Publications by authors named "Taichiro Goto"

114 Publications

Lymph Node Dissection for NSCLC at Whose Discretion?

Authors:
Taichiro Goto

J Thorac Oncol 2021 Apr;16(4):e25

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.11.001DOI Listing
April 2021

Midterm outcomes of early versus late surgery for infective endocarditis with neurologic complications: a meta-analysis.

J Cardiothorac Surg 2021 Mar 25;16(1):49. Epub 2021 Mar 25.

Department of General Thoracic Surgery, Yamanashi Central Hospital, Yamanashi, 400-8506, Japan.

Background: Cerebral infarction (CI) remains one of the most common and fatal complications of infective endocarditis (IE), and the timing of surgery for IE with neurologic complications is controversial. As outcomes beyond the perioperative period have not been assessed with a meta-analysis previously, we conducted a meta-analysis comparing mid- to long-term outcomes of early and late surgery in patients with IE and neurologic complications.

Methods: All studies that investigated early and late surgery in patients with IE and neurologic complications were identified. The primary and secondary endpoints were all-cause mortality and recurrence, respectively. Hazard ratios (HRs) for all-cause mortality and recurrence were extracted from each study.

Results: Our search identified five eligible studies, which were all observational studies consisting of a total of 624 patients with IE and neurologic complications. Pooled analyses demonstrated that all-cause mortality was similar between the early and late surgery groups (HR [95% confidence interval [CI]] = 0.90 [0.49-1.64]; P = 0.10; I = 49%). Similarly, the recurrence rates were similar between both groups (HR [95% CI] = 1.86 [0.76-4.52]; P = 0.43; I = 0%).

Conclusions: Our meta-analysis showed similar mortality and recurrent rates between the early and late surgery groups. The optimal timing of surgery should be individualized on a case-to-case basis.
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http://dx.doi.org/10.1186/s13019-021-01425-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992857PMC
March 2021

Comprehensive genomic profiling of combined small cell lung cancer.

Transl Lung Cancer Res 2021 Feb;10(2):636-650

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Combined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC.

Methods: The clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC.

Results: There were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that and were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components.

Conclusions: There were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations.
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http://dx.doi.org/10.21037/tlcr-20-1099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947408PMC
February 2021

Is rigid tracheobronchoscopy safe enough for airway disease?

Authors:
Taichiro Goto

Respirology 2021 Mar 2. Epub 2021 Mar 2.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.1111/resp.14030DOI Listing
March 2021

Virtual-assisted lung mapping: is it actually better than finger palpation?

Authors:
Taichiro Goto

J Thorac Dis 2021 Jan;13(1):414-416

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.21037/jtd-20-2908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867854PMC
January 2021

Robotic bronchoscopy: is it classic?

Authors:
Taichiro Goto

J Thorac Dis 2021 Jan;13(1):409-410

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.21037/jtd-20-3088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867816PMC
January 2021

Links between Inflammation and Postoperative Cancer Recurrence.

J Clin Med 2021 Jan 10;10(2). Epub 2021 Jan 10.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Despite complete resection, cancer recurrence frequently occurs in clinical practice. This indicates that cancer cells had already metastasized from their organ of origin at the time of resection or had circulated throughout the body via the lymphatic and vascular systems. To obtain this potential for metastasis, cancer cells must undergo essential and intrinsic processes that are supported by the tumor microenvironment. Cancer-associated inflammation may be engaged in cancer development, progression, and metastasis. Despite numerous reports detailing the interplays between cancer and its microenvironment via the inflammatory network, the status of cancer-associated inflammation remains difficult to recognize in clinical settings. In the current paper, we reviewed clinical reports on the relevance between inflammation and cancer recurrence after surgical resection, focusing on inflammatory indicators and cancer recurrence predictors according to cancer type and clinical indicators.
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http://dx.doi.org/10.3390/jcm10020228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827039PMC
January 2021

Role of Surgical Intervention in Unresectable Non-Small Cell Lung Cancer.

J Clin Med 2020 Nov 29;9(12). Epub 2020 Nov 29.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Kofu 400-8506, Japan.

With the development of systemic treatments with high response rates, including tyrosine kinase inhibitors and immune checkpoint inhibitors, some patients with unresectable lung cancer now have a chance to undergo radical resection after primary treatment. Although there is no general consensus regarding the definition of "unresectable" in lung cancer, the term "resectable" refers to technically resectable and indicates that resection can provide a favorable prognosis to some extent. Unresectable lung cancer is typically represented by stage III and IV disease. Stage III lung cancer is a heterogeneous disease, and in some patients with technically resectable non-small cell lung cancer (NSCLC), multimodality treatments, including induction chemoradiotherapy followed by surgery, are the treatments of choice. The representative surgical intervention for unresectable stage III/IV NSCLC is salvage surgery, which refers to surgical treatment for local residual/recurrent lesions after definitive non-surgical treatment. Surgical intervention is also used for an oligometastatic stage IV NSCLC. In this review, we highlight the role of surgical intervention in patients with unresectable NSCLC, for whom an initial complete resection is technically difficult. We further describe the history of and new findings on salvage surgery for unresectable NSCLC and surgery for oligometastatic NSCLC.
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http://dx.doi.org/10.3390/jcm9123881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760873PMC
November 2020

Association of Mutation Profiles with Postoperative Survival in Patients with Non-Small Cell Lung Cancer.

Cancers (Basel) 2020 Nov 21;12(11). Epub 2020 Nov 21.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Findings on mutations, associated with lung cancer, have led to advancements in mutation-based precision medicine. This study aimed to comprehensively and synthetically analyze mutations in lung cancer, based on the next generation sequencing data of surgically removed lung tumors, and identify the mutation-related factors that can affect clinical outcomes. Targeted sequencing was performed on formalin-fixed paraffin-embedded surgical specimens obtained from 172 patients with lung cancer who underwent surgery in our hospital. The clinical and genomic databases of the hospital were combined to determine correlations between clinical factors and mutation profiles in lung cancer. Multivariate analyses of mutation-related factors that may affect the prognosis were also performed. Based on histology, was the driver gene in 70.0% of the cases of squamous cell carcinoma. In adenocarcinoma cases, driver mutations were detected in (26.0%), (25.0%), and epidermal growth factor receptor () (23.1%). According to multivariate analysis, the number of pathogenic mutations (≥3), presence of a mutation, and allele fraction >60 were poor prognostic mutational factors. The allele fraction tended to be high in caudally and dorsally located tumors. Moreover, -mutated lung cancers located in segments 9 and 10 were associated with significantly poorer prognosis than those located in segments 1-8. This study has identified mutation-related factors that affect the postoperative prognosis of lung cancer. To our knowledge, this is the first study to demonstrate that the mutation profile varies with the site of lung tumor, and that postoperative prognosis varies accordingly.
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http://dx.doi.org/10.3390/cancers12113472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700403PMC
November 2020

Is tomosynthesis an ingenious scheme for bronchoscopic diagnosis of lung nodules?

Authors:
Taichiro Goto

Respirology 2021 Jan 17;26(1):125. Epub 2020 Nov 17.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.1111/resp.13975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756326PMC
January 2021

Impact of coronavirus disease pandemic on surgery for lung cancer in a provincial city in Japan.

Authors:
Taichiro Goto

J Thorac Dis 2020 Sep;12(9):5056-5059

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.21037/jtd-20-2427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578453PMC
September 2020

Multiregional sequence revealed SMARCA4 R1192C mutant clones acquired EGFR C797S mutation in the metastatic site of an EGFR-mutated NSCLC patient.

Lung Cancer 2020 10 3;148:28-32. Epub 2020 Aug 3.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Objectives: Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR-mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment.

Materials And Methods: We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site.

Results: MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation.

Conclusion: MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.035DOI Listing
October 2020

Primary Driver Mutations in Specific to the Development of Thymomas.

Cancers (Basel) 2020 Jul 24;12(8). Epub 2020 Jul 24.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Thymomas are rare mediastinal tumors that are difficult to treat and pose a major public health concern. Identifying mutations in target genes is vital for the development of novel therapeutic strategies. Type A thymomas possess a missense mutation in (chromosome 7 c.74146970T>A) with high frequency. However, the molecular pathways underlying the tumorigenesis of other thymomas remain to be elucidated. We aimed to detect this missense mutation in in other thymoma subtypes (types B). This study involved 22 patients who underwent surgery for thymomas between January 2014 and August 2019. We isolated tumor cells from formalin-fixed paraffin-embedded tissues from the primary lesions using laser-capture microdissection. Subsequently, we performed targeted sequencing to detect mutant coupled with molecular barcoding. We used PyClone analysis to determine the fraction of tumor cells harboring mutant . We detected the missense mutation (chromosome 7 c.74146970T>A) in in 14 thymomas among the 22 samples (64%). This mutation was harbored in many type B thymomas as well as type A and AB thymomas. The allele fraction for the tumors containing the mutations was variable, primarily owing to the coexistence of normal lymphocytes in the tumors, especially in type B thymomas. PyClone analysis revealed a high cellular prevalence of mutant in tumor cells. Mutant was not detected in other carcinomas (lung, gastric, colorectal, or hepatocellular carcinoma) or lymphomas. In conclusion, the majority of thymomas harbor mutations in that can be potentially used as a novel therapeutic target in patients with thymomas.
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http://dx.doi.org/10.3390/cancers12082032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466068PMC
July 2020

Patient-Derived Tumor Xenograft Models: Toward the Establishment of Precision Cancer Medicine.

Authors:
Taichiro Goto

J Pers Med 2020 Jul 18;10(3). Epub 2020 Jul 18.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Kofu, Yamanashi 4008506, Japan.

Patient-derived xenografts (PDXs) describe models involving the implantation of patient-derived tumor tissue into immunodeficient mice. Compared with conventional preclinical models involving the implantation of cancer cell lines into mice, PDXs can be characterized by the preservation of tumor heterogeneity, and the tumor microenvironment (including stroma/vasculature) more closely resembles that in patients. Consequently, the use of PDX models has improved the predictability of clinical therapeutic responses to 80% or greater, compared with approximately 5% for existing models. In the future, molecular biological analyses, omics analyses, and other experiments will be conducted using recently prepared PDX models under the strong expectation that the analysis of cancer pathophysiology, stem cells, and novel treatment targets and biomarkers will be improved, thereby promoting drug development. This review outlines the methods for preparing PDX models, advances in cancer research using PDX mice, and perspectives for the establishment of precision cancer medicine within the framework of personalized cancer medicine.
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http://dx.doi.org/10.3390/jpm10030064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565668PMC
July 2020

Squamous Cell Carcinoma of the Lung With Micropapillary Pattern.

J Thorac Oncol 2020 09 12;15(9):1541-1544. Epub 2020 Jun 12.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.1016/j.jtho.2020.05.023DOI Listing
September 2020

Double Dumon Stents for Persistent Tracheoesophageal Fistula.

Ann Thorac Surg 2020 09 30;110(3):e251. Epub 2020 May 30.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.04.043DOI Listing
September 2020

Airway Microbiota as a Modulator of Lung Cancer.

Authors:
Taichiro Goto

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Kofu, Yamanashi 4008506, Japan.

Recent research on cancer-associated microbial communities has elucidated the interplay between bacteria, immune cells, and tumor cells; the bacterial pathways involved in the induction of carcinogenesis; and their clinical significance. Although accumulating evidence shows that a dysbiotic condition is associated with lung carcinogenesis, the underlying mechanisms remain unclear. Microorganisms possibly trigger tumor initiation and progression, presumably via the production of bacterial toxins and other pro-inflammatory factors. The purpose of this review is to discuss the basic role of the airway microbiome in carcinogenesis and the underlying molecular mechanisms, with the aim of developing anticancer strategies involving the airway microbiota. In addition, the mechanisms via which the microbiome acts as a modulator of immunotherapies in lung cancer are summarized.
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http://dx.doi.org/10.3390/ijms21093044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246469PMC
April 2020

Genome analysis of peeling archival cytology samples detects driver mutations in lung cancer.

Cancer Med 2020 07 29;9(13):4501-4511. Epub 2020 Apr 29.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan.

Introductions: When tumor tissue samples are unavailable to search for actionable driver mutations, archival cytology samples can be useful. We investigate whether archival cytology samples can yield reliable genomic information compared to corresponding formalin-fixed paraffin-embedded (FFPE) tumor samples.

Patients And Methods: Pretreatment class V archival cytology samples with adequate tumor cells were selected from 172 lung cancer patients. The genomic profiles of the primary lung tumors have been analyzed through whole-exome regions of 53 genes. We compared the genomic profiles based on the oncogenicity and variant allele frequency (VAF) between the archival cytology and the corresponding primary tumors. We also analyzed the genomic profiles of serial cytological samples during the treatment of EGFR-TKI.

Results: A total of 43 patients were analyzed with the paired samples for DNA mutations and other three patients were analyzed for their fusion genes. A total of 672 mutations were detected. Of those, 106 mutations (15.8%) were shared with both samples. Sixty of seventy-seven (77.9%) shared mutations were oncogenic or likely oncogenic mutations with VAF ≧10%. As high as 90% (9/10) actionable driver mutations and ALK and ROS1 fusion genes were successfully detected from archival cytology samples. Sequential analysis revealed the dynamic changes in EGFR-TKI-resistant mutation (EGFR p.T790M) during the course of treatment.

Conclusion: Archival cytology sample with adequate tumor cells can yield genetic information compared to the primary tumors. If tumor tissue samples are unavailable, we can use archival cytology samples to search for actionable driver mutations.
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http://dx.doi.org/10.1002/cam4.3089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333826PMC
July 2020

Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma.

Int J Mol Sci 2020 Feb 23;21(4). Epub 2020 Feb 23.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.
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http://dx.doi.org/10.3390/ijms21041525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073210PMC
February 2020

Dual-molecular barcode sequencing detects rare variants in tumor and cell free DNA in plasma.

Sci Rep 2020 02 25;10(1):3391. Epub 2020 Feb 25.

Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.

Conventional next generation sequencing analysis has provided important insights into cancer genetics. However, the detection of rare (low allele fraction) variants remains difficult because of the error-prone nucleotide changes derived from sequencing/PCR errors. To eliminate the false-positive variants and detect genuine rare variants, sequencing technology combined with molecular barcodes will be useful. Here, we used the newly developed dual-molecular barcode technology (Ion AmpliSeq HD) to analyze somatic mutations in 24 samples (12 tumor tissues and 12 plasma) from 12 patients with biliary-pancreatic and non-small cell lung cancers. We compared the results between next generation sequencing analysis with or without molecular barcode technologies. The variant allele fraction (VAF) between non-molecular barcode and molecular barcode sequencing was correlated in plasma DNA (R = 0.956) and tumor (R = 0.935). Both methods successfully detected high VAF mutations, however, rare variants were only identified by molecular barcode sequencing and not by non-molecular barcode sequencing. Some of these rare variants in tumors were annotated as pathogenic, and therefore subclonal driver mutations could be observed. Furthermore, the very low VAF down to 0.17% were identified in cell free DNA in plasma. These results demonstrate that the dual molecular barcode sequencing technologies can sensitively detect rare somatic mutations, and will be important in the investigation of the clonal and subclonal architectures of tumor heterogeneity.
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http://dx.doi.org/10.1038/s41598-020-60361-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042261PMC
February 2020

Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers.

J Clin Med 2020 Feb 20;9(2). Epub 2020 Feb 20.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

In cases of multiple lung cancers, individual tumors may represent either a primary lung cancer or both primary and metastatic lung cancers. In this study, we investigated the differences between clinical/histopathological and genomic diagnoses to determine whether they are primary or metastatic. 37 patients with multiple lung cancers were enrolled in this study. Tumor cells were selected from tissue samples using laser capture microdissection. DNA was extracted from those cells and subjected to targeted deep sequencing. In multicentric primary lung cancers, the driver mutation profile was mutually exclusive among the individual tumors, while it was consistent between metastasized tumors and the primary lesion. In 11 patients (29.7%), discrepancies were observed between genomic and clinical/histopathological diagnoses. For the lymph node metastatic lesions, the mutation profile was consistent with only one of the two primary lesions. In three of five cases with lymph node metastases, the lymph node metastatic route detected by genomic diagnosis differed from the clinical and/or pathological diagnoses. In conclusion, in patients with multiple primary lung cancers, cancer-specific mutations can serve as clonal markers, affording a more accurate understanding of the pathology of multiple lung cancers and their lymphatic metastases and thus improving both the treatment selection and outcome.
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http://dx.doi.org/10.3390/jcm9020573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074554PMC
February 2020

Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges.

Int J Mol Sci 2020 Jan 17;21(2). Epub 2020 Jan 17.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.
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http://dx.doi.org/10.3390/ijms21020597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014343PMC
January 2020

Rapid progressive lung cancers harbouring multiple clonal driver mutations with big bang evolution model.

Cancer Genet 2020 02 25;241:51-56. Epub 2019 Dec 25.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi, Japan; The University of Tokyo, Tokyo, Japan.

Introduction: Next-generation sequencing (NGS) of multiple metastases in an advanced cancer patient reveals the evolutional history of the tumor. The evolutionary model is clinically valuable because it reflects the future course of the tumorigenic process and prognosis of the patient.

Materials And Methods: We experienced two lung cancer patients whose clinical courses were abruptly deteriorating resulting in very poor prognosis. To investigate the evolutionary model of these patients, we performed targeted sequencing covering whole exons of 53 significantly mutated genes associated with lung cancer of multiple metastases by autopsy. We conducted PyClone analysis to infer subclonal archtecture of multi-lesional samples.

Results: The NGS analysis revealed both patients harboring multiple clonal driver mutations. In Case.1, KRAS Q61H, KEAP1 G333C, STK11 K312*, RBM10 Q320* and MGA I1429V and in Case.2, TP53 R337L, TP53 Q192*, PTEN W274C, RB1 P29fs and CREBBP P696L with high allele fraction were detected in all lesions. These mutations were clustered and occupied major population across multi-lesional tumor samples. Our data suggested their lung cancers progressed with punctuated and big bang evolutional model.

Conclusion: We should pay attention to clinical course of lung cancer patients harboring multiple clonal driver mutations in their primary lesions. Their punctuated and big bang evolutionary process could develop systemic clinically undetectable metastases with an unexpected speed.
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http://dx.doi.org/10.1016/j.cancergen.2019.12.006DOI Listing
February 2020

Is local consolidative therapy adequate for the treatment of oligometastatic non-small cell lung cancer?

Authors:
Taichiro Goto

J Thorac Dis 2019 Oct;11(10):E154-E157

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.21037/jtd.2019.09.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837952PMC
October 2019

PD-L1 Expression and Tumor-Infiltrating Lymphocytes in Thymic Epithelial Neoplasms.

J Clin Med 2019 Nov 1;8(11). Epub 2019 Nov 1.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Thymic epithelial tumors (TETs) are rare malignant mediastinal tumors that are difficult to diagnose and treat. The programmed death 1 (PD-1) receptor and its ligand (PD-L1) are expressed in various malignant tumors and have emerged as potential immunotherapeutic targets. However, the immunobiology of TETs is poorly understood. We evaluated PD-L1 expression and the presence of tumor-infiltrating lymphocytes (CD8 and CD3 expression) in surgical TET specimens from 39 patients via immunohistochemistry and determined their relation to clinicopathological parameters. Cases with membranous reactivity of the PD-L1 antibody in ≥1% of tumor cells were considered positive. Positive PD-L1 expression was observed in 53.9% of cases. Histologically, PD-L1 expression was positive in 2/6 type A, 2/6 type AB, 3/9 type B1, 4/4 type B2, 5/6 type B3, and 5/8 type C TET cases. Thus, the number of cases with PD-L1 expression and the percent expression of PD-L1 were significantly higher in more aggressive thymomas (type B2 or B3). CD3+ and CD8+ tumor-infiltrating lymphocytes were diffusely and abundantly distributed in all cases. These data suggest that a PD-1/PD-L1 blockade is a promising treatment for TETs, with more beneficial treatment effects for aggressive thymomas such as type B2 or B3.
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http://dx.doi.org/10.3390/jcm8111833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912585PMC
November 2019

Radiation as an In Situ Auto-Vaccination: Current Perspectives and Challenges.

Authors:
Taichiro Goto

Vaccines (Basel) 2019 Aug 26;7(3). Epub 2019 Aug 26.

Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Radiotherapy is generally considered to be a local treatment, but there have been reports of rare cases demonstrating abscopal effects in which antitumor effects have been observed in cancer lesions other than the irradiated site. This result is more likely to occur when immune checkpoint inhibitors are used in addition to radiotherapy. Certain radiation-induced chemokines and cytokines have immune-enhancing effects. Immune checkpoint inhibitors may strengthen these effects by stimulating antigen-presenting cells and effector cytotoxic T cells. To date, there is no consensus regarding the applicability of the abscopal effect in the clinical setting, including optimal methods for combining immune checkpoint inhibitors and irradiation. In this review, we highlight the evidence for interactions between cancer immunotherapy and radiotherapy and discuss the potential of such interactions for use in designing novel combination therapies.
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http://dx.doi.org/10.3390/vaccines7030100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789649PMC
August 2019

Sarcoma with MGA-NUTM1 fusion in the lung: an emerging entity.

Virchows Arch 2020 Feb 5;476(2):317-322. Epub 2019 Aug 5.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

We here document a sarcoma with a recently reported MGA-NUTM1 fusion. A 49-year-old man presented with a nodule in the right lung, which grew to a giant mass in 5 years. The tumor showed uniform oval to spindle cell proliferation in a hypervascular stroma, associated with focal myxoid change and peculiar collagen deposition resembling an osteoid. The tumor showed an undifferentiated phenotype, including negativity for cytokeratin, although it was immunoreactive to BCOR and MUC4, and was initially suspected as BCOR-associated sarcoma. After complete resection, the tumor recurred in the mediastinal lymph node, and the patient died of the disease. RNA sequencing detected MGA (exon 22)-NUTM1 (exon 3), which was confirmed by reverse transcriptase-polymerase chain reaction, Sanger sequencing, fluorescence in situ hybridization, and NUT immunohistochemistry. Clinicopathological features of the present case were similar to some of the reported cases of MGA-NUTM1 sarcomas, suggesting the emergence of a distinct tumor subtype.
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http://dx.doi.org/10.1007/s00428-019-02623-8DOI Listing
February 2020

Is surgery the choice for treatment for first presentation of pneumothorax?

Authors:
Taichiro Goto

J Thorac Dis 2019 May;11(Suppl 9):S1398-S1401

Department of General Thoracic Surgery, Yamanashi Central Hospital, Yamanashi, Japan.

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http://dx.doi.org/10.21037/jtd.2019.03.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560611PMC
May 2019

Clinical Implications of Noncoding Indels in the Surfactant-Encoding Genes in Lung Cancer.

Cancers (Basel) 2019 Apr 17;11(4). Epub 2019 Apr 17.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Lung cancer arises from the accumulation of genetic mutations, usually in exons. A recent study identified indel mutations in the noncoding region of surfactant-encoding genes in lung adenocarcinoma cases. In this study, we recruited 94 patients with 113 lung cancers (88 adenocarcinomas, 16 squamous cell carcinomas, and nine other histologies) who had undergone surgery in our department. A cancer panel was designed in-house for analyzing the noncoding regions, and targeted sequencing was performed. Indels in the noncoding region of surfactant-encoding genes were identified in 29/113 (25.7%) cases and represent the precise cell of origin for the lung cancer, irrespective of histological type and/or disease stage. In clinical practice, these indels may be used as clonal markers in patients with multiple cancers and to determine the origin of cancer of unknown primary site.
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http://dx.doi.org/10.3390/cancers11040552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520783PMC
April 2019