Publications by authors named "Ichiro Yoshino"

327 Publications

Surgical outcomes of pulmonary metastasectomy for head and neck cancer in the current era of advances in chemotherapy and immunotherapy.

Gen Thorac Cardiovasc Surg 2021 Mar 23. Epub 2021 Mar 23.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Objective: The innovation of novel systemic chemo/immunotherapy for metastatic head and neck cancer might contribute to prognostic improvement. We aimed to clarify the recent characteristics and outcomes of pulmonary metastasectomy for head and neck cancer.

Methods: Twenty-five patients who underwent pulmonary metastasectomy from January 2011 to December 2016 were included. The clinicopathological factors and survival were assessed by retrospective chart reviews.

Results: The median follow-up period was 39 months (range, 7-94 months). The median age was 66 years (range, 20-89 years), and 23 males were included. The primary tumor locations were as follows: pharynx (n = 12), nasal/paranasal cavity (n = 5), larynx (n = 4), and others (n = 4). The 5-year overall survival rate was 49%. In the univariate analysis, a history of local recurrence before pulmonary metastasis was an independent predictor of a poor prognosis. In 90% of patients with recurrence after pulmonary metastasectomy, the site of recurrence was the lung. Eight patients achieved long-term survival without any evidence of recurrence (median: 45 months). Molecular targeting chemotherapy and immune-checkpoint inhibitors were used in five patients with systemic recurrence after pulmonary metastasectomy, leading to preferable survival.

Conclusions: In the current era of advances in systemic chemotherapy and immunotherapy, surgical indication has not changed for resectable pulmonary metastases and selected patients can still benefit from pulmonary metastasectomy. Further investigation is needed to clarify the significance of systemic therapy in patients with pulmonary metastasis of head and neck cancer.
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http://dx.doi.org/10.1007/s11748-021-01611-7DOI Listing
March 2021

Alternative approaches for clinical clerkship during the COVID-19 pandemic: online simulated clinical practice for inpatients and outpatients-A mixed method.

BMC Med Educ 2021 Mar 8;21(1):149. Epub 2021 Mar 8.

Health Professional Development Center, Chiba University Hospital, Chiba, Japan.

Background: The COVID-19 pandemic has created a need for educational materials and methods that can replace clinical clerkships (CCs) for online simulated clinical practice (online-sCP). This study evaluates the impact of using simulated electronic health records (sEHR) for inpatients, and electronic problem-based learning (e-PBL) and online virtual medical interviews (online-VMI) for outpatients, for an online-sCP using a learning management system (LMS) and online meeting system facilitated by a supervising physician.

Methods: The sEHR was reviewed by medical students and subsequently discussed with a supervising physician using an online meeting system. In the e-PBL, medical students reviewed the simulated patients and discussed on the LMS. For the online-VMI, a faculty member acted as an outpatient and a student acted as the doctor. Small groups of students discussed the clinical reasoning process using the online meeting system. A mixed-method design was implemented. Medical students self-assessed their clinical competence before and after the online-sCP. They answered questionnaires and participated in semi-structured focus group interviews (FGIs) regarding the advantages and disadvantages of the practice.

Results: Forty-three students completed the online-sCP during May and June 2020. All students indicated significant improvement in all aspects of self-evaluation of clinical performance after the online-sCP. Students using sEHR reported significant improvement in writing daily medical records and medical summaries. Students using e-PBL and online-VMI reported significant improvement in medical interviews and counseling. Students also indicated CCs as more useful for learning associated with medical interviews, physical examinations, and humanistic qualities like professionalism than the online-sCP. Eight FGIs were conducted (n = 42). The advantages of online-sCP were segregated into five categories (learning environment, efficiency, accessibility, self-paced learning, and interactivity); meanwhile, the disadvantages of online-sCP were classified into seven categories (clinical practice experience, learning environment, interactivity, motivation, memory retention, accessibility, and extraneous cognitive load).

Conclusions: Online-sCP with sEHR, e-PBL, and online-VMI could be useful in learning some of the clinical skills acquired through CC. These methods can be implemented with limited preparation and resources.
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http://dx.doi.org/10.1186/s12909-021-02586-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938264PMC
March 2021

Cell tracking suggests pathophysiological and therapeutic role of bone marrow cells in Sugen5416/hypoxia rat model of pulmonary arterial hypertension.

Can J Cardiol 2021 Feb 17. Epub 2021 Feb 17.

Department of Respirology (B2).

Background: The mechanism of vascular remodeling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT).

Methods: To trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx).

Results: In the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared to wild-type Su/Hx rats without BM transplantation (p = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats.

Conclusions: BM-derived cells participate in pulmonary vascular remodeling in the Su/Hx rat model; while BM transplantation may contribute to suppression of PAH development.
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http://dx.doi.org/10.1016/j.cjca.2021.02.006DOI Listing
February 2021

Outcomes of lung transplantation for idiopathic pleuroparenchymal fibroelastosis.

Surg Today 2021 Feb 12. Epub 2021 Feb 12.

Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF).

Methods: We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018.

Results: There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m, respectively; P < 0.01). However, Kaplan-Meier survival curves showed no significant difference in overall survival between the groups. The BMI did not increase in patients with IPPFE, even 1 year after LT (pretransplant, 16.5 ± 3.2 kg/m vs. 1 year post-transplant, 15.6 ± 2.5 kg/m; P = 0.08). The percent predicted forced vital capacity (%FVC) 1 year after LT was significantly lower in the IPPFE group than in the IPF group (48.4% ± 19.5% vs. 68.6% ± 15.5%, respectively; P < 0.01).

Conclusions: Despite extrapulmonary problems such as a flat chest, low BMI, and associated restrictive impairment persisting in patients with IPPFE, patient survival after LT for IPPFE or IPF was equivalent.
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http://dx.doi.org/10.1007/s00595-021-02232-6DOI Listing
February 2021

Genetic alterations in squamous cell lung cancer associated with idiopathic pulmonary fibrosis.

Int J Cancer 2021 Feb 3. Epub 2021 Feb 3.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.
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http://dx.doi.org/10.1002/ijc.33499DOI Listing
February 2021

Certified thoracic surgeons in Japan: a national database survey on risk-adjusted mortality associated with lung resection.

Surg Today 2021 Jan 30. Epub 2021 Jan 30.

Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.

Purpose: We investigated the association between the number of certified general thoracic surgeons (GTSs) and the mortality after lung cancer surgery, based on the data from the National Clinical Database (NCD).

Methods: We analyzed the characteristics and operative and postoperative data of 120,946 patients who underwent lung cancer surgery in one of the 905 hospitals in Japan. The number of GTSs in each hospital was categorized as 0, 1-2, or 3 or more. Multivariable analysis was applied to adjust the patients' preoperative risk factors, as identified in a previous study. We calculated 95% confidence intervals (CI) for the mortality rate based on the odds ratios (ORs).

Results: The patients' characteristics were distributed almost uniformly regardless of the number of GTSs. Crude mortality according to the number of GTSs of 0, 1-2, or 3 or more was 0.9%, 0.8%, and 0.7%, respectively (p = 0.03). However, after adjustment, the ORs for 1-2 and 3 or more GTSs (reference: 0) were 0.86 (p = 0.23, 95% CI: 0.67-1.10) and 0.84 (p = 0.18, 95% CI: 0.64-1.09), respectively. The number of GTSs did not have a significant association with mortality. Similar results were observed for patients in the lobectomy cohort.

Conclusion: Low surgical mortality was consistent, regardless of the number of GTSs in each hospital.
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http://dx.doi.org/10.1007/s00595-021-02227-3DOI Listing
January 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.
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http://dx.doi.org/10.1016/j.jtcvs.2020.09.146DOI Listing
November 2020

Left superior segmentectomy for a patient with displaced anomalous apicoposterior branches of the pulmonary vein and bronchus: a case report.

Surg Case Rep 2021 Jan 6;7(1). Epub 2021 Jan 6.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Knowledge of anatomical abnormalities and variations in pulmonary vessels and bronchi is critical for patients requiring a lung segmentectomy. To the best of our knowledge, this is the first case of a tumor existing in the lower lobe in conjunction with a displaced B in which the B was not accidentally cut during surgery.

Case Presentation: A 71-year-old woman was referred to our hospital after a part-solid lung cancer was found in the superior segment of her left lung on chest computed tomography. Preoperative three-dimensional computed tomography revealed a displaced anomalous left B arising from the left main bronchus and anomalous V returning to the inferior pulmonary vein. We identified these anomalies during surgery and performed a left superior segmentectomy. After an unremarkable recovery, the patient was discharged from the hospital on the eighth day postoperative.

Conclusions: We used a three-dimensional construction system during the preoperative planning of the pulmonary segmentectomy to better understand the bronchovascular structures. When performing surgery where anatomical abnormalities are present, there is the possibility of misidentification. Using the three-dimensional construction system, it was possible to perform safer surgery, as the surgeons were able to preoperatively prepare for any abnormalities.
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http://dx.doi.org/10.1186/s40792-020-01097-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788113PMC
January 2021

Risk factors for skeletal-related events in non-small cell lung cancer patients treated with bone-modifying agents.

Support Care Cancer 2021 Jan 6. Epub 2021 Jan 6.

Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Purpose: The risk factors for skeletal-related events (SREs) among non-small cell lung cancer (NSCLC) patients during treatment with bone-modifying agents (BMAs) are not yet well-understood.

Methods: The medical records of 238 consecutive NSCLC patients treated with BMAs, including zoledronic acid and denosumab, at the Chiba University Hospital from 2012 to 2016 were reviewed in the present study. SREs were defined as either pathologic fractures, spinal cord compression, the need for bone irradiation or surgery, or hypercalcemia. The risk factors for earlier occurrence of the first SRE from the time of the first bone metastasis diagnosis after the initiation of BMA treatment were identified.

Results: Of the 238 included patients, 92% (n = 220) had a performance status (PS) of 0-2 at diagnosis of bone metastasis. Forty-eight (20%) patients developed at least one SRE. The most common first SRE was the need for bone irradiation surgery (n = 27, 56%). Significant risk factors included poor PS (hazard ratio [HR]: 4.36; p = .024), male sex (HR: 2.17; p = .022), and the use of zoledronic acid (HR: 1.91; p = .032). The overall survival (OS) from the first bone metastasis diagnosis was 394 days (95% confidence interval [CI]: 331-465). The OS of patients with PS 3 and 4 at the diagnosis of bone metastasis (median: 36 days; 95% CI: 13-50) was significantly (p < 0.0001) shorter than that of patients with PS 0-2 (median: 411 days; 95% CI: 354-558) (HR: 4.53; 95% CI: 2.62-7.35).

Conclusions: Careful observation is needed for patients with the identified risk factors, which include poor PS and male sex, despite the BMA treatment.
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http://dx.doi.org/10.1007/s00520-020-05880-5DOI Listing
January 2021

Management of thoracic empyema with broncho-pulmonary fistula in combination with negative-pressure wound therapy.

Gen Thorac Cardiovasc Surg 2021 Jan 3. Epub 2021 Jan 3.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.

Objective: Intrathoracic negative-pressure wound therapy (NPWT) has been introduced as a novel therapeutic device for the management of empyema. NPWT is expected to reduce the empyema cavity more rapidly than standard treatments; however, no objective analysis of the function of NPWT has yet been conducted. The study objective was to evaluate the efficacy of NPWT in the management of thoracic empyema.

Methods: Ten patients with stage II or III thoracic empyema treated with NPWT were retrospectively analyzed. The volume of the empyema cavity was measured, and the volume change after the administration of NPWT was calculated. A comparison with the institutional historical controls was also performed.

Results: The patients had initially undergone fenestration of the chest wall for empyema, and eight had bronchopleural fistula and required procedures to close the fistula. The mean duration of NPWT was 71.1 days (4-190 days). The mean volume of the empyema cavity decreased from 230.2 ml (42.8-788.4 ml) to 78.5 ml (5.2-185.3 ml) by applying NPWT (P = 0.02), and the mean % decrease was 58.7% (0-87.9%). Ultimately, the empyema cavity was able to be cleaned in nine, including seven who were cured by subsequent thoracoplasty and two who were cured without thoracoplasty. The current study group had a tendency toward an early cure with less chest wall destruction, a less hospital stay after open window thoracotomy compared to historical control.

Conclusions: NPWT enables the effective volume reduction and cleaning of the empyema cavity and achieves an early cure and reduced destruction of the chest wall.
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http://dx.doi.org/10.1007/s11748-020-01554-5DOI Listing
January 2021

Pulmonary metastasectomy for pulmonary metastasis of breast cancer has a limited prognostic impact: a multi-institutional retrospective analysis.

J Thorac Dis 2020 Nov;12(11):6552-6562

Division of General Thoracic Surgery, Teikyo University, School of Medicine, Tokyo, Japan.

Background: Pulmonary metastasectomy (PM) for breast cancer-derived pulmonary metastasis is controversial. This study aimed to assess the prognostic factors and implication of PM for metastatic breast cancer using a multi-institutional database.

Methods: Clinical data of 253 females with pulmonary metastasis of breast cancer who underwent PM between 1982 and 2017 were analyzed retrospectively.

Results: The median patient age was 56 years. The median follow-up period was 5.4 years, and the median disease-free interval (DFI) was 4.8 years. The 5- and 10-year survival rates after PM were 64.9% and 50.4%, respectively, and the median overall survival was 10.1 years. Univariate analysis revealed that the period of PM before 2000, a DFI <36 months, lobectomy/pneumonectomy, large tumor size, and lymph node metastasis were predictive of a worse overall survival. In the multivariate analysis, a DFI <36 months, large tumor size, and lymph node metastasis remained significantly related to overall survival. The 5- and 10-year cancer-specific survival rates after PM were 66.9% and 54.7%, respectively, and the median cancer-specific survival was 13.1 years. Univariate analyses revealed that the period of PM before 2000, DFI <36 months, lobectomy/pneumonectomy, large tumor size, lymph node metastasis, and incomplete resection were predictive of a worse cancer-specific survival. Multivariate analysis confirmed that a DFI <36 months, large tumor size and incomplete resection were significantly related to cancer-specific survival.

Conclusions: As PM has limited efficacy in breast cancer, it should be considered an optional treatment for pulmonary metastasis of breast cancer.
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http://dx.doi.org/10.21037/jtd-20-1788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711388PMC
November 2020

Risk factors of postoperative recurrence of primary spontaneous pneumothorax.

J Thorac Dis 2020 Nov;12(11):6458-6465

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Spontaneous pneumothorax is common in relatively young, healthy patients. The risk factors for postoperative recurrence after correction are not fully understood.

Methods: We retrospectively reviewed the records of patients who underwent surgery for spontaneous pneumothorax between January 2006 and October 2017. We assessed the possible factors causing postoperative recurrence using univariate and multivariate analyses. We then used the inverse probability of treatment-weighted method to correct for confounding factors.

Results: Postoperative recurrence was observed in 41 of 233 patients (17.6%). A significant association with recurrence was noted for primary spontaneous pneumothorax (PSP), never smokers, thoracoscopic surgery, patients younger than 30 years, operative time less than 100 minutes, and surgery by a resident surgeon. Patients younger than 30 years of age had a 5-year recurrence-free probability of 46.3%. On multivariate analysis, patients younger than 30 years was an independent risk factor for recurrence. The confounding factors for recurrence of PSP included patients younger than 30 years, surgery by a resident surgeon, and thoracoscopic surgery. After adjusting for confounders, patients younger than 30 years was the only factor associated with recurrence (P=0.015). Patients who underwent bulla ligation with pleural reinforcement using an absorbable polyglycolic acid (PGA) sheet had a 4% recurrence rate and a 5-year recurrence-free probability of 90.0%.

Conclusions: Patients younger than 30 years of age is a significant factor for postoperative recurrence in patients with PSP. Surgeons may attempt to prevent postoperative recurrence by devising the operative method and pleural reinforcement methods.
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http://dx.doi.org/10.21037/jtd-20-2436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711412PMC
November 2020

Clinical features and outcomes of patients with stage I multiple primary lung cancers.

Cancer Sci 2020 Nov 25. Epub 2020 Nov 25.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

The number of patients with multiple primary lung cancers (MPLC) is rising. We studied the clinical features and factors related to outcomes of MPLC patients using the database of surgically resected lung cancer (LC) cases compiled by the Japanese Joint Committee of Lung Cancer Registry. From the 18 978 registered cases, 9689 patients with clinical stage I non-small-cell lung cancer who achieved complete resection were extracted. Tumors were defined as synchronous MPLC when multiple LC was simultaneously resected or treatment was carried out within 2 years after the initial surgery; metachronous MPLC was defined as second LC treated more than 2 years after the initial surgery. Of these cases, 579 (6.0%) were synchronous MPLC and 477 (5.0%) metachronous MPLC, with 51 overlapping cases. Female sex, nonsmoker, low consolidation-tumor ratio (CTR), and adenocarcinoma were significantly more frequent in the synchronous MPLC group, whereas patients with metachronous MPLC had higher frequencies of male sex, smoker, chronic obstructive pulmonary disease (COPD), and nonadenocarcinoma. There was no significant difference in survival rate between patients with and without synchronous or metachronous MPLC. Age, gender, CTR for second LC, and histological combination of primary and second LC were prognostic indicators for both types of MPLC. Logistic regression analysis showed that female sex, history of malignant disease other than LC, and COPD were risk factors for MPLC incidence. The present findings could have major implications regarding MPLC diagnosis and identification of independent prognostic factors, and provide valuable information for postoperative management of patients with MPLC.
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http://dx.doi.org/10.1111/cas.14748DOI Listing
November 2020

Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206.

J Clin Oncol 2020 12 2;38(36):4292-4301. Epub 2020 Nov 2.

Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

Purpose: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung.

Methods: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m, days 1-3) plus cisplatin (80 mg/m, day 1) or irinotecan (60 mg/m, days 1, 8, 15) plus cisplatin (60 mg/m, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216).

Results: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients 4% of 107 patients) and neutropenia (97% 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% 11%) and diarrhea (1% 8%) were more frequently observed in the irinotecan plus cisplatin arm.

Conclusion: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.
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http://dx.doi.org/10.1200/JCO.20.01806DOI Listing
December 2020

[Surgical Resection and Perioperative Management of Lung Cancer Requiring Vertebrectomy].

Kyobu Geka 2020 Sep;73(10):829-833

Department of General Thoracic Surgery, Chiba University, Chiba, Japan.

While cases of surgical resection for primary lung cancers are increasing, lung cancer requiring vertebrectomy is rare. A high complication rate and recurrence rate have been reported after surgical resection for lung cancer with vertebral invasion. However, select patients who achieve complete resection after effective preoperative chemoradiotherapy show a better survival rate than others. Preoperative computed tomography and magnetic resonance imaging are necessary to consider surgical strategies and how to resect and reconstruct the vertebral body and chest wall with a clear margin before surgery. A 3-dimensional imaging or simulation model is useful for such ends. Several surgical approaches have been developed, such as the transmanubrial, posterior, posterolateral, or the combination thereof. Proper vertebrectomy( total, hemi, part of a vertebra, or only the transverse process of a vertebra) and reconstruction approaches should be decided in conjunction with orthopedic surgeons. While evidence is lacking, establishing proper surgical indications and developing effective strategies to achieve complete resection with a clear margin are the most critical points in lung cancer requiring vertebrectomy.
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September 2020

Evaluation of tacrolimus and mycophenolic acid removal by simultaneous continuous hemodiafiltration and plasma exchange in a lung transplant patient.

J Clin Pharm Ther 2021 Apr 10;46(2):515-518. Epub 2020 Oct 10.

Division of Pharmacy, Chiba University Hospital, Chiba, Japan.

What Is Known And Objective: The removal rates of tacrolimus (TAC) and mycophenolic acid (MPA) by simultaneous plasma exchange (PE) and continuous hemodiafiltration (CHDF) are not clear.

Case Summary: We evaluated the removal rates of TAC and MPA by PE and CHDF started simultaneously 5 hours after administration in a lung transplant patient. TAC was not removed. MPA was transferred into the PE effluent, but the total amount in the effluent was only 1% of the dosage.

What Is New And Conclusion: TAC and MPA were less likely to be removed by PE and CHDF initiated 5 hours after administration.
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http://dx.doi.org/10.1111/jcpt.13286DOI Listing
April 2021

Impact of the preoperative body mass index on the postoperative outcomes in patients with completely resected non-small cell lung cancer: A retrospective analysis of 16,503 cases in a Japanese Lung Cancer Registry Study.

Lung Cancer 2020 11 19;149:120-129. Epub 2020 Sep 19.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objectives: The aim of this study was to evaluate the impact of the preoperative body mass index (BMI) on the postoperative outcomes in patients with completely resected non-small cell lung cancer (NSCLC).

Materials And Methods: The data of patients with NSCLC in whom R0 resection was achieved were extracted from the database of NSCLC samples accumulated by the Japanese Joint Committee of Lung Cancer Registry in the year 2010, and the surgical outcomes including postoperative morbidity, mortality and the prognosis, were evaluated.

Results: Among 18,978 registered lung cancer cases, 16,509 patients (9996 men and 6513 women) were extracted. The median of age was 69 years old, and the histologic types included adenocarcinoma (n = 12,029), squamous cell carcinoma (n = 3286), large-cell carcinoma (n = 488) and others. The patients were divided into three groups according to their BMI: normal (BMI 18.5 to <25), underweight (BMI < 18.5) and overweight (BMI ≥ 25). Multivariate logistic regression analyses of factors associated with postoperative morbidity and mortality showed no significant differences among the three groups. In comparison to the normal group, the overall survival (OS) of the underweight group was significantly worse (p < 0.001) while that of the overweight group was marginally better (p = 0.075). A multivariate analysis of factors associated with OS showed that in addition to the age, sex and clinical stage, the preoperative BMI (underweight group vs. normal group: hazard ratio [HR] 1.417 [95% confidence interval {CI}: 1.278-1.572, p < 0.001], overweight group vs. normal group: HR 0.883 [95% CI: 0.806-0.967, p = 0.007]) was an independent prognostic factor. A multivariate analysis for the disease-free survival (DFS) also showed the preoperative BMI to be an independent significant prognostic factor.

Conclusions: The preoperative BMI is an independent prognostic factor in patients with completely resected NSCLC. A low preoperative BMI was associated with significantly poor survival in Japan.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.011DOI Listing
November 2020

Endobronchial ultrasound-guided transbronchial needle aspiration in patients with previously treated lung cancer.

Surg Today 2021 Mar 17;51(3):415-421. Epub 2020 Aug 17.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Purpose: The sampling and accurate diagnosis of lymph nodes during the clinical history of lung cancer are essential for selecting the appropriate treatment strategies. This study aims to evaluate the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with previously treated lung cancer.

Methods: Patients who underwent EBUS-TBNA after treatment for lung cancer were retrospectively reviewed. We classified the patients into two groups; Group 1 (G1): Indicated to have a recurrence of new lesions after radical surgery or chemo/radiotherapy with a curative intent; and Group 2 (G2): Indicated to have residual tumor cells after undergoing primary treatment for chemo/radiotherapy or re-staging after induction therapy prior to surgery.

Results: Seventy previously treated lung cancer cases (G1, n = 52; G2, n = 18) were enrolled. Thirty-two cases (61.5%) had recurrent disease in G1, and 9 cases (50.0%) had nodal metastasis in G2. The diagnostic accuracy was 95.2% in G1 and 88.9% in G2. Twenty-four cases were examined for epidermal growth factor receptor (EGFR) mutations, and 9 (37.5%) cases had mutations, including two cases with a T790M mutation. Furthermore, in one case, a re-biopsy revealed that the initial adenocarcinoma had transformed into small cell lung cancer.

Conclusion: Performing EBUS-TBNA during lung cancer treatment showed a high diagnostic yield. Samples obtained by EBUS-TBNA were helpful in determining when to perform repeat biomarker testing as well as for making pathological re-evaluations.
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http://dx.doi.org/10.1007/s00595-020-02101-8DOI Listing
March 2021

18F-FDG-PET/CT predicts grade of malignancy and invasive potential of thymic epithelial tumors.

Gen Thorac Cardiovasc Surg 2021 Feb 30;69(2):274-281. Epub 2020 Jul 30.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan.

Purpose: The aim of this study was to evaluate the ability of fluorine-18-fluorodeoxyglucose positron emission tomography coupled with computed tomography (18F-FDG-PET/CT) to predict the WHO malignancy grade, initial staging, and invasive potential of thymic epithelial tumors.

Methods: We retrospectively reviewed the medical records of 56 patients with thymic epithelial tumors who were evaluated by PET/CT before surgery and underwent surgical resection. We analyzed the relationship of the maximum standardized uptake value (SUVmax) with the WHO histological classification, tumor invasion, TNM classification, and the Masaoka-Koga classification.

Results: There were differences of SUVmax of the FDG-PET between thymic carcinoma (9.09 ± 3.34) and thymoma (4.86 ± 2.45; p < 0.01), thymic carcinoma (9.09 ± 3.34) and high-grade thymoma (6.01 ± 2.78; p < 0.01), and high-grade thymoma (6.01 ± 2.78) and low-grade thymoma (4.06 ± 1.86; p < 0.01). The cut-off value for the SUVmax was 7.40 and 5.40, and the sensitivity/specificity for predicting the histologic subtype of each group was 0.72/0.79 and 0.61/0.85, respectively. According to T classification, SUVmax was significantly higher in T3 (8.31 ± 2.57) than in T1a (4.45 ± 2.06; p < 0.01). Regarding Masaoka-Koga classification and WHO histological classification, a significantly higher SUVmax was detected in patients with stage III and IV disease than in those with stage I and II diseases (p < 0.01). The cut-off value for SUVmax was 5.40 in Masaoka-Koga stage and 5.60 in the WHO classification; the sensitivity/specificity for predicting the histologic subtype was 0.85/0.80 and 0.89/0.78, respectively.

Conclusions: FDG-PET is a useful tool to predict aggressiveness of thymic epithelial tumors.
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http://dx.doi.org/10.1007/s11748-020-01439-7DOI Listing
February 2021

Is needle biopsy a risk factor of pleural recurrence after surgery for non-small cell lung cancer?

J Thorac Dis 2020 May;12(5):2635-2643

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Tumor seeding, whereby malignant cells are deposited along the needle tract, is considered to be a potential hazard of needle biopsies. The aim of this study is to elucidate the relationship between needle biopsies for lung tumor, such as a preoperative computed tomography-guided needle biopsy (PCTGNB) or an intraoperative fine-needle aspiration biopsy (IFNAB), and ipsilateral pleural recurrence (PR) after lung cancer surgery.

Methods: Between 2008 and 2017, 1,047 patients with non-small cell lung cancer (NSCLC) underwent curative lung resection in our institution. They were divided into two groups: those in whom the first recurrent site was the ipsilateral pleural cavity (PR group) and the others (control group). Risk factors of PR were investigated retrospectively.

Results: Recurrence was observed in 191 patients (18.2%), 25 of whom were categorized to the PR group (17 malignant effusion, 10 dissemination). Pathological tumor [2-4], lymph nodes [1-2], pleural, lymphatic and vascular invasion (each ≥1) factors and patients who underwent PCTGNB were more frequently observed in the PR group than in the control group (each P<0.01) whereas the proportion of patients who underwent IFNAB was not significant. A multivariate analysis identified pathological lymph node factor and the frequency of PCTGNB as independent risk factors for PR with hazard ratios of 7.33 (95% CI, 2.93-19.8; P<0.01) and 6.92 (95% CI, 2.25-17.8; P<0.01), respectively.

Conclusions: PCTGNB is a risk factor of PR but IFNAB is not. Indications for PCTGNB should be carefully determined.
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http://dx.doi.org/10.21037/jtd.2020.03.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330316PMC
May 2020

Clinical Impacts of EGFR Mutation Status: Analysis of 5780 Surgically Resected Lung Cancer Cases.

Ann Thorac Surg 2021 01 29;111(1):269-276. Epub 2020 Jun 29.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973).

Methods: Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study.

Results: An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P < .001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < .001), a higher rate of pure solid tumors (P < .001), advanced pathologic stage (trend P < .001), and poorer recurrence-free survival (P = .001).

Conclusions: In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.041DOI Listing
January 2021

Key prognostic factors for EGFR-mutated non-adenocarcinoma lung cancer patients in the Japanese Joint Committee of Lung Cancer Registry Database.

Lung Cancer 2020 08 18;146:236-243. Epub 2020 Jun 18.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients.

Methods: A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016.

Results: EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients [hazard ratio (HR) 1.3 (95 % CI, 0.97-1.8, P = 0.072)-29.5 months (95 % CI, 27.9-31.1 months) versus 19.5 months (95 % CI, 10.8-28.2 months) (P = 0.068)]. There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not [HR 4.5 (95 % CI, 2.1-9.8, P < 0.001)-25.5 months (95 % CI, 8.1-42.9 months) versus 7.5 months (95 % CI, 3.4-11.6 months) (P < 0.001)]. While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 [95 % CI, 1.5-6.9, P = 0.004]; it was not reached for 19 del and was 15.5 months for L858R [95 % CI, 6.6-24.4 months], P = 0.002).

Discussion: EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.015DOI Listing
August 2020

Survival and prognostic factors in elderly patients receiving second-line chemotherapy for relapsed small-cell lung cancer: Results from the Japanese Joint Committee of Lung Cancer Registry.

Lung Cancer 2020 08 6;146:160-164. Epub 2020 Jun 6.

Department of General Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Objectives: Most patients with small-cell lung cancer (SCLC) experience relapse because of the emergence of drug-resistant tumor cells. Therefore, second-line therapy is subsequently required to prolong their survival. However, it is unclear whether second-line chemotherapy can provide a survival benefit to elderly patients with relapsed SCLC. Therefore, this study aimed to evaluate survival and identify prognostic factors in an elderly population.

Materials And Methods: Based on a nationwide registry database of patients with SCLC (the Japanese Joint Committee of Lung Cancer Registry), we retrospectively reviewed medical records of patients aged ≥ 75 years with relapsed SCLC who subsequently received second-line chemotherapy. Survival time since the initiation of second-line chemotherapy was evaluated.

Results: Among 731 patients aged ≥ 75 years with SCLC who were accumulated by the nationwide registry database, this study included 228 patients, comprising 190 men and 38 women with a median age of 78 years. The number of patients with performance status (PS) of 0-1 and 2-4 was 196 and 32, respectively. The overall survival (OS) and 1-year survival rates were 7.5 months and 24 %, respectively. A multivariate analysis identified PS, clinical stage at the time of starting first-line therapy, and the interval from the start of first-line therapy to that of second-line therapy as independent prognostic factors.

Conclusion: This study with the nationwide registry database showed that among the relapsed elderly SCLC patients who received second-line chemotherapy, a substantial OS may be expected in patients with good PS, at an early clinical stage at the time of starting first-line therapy, and with a longer interval from the start of first-line therapy to that of second-line chemotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.038DOI Listing
August 2020

Successful pulmonary embolectomy with central extra-corporeal membranous oxygenation for acute pulmonary thromboembolism.

Surg Today 2020 Dec 12;50(12):1712-1715. Epub 2020 Jun 12.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1, Inohana, Chiba, 260-8670, Japan.

The treatment of acute pulmonary thromboembolism with a hemorrhagic condition is quite challenging and it usually presents a clinical dilemma. Pulmonary embolectomy is generally performed with cardiopulmonary bypass; however, cardiopulmonary bypass usually requires full anticoagulation which cannot be used for patients with a hemorrhagic condition. We herein report a successful case of pulmonary embolectomy that was accomplished using central veno-arterial extracorporeal membranous oxygenation, instead of cardiopulmonary bypass, for a patient with an acute fatal pulmonary thromboembolism and hemorrhagic cerebral infarction following lung cancer surgery. Our strategy consists of surgical embolectomy under central veno-arterial extracorporeal membranous oxygenation with partial anticoagulation and the placement of an inferior vena cava filter to prevent recurrence without the use of anticoagulation therapy.
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http://dx.doi.org/10.1007/s00595-020-02046-yDOI Listing
December 2020

High expression of CXCL14 is a biomarker of lung adenocarcinoma with micropapillary pattern.

Cancer Sci 2020 Jul 30;111(7):2588-2597. Epub 2020 May 30.

Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lung adenocarcinoma with micropapillary pattern (MPP) has an aggressive malignant behavior. Limited resection should be avoided because of its high recurrence rate. If adenocarcinoma with MPP is diagnosed preoperatively, the selection of proper treatment is possible. To explore a preoperative biomarker for diagnosing MPP, we undertook RNA sequencing analysis of 25 clinical samples as the training set, including 6 MPP, 16 other adenocarcinoma subtypes, and 3 normal lung tissues. Unsupervised hierarchical clustering analysis suggested a presence of subgroup with MPP showing different gene expression phenotype. We extracted differentially expressed genes with high expression levels in MPP samples, and chose VSIG1, CXCL14, and BAMBI as candidate biomarkers for MPP. Reverse transcription-quantitative PCR analysis confirmed a significantly higher expression of VSIG1 (P = .03) and CXCL14 (P = .02) in MPP than others. In a validation set of 4 MPP and 4 non-MPP samples, CXCL14 expression was validated to be significantly higher in MPP than in non-MPP (P = .04). Comparing a total of 10 MPP and 20 non-MPP samples, the area under the curve of CXCL14 to distinguish MPP from others was 0.89. The threshold value was 0.0116, corresponding to sensitivity 80% and specificity 90%. In immunostaining of CXCL14, the staining score was significantly higher in MPP cases than others, where not only the MPP component but also other components showed heterogeneous staining in adenocarcinoma tissues with MPP. Moreover, a higher staining score of CXCL14 was significantly associated with poorer prognosis in all patients (P = .01) or within cases in stage I-III (P = .01). In summary, we identified CXCL14 as a possible diagnostic biomarker of MPP.
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http://dx.doi.org/10.1111/cas.14456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385370PMC
July 2020

A phase I study of loco-regional immunotherapy by transbronchial injection of α-galactosylceramide-pulsed antigen presenting cells in patients with lung cancer.

Clin Immunol 2020 06 6;215:108457. Epub 2020 May 6.

Department of Medical Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Electronic address:

We conducted a phase I study of the trans-bronchial injection of α-galactosylceramide (αGalCer)-pulsed antigen presenting cells (APCs) to evaluate their safety, immune responses, and anti-tumor activities. Patients with advanced or recurrent non-small cell lung cancer (NSCLC) refractory to standard treatments were eligible. αGalCer-pulsed APCs were administered intratumorally or intranodally by bronchoscopy. Twenty-one patients were enrolled in this study. No severe adverse events related to the cell therapy were observed during this study in any patient. After αGalCer-pulsed APCs were administrated, increased iNKT cell numbers were observed in PBMCs from eight cases, and IFN-γ producing cells were increased in the peripheral blood of 10 cases. Regarding clinical responses, one case exhibited a partial response and eight were classified as stable disease. In the tumor microenvironment, IFN-γ expression was upregulated after treatment in partial response or stable disease cases and TGF-β was upregulated in progressive disease cases.
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http://dx.doi.org/10.1016/j.clim.2020.108457DOI Listing
June 2020

Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis.

PLoS One 2020 8;15(5):e0232884. Epub 2020 May 8.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: Obliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis.

Methods: Left lungs from C57BL/10(H-2b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs).

Results: A total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs.

Conclusions: Adaptive and innate immune reactions were involved in OB after lung transplantation, and genetic examination of related genes could be used for detection of OB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232884PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209239PMC
August 2020

Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer.

J Immunother Cancer 2020 03;8(1)

Department of Medical Immnunology, Graduate School of Medicine, Chiba University, Chiba, Japan

Background: Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC.

Methods: Patients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan.

Results: Thirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs.

Conclusions: The intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy.

Trial Registration Number: UMIN000007321.
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http://dx.doi.org/10.1136/jitc-2019-000316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078938PMC
March 2020

ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib.

Onco Targets Ther 2020 19;13:1557-1560. Epub 2020 Feb 19.

Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib.
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http://dx.doi.org/10.2147/OTT.S236706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039243PMC
February 2020