Publications by authors named "Makoto Sonobe"

165 Publications

Lymph node dissection in thymic carcinomas and neuroendocrine carcinomas.

Interact Cardiovasc Thorac Surg 2021 Jul;33(2):242-249

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.

Objectives: Although lymph node (LN) metastases are not uncommon in thymic carcinomas, preoperative LN evaluation, intraoperative lymph node dissection (LND) and postoperative outcomes remain unknown. The aim of this study was to elucidate the characteristics of and outcomes in patients with thymic carcinomas and thymic neuroendocrine carcinomas undergoing LND.

Methods: A retrospective chart review was performed using our multi-institutional database to identify patients who underwent resection and LND for thymic carcinoma or thymic neuroendocrine carcinoma between 1991 and 2018. An enlarged mediastinal LN was defined as having a short-axis diameter >1 cm. We assessed survival outcomes using the Kaplan-Meier analysis.

Results: N1-level LND was performed in 41 patients (54.6%), N2-level LND in 14 patients (18.7%) and both-level LND in 16 patients (21.3%). Pathological LN metastasis was detected in 20 patients (26.7%) among the 75 patients undergoing LND. There was a significant difference in the number of LN stations (P = 0.015) and metastasis factor (P = 0.0042) between pathologically LN-positive and pathologically LN-negative patients. The sensitivity of enlarged LNs on preoperative computed tomography was 18.2%. There was a tendency towards worse overall survival of pathologically N2-positive patients, although the difference was not statistically significant (P = 0.15).

Conclusions: Preoperative CT appears to play a limited role in detecting pathological LN metastases. Our findings suggest that the significance of N1- and N2-level LND should be evaluated in prospective studies to optimize the postoperative management of patients with thymic carcinomas and neuroendocrine carcinomas.
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http://dx.doi.org/10.1093/icvts/ivab079DOI Listing
July 2021

[Surgery for Right Pulmonary Arteriovenous Malformation with Recurrent Brain Abscess:Report of a Case].

Kyobu Geka 2021 Jun;74(6):477-480

Department of Thoracic Surgery, Japanese Red Cross Osaka Hospital, Osaka, Japan.

A 68-year-old man was referred to our hospital for further examination for chest abnormal shadow in the right lung field. He had a past history of subarachnoid hemorrhage. He was diagnosed with pulmonary arteriovenous malformation (PAVM) and recommended early treatment, but he didnot accept immediate surgical treatment. Three months later, he was transferred to other hospital emergently to treat nausea and dizziness. After being diagnosed with cerebellum abscess, external drainage was performed at our hospital. First drainage had a temporary efficacy, so second drainage was performed before referring to our department. Considering his condition and brain abscess, surgery for PAVM was done.
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June 2021

Randomized phase II study of daily and alternate-day administration of S-1 for adjuvant chemotherapy in completely-resected stage I non-small cell lung cancer: results of the Setouchi Lung Cancer Group Study 1301.

BMC Cancer 2021 May 6;21(1):506. Epub 2021 May 6.

Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan.

Background: The aim of this multicenter, randomized phase II study was to analyze the feasibility and safety of alternate-day S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely resected pathological stage I (tumor diameter > 2 cm) non-small cell lung cancer (NSCLC).

Methods: Patients were randomly assigned to receive adjuvant chemotherapy for 1 year comprising either alternate-day oral administration of S-1 (80 mg/m/day) for 4 days a week (Group A) or a 2-week oral administration of S-1 (80 mg/m/day) followed by 1 week of rest (Group B). The primary endpoint was feasibility, which was defined as the proportion of patients who completed the allocated intervention for 6 months with a relative dose intensity (RDI) of 70% or more.

Results: Ninety-three patients were enrolled of whom 90 patients received S-1 treatment. Median follow-up was 66.9 months. The treatment completion rate based on an RDI of 70% or more for 6 months was 84.4% (95%CI; 70.5-93.5%) in group A and 64.4% (95%CI; 48.8-78.1%) in group B. There were no grade 4 adverse events in either group. Moderate or severe adverse events (grade 2 or grade 3) were significantly more frequent in group B (67%) compared with group A (29%, P = 0.001). The 5-year relapse-free survival rate was 87.0 and 80.9% for group A and B, respectively (P = 0.451). The 5-year overall survival rate for all patients (n = 93) was 100 and 89.4% for group A and B, respectively (P = 0.136).

Conclusion: Alternate-day oral administration of S-1 for 1 year as adjuvant chemotherapy was demonstrated to be feasible with low toxicity in completely resected stage I (tumor diameter > 2 cm) NSCLC.

Trial Registration: Trial registration number: UMIN000011994 . Date of registration: 10/8/2013.
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http://dx.doi.org/10.1186/s12885-021-08232-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101150PMC
May 2021

Validation Study of the International Association for the Study of Lung Cancer Histologic Grading System of Invasive Lung Adenocarcinoma.

J Thorac Oncol 2021 Apr 24. Epub 2021 Apr 24.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Introduction: A histologic grading system for invasive lung adenocarcinoma (ADC) has been proposed by the International Association for the Study of Lung Cancer (IASLC) Pathology Committee in June 2020. This study evaluated the prognostic value of the IASLC histologic grading system (the IASLC system) in a large Japanese cohort.

Methods: We performed comprehensive histologic subtyping using the semiquantitative estimation of five major patterns and complex glandular patterns in patients with a completely resected lung ADC and determined the histologic grade using the IASLC system. Concordance index and receiver-operating characteristic curves were used to evaluate the clinical utility of the IASLC system for recurrence and death; the comparison was performed with the architectural-pattern system (the Arch system) and the grading system on the basis of the two most predominant patterns (the Sica's system).

Results: Of 1002 patients with invasive ADC, 235 had recurrent disease and 166 died of lung cancer. The concordance index and area under the curve of the IASLC system were 0.777 and 0.807 for recurrence and 0.767 and 0.776 for death, respectively. These were similar to those of the Arch system (0.763 and 0.796 for recurrence, 0.743 and 0.755 for death) and the Sica's system (0.786 and 0.814 for recurrence, 0.762 and 0.773 for death).

Conclusions: We reported that the IASLC system for invasive lung ADC has prognostic significance by evaluating a large Japanese cohort. We believe that the IASLC grading system will provide physicians with better information for postsurgery treatment.
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http://dx.doi.org/10.1016/j.jtho.2021.04.008DOI Listing
April 2021

Survival of Octogenarians with Early-Stage Non-small Cell Lung Cancer is Comparable Between Wedge Resection and Lobectomy/Segmentectomy: JACS1303.

Ann Surg Oncol 2021 Apr 26. Epub 2021 Apr 26.

Department of General Thoracic Surgery, Dokkyo Medical University, Shimotsuga, Japan.

Background: Anatomic resection with lymph node dissection or sampling is the standard treatment for early non-small cell lung cancer (NSCLC), and wedge resection is an option for compromised patients. This study aimed to determine whether wedge resection can provide comparable prognoses for elderly patients with NSCLC.

Methods: The study analyzed the clinicopathologic findings and surgical outcomes during a median follow-up period of 39.6 months for 156 patients with solid dominant (consolidation-to-tumor ratio > 0.5) small (whole tumor size ≤ 2 cm) NSCLC among 892 patients 80 years of age or older with medically operable lung cancer between April 2015 and December 2016.

Results: The 3-year overall survival (OS) rates after wedge resection and after segmentectomy plus lobectomy did not differ significantly (86.5 %; 95 % confidence interval [CI], 74.6-93.0 % vs 83.7 % 95 % CI, 74.0-90.0 %; P = 0.92). Multivariable Cox regression analysis of OS with propensity scores showed that the surgical procedure was not an independent prognostic predictor (hazard ratio [HR], 0.84; 95 % CI, 0.39-1.8; P = 0.64). The 3-year OS rates were slightly better after wedge resection for 97 patients who could tolerate lobectomy than after segmentectomy plus lobectomy (89.4 %; 95 % CI, 73.8-95.9 % vs 75.8 %; 95 % CI, 62.0-85.2 %; P = 0.14). The cumulative incidence of other causes for death was marginally higher after segmentectomy plus lobectomy than after wedge resection (P = 0.079).

Conclusions: Wedge resection might be equivalent to lobectomy or segmentectomy for selected patients 80 years of age or older with early-stage NSCLC who can tolerate lobectomy.
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http://dx.doi.org/10.1245/s10434-021-09835-wDOI Listing
April 2021

Prognostic significance of cribriform adenocarcinoma of the lung: validation analysis of 1,057 Japanese patients with resected lung adenocarcinoma and a review of the literature.

Transl Lung Cancer Res 2021 Jan;10(1):117-127

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Background: Cribriform-predominant adenocarcinoma of the lung (Cribri-ADC) is a recently described tumor growth pattern. However, its prognostic impact has not been clearly determined. We analyzed the data of a series of 1,057 Japanese patients with resected lung adenocarcinoma to identify the clinical significance of Cribri-ADC.

Methods: Cribriform pattern (Cribri-p) is defined as invasive back-to-back fused tumor glands with poorly formed glandular spaces or invasive tumor nests comprising tumors cells that produced glandular lumina. We investigated the correlations of Cribri-p and Cribri-ADC with clinicopathological factors as well as disease-free survival (DFS) and overall survival (OS).

Results: Cribri-p was present in 217 patients (20.5%) and Cribri-ADC was determined in 25 patients (2.4%). Cribri-p was associated with larger tumor size, pleural invasion, vascular invasion, lymphatic invasion, and spreading through air spaces (STAS) (all, P<0.0001). Cribri-ADC was associated with younger age (P=0.019), vascular invasion (P=0.0025), STAS (P<0.0001), and rearrangement (P=0.012). The DFS curve of patients with Cribri-ADC was identical to that of patients with solid adenocarcinoma; however, the OS curve was located between that of patients with papillary and acinar adenocarcinoma. Of the 10 patients who had tumor recurrences, eight had mutations or rearrangement, six of whom achieved relatively long survival (median, 64.6, range, 37.4-113 months) following treatment with tyrosine kinase inhibitors (TKIs). In multivariate analysis, Cribri-ADC was not an independent prognostic factor of either recurrence or death.

Conclusions: Cribri-ADC is associated with a higher risk of recurrence; however, most patients can be successfully treated with TKIs.
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http://dx.doi.org/10.21037/tlcr-20-612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867753PMC
January 2021

[Pulmonary Blastoma with the Differentiation of Adenocarcinoma and Large Cell Neuroendocrine Carcinoma in an Adult Patient;Report of a Case].

Kyobu Geka 2020 Sep;73(9):712-715

Department of Thoracic Surgery, Japanese Red Cross Osaka Hospital, Osaka, Japan.

A 63-year-old man was pointed out a mass lesion in his chest X-ray at a medical checkup and referred to our hospital for further examination. Chest computed tomography showed a 4 cm-diameter tumor in the left upper lobe. He was diagnosed with adenocarcinoma by bronchoscopic biopsy. Therefore, we performed left upper lobectomy. The tumor was diagnosed as pulmonary blastoma with the differentiation of adenocarcinoma and large cell neuroendocrine carcinoma.
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September 2020

The treatment and survival of patients with postoperative recurrent thymic carcinoma and neuroendocrine carcinoma: a multicenter retrospective study.

Surg Today 2021 Apr 10;51(4):502-510. Epub 2020 Aug 10.

Department of Thoracic Surgery, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Purpose: There are few data available on the outcomes of postoperative recurrent thymic carcinoma (TC) and thymic neuroendocrine carcinoma (TNEC). The aim of this study is to evaluate the treatment and survival in patients with recurrent TC and TNEC after undergoing surgical resection.

Methods: A retrospective chart review was performed using our multicenter database to identify patients with a postoperative recurrence of TC and TNEC from 1995 to 2018. The clinicopathological factors were reviewed and the survival outcomes were analyzed.

Results: Sixty patients were identified among 152 patients who underwent resection of TC and TNEC. The median follow-up period from the first recurrence was 14.8 months (range 0-144). The 5-year post-recurrence survival was 23% for the whole cohort. According to a univariable analysis, advanced stage [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.09-9.54], interval between primary surgery and recurrence (HR 0.97, 95% CI 0.95-0.99), any treatment for recurrence (HR: 0.27, 95% CI 0.13-0.58) and chemotherapy for recurrence (HR: 0.46, 95% CI 0.22-0.95) were significant factors related to post-recurrence survival.

Conclusions: Chemotherapy rather than surgery appears to be the mainstay treatment for managing patients with postoperative recurrent TC and TNEC and it may also be considered in multidisciplinary management. Further studies with a larger sample size are required to confirm our findings.
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http://dx.doi.org/10.1007/s00595-020-02102-7DOI Listing
April 2021

Large nest micropapillary pattern of lung adenocarcinoma has poorer prognosis than typical floret pattern: analysis of 1,062 resected tumors.

Transl Lung Cancer Res 2020 Jun;9(3):587-602

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Background: A micropapillary pattern (MP-p) is related to poor prognosis in patients with lung adenocarcinoma (L-ADC). In 2015, the WHO defined the MP-p as "papillary tufts forming florets that lack fibrovascular cores and may appear detached from alveolar walls"; however, the sizes of tumor clusters in air space were not mentioned in this classification.

Methods: We evaluated the MP-p dividing the cluster sizes in the air space by reviewing 1,062 cases of resected L-ADCs. We classified MP-p into two types according to cluster size as follows: typical floret MP-p, tumors with small-to-medium-sized clusters (1-20 tumor cells); and large nest MP-p, tumors with large-sized clusters (>20 tumor cells, large nest). We then recorded the frequency of each type and investigated the association between the MP-p type and clinicopathological factors.

Results: Twenty-nine percent of L-ADCs (n=308) were MP-p-positive. Typical floret MP-p and large nest MP-p were observed in 244 tumors (22.9%) and 64 tumors (6.0%), respectively. Only 7 additional micropapillary ADCs were detected when we reclassified ADCs in addition to large nest MP-p. Tumors with large nest MP-p showed the highest frequency of node metastasis and worse prognosis compared to those with typical floret MP-p and absent (P<0.001). In multivariate analysis, patients with L-ADC with typical floret MP-p and large nest MP-p showed a higher recurrence rate [hazard ratio (HR): 1.762 (type 1 absent), HR: 2.450 (type 2 absent)].

Conclusions: Large nest MP-p should be included in the original MP-p and recorded separately.
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http://dx.doi.org/10.21037/tlcr-19-731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354135PMC
June 2020

Tranilast Inhibits TGF-β1-induced Epithelial-mesenchymal Transition and Invasion/Metastasis the Suppression of Smad4 in Human Lung Cancer Cell Lines.

Anticancer Res 2020 Jun;40(6):3287-3296

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/aim: Transforming growth factor β1 (TGF-β1) is an important epithelial-mesenchymal transition (EMT) activator that regulates the expression of E-cadherin and vimentin through Smad signalling. Tranilast is an anti-allergic drug that inhibits TGF-β1, and is used in the treatment of keloids and hypertrophic scars. We investigated whether tranilast inhibits TGF-β1-induced EMT and invasiveness in human non-small cell lung cancer cell lines.

Materials And Methods: We examined the effects of tranilast treatment on EMT markers, TGF-β1/Smad signalling, and cell invasiveness in A549 and PC14 cells. Tumours from a mouse orthotopic lung cancer model with or without tranilast treatment were also immunohistochemically evaluated.

Results: Tranilast increased E-cadherin expression via Smad4 suppression and inhibited cell invasion in TGF-β1-stimulated cells. Tranilast treatment of the in vivo mouse model reduced the pleural dissemination of cancer cells and suppressed vimentin and Smad4 expression.

Conclusion: Tranilast inhibited TGF-β1-induced EMT and cellular invasion/metastasis by suppressing Smad4 expression in cancer cells.
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http://dx.doi.org/10.21873/anticanres.14311DOI Listing
June 2020

Discohesive growth pattern (Disco-p) as an unfavorable prognostic factor in lung adenocarcinoma: an analysis of 1062 Japanese patients with resected lung adenocarcinoma.

Mod Pathol 2020 09 20;33(9):1722-1731. Epub 2020 Apr 20.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Discohesive growth pattern (Disco-p) is often observed in lung adenocarcinoma (ADC) and mimics tumor budding (TB), stromal invasive-type micropapillary pattern (SMPP), and complex glandular pattern. However, the clinical impact of Disco-p in lung ADC has not been well studied. To investigate the prognostic significance of Disco-p, we analyzed 1062 Japanese patients with resected lung ADC. Disco-p was defined as an invasive growth pattern composed of single tumor cells, or trabeculae or small nests of tumor cells associated with desmoplastic fibrous stroma. We recorded the percentage of Disco-p in 5% increments independent of the major histologic pattern and investigated its correlation with different clinicopathological factors. We also analyzed the overall survival (OS) and disease-free survival (DFS). Disco-p was observed in 203 tumors (19.1%). Disco-p was significantly associated with male sex, smoking, lymph node metastasis, large tumor size, high TNM stage, lymphovascular and pleural invasion, spread through air spaces, and TB (all, p < 0.001). Of the total cases, only eight cases exhibited a dubious pattern between SMPP and Disco-p. Disco-p was also associated with wild-type EGFR (p < 0.001) and ALK fusion (p = 0.008). Patients harboring tumors with Disco-p had significantly worse prognoses (OS and DFS (both, p < 0.001)) compared with those without Disco-p. On multivariate analysis, Disco-p was an independent prognostic factor of worse OS (hazard ratio (HR), 2.572; 95% confidence interval (CI), 1.789-3.680; p < 0.001), and DFS (HR, 3.413; 95% CI, 2.482-4.683; p < 0.001), whereas TB was not an independent unfavorable prognostic factor. Disco-p was an independent unfavorable prognostic factor in patients with resected lung ADC, although a careful evaluation is necessary to distinguish it from similar patterns. We proposed that Disco-p should be recognized as a new invasive pattern and accurately recorded for the better management of patients with lung ADCs.
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http://dx.doi.org/10.1038/s41379-020-0537-9DOI Listing
September 2020

LPS-induced Airway-centered Inflammation Leading to BOS-like Airway Remodeling Distinct From RAS-like Fibrosis in Rat Lung Transplantation.

Transplantation 2020 06;104(6):1150-1158

Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Localization of inflammatory stimuli may direct lung allografts to different phenotypes of chronic dysfunction, such as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). We hypothesized that airway stimulation with lipopolysaccharide (LPS) in rats leads to airway-centered inflammation similar to human BOS.

Methods: Rat left lung transplantation was conducted (donor: Brown Norway, recipient: Lewis). Allotransplant recipients received cyclosporine A (CsA) until postoperative day 56 with airway instillation of LPS (Allo-LPS, n = 8), phosphate buffered saline (Allo-PBS, n = 5) from days 35 to 46 (3 times a wk), or no further treatment (n = 4). Some allotransplant recipients received CsA until day 14 and were immunosuppression free after day 15 until day 56. Bronchial and pleural fibrosis were semiquantified; alveolar fibrosis was evaluated with a histological scale.

Results: The Allo-LPS group had significantly increased International Society for Heart and Lung Transplantation rejection grades (grade A, P = 0.005; grade B, P = 0.004), bronchial obstructive proportion (0.34 ± 0.04% [Allo-LPS] versus 0.11 ± 0.04% [Allo-PBS], P = 0.006), and airway resistance (3.05 ± 1.78 cm H2O·s/mL [Allo-LPS] versus 0.83 ± 0.58 cm H2O·s/mL [Allo-PBS], P = 0.007) compared with other groups. Allotransplant recipients that underwent a short course of CsA developed RAS-like fibrosis involving the airways, alveoli, and pleura.

Conclusions: Airway instillation of LPS in allografts under immunosuppression resulted in BOS-like airway-centered inflammation and fibrosis distinct from RAS-like diffuse fibrosis, which was induced by a shortened course of immunosuppression. We propose novel animal models for BOS and RAS after lung transplantation.
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http://dx.doi.org/10.1097/TP.0000000000003097DOI Listing
June 2020

[Segmentectomy for Congenital Left Upper Lobar Bronchial Atresia].

Kyobu Geka 2019 Nov;72(12):1001-1004

Department of Thoracic Surgery, Osaka Red Cross Hospital, Osaka, Japan.

A 22-year-old woman visited a hospital to treat her dyspnea which had lasted for some months. Chest X-ray showed hyperlucency in her left upper lung field and chest computed tomography suggested left upper bronchial obstruction with mucoid impaction. She was referred to our hospital for further examination and treatment. Bronchoscopy showed left upper lobar bronchial atresia. Considering her dyspnea worsened in relatively short terms, surgical treatment was chosen and the resection of left upper division was successfully performed.
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November 2019

Prognostic factors related to postoperative survival in the newly classified clinical T4 lung cancer.

Eur J Cardiothorac Surg 2020 04;57(4):754-761

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: T4 lung cancer has become a more heterogeneous group since the 8th edition of tumour, node, metastasis classification. The aim of this study was to identify predictive factors related to post-surgical survival in patients with clinical T4 non-small-cell lung cancer (NSCLC), based on the 8th edition of the classification.

Methods: We retrospectively reviewed consecutive patients with clinical T4 NSCLC who underwent resection between January 2006 and December 2016, to identify factors associated with overall survival.

Results: Ninety-three patients were identified. The criteria for clinical T4 disease included tumours larger than 7 cm (n = 54), great vessels or left atrial invasion (n = 22), mediastinal invasion (n = 11), vertebral invasion (n = 3), tracheal or carina invasion (n = 3), diaphragm invasion (n = 1) and ipsilateral different lobe pulmonary metastasis (n = 2). The postoperative nodal status was 0, 1, 2 and 3 in 59, 18, 15 and 1 patient, respectively. R0 resection was achieved in 80 patients, and the 30-day mortality was 0%. The median follow-up time was 37.6 months, and the 5-year overall survival rate was 56.3%. The multivariable analysis revealed that nodal status and R-status were significant prognostic factors for postoperative survival [hazard ratio (HR) 2.62, 95% confidence interval (CI) 1.20-5.72, P = 0.016 and HR 3.29, 95% CI 1.45-7.44, P = 0.004].

Conclusions: Surgery provided encouraging survival outcomes for clinical T4 NSCLC based on the 8th edition of classification. The nodal status and R-status were significant prognostic factors for postoperative survival.
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http://dx.doi.org/10.1093/ejcts/ezz288DOI Listing
April 2020

Salvage Surgery After Chemotherapy or Chemoradiotherapy for Initially Unresectable Lung Carcinoma.

Ann Thorac Surg 2019 12 21;108(6):1664-1670. Epub 2019 Aug 21.

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.

Background: Salvage surgery is used for resection of locoregionally recurrent or regrowing lesions after treatment for unresectable non-small cell lung cancer. It is also used to resect lesions that have regressed after treatment and that had not initially been indicated for resection. Relationships between salvage surgery, safety, and prognosis, however, have remained unclear.

Methods: Between 2006 and 2017, 29 patients received salvage resection (median age, 60 years; 25 men and 4 women). Safety and prognosis were analyzed.

Results: Tumor grade at the time of initial treatment was stage III or IV in 23 and 6 patients, respectively. Twenty-two patients received chemoradiotherapy (radiation, 40-66 Gy) and 7 received chemotherapy. Time from initial treatment to surgery ranged from 2 to 60 months. Segmentectomy, lobectomy, bilobectomy and pneumonectomy were performed in 1, 25, 2, and 1 patients, respectively. Combined resections were needed in 17 patients; this included 10 bronchoplasties, 9 pulmonary arterioplasties, 4 chest wall resections, and 1 great vessel resection. There was no 30-day postoperative mortality. Grade 3 or higher-grade postoperative complications (mostly cardiopulmonary) were observed in 11 patients. Five-year overall survival after initial treatment was 61%; after surgery it was 51%. Five-year relapse-free survival after surgery was 49%. On recurrent-free survival patients with clinical stage III at the initial treatment, pathologic stage 0-II, or a good response to initial treatment showed a favorable prognosis.

Conclusions: Although cardiopulmonary complications can accompany salvage surgery, the procedure is generally safe. Survival outcome is encouraging, especially in cases with good response to initial treatment.
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http://dx.doi.org/10.1016/j.athoracsur.2019.06.087DOI Listing
December 2019

Dedifferentiated liposarcoma of the thyroid gland: A case report.

Mol Clin Oncol 2019 Sep 18;11(3):219-224. Epub 2019 Jun 18.

Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Liposarcoma is one of the most common soft tissue tumors that affect adults. Liposarcoma is typically identified in the retroperitoneum, trunk and extremities as a slow-growing mass, yet is rare in the thyroid gland. Herein, we report a case of dedifferentiated liposarcoma that developed in the thyroid gland, and performed a literature review. A 66-year-old male with a history of well-differentiated liposarcoma in the thymus presented with a rapidly enlarging mass in the thyroid gland. Malignancy was suspected due to the local extension of the tumor, and complete resection of the tumor was achieved. Tissue diagnosis from the tumor following surgery revealed that dedifferentiated liposarcoma, and tumor progression was difficult to control with adjuvant radiation and chemotherapy. This is, to the best of our knowledge, the first case to report dedifferentiated liposarcoma in the thyroid gland, and the difficulty in initial diagnosis as well as the aggressive features of dedifferentiated liposarcoma are highlighted.
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http://dx.doi.org/10.3892/mco.2019.1882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636207PMC
September 2019

Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.

Sci Rep 2019 07 12;9(1):10144. Epub 2019 Jul 12.

Kyoto University Institute for Advanced Study, Kyoto, Japan.

Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients' immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.
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http://dx.doi.org/10.1038/s41598-019-46548-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626008PMC
July 2019

Prognostic Significance of Phosphorylated Fyn in Patients with Lung Adenocarcinoma after Lung Resection.

Ann Thorac Cardiovasc Surg 2019 Oct 12;25(5):246-252. Epub 2019 Jun 12.

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan.

Purpose: Src family tyrosine kinases, including Fyn, are non-receptor tyrosine kinases that drive malignancy in various kinds of cancers. Fyn has also been suggested to be an effector of epidermal growth factor receptor (EGFR) signaling, and is recognized as a potential therapeutic target. However, little is known about the clinical importance of phosphorylated Fyn (pFyn) in lung adenocarcinoma. The purpose of this study is to examine the prognostic significance of pFyn in this disease.

Methods: A total of 282 lung adenocarcinoma specimens were collected from patients who underwent surgery at our institute. A tissue microarray was assembled from paraffin-embedded tumor blocks. pFyn expression was analyzed through immunostaining of the tissue microarray and each case was classified as positive or negative. The association of clinical information with pFyn expression was analyzed statistically.

Results: pFyn was positive in 107 cases. A pFyn-positive status was significantly associated with male gender, p53 mutant, pathological stage, tumor size, plural invasion, lymphatic invasion, vascular invasion, and differentiation. pFyn positivity was associated with poor relapse-free survival (RFS; hazard ratio [HR]: 2.11, 95% confidence interval [CI]: 1.32-3.42, p <0.01) and poor overall survival (OS; HR: 1.95, 95% CI: 1.17-3.33, p = 0.01).

Conclusion: pFyn expression may affect the prognosis of patients with lung adenocarcinoma after lung resection.
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http://dx.doi.org/10.5761/atcs.oa.19-00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823168PMC
October 2019

Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection.

Cancer Manag Res 2019 18;11:3419-3432. Epub 2019 Apr 18.

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma. Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model. Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14-3.85). Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.
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http://dx.doi.org/10.2147/CMAR.S200819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497483PMC
April 2019

P40 expression in small cell lung cancer: The presence of p40-positive cells does not always indicate squamous differentiation.

Thorac Cancer 2019 05 7;10(5):1188-1192. Epub 2019 Apr 7.

Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.

Background: Small cell lung cancer (SCLC) is normally diagnosed with hematoxylin and eosin stains, although some cases require immunohistochemistry (IHC). P40 is highly sensitive and specific for squamous cell carcinoma and is thus considered the best marker for this cancer. However, the status of p40 expression in SCLC is not well known. The aim of this study was to analyze p40 expression in resected SCLC using IHC.

Methods: Forty-four surgically resected SCLC cases were enrolled. Clinical data were obtained from the patients' medical records. Pathologists blinded to the patients' clinical data reviewed the SCLC slides. IHC was performed on a representative slide of each case.

Results: Although p40 was not diffusely expressed in any of the SCLC cases, p40-positive cells were observed in the tumors in 15 cases (34.1%). Ten of these exhibited p40 in < 1% of tumor cells. In the remaining five cases, 1-5% of tumor cells expressed p40, and in three of these, the cells expressing p40 also expressed TTF-1 and neuroendocrine markers. There was no statistically significant relationship between p40 positivity and any other clinicopathological characteristics.

Conclusions: Some resected SCLCs express p40 focally. This result suggests that the presence of positive p40 cells does not exclude a diagnosis of SCLC. Thus, small biopsy or cytology specimens with p40-positive cells must be diagnosed carefully.
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http://dx.doi.org/10.1111/1759-7714.13062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501015PMC
May 2019

Manifestation of congenital pulmonary airway malformation in a 26-year-old adult, requiring surgery.

Interact Cardiovasc Thorac Surg 2019 07;29(1):154-156

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.

This is a case of type 1 congenital pulmonary airway malformation in the left lower lobe of a 26-year-old male. At the age of 1 year, he developed a pulmonary cystic lesion, which was considered to be bronchopulmonary sequestration. He grew up healthy and showed no impairment during exercise; however, giant bullous lesion development along with compressed left upper lobe and mediastinum was recently noted; consequently, the patient was referred to our hospital for further examination. We diagnosed congenital pulmonary airway malformation and performed left lower lobectomy. Postoperative course was uneventful, but a restrictive change on pulmonary function test did not improve. This unusual course of congenital pulmonary airway malformation with bullous changes suggests the importance of early-stage resection.
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http://dx.doi.org/10.1093/icvts/ivz032DOI Listing
July 2019

Prognostic impact of microscopic vessel invasion and visceral pleural invasion and their correlations with epithelial-mesenchymal transition, cancer stemness, and treatment failure in lung adenocarcinoma.

Lung Cancer 2019 02 6;128:13-19. Epub 2018 Dec 6.

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: Microscopic vessel invasion (MVI) and visceral pleural invasion (VPI) have been recently reported as poor prognostic factors of non-small cell lung cancer. Epithelial-mesenchymal transition (EMT) and cancer stemness (CS) are known malignant phenotypes that induce resistance to cancer therapy. We aimed to assess the prognostic significance of MVI and the correlations among VPI/MVI, EMT, CS, and treatment failure for recurrent tumor.

Materials And Methods: From 2002 to 2013, 1034 consecutive patients with pathological T1-4N0-2M0 lung adenocarcinoma underwent complete resection. Moreover, we established 206 tissue microarray (TMA) samples from 2002 to 2007. We then evaluated the prognostic impact of MVI, including conventional clinicopathological factors, and analyzed the VPI/MVI, EMT, CS, and treatment failure by TMA immunohistochemical staining.

Results: Among the 1034 cases, the proportion of patients with a 5-year overall survival (OS) period was 63.9% and 88.2% (MVI: +/-; p < .001). Multivariate analysis revealed that both MVI and VPI were independent predictors of OS (HR 1.57 and 1.47, respectively). Significant separation of the OS rate curves was observed among the 3 groups [VPI/MVI: both positive (2), either positive (1), and both negative (0)]. Among the 206 TMA cases, these 3 groups of VPI/MVI were significantly correlated with EMT and CS. The median time to progression after recurrence were 3.8, 8.9, and 15.9 months, respectively (VPI/MVI: 2/1/0; p =  0.016).

Conclusion: MVI and VPI are significant prognostic factors of lung cancer, and they are correlated with EMT, CS, and treatment failure for recurrent tumor.
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http://dx.doi.org/10.1016/j.lungcan.2018.12.001DOI Listing
February 2019

Ex Vivo Sleeve Lobectomy and Autotransplantation After Chemoradiation.

Ann Thorac Surg 2019 May 25;107(5):e341-e343. Epub 2018 Oct 25.

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan. Electronic address:

A 51-year-old man presented to us for potential salvage surgery for local recurrence of a squamous cell carcinoma originating in the left lower lobe after definitive chemoradiotherapy. Salvage sleeve lower lobectomy was initially planned; however, intraoperatively the interlobar pulmonary artery was difficult to separate from the bronchus. To safely spare the upper lobe, we performed ex vivo sleeve lower lobectomy, followed by autotransplantation of the upper lobe. No major postoperative complication was noted and the patient has returned to normal life without recurrence for 9 months.
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http://dx.doi.org/10.1016/j.athoracsur.2018.09.013DOI Listing
May 2019

Survival outcomes after minimally invasive thymectomy for early-stage thymic carcinoma.

Surg Today 2019 Apr 14;49(4):357-360. Epub 2018 Nov 14.

Department of Thoracic Surgery, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Minimally invasive surgery (MIS) has occasionally been used for selected patients with thymoma, but there is little information on the MIS approach for thymic carcinoma. The aim of this study was to evaluate survival outcomes after MIS for early-stage (Masaoka stage I-II) thymic carcinoma and thymic neuroendocrine carcinoma. A retrospective chart review of the cases recorded in our multi-institutional database was performed to identify patients who underwent resection for thymic carcinoma between 1995 and 2017. MIS thymectomy was performed in 17 cases (VATS, n = 14; RATS, n = 3. male, 41%; median age, 72 years). The median follow-up period was 32.7 (range 7.4-106) months. The five-year overall survival and relapse-free survival rates were 84.4% and 77.8%, respectively. The present study demonstrated encouraging preliminary results regarding MIS for the treatment of early-stage thymic carcinoma and thymic neuroendocrine carcinoma. Further studies with a larger sample size are required to evaluate the indications for this surgery.
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http://dx.doi.org/10.1007/s00595-018-1740-xDOI Listing
April 2019

Prognostic impact of preoperative comorbidities in geriatric patients with early-stage lung cancer: Significance of sublobar resection as a compromise procedure.

Lung Cancer 2018 11 29;125:192-197. Epub 2018 Sep 29.

Department of Thoracic Surgery, Kyoto University Hospital, 54 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 6068507, Japan.

Objectives: In high-risk operable geriatric patients undergoing palliative sublobar resection (SR), noncancerous comorbidities may contribute to unfavorable outcomes. The purpose of this retrospective study was to evaluate the perioperative safety and long-term survival of palliative SR in this patient population.

Materials And Methods: We reviewed 232 patients (141 male, 91 female) aged ≥75 years who underwent surgical resection of clinical stage I lung cancer from 2006 to 2014. The patients were divided into two groups, lobectomy and SR, and preoperative comprehensive comorbidities were assessed using the Adult Comorbidity Evaluation 27 (ACE-27) and compared between the two groups. The operative safety was compared using the Clavien-Dindo classification. Survival rates were calculated with a Kaplan-Meier model under propensity score matching, and prognostic factors were analyzed using a Cox proportional hazard model.

Results: Lobectomy was performed in 156 patients and SR in 76 (segmentectomy, n = 50; wedge resection, n = 26). Age (p = 0.0137), tumor size on computed tomography (p < 0.0001), central tumor location (p = 0.0008), and high ACE-27 scores (p = 0.0202) were significantly associated with selection of SR. No mortality occurred, and the incidence of Grade 3b or greater postoperative complications in lobectomy and SR was 5.1% and 5.3%, respectively. According to the analysis of propensity score-matched patients (n = 57, tumor size = 23 mm, and consolidation/tumor ratio = 83%), the 5-year survival rate in lobectomy and SR was 81.1% and 73.5%, respectively (p = 0.4374). The ACE-27 score was a more significant prognostic factor than the type of surgical procedure, as well as consolidation/tumor ratio and nodal metastatic status.

Conclusions: The severity of preoperative comorbidities is a significant prognostic factor, and SR as a compromise surgical procedure may provide promising short- and long-term outcomes in selected geriatric patients with clinical stage I lung cancer.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.023DOI Listing
November 2018

Native upper lobe-sparing living-donor lobar lung transplantation maximizes respiratory function of the donor graft.

J Heart Lung Transplant 2019 01 25;38(1):66-72. Epub 2018 Sep 25.

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address:

Background: We have developed a novel method for native upper lobe-sparing living-donor lobar lung transplantation (LDLLT) to overcome a small-for-size graft in standard LDLLT with acceptable results. We hypothesized that grafts implanted with this procedure might work more efficiently than those in standard lobe transplantation.

Methods: Bilateral LDLLT was performed in 31 patients with a functional graft matching of less than 60% at our institution between August 2008 and December 2015. Of these, 22 patients were available for evaluation of pulmonary function more than 1 year later: 15 undergoing standard LDLLT with less than 60% functional matching and 7 undergoing native upper lobe-sparing LDLLT.

Results: Overall survival at 2 years was 87.5% in the lobe-sparing LDLLT patients and 79.0% in the standard LDLLT patients (p = 0.401). The median forced vital capacity size-matching levels were 50.7% ± 1.6% in the standard LDLLT and 45.2% ± 2.3% in the sparing LDLLT group (p = 0.074). The 1-year and 2-year post-operative volume ratios of inspiration to expiration were significantly different between the 2 groups, at 1.76 and 1.45 after standard LDLLT (p = 0.019) vs 2.41 and 2.23 after lobe-sparing LDLLT (p = 0.015).

Conclusions: The grafts in lobe-sparing LDLLT functioned more effectively than those in standard LDLLT. This advantage was associated with the improvement of pulmonary functions.
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http://dx.doi.org/10.1016/j.healun.2018.09.012DOI Listing
January 2019

Low incidence of and mortality from a second malignancy after resection of thymic carcinoma†.

Interact Cardiovasc Thorac Surg 2019 03;28(3):375-379

Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: Previous studies have suggested that a second malignancy often develops after resection of thymoma; however, it remains unknown whether this is applicable to thymic carcinoma.

Methods: A retrospective chart review was performed based on our multi-institutional database of resected thymic epithelial tumours between 1991 and 2016. A second malignancy was defined as newly diagnosed after thymic tumour resection. The cumulative incidence of and related death from a second malignancy after thymic and neuroendocrine carcinoma resections were estimated using a competing risk model and were compared to those of patients undergoing a thymoma resection.

Results: Two hundred and thirty-eight patients were identified (thymic carcinoma 59; thymoma 179). A second malignancy developed in 1 patient (1.7%) with thymic carcinoma and in 17 patients (9.5%) with thymoma. Deaths from second malignancies were noted in 7 patients with thymoma. There was a tendency towards a lower cumulative incidence of and a lower cumulative death from a second malignancy after thymic carcinoma resection (P = 0.139 and P = 0.20, respectively) than after thymoma resection. The cumulative incidence of a second malignancy in patients with thymic carcinoma was 2.8% at 5 years and at 10 years (8.0% at 5 years and 11.8% at 10 years in patients with thymoma).

Conclusions: After resection of thymic and thymic neuroendocrine carcinoma, the probability of developing a second malignancy, as well as mortality from a second malignancy, is very low. A prospective study with a larger sample size is required to validate our results.
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http://dx.doi.org/10.1093/icvts/ivy260DOI Listing
March 2019

Diagnostic yield of electromagnetic navigational bronchoscopy: results of initial 35 cases in a Japanese institute.

J Thorac Dis 2018 Jun;10(Suppl 14):S1615-S1619

Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.

Background: Electromagnetic navigational bronchoscopy (ENB) is a new bronchoscopic technique for navigational transbronchial lung biopsy (TBLB) that guides the sheath to the target lesion in real time. Herein, we report our experience with this navigational system, its diagnostic yields, and associated complications.

Methods: A single-center, single-operator retrospective chart review was performed. We included 35 consecutive patients who underwent ENB with superDimension (Medtronic, MN, USA) for the diagnosis of pulmonary lesions from February 2016 to May 2017 in Kyoto University Hospital. The size of the target lesion varied from 8 to 25 mm (median, 15.28±5.48 mm). All ENB procedures were performed under conscious sedation using 2 to 10 mg midazolam and 1 to 10 mg morphine hydrochloride. No fluoroscopic guide was employed except in three cases.

Results: A total of 25 patients were diagnosed via ENB, yielding a diagnostic rate of 71.4% (25/35). The average lesion size of the diagnosed group was 16.44±5.44 mm (range, 8-25 mm). Eighteen cases were diagnosed as primary lung cancer, 3 were metastatic lung cancer, and 4 were inflammatory diseases. The average lesion size of the 10 undiagnosed cases was 12.40±5.21 mm (range, 8-24 mm). The lesion size of the undiagnosed group was significantly smaller than that of the diagnosed group (P=0.02). The average time required for the procedure was 16.78±9.57 minutes (range, 3-46 minutes), independent of the diagnosis, the lesion size, and the tumor location. We encountered one pneumothorax which required chest drainage and one hemopneumothorax which required non-elective thoracotomy and wedge resection. One patient developed high fever over 38 °C for one day following the procedure.

Conclusions: In our initial series of 35 cases, ENB-guided TBLB showed an acceptable diagnostic yield.
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http://dx.doi.org/10.21037/jtd.2018.04.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035916PMC
June 2018

Thoracoscopic rebiopsy to detect the T790M mutation after postoperative recurrence.

Interact Cardiovasc Thorac Surg 2018 10;27(4):606-608

Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.

After pulmonary resection for non-small-cell lung cancer, some patients with postoperative recurrence and mutated epidermal growth factor receptor (EGFR) subsequently receive EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib may be efficacious if those patients become resistant to the 1st-line EGFR-TKI because of the T790M mutation. We recently performed thoracoscopic rebiopsy to detect the T790M mutation in 4 patients who became resistant to the 1st-line EGFR-TKI treatment for postoperative recurrence. Our limited experience suggests that thoracoscopic biopsy is associated with limited morbidity, can help detect the T790M mutation and may improve the management of select patients with acquired resistance to the 1st-line EGFR-TKIs.
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http://dx.doi.org/10.1093/icvts/ivy107DOI Listing
October 2018

Salvage Pulmonary Metastasectomy for Local Relapse After Stereotactic Body Radiotherapy.

Ann Thorac Surg 2018 04;105(4):e165-e168

Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.

Although several studies have evaluated the local control and survival outcomes in patients undergoing stereotactic body radiotherapy (SBRT) for pulmonary oligometastases, little data are available on the management of local relapse. Here, we present 3 patients who underwent lobectomy and mediastinal lymph node dissection as salvage pulmonary metastasectomy for local relapse after SBRT. The postoperative course has been uneventful for all 3 patients, with no evidence of disease at 40, 51, and 6 months from the salvage metastasectomy. Our experience suggests that salvage pulmonary metastasectomy may be associated with local control and long-term survival in carefully selected patients.
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http://dx.doi.org/10.1016/j.athoracsur.2017.11.003DOI Listing
April 2018
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