survival rates after BDLT were comparable between the groups (73.5% in the pre-revision group vs. 73.2% in the post-revision group, p = 0.32). CONCLUSIONS: The organ transplant law revision shortened the waiting time for BDLT significantly and decreased the mortality rate while waiting for BDLT. The posttransplant outcomes in Japan remained favorable throughout the study period.

Stereotactic ablative body radiotherapy with a central high dose using CyberKnife for metastatic lung tumors.

BACKGROUND: The CyberKnife system features a robotically-positioned linear accelerator to deliver real-time image-guided stereotactic ablative body radiotherapy (SABR). It achieves steep dose gradients using irradiation from hundreds of different directions and increases the central dose of the gross tumor volume (GTV) without increasing the marginal dose to the planning target volume. We evaluated the effectiveness and safety of SABR with a central high dose using CyberKnife for metastatic lung tumors. METHODS: A total of 73 patients with 112 metastatic lung tumors treated with CyberKnife were retrospectively analyzed. Local control, progression-free survival, and overall survival were calculated using the Kaplan-Meier method. The median age was 69.2 years. The most common primary sites were the uterus (n = 34), colorectum (n = 24), head and neck (n = 17), and esophagus (n = 16). For peripheral lung tumors, the median radiation dose was 52 Gy in 4 fractions, whereas for centrally located lung tumors, it was 60 Gy in 8-10 fractions. The dose prescription was defined as 99% of the solid tumor components of the GTV. The median maximum dose within the GTV was 61.0 Gy. The GTV and planning target volume were enclosed conformally by the 80% and 70% isodose lines of the maximum dose, respectively. The median follow-up period was extended to 24.7 months; it was 33.0 months for survivors. RESULTS: The 2-year local control, progression-free survival, and overall survival rates were 89.1%, 37.1%, and 71.3%, respectively. Toxicities of grade ≥ 2 were noted as grade 2 and 3 radiation pneumonitis in one patient each. The two patients with grade 2 or higher radiation pneumonitis had both received simultaneous irradiation at two or three metastatic lung tumor sites. No toxicity of grade ≥ 2 was observed in patients with metastasis in one lung only. CONCLUSIONS: SABR with a central high dose using CyberKnife for metastatic lung tumors is effective with acceptable toxicity. TRIAL REGISTRATION: Number: 20557, Name: Stereotactic ablative radiotherapy using CyberKnife for metastatic lung tumor, URL: http://www.radonc.med.osaka-u.ac.jp/pdf/SBRT.pdf , Date of registration: April 1, 2021 (retrospectively registered), Date of enrollment: May 1, 2014.

Features of anaplastic lymphoma kinase rearrangement in early-stage lung cancer: Analysis of a nationwide Japanese database.

BACKGROUND AND OBJECTIVES: Anaplastic lymphoma kinase (ALK) rearrangement is a representative driver mutation in lung cancer. However, the biology of early-stage ALK-rearranged lung cancer remains unclear. We aimed to assess the clinicopathological features, prognostic implications, and influence of ALK rearrangement on the postoperative course in surgically resected lung cancer. METHODS: We retrospectively analyzed data from the Japanese Joint Committee of Lung Cancer Registry database. Of the 12 730 patients with lung adenocarcinoma, 794 (6.2%) were tested for ALK rearrangement and were included. RESULTS: ALK rearrangements were detected in 76 patients (10%). The 5-year overall survival (OS) rate was significantly higher in the ALK rearrangement-positive group than in the ALK rearrangement-negative group (p = 0.030). Multivariable analysis revealed that ALK rearrangement was an independent prognostic factor for improved OS (hazard ratio, 0.521; 95% confidence interval, 0.298-0.911; p = 0.022). Regarding the postrecurrence state, there was no difference in the initial recurrence sites between both groups. Administration of ALK-tyrosine kinase inhibitors (TKIs) improved postrecurrence survival in any treatment lines. CONCLUSION: In one of the largest national surveys, ALK rearrangement was associated with improved long-term outcomes in surgically resected patients. ALK-TKIs may be an important treatment strategy for ALK rearrangement-positive lung adenocarcinoma in the postrecurrence state.

Is adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer beneficial for elderly patients? A large, retrospective cohort study based on real-world data from Japan.

OBJECTIVE: The efficacy of tegafur-uracil as adjuvant chemotherapy for patients with completely resected stage I non-small-cell lung cancer is proven; however, its efficacy for elderly patients remains unclear. Herein, we evaluated the effectiveness of adjuvant chemotherapy for elderly patients with completely resected stage I non-small-cell lung cancer based on real-world Japanese data using propensity score matching. METHODS: This retrospective study extracted data from a nationwide registry study, performed in 2016, on patients ≥75 years who underwent lobectomy with mediastinal nodal dissection for non-small-cell lung cancer in 2010 and were diagnosed with p-stage IA (>2 cm) or stage IB non-small-cell lung cancer. We classified the 1294 patients into two groups-Group A, postoperative adjuvant chemotherapy (n = 295, 22.8%) and Group N, no adjuvant chemotherapy (n = 999, 77.2%)-and analyzed differences in postoperative overall survival between groups. RESULTS: Group A showed no advantage in overall survival over Group N as a whole (hazard ratio: 0.824 [95% confidence interval: 0.631-1.076]), in p-stage IA (hazard ratio: 0.617 [95% confidence interval: 0.330-1.156]) and in p-stage IB (hazard ratio: 0.806 [95% confidence interval: 0.597-1.088]) subsets. Even after propensity score matching, Group A showed no significant advantage in overall survival over Group N as a whole (hazard ratio: 0.975 [95% confidence interval: 0.688-1.381]), in p-stage IA (hazard ratio: 1.390 [95% confidence interval: 0.539-3.586]) and in p-stage IB (hazard ratio: 0.922 [95% confidence interval: 0.633-1.343]). CONCLUSIONS: adjuvant chemotherapy for completely resected p-stage IA (>2 cm) and stage IB non-small-cell lung cancer showed no benefit for recommendation for elderly patients; considering the risk of adverse events, we do not recommend adjuvant chemotherapy for elderly patients.

Association of the psoas muscle index with the survival of patients on a waiting list for lung transplantation: a Japanese single-institution study.

PURPOSES: Some predictive markers of death have been reported for patients on the waiting list for lung transplantation (LTx). We assessed whether or not the preoperative psoas muscle index (PMI) correlates with waitlist mortality. METHODS: In 81 patients with end-stage lung disease on the waiting list for LTx between 2011 and 2020 at Osaka University Hospital, we examined the association between baseline characteristics, including the diagnosis, respiratory function test results, blood collection items, steroid use, and psoas muscle mass on computed tomography, and survival during the waiting period using Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS: Thirty-three patients (41%) died during follow-up. Univariate and multivariate analyses showed that patients with a low PMI had a higher rate of death during follow-up than those with a high PMI (p < 0.0001 and 0.0002, respectively). In addition, a diagnosis of interstitial pneumonia (hazard ratio 3.30, 95% confidence interval 1.52-7.17, p = 0.0025) and low albumin level (hazard ratio 2.21, 95% confidence interval 1.02-4.80, p = 0.0449) were also significant predictors of survival. CONCLUSION: A low PMI at registration is associated with a decreased survival time among LTx candidates and it may be a predictive factor of mortality in patients waiting for LTx.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

PURPOSE: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. METHOD: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. RESULTS: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. CONCLUSION: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis.

Prognostic factors for lung transplant recipients focusing on age and gender: the Japanese lung transplantation report 2022.

PURPOSE: To clarify the impact of donor and recipient characteristics on the survival of recipients before and after lung transplantation in the Japanese population. METHODS: Patients' data were collected for retrospective analysis from all authorized lung transplant centers in Japan. We included 1963 patients listed for lung transplantation by the end of December 2021, comprised of 658 deceased-donor and 270 living-donor lung transplants. RESULTS: Primary disease had a significant impact on the mortality of patients waiting for transplantation. The indications for transplant significantly affected the post-transplant survival rate of deceased-donor lung transplant recipients. The recipient's age also significantly affected the post-transplant survival rate of the deceased-donor and living-donor lung transplant recipients. The recipients of grafts transplanted from donors aged 61 years or older showed a worse post-transplant survival rate (≧60 years old). The survival rate for the combination of a female donor to a male recipient among the deceased-donor lung transplant recipients was the worst among the four combinations. CONCLUSION: The donor and recipient characteristics significantly impacted the survival of recipients after lung transplantation. The underlying mechanism of the negative impact of the gender mismatch of female donor to male recipient on post-transplant survival needs to be investigated further.

[Perioperative Management of Deep Vein Thrombosis and Treatment of Pulmonary Embolism].

Preoperative evaluation of deep vein thrombosis( DVT), which is a known risk factor for the development of pulmonary embolism( PE), is important prior to performing thoracic surgery. The incidence of DVT after thoracic surgery is estimated to be 4% and the incidence of PE 0.6%. Lung cancer may be responsible for the highest incidence of thrombotic events associated with cancer. Longer operative time, intraoperative bleeding, extended surgical injury, pneumonectomy, and incomplete resection are all correlated to higher chance of acute PE after thoracic surgery. Risk-assessment models for DVT or PE can be utilized in thoracic surgery, and prophylaxis pre and post operation is highly recommended. Estimation of D-dimer levels is a valid preoperative screening strategy to evaluate the risk of DVT, and ultrasonographic examination should be performed in patients whose D-dimer levels are more than 1.0 µg/ ml. Computed tomographic pulmonary angiography is the gold standard in diagnosis of acute PE. Postoperative PE needs to be diagnosed and treated promptly as delay may be fatal. Anticoagulants and thrombolytic therapy have shown a great success in treatment of acute PE. Surgical approach for acute PE has also shown to be a lifesaving in some cases, and percutaneous cardiopulmonary support may be useful for patients with circulatory collapse or cardiopulmonary arrest.

[Ingenuities of Segmentectomy for Small Lung Cancer in Uniportal Video-assisted Thoracic Surgery].

Our department has been performing uniportal thoracoscopic lobectomy since April 2019 and now also performs segmentectomy for small malignant tumors. A skin incision of approximately 4 cm is created between the anterior fifth intercostal space on the left and right sides. Based on our experience, uniportal segmentectomy does not follow the learning curve unique to segmentectomy. For dissection of segmental surface, an automatic suture is used to prevent pulmonary fistulas. If the cutting line between the segments is straight, dissection can be performed easily even in uniportal surgery, in which the automatic suturing device is inserted from one direction. For inter-area identification, we use an air-containing collapsed line with normal ventilation, after which thoracoscopic indocyanine green( ICG) imaging is introduced. However, there have been cases in which a difference in inter-area identification occurred between ICG identification and the air-containing collapsed line. As such, it is better to utilize both methods in cases with masses close to the inter-areas.

Prognostic Impact of Number of Organ Invasions in Patients with Surgically Resected Thymoma.

PURPOSE: This study aimed to explore the clinical implications and prognostic value of the number of organ/structure invasions (NOI) in patients with thymoma after curative surgical resection. METHODS: We retrospectively analyzed 306 consecutive Japanese patients with thymoma who underwent curative surgical resection. Tumor invasions of pericardium, mediastinal pleura, phrenic nerve, lung, and venous structures were examined histopathologically. Cases were classified into four subgroups according to NOI: group 0, no tumor invasion; group 1, tumor invasion into single organ/structure; group 2, tumor invasion of two organs/structures; group 3, invasion of three or more organs/structures. Associations with NOI and several clinical characteristics and their prognostic significance were analyzed. RESULTS: Pleural invasion was found in 100 cases (32.7%), lung invasion in 48 cases (15.7%), pericardial invasion in 46 cases (15%), phrenic nerve invasion in 29 (9.5%), and venous invasion in 22 cases (7.2%). NOI was classed as group 0 in 201 cases (65.0%), group 1 in 42 cases (13.7%), group 2 in 20 cases (6.5%), and group 3 in 43 cases (14.1%). Cases with higher NOI showed significantly worse relapse-free survival (RFS) and overall survival (OS). Cox's proportional hazard model analysis also identified NOI as a prognostic factor affecting RFS and OS. CONCLUSIONS: Cases with higher NOI of thymoma after radical surgical resection showed significantly worse recurrence rates and survival.

Time to Incurable Recurrence for Patients Treated With Pulmonary Metastasectomy for Colorectal Cancer.

BACKGROUND: Probability of cure is important for patients with lung metastasis who must decide whether to undergo metastasectomy. Although progression-free survival (PFS) is thought to reflect this, it does not include curative effects by repeat metastasectomy. Thus, the authors developed a new indicator, time to incurable recurrence (TTIR), in which only incurable recurrence was set as an event that included death, with incurable recurrence defined as recurrence not treated by definitive local therapy (DLT), recurrence treated by DLT but with PFS maintained less than 2 years, or recurrence followed by re-recurrence. METHODS: This multi-institutional study included 339 patients who underwent lung metastasectomy for colorectal cancer between 1990 and 2008. RESULTS: Among the 339 patients, 191 experienced recurrence, 77 received DLT for recurrence, 38 had a PFS of 2 years or longer after the treatment, and 33 had maintained a PFS at the last follow-up date. The patients had PFS ranging from 39 to 212 months (median, 101 months). The 5-year OS, PFS, and TTIR rates were respectively 63.4%, 42.2%, and 51.9%. The TTIR curve was similar to the OS curve 7 years after the initial metastasectomy. The difference between TTIR and PFS at 7 years was 9.7%, indicating probability of cure by repeat DLT. Multivariable analysis showed different prognostic factors among OS, PFS, and TTIR. CONCLUSION: At the initial metastasectomy, TTIR may reflect probability of a cure, including cure by repeat DLT, and can be used to analyze prognostic factors associated with cure.

The prognostic impact of lung adenocarcinoma predominance classification relating to pathological factors in lobectomy, the Japanese Joint Committee of Lung Cancer Registry Database in 2010.

OBJECTIVE: We studied the prognosis and clinicopathological background of lung adenocarcinoma predominance among patients who underwent lobectomy using data from the Japanese Joint Committee of Lung Cancer Registry. METHODS: Two thousand eight hundred sixty-three cases were extracted. Recurrence free survival (RFS) rates, overall survival (OS) rates and clinicopathological factors and epidermal growth factor receptor (EGFR) mutation status were examined. RESULTS: Median follow-up period was 65.5 months. Adenocarcinoma predominance was sub-grouped according to OS and RFS rate. In pathological stage I, 5-year RFS and OS rates were respectively 92.2% and 95.8% in group A (adenocarcinoma-in-situ + minimally invasive adenocarcinoma), 89.3% and 92.1% in group B (lepidic), 79.2% and 89.7% in group C (papillary + acinar + variants) and 69.0% and 79.0% in group D (solid + micropapillary). In pathological stage II + IIIA, they were, 43.6% and 72.4% in B, 39.5% and 66.9% in C and 31.0% and 53.7% in D. Group D showed significant worst outcome both in stage I and II + IIIA. Up stage rate from clinical stage I to pathological stage II + IIIA was 0.0%, 3.7%, 15.9% and 33.3%. The frequency of lymph-vessel, vascular, pleura invasion and positive EGFR mutation were 0.0%, 0.0%, 0.0% and 57.1% in group A, 15.6%, 10.0%, 12.1% and 55.1% in B, 36.6%, 31.8%, 29.7% and 44.9% in C, 50.2%, 57.8%, 38.9% and 21.3% in D. In group D, lymph-vessel, vascular and pleura invasion were most, EGFR mutation was least frequent not only in pathological stage I but also stage II + IIIA. In multivariate analysis, age, pathological stage, vascular invasion, and group D were independent factors affected RFS and OS. CONCLUSION: Limited to lobectomy cases, solid + micropapillary was independent prognostic factor both in early and locally advanced stage. Its malignant degree was related to the frequency of pathological invasive factors and EGFR mutation status.

Efficacy of platinum agents for stage III non-small-cell lung cancer following platinum-based chemoradiotherapy: a retrospective study.

BACKGROUND: Platinum-based chemoradiotherapy is the standard treatment for unresectable stage III non-small-cell lung cancer (NSCLC). However, few studies have evaluated the efficacy of subsequent chemotherapy for relapsed NSCLC following platinum-based chemoradiotherapy. This study aimed to evaluate the efficacy of platinum-doublet chemotherapy as a second-line treatment for patients with unresectable stage III NSCLC. METHODS: We retrospectively evaluated patients with unresectable stage III NSCLC treated with cytotoxic chemotherapy following platinum-based chemoradiotherapy who were registered in a nationwide registry NSCLC database. Patients were divided into the platinum-doublet chemotherapy (platinum) group and single-agent chemotherapy (non-platinum) group based on the type of second-line chemotherapy. RESULTS: The platinum group (n = 119) showed significantly better overall survival (OS) than the non-platinum group (n = 201) (median OS: 21.5 vs. 10.5 months, hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.40-0.73, p < 0.001). OS from the beginning of chemoradiotherapy was also significantly better in the platinum group than in the non-platinum group (median OS: 34.9 vs. 21.8 months, HR: 0.58, 95% CI: 0.43-0.79, p = 0.001). In the multivariate analysis, platinum-doublet chemotherapy as second-line therapy, female sex, clinical stage IIIA, and duration of ≥ 8.6 months from the beginning of first-line therapy to the beginning of second-line therapy were associated with significantly better OS. CONCLUSION: Platinum-doublet chemotherapy as a second-line therapy may prolong survival in unresectable stage III NSCLC patients following platinum-based chemoradiotherapy. Thus, re-administration of platinum agents may be a promising treatment for unresectable stage III NSCLC treated with platinum-based chemoradiotherapy.