Publications by authors named "Masahiro Tsuboi"

248 Publications

Prognostic influence of epidermal growth factor receptor mutation and radiological ground glass appearance in patients with early-stage lung adenocarcinoma.

Lung Cancer 2021 Aug 3;160:8-16. Epub 2021 Aug 3.

Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Objectives: The ADAURA demonstrated the efficacy of osimertinib as adjuvant therapy in patients with resected stage IB-IIIA adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutations. However, it is controversial whether adjuvant therapy should be applied to all these patients because of their heterogeneities. This study aimed to examine the influence of GGO and EGFR mutations on the prognosis and to identify optimal targets for the development of perioperative therapy.

Material And Methods: Among the patients who underwent complete resection between 2003 and 2014 and had pathological stage IA3-IIA adenocarcinoma, 505 consecutive patients were examined for EGFR mutation status. The prognosis was analyzed among the clinicopathological factors including EGFR status and presence or absence of GGO.

Results: Of the 489 patients, 193 (39.5%) showed EGFR mutations. The recurrence-free survival (RFS) and overall survival (OS) of the EGFR mutant were slightly better than those of the EGFR wild type. There was no difference in RFS and OS between EGFR mutant and wild type in patients with GGO; however, EGFR mutant showed better OS than EGFR wild type in patients without GGO. The presence of GGO was a strong independent prognostic predictor in OS and RFS, but EGFR mutations was not predictors. In patients without GGO, EGFR mutants showed slightly higher recurrence, especially with a hazard ratio of 1.427 in stage IB.

Conclusions: Adenocarcinoma with GGO show a very good prognosis, so may not require adjuvant therapy. It will be necessary to further develop perioperative therapy in patients with poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.07.018DOI Listing
August 2021

Multicentre prospective observational study for pulmonary vein stump thrombus after anatomical lung resections.

Eur J Cardiothorac Surg 2021 Aug 7. Epub 2021 Aug 7.

Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan.

Objectives: Our goal was to evaluate the incidence and frequent sites of pulmonary vein stump thrombus (PVST) formation after pulmonary resection.

Methods: This is a prospective multicentre observational study conducted by 14 institutions in Japan. Enrolled patients underwent anatomical pulmonary resection including lobectomy, bilobectomy, pneumonectomy, left upper trisegmentectomy or lingular segmentectomy. Postoperative contrast-enhanced computed tomography was performed in the early period after the pulmonary resection to evaluate the incidence of PVST. Furthermore, univariable and multivariable analyses were performed to assess the risk factors associated with PVST using a logistic regression model.

Results: The status of PVST based on postoperative contrast-enhanced computed tomography scans was prospectively evaluated for 1040 patients. Postoperative computed tomography evaluation was performed for 3 (range: 1-84) days on average after the pulmonary resection. PVST was found in 127 (12.2%) patients with left-sided (23.3%) predominance compared to the right side (4.9%) (P < 0.001). Furthermore, left upper lobectomy was the most frequent operative procedure (30.8%). Multivariable analyses demonstrated that left upper lobectomy (P = 0.001) and left-sided pulmonary resection (P < 0.001) were independent significant predictors of PVST. Cerebral infarction was observed in 9 (0.87%) patients during this period and included 6 (1.46%) in whom it developed after the operation was performed on the left side. Especially in the early postoperative phase, left pulmonary resection was significantly associated with the incidence of cerebral infarction (0.16% vs 1.21%; P = 0.028).

Conclusions: PVST is an early postoperative event that is frequently observed in patients undergoing left anatomical pulmonary resection, especially a left upper lobectomy.

Irb Number: 16-205, Clinical trial registry: UMIN000027118.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezab370DOI Listing
August 2021

Surgical perspective on neoadjuvant immunotherapy in non-small cell lung cancer.

Ann Thorac Surg 2021 Jul 30. Epub 2021 Jul 30.

University of Leeds and St. James's University Hospital, Leeds, UK, Department of Thoracic Surgery.

Background: With a 5% improvement in 5-year overall survival achieved with current neoadjuvant or adjuvant chemotherapy, new treatments for resectable non-small cell lung cancer (NSCLC) are urgently needed. The use of immune checkpoint inhibitors (ICI) is established in metastatic NSCLC and is being evaluated in resectable NSCLC.

Methods: Publications and conference databases and clinicaltrials.gov were searched for reports on clinical studies of neoadjuvant immunotherapy in patients with early resectable NSCLC.

Results: Potential advantages of neoadjuvant ICI include earlier treatment of micrometastatic disease; activation of a broader, potentially durable immune response by the whole tumor and associated lymph nodes; and pathologic assessment of neoadjuvant treatment response, which may guide adjuvant therapy. Surgical considerations include delays to surgery, potential disease progression preventing curative resection, and perioperative morbidity and mortality. Surrogate endpoints of efficacy (pathologic complete response, major pathologic response) and biomarkers predictive of outcome (programmed death ligand 1 expression, tumor mutational burden and circulating tumor DNA) can accelerate clinical trial completion and early-stage treatment development; their application in neoadjuvant ICI studies in NSCLC is reviewed.

Conclusions: Phase 2 trials of neoadjuvant ICI alone or with chemotherapy showed encouraging safety and efficacy in patients with resectable NSCLC, warranting the ongoing phase 3 studies of neoadjuvant immunotherapy plus chemotherapy. Preoperative and intraoperative unresectability following neoadjuvant ICI appear comparable to neoadjuvant chemotherapy. To help thoracic surgeons and medical oncologists to distinguish amongst ICI beyond efficacy as phase 3 data emerge, surgery-related endpoints for perioperative morbidity, mortality, and complexity should be defined, standardized, incorporated into trial designs, and reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.athoracsur.2021.06.069DOI Listing
July 2021

Clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Lung Cancer 2021 09 16;159:74-83. Epub 2021 Jul 16.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan. Electronic address:

Objectives: The purpose of this study was to investigate the clinicopathological, gene expression and genetic features of stage I lung adenocarcinoma with necrosis.

Methods: We retrospectively reviewed 521 cases with pathologic stage I lung adenocarcinoma resected by lobectomy and lymph node dissection. We calculated the ratio of tumor necrotic area by digital image analysis and investigated the relationship between tumor necrosis and prognosis. Furthermore, we analyzed the differentially expressed genes between cases with and without necrosis using The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) dataset. Using whole exon sequencing data (n = 97), we examined whether tumor necrosis correlates with single nucleotide variants (SNVs) and driver mutations.

Results: Eighty four (16%) cases of the study cohort had tumor necrosis. The presence of necrosis significantly correlated with poorer prognosis (5-year overall survival: 91.9% vs. 75.4%, p < 0.001; 5-year recurrence-free survival: 86.0% vs. 59.0%, p < 0.001); however, the ratio of necrotic area did not correlate with prognosis. In multivariable analysis, invasive component size, vascular invasion, and tumor necrosis were independently associated with a higher risk of recurrence (hazard ratio, 1.652; 95% confidence interval, 1.033-2.641; p = 0.036). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as cell cycle and response to hypoxia, in cases with necrosis. The cases with tumor necrosis had more SNVs than those without tumor necrosis (p = 0.027), especially in smokers.

Conclusion: Stage I lung adenocarcinoma with tumor necrosis has worse prognosis than that without, and has distinctclinicopathological features in terms of gene expression and genetic features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.07.001DOI Listing
September 2021

Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for -mutated resectable non-small-cell lung cancer: NeoADAURA.

Future Oncol 2021 Jul 19. Epub 2021 Jul 19.

Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center & Weill Cornell Medical College, New York, NY 10021, USA.

Osimertinib is a third-generation, irreversible oral EGFR-tyrosine kinase inhibitor), that potently inhibits EGFR-tyrosine kinase inhibitor-sensitizing mutations and T790M resistance mutations together with efficacy in CNS metastases in patients with non-small-cell lung cancer (NSCLC). Here we describe the rationale and design for the Phase III NeoADAURA study (NCT04351555), which will evaluate neoadjuvant osimertinib with or without chemotherapy versus chemotherapy alone prior to surgery, in patients with resectable stage II-IIIB N2 mutation-positive NSCLC. The primary end point is centrally assessed major pathological response at the time of resection. Secondary end points include event-free survival, pathological complete response, nodal downstaging at the time of surgery, disease-free survival, overall survival and health-related quality of life. Safety and tolerability will also be assessed. Trial Registration number: NCT04351555 (ClinicalTrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2021-0549DOI Listing
July 2021

Lymph node metastasis and predictive factors in clinical stage IA squamous cell carcinoma of the lung based on radiological findings.

Gen Thorac Cardiovasc Surg 2021 Jul 15. Epub 2021 Jul 15.

Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Objectives: We aimed to clarify the incidence of lymph node (LN) metastasis and its predictive factors in clinical stage IA squamous cell carcinoma (SqCC) based on radiological classification to provide surgical indications for segmentectomy.

Methods: We retrospectively reviewed 192 patients with clinical stage IA SqCC who underwent complete resection with lobectomy and LN dissection at our institution between 2003 and 2019. To evaluate the incidence of LN metastasis from the perspective of indications for segmentectomy, we classified them into outer and inner groups based on the location of the tumor in the radiological findings.

Results: Regarding tumor location, 123 patients had tumors in the outer location and 69 patients had tumors in the inner location. The incidence of LN metastasis was 6% in clinical stage IA SqCC, which included 6% in the outer location and 7% in the inner location (p = 0.669). In the outer location, all LN metastases were in N1 (6%); whereas in the inner location, the incidence of N1 and N2 metastasis were 6% and 1%, respectively. Only tumors sized > 2.0 cm were found to be significantly associated with LN metastasis in clinical stage IA SqCC.

Conclusions: We demonstrated that the incidence of LN metastasis in clinical stage IA SqCC was comparable to that of the previously reported clinical stage IA NSCLC. The incidence of LN metastasis in the outer location was similar to that in the inner location. Tumor size was only a significant factor affecting LN metastasis in clinical stage IA SqCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11748-021-01681-7DOI Listing
July 2021

Predictive markers based on transcriptome modules for vinorelbine-based adjuvant chemotherapy for lung adenocarcinoma patients.

Lung Cancer 2021 08 10;158:115-125. Epub 2021 Jun 10.

Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. Electronic address:

Objectives: Microtubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy.

Materials And Methods: We explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine.

Results: We identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance.

Conclusion: We demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.06.011DOI Listing
August 2021

Correlation between the number of viable tumor cells and immune cells in the tumor microenvironment in non-small cell lung cancer after induction therapy.

Pathol Int 2021 Aug 11;71(8):512-520. Epub 2021 Jun 11.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan.

This study aims to determine the correlation between the percent viable tumor cells (%VTC) and the tumor microenvironment in resected non-small cell lung cancer after induction therapy. We enrolled 72 patients with non-small cell lung cancer (NSCLC) who received chemoradiotherapy (CRT) or chemotherapy (CT) prior to surgery. The ratio of the area of viable tumor cells to the total tumor area was calculated to obtain the %VTC. We also examined the number of CD4 (+), CD8 (+), CD20 (+) and FOXP3 (+) tumor-infiltrating lymphocytes (TILs), podoplanin (PDPN) (+) cancer-associated fibroblasts (CAFs), and CD204 (+) tumor-associated macrophages (TAMs) by immunohistochemistry (IHC). In the CRT group (n = 37), the tumors had significantly lower %VTC than the CT group (n = 35) (P < 0.001). In both of the CT group and CRT group, the %VTC showed a significant positive correlation with the number of CD204 (+)-TAMs (P = 0.014 and 0.005, respectively). Only in the CRT group, a higher number of CD204 (+) TAMs was associated with a shorter overall survival (OS) (P = 0.007) and recurrence-free survival (RFS) (P = 0.015). In the CRT group, the number of CD204 (+) TAMs is associated with %VTC and prognosis, suggesting that these cells may have tumor-promoting effects on the residual lung cancer in specific microenvironments after CRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pin.13110DOI Listing
August 2021

Mediastinal lymph node dissection for the elderly with clinical stage I non-small cell lung cancer.

Gen Thorac Cardiovasc Surg 2021 May 29. Epub 2021 May 29.

Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Objectives: We aimed to compare the differences in prognosis and perioperative complications between patients with and without mediastinal lymph node dissection (MLND) among elderly patients with clinical stage I non-small cell lung cancer (NSCLC).

Methods: We analysed 439 patients ≥ 75 years of age with NSCLC classified as clinical stage I who underwent complete resection with lobectomy. We divided the patients into two groups. Those with MLND were included in the MLND group (n = 365), and those without MLND or adequate systematic mediastinal lymph node sampling were included in the non-MLND group (n = 74). To reduce selection bias, a propensity score matching method (3:1) was implemented. We compared survival and the incidence of perioperative complications.

Results: After matching, we compared 171 patients in the MLND group to 57 patients in the non-MLND group. There were no significant differences in clinicopathological characteristics between the groups. The non-MLND group did not show a significantly better prognosis than the MLND group in overall survival and cancer-specific survival (p = 0.246 and 0.150, respectively). The cumulative incidence of recurrence was similar in the two groups. MLND did not affect chest drain duration or hospitalization. The numbers of patients with perioperative complications ≥ grade 2 or ≥ grade 3 did not differ between the groups (p = 0.312 and > 0.999, respectively).

Conclusions: Anatomical pulmonary resection without MLND might be a treatment option for elderly patients with clinical stage I NSCLC. Further investigation is needed to clarify the value of MLND, especially for vulnerable elderly individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11748-021-01656-8DOI Listing
May 2021

High proportion of tumor necrosis predicts poor survival in surgically resected high-grade neuroendocrine carcinoma of the lung.

Lung Cancer 2021 07 24;157:1-8. Epub 2021 May 24.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan; Division of Innovative Pathology and Laboratory Medicine, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan. Electronic address:

Objectives: Tumor necrosis is a negative prognostic factor in various cancers. High-grade neuroendocrine carcinomas (HGNEC) of the lung, such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), commonly have histopathological features of tumor necrosis. However, the prognostic value of tumor necrosis remains unknown.

Materials And Methods: A total of 81 patients with HGNEC (SCLC, n = 42; LCNEC, n = 39) who underwent complete resection were enrolled. The proportion of necrosis in the tumor tissues was quantified using digital image analysis. We analyzed the relationship between the proportion of necrosis, clinicopathological factors, and prognosis. Moreover, we examined the correlation between genomic alterations and proportion of necrosis.

Results: The median proportion of necrosis was 10.6 % (range, 0-62.8 %). The proportion of necrosis was not significantly different between SCLC (median, 5.1 %; range, 0-62.8 %) and LCNEC (median: 14.2 %; range, 0-59.3 %) (p =  0.14). The cumulative incidence of recurrence (CIR) and lung cancer-specific cumulative incidence of death (LC-CID) were significantly higher in patients with 10 % or higher necrosis (necrosis ≥ 10 %) than in those with less than 10 % (necrosis < 10 %) (hazard ratio [HR], 2.94; 95 % confidence interval [CI], 1.30-6.64, and HR, 2.87; 95 % CI, 1.13-7.29, respectively). In the bivariate analysis, necrosis ≥ 10 % was independently associated with higher CIR and tended to be associated with higher LC-CID. The frequency of genomic alterations in the PI3K/AKT/mTOR pathway, MYC family, MAPK/ERK pathway, and major RTK signaling pathways were not different between the necrosis ≥ 10 % and necrosis < 10 % groups for both SCLC and LCNEC.

Conclusion: High proportion of tumor necrosis (≥ 10 %) had a negative prognostic value in surgically resected HGNEC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.05.018DOI Listing
July 2021

Phase II Study of Neoadjuvant Concurrent Chemo-immuno-radiation Therapy Followed by Surgery and Adjuvant Immunotherapy for Resectable Stage IIIA-B (Discrete N2) Non-small-cell Lung Cancer: SQUAT trial (WJOG 12119L).

Clin Lung Cancer 2021 Apr 27. Epub 2021 Apr 27.

Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address:

Introduction: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069).

Patients And Methods: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%.

Conclusion: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2021.04.006DOI Listing
April 2021

Prognostic impact of extranodal extension in patients with pN1-N2 lung adenocarcinoma.

J Cancer Res Clin Oncol 2021 Apr 2. Epub 2021 Apr 2.

Department of Pathology and Clinical Laboratories, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Purpose: Lymph node involvement is one of the important prognostic factors of patients with lung adenocarcinoma. In the tumor, node, and metastasis classification, lymph node involvement is categorized only according to the anatomical station and not the involvement pattern. The aim of this study was to investigate which morphological pattern of lymph node involvement affects the prognosis of patients with surgically resected lung adenocarcinoma.

Methods: We retrospectively reviewed 168 consecutive patients who underwent surgical resection for primary lung adenocarcinoma with lymph node involvement. The morphological patterns of lymph node involvement (tumor area, number of metastatic lymph nodes, presence of necrosis, and extranodal extension) were histologically examined. The relationships between the patterns of lymph node involvement, clinicopathological features, and survival of patients were analyzed.

Results: Eighty patients had N1 disease, and 88 patients had N2 disease. Univariate analysis revealed that invasive size, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N1 patients, and vascular invasion, pleural invasion, presence of epidermal growth factor receptor mutation, history of adjuvant chemotherapy, and presence of extranodal extension were significant prognostic factors in N2 patients. In a bivariate analysis including other clinicopathological factors and patterns of lymph node involvement, the presence of extranodal extension was significantly associated with poor 3-year overall and recurrence-free survival of both N1 and N2 patients.

Conclusions: In patients who underwent surgical resection for lung adenocarcinoma with lymph node involvement, the extranodal extension was the most important prognostic factor among morphological lymph node involvement patterns.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-021-03608-4DOI Listing
April 2021

Pathological features and prognostic implications of ground-glass opacity components on computed tomography for clinical stage I lung adenocarcinoma.

Surg Today 2021 Jul 20;51(7):1188-1202. Epub 2021 Mar 20.

Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Purpose: To investigate the prognostic implications and pathological features of clinical stage I lung adenocarcinoma with ground-glass opacity (GGO) on computed tomography (CT).

Methods: The subjects of this retrospective study were 1228 patients with lung adenocarcinoma classified as clinical stage I, who underwent complete resection by lobectomy. The patients were divided into four groups based on the presence and proportion of GGO according to the consolidation-to-tumor ratio (CTR); A, CTR ≤ 0.5; B, 0.5 < CTR ≤ 0.75; C, 0.75 < CTR ≤ 1.0 with GGO; D, without GGO (pure-solid). We compared overall survival, pathological findings (N/ly/v/STAS), and histological subtypes within each clinical stage among the four groups.

Results: We found no significant differences among tumors with GGO (groups A, B and C) for prognosis or pathological findings in all the clinical stages. The prognoses of groups A, B and C were significantly better than that of group D for patients with clinical stages IA2-IB disease. Tumors without GGO on CT had a significantly larger number of positive N, ly, v and STAS in almost all stages than tumors with GGO on CT. Tumors without GGO on CT had significantly more solid predominant and less lepidic predominant adenocarcinoma.

Conclusion: Not the proportion of GGO, but its presence on CT, as well as the size of the solid component, were correlated significantly with pathological characteristics and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-021-02235-3DOI Listing
July 2021

Preoperative nivolumab to evaluate pathological response in patients with stage I non-small cell lung cancer: a study protocol of phase II trial (POTENTIAL).

BMJ Open 2021 03 17;11(3):e043234. Epub 2021 Mar 17.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan.

Introduction: Recently, inhibition of programmed cell death 1 or its ligand has shown therapeutic effects on non-small cell lung cancer (NSCLC). However, the effectiveness of preoperative nivolumab monotherapy for stage I NSCLC remains unknown. The present study aimed to investigate the pathological response of preoperative treatment with nivolumab for clinically node negative but having a high risk of NSCLC recurrence.

Methods And Analysis: The Preoperative Nivolumab (Opdivo) to evaluate pathologic response in patients with stage I non-small cell lung cancer: a phase 2 trial (POTENTIAL) study is a multicentre phase II trial investigating efficacy of preoperative nivolumab for clinical stage I patients at high risk of recurrence. This study includes histologically or cytologically confirmed NSCLC patients with clinical N0 who were found on preoperative high-resolution CT to have a pure solid tumour without a ground-glass opacity component (clinical T1b, T1c or T2a) or a solid component measuring 2-4 cm in size (clinical T1c or T2a). Patients with epidermal growth factor receptor (EGFR) mutation (deletion of exon 19 or point mutation on exon21, L858R), anaplastic lymphoma kinase (ALK) translocation or c-ros oncogene 1 (ROS-1) translocation are excluded from this study. Nivolumab (240 mg/body) is administrated intravenously as preoperative therapy every 2 weeks for three cycles. Afterward, lobectomy and mediastinal lymph node dissection (ND 2a-1 or ND 2a-2) are performed. The primary endpoint is a pathological complete response in the resected specimens. The secondary endpoints are safety, response rates and major pathological response. The planed sample size is 50 patients. Patients have been enrolled since April 2019.

Ethics And Dissemination: This trial was approved by the Institutional Review Board of Hiroshima University Hospital and other participating institutions. This trial will help examine the efficacy of preoperative nivolumab therapy for clinical stage I NSCLC.

Trial Registration Number: jRCT2061180016.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-043234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978092PMC
March 2021

Effect of Second-generation vs Third-generation Chemotherapy Regimens With Thoracic Radiotherapy on Unresectable Stage III Non-Small-Cell Lung Cancer: 10-Year Follow-up of a WJTOG0105 Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Jun;7(6):904-909

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

Importance: Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non-small-cell lung cancer.

Objective: To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT.

Design, Setting, And Participants: This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non-small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019.

Interventions: A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation.

Main Outcomes And Measures: The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT.

Results: From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report.

Conclusion And Relevance: In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT.

Trial Registration: UMIN Clinical Trial Registry: UMIN000030811.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974833PMC
June 2021

Refractory Hepatic Lymphorrhea: Percutaneous Transhepatic Lymphangiography and Embolization with n-Butyl-2-Cyanoacrylate Glue.

Cardiovasc Intervent Radiol 2021 Jul 15;44(7):1127-1130. Epub 2021 Mar 15.

Department of Diagnostic Radiology, Osaki Citizen Hospital, 3-8-1 Honami, Furukawa, Osaki-shi, Miyagi, 9896183, Japan.

Hepatic lymphorrhea is a leakage from the liver's lymphatic ducts into the abdominal cavity and an extremely rare complication associated with injury of the hepatoduodenal ligament, which can lead to refractory ascites. Hepatic lymphorrhea is constituted by non-chylous ascites and can be visualized by transhepatic lymphangiography instead of pedal or intranodal lymphangiography. To date, only a few successfully treated cases using interventional procedures have been reported. Although n-butyl-2-cyanoacrylate (NBCA) glue is widely used in various cases of vascular embolization and other lymphatic leak treatments, there have been no reports of its use for post-surgical hepatic lymphorrhea. The NBCA glue embolization described in this case report may be one of the treatment options to control the refractory ascites derived from hepatic lymphorrhea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00270-021-02802-8DOI Listing
July 2021

Targeted therapies for resectable lung adenocarcinoma: ADAURA opens for thoracic oncologic surgeons.

J Thorac Cardiovasc Surg 2021 07 9;162(1):288-292. Epub 2021 Feb 9.

Yale School of Medicine and Yale Cancer Center, New Haven, Conn.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2021.02.008DOI Listing
July 2021

Reply to J. L. Derks et al.

J Clin Oncol 2021 May 4;39(13):1509-1510. Epub 2021 Mar 4.

Hirotsugu Kenmotsu, MD, PhD, Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-cho Sunto-gun, Japan; Seiji Niho, MD, PhD, Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Masahiro Tsuboi, MD, PhD, Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan; Masashi Wakabayashi, ME, and Junko Eba MD, Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan; Hisao Asamura, MD, PhD, Division of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan; Yuichiro Ohe, MD, PhD, Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; and Shun-ichi Watanabe, MD, PhD, Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.21.00107DOI Listing
May 2021

Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design.

Future Oncol 2021 Apr 2;17(12):1459-1472. Epub 2021 Mar 2.

The Chinese University of Hong Kong, Hong Kong, 999077, China.

Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics. NCT03968419 (ClinicalTrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-1098DOI Listing
April 2021

Osimertinib in EGFR-Mutated Lung Cancer. Reply.

N Engl J Med 2021 02;384(7):675-676

National Cancer Center Hospital East, Kashiwa, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc2033951DOI Listing
February 2021

Rare presentation of annular and polypoid heterotopic gastric mucosa in duodenum.

JGH Open 2021 Feb 31;5(2):312-313. Epub 2020 Dec 31.

Department of Neurosugery Saiseikai Kibi Hospital Okayama Japan.

In this case, Esophagogastroduodenoscopy showed an approximately 25-mm diameter annular and polypoid mucosa at the opposite side of Pylorus ring in first part of duodenum. The biopsy specimens were diagnosed with the heterotopic gastric mucosa (HGM) pathologically. This is a rare presentation of annular and polypoid HGM in duodenum. This may indicate the needs for other documents as well as analysis regarding the mechanism for the development of HGM in duodenum.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgh3.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857297PMC
February 2021

A single-arm study of sublobar resection for ground-glass opacity dominant peripheral lung cancer.

J Thorac Cardiovasc Surg 2020 Nov 12. Epub 2020 Nov 12.

Division of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan.

Background: The optimal mode of surgery for ground-glass opacity dominant peripheral lung cancer defined with thoracic thin-section computed tomography remains unknown.

Methods: We conducted a single-arm confirmatory trial to evaluate the efficacy and safety of sublobar resection for ground-glass opacity dominant peripheral lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with consolidation tumor ratio 0.25 or less based on thin-section computed tomography were registered. The primary end point was 5-year relapse-free survival. The planned sample size was 330 with the expected 5-year relapse-free survival of 98%, threshold of 95%, 1-sided α of 5%, and power of 90%. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number University Hospital Medical Information Network 000002008.

Results: Between May 2009 and April 2011, 333 patients were enrolled from 51 institutions. Median age was 62 years (interquartile range, 56-68), and 109 were smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end point, 5-year relapse-free survival, was estimated on 314 patients who underwent sublobar resection. Operative modes were 258 wide wedge resections and 56 segmentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met the primary end point. There was no local relapse. Grade 3 or higher postoperative complications based on Common Terminology Criteria for Adverse Effect v3.0 were observed in 17 patients (5.4%), without any grade 4 or 5.

Conclusions: Sublobar resection with enough surgical margin offered sufficient local control and relapse-free survival for lung cancer clinically resectable N0 staged by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or less.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2020.09.146DOI Listing
November 2020

Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment.

Lung Cancer 2021 03 10;153:108-116. Epub 2021 Jan 10.

Department of General Thoracic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

Objectives: The prognostic impact of surgical intervention for recurrent or residual non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement after tyrosine-kinase inhibitor (TKI) treatment remains unclear. We aimed to describe the characteristics and outcomes of patients undergoing salvage surgery in this setting.

Methods: We retrospectively collected and analyzed nationwide Japanese data on perioperative and postoperative outcomes of patients who underwent salvage surgery after EGFR or ALK-TKI during 2010-2015. The primary endpoint was a 3-year overall survival (OS) rate and secondary endpoints were the rate of adverse events, perioperative mortality rate, 3-year recurrence-free survival (RFS) rate, and median survival time after salvage lung resection. Univariate and multivariate analyses were performed to identify independent prognostic factors of OS and RFS.

Results: Thirty-six patients were included (EGFR-TKI: 33, ALK-TKI: 3). The 3-year OS and RFS after the surgery were 75.1 % (95 % confidence interval [CI] 55.9-86.9 %) and 22.2 % (95 % CI 8.6-39.7 %), respectively. Of clinicopathological factors, the progression of disease while on TKI and preoperative carcinoembryonic antigen (CEA) levels (≥5 ng/mL) were shown to be worse independent prognosticators of OS (hazard ratio [HR] 9.38, 95 % CI 1.57-55.88, P = .014; HR 4.84, 95 % CI 1.62-14.46, P = .005, respectively). Older age at initial treatment (≥70 years) and advanced pathological T stage (T2-T4) were the worse prognosticators for RFS (HR 12.58, 95 % CI 2.51-62.97, P = .002; HR 3.06, 95 % CI 1.04-9.03, P = .043, respectively). Grade 3 adverse events occurred in 5.6 % (2/36) patients, but no deaths were reported within 90 days after surgery.

Conclusion: Our study showed that salvage surgery after TKI treatment was safe and feasible and may contribute to prolonged OS time by reducing the local tumor burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.12.037DOI Listing
March 2021

Prognostic impact of the tumor immune microenvironment in pulmonary pleomorphic carcinoma.

Lung Cancer 2021 03 8;153:56-65. Epub 2021 Jan 8.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Japan. Electronic address:

Introduction: Pulmonary pleomorphic carcinoma (PC) is a rare non-small cell lung carcinoma (NSCLC) and is characterized by sarcomatoid and NSCLC components. This study aimed to characterize the association between immune microenvironmental factors and clinicopathological characteristics of PC.

Methods: Eighty consecutive PC patients who had undergone complete surgical resection were enrolled. We calculated the immunohistochemical staining scores for E-cadherin, vimentin, programmed death ligand 1 (PD-L1), and carbonic anhydrase IX in cancer cells and counted the numbers of CD204-positive tumor-associated macrophages (TAMs) and Foxp3-, CD8-, and CD20-positive tumor-infiltrating lymphocytes (TILs). We also examined the association between these scores and the prognostic outcomes.

Results: The staining score for PD-L1 in cancer cells and the number of CD204-positive TAMs in the sarcomatoid component were significantly higher than those in the NSCLC component; E-cadherin score in the sarcomatoid component was significantly lower. Patients with high PD-L1 expression in the NSCLC component had significantly longer overall survival (OS) and recurrence-free survival (RFS) than those with low PD-L1 expression in the NSCLC component (OS: p = 0.001, RFS: p = 0.038). Multivariate analysis revealed that high PD-L1 expression in the NSCLC component was an independent favorable prognostic factor for OS (p = 0.018), whereas high PD-L1 expression in the sarcomatoid component was not. The number of CD8-positive TILs was significantly higher in the high PD-L1 expression group than in the low expression group (NSCLC components: p < 0.001).

Conclusion: High PD-L1 expression in the NSCLC component may be associated with a favorable prognostic value in pulmonary PC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.01.007DOI Listing
March 2021

Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma.

Lung Cancer 2021 03 24;153:1-10. Epub 2020 Dec 24.

Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. Electronic address:

Aim: Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) harbor a fibrous tumor microenvironment that promotes cancer progression in lung adenocarcinoma. In this study, we investigated whether tumor-promoting PDPN CAFs contribute to the immunosuppressive microenvironment in lung squamous cell carcinoma (SqCC). M&M: The gene expression profiles of immunosuppressive cytokines were compared using The Cancer Genome Atlas (TCGA) microarray lung SqCC data (n = 484) between a PDPN-high group and a PDPN-low group. Further, using patient-derived CAFs from surgically resected lung SqCC, the PDPN fraction was sorted and gene and protein expressions were analyzed. Finally, immunohistochemical staining was conducted on 131 surgically resected lung SqCC; CD8 and FOXP3 tumor infiltrating lymphocytes (TILs), and CD204 tumor-associated macrophages (TAMs) were evaluated in cases with PDPN and PDPN CAFs.

Results: Analysis of TCGA database revealed that the PDPN-high group exhibited significantly higher expression of interleukin (IL)-1A, IL-1B, IL-6, IL-10, monocyte chemoattractant protein-1 (CCL2), colony stimulating factor 1 (CSF1), fibroblast growth factor 2 (FGF2), galectin 1 (LGALS1), platelet derived growth factor subunit A (PDGFA), PDGFB, and transforming growth factor-β1 (TGFB1) than those in the PDPN-low group. Among them, it was found that TGFB1 expression was higher in patient-derived PDPN CAFs. Immunohistochemical analyses revealed that more CD204 TAMs infiltrated the tumor tissues in cases with PDPN CAFs than in cases with PDPN CAFs (P <  0.03), while CD8 and FOXP3 TILs did not. Furthermore, in the same tumor, CD204 TAMs infiltrated more in PDPN CAF-rich areas (P =  0.005).

Conclusion: PDPN CAFs showed higher expression of TGFB1 and were associated with CD204 TAM infiltration in stage-I lung SqCC, suggesting that PDPN CAFs were associated with the immunosuppressive tumor microenvironment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2020.12.020DOI Listing
March 2021

Prognostic impact of home oxygen therapy on patients with resected non-small-cell lung cancer with interstitial lung disease.

Surg Today 2021 Jun 3;51(6):1036-1043. Epub 2021 Jan 3.

Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, Japan.

Purpose: Non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) have a poor prognosis. The present study evaluated the prognostic impact of home oxygen therapy (HOT) in NSCLC patients with ILD.

Methods: Overall, 3099 consecutive patients underwent complete resection of stage IA to IIIA NSCLC at our institution between 2002 and 2016. ILD was diagnosed and categorized based on high-resolution computed tomography. The criteria for HOT included less than 90% resting oxygen saturation in the peripheral arteries and severe exertional dyspnea. We retrospectively compared the overall survival between ILD patients with and without HOT.

Results: ILD was observed in 150 (5%) patients. Seventeen (11%) patients needed HOT at discharge. The incidences of usual interstitial pneumonia (UIP) pattern (p = 0.03) and blood loss (p < 0.01) were significantly higher in the patients requiring HOT than in those without HOT. Significantly more patients developed complications (p = 0.04) in the HOT group than in the non-HOT group, with three (18%) having acute exacerbations. The 3-year overall survival rate was significantly lower in the HOT patients than in those without HOT (28% vs. 63%, p = 0.03).

Conclusions: Patients requiring postoperative HOT showed a significantly poorer prognosis after complete resection than those without HOT. Therefore, the indication for surgery should be investigated cautiously in order to prevent the need for postoperative HOT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-020-02186-1DOI Listing
June 2021

Continuation of aspirin perioperatively for lung resection: a propensity matched analysis.

Surg Today 2021 Jun 3;51(6):1054-1060. Epub 2021 Jan 3.

Department of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.

Purpose: To clarify the safety and effectiveness of continuing aspirin during the perioperative period of lung resection.

Methods: We analyzed, retrospectively, consecutive patients who underwent lung resection between 2008 and 2017. To investigate the safety of aspirin continuation, patients who continued taking aspirin perioperatively (Group C) were matched to other patients (Group O), using a propensity score, and bleeding outcomes were compared. To assess the effect of aspirin interruption, Group C was matched to a group of patients whose aspirin regimen was interrupted (Group I), and the postoperative complications related to thromboembolism were compared.

Results: Among 3393 patients, 52 continued on aspirin (Group C) perioperatively, whereas 184 had their aspirin discontinued (Group I). Comparing the matched cohorts extracted from Group C and Group O (n = 45), there were no significant differences in bleeding outcomes. Comparing the matched cohorts extracted from Group C and Group I (n = 40), group C had fewer postoperative complications related to thromboembolism (0% vs. 7.5%, p = 0.039).

Conclusion: Bleeding complications did not increase by continuing aspirin, but thromboembolic complications increased when the aspirin regimen was interrupted during the perioperative period of lung resection. Thus, in the absence of a prohibitive bleeding risk, the continuation of aspirin during the perioperative period of lung resection appears to be desirable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-020-02202-4DOI Listing
June 2021

Tumor-Infiltrating T Cells Concurrently Overexpress CD200R with Immune Checkpoints PD-1, CTLA-4, and TIM-3 in Non-Small-Cell Lung Cancer.

Pathobiology 2021 15;88(3):218-227. Epub 2020 Dec 15.

Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan,

Introduction: CD200R has been reported to be the receptor for the immune checkpoint molecule CD200 and can transduce immune-suppressive signals. In this study, we mainly focused on the expression level of CD200R in T cells in pulmonary artery (PA) blood and non-small-cell lung cancer (NSCLC) tumor tissue.

Methods: Immune cells were isolated from dissected tumor samples and PA blood of NSCLC patients and analyzed with multiparameter flow cytometry. The co-expression of CD200R with other immune checkpoints, including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), was also investigated.

Results: CD200R expression was observed on the surface of approximately 75% of T cells among tumor-infiltrating leukocytes (TILs). Compared to T cells extracted from TILs, only 55% of T cells extracted from PA blood exhibited CD200R expression. Moreover, with higher expression of CD200R, the expression of other immune checkpoints, including PD-1, CTLA-4, and TIM-3, was also increased in tumor-infiltrating T cells compared to T cells in PA blood.

Conclusions: Our results showed that those tumors were dominated by T cells expressing CD200R together with other checkpoints, which suggests a phenotypic change after T cell infiltration into the tumor, such as T cell exhaustion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511557DOI Listing
December 2020

Clinical features and prognostic impact of coexisting autoimmune disease other than myasthenia gravis in resected thymomas: analysis of a Japanese multi-institutional retrospective database.

Eur J Cardiothorac Surg 2021 04;59(3):641-649

Department of General Thoracic Surgery, National Hospital Organization Osaka Toneyama Medical Centre, Osaka, Japan.

Objectives: The purpose of this study was to clarify the prevalence, clinical features and survival of patients with thymoma and non-myasthenia gravis autoimmune disease (NMAD) using a nationwide cohort.

Methods: The Japanese Association for Research on the Thymus nationwide database, which includes data from 32 institutions, was examined to clarify the prevalence and characteristics of NMAD associated with thymomas and elucidate the prognostic impact of NMAD for thymoma patients.

Results: Among the 2423 patients with thymomas who were surgically treated between 1991 and 2010, 114 (4.7%) were identified with NMAD. The most frequently observed NMAD was pure red cell aplasia (PRCA) in 44 (1.8%), followed by hypogammaglobulinaemia (0.5%) and rheumatic arthritis (0.5%). Twenty-eight percent of patients with NMAD had concomitant myasthenia gravis. The presence of NMAD was not an independent prognostic factor for overall survival (OS) irrespective of the type of NMAD [PRCA+: hazard ratio (HR) 1.99, 95% confidence interval 0.74-4.47; PRCA- NMAD: HR 1.28, 0.30-3.56]; however, there were more cases with advanced age and disease of the thymoma amongst PRCA+ patients and these showed a worse OS than patients with PRCA- NMAD (P < 0.001), who had an OS similar to those without NMAD (P = 0.489). The 10-year OS rates in PRCA+, PRCA- NMAD and NMAD- groups were 45.5%, 97.4% and 89.5%, respectively. The main causes of death in PRCA+ patients were the progression of thymoma and other diseases including pneumonia.

Conclusions: Although the presence of NMAD itself did not significantly affect survival after surgery for thymoma, the type of NMAD was associated with different clinical features and prognosis. The NMAD+ thymomas should be separately categorized according to the presence or absence of PRCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezaa362DOI Listing
April 2021

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

Cancer Sci 2021 Jan 30;112(1):388-396. Epub 2020 Nov 30.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780021PMC
January 2021
-->