Publications by authors named "Makoto Edagawa"

20 Publications

  • Page 1 of 1

Prognostic Impact of Lymphocyte-C-Reactive Protein Ratio in Patients Who Underwent Surgical Resection for Hepatocellular Carcinoma.

J Gastrointest Surg 2021 Jul 13. Epub 2021 Jul 13.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, 730-0052, Japan.

Background: Systemic inflammation-related factors, either independently or in combination, are recognized as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of the LCR in patients with hepatocellular carcinoma (HCC).

Methods: This was a single-center retrospective study of patients who underwent surgical resection for HCC between 2004 and 2017. Patients were divided into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed.

Results: A total of 454 patients with HCC were enrolled and assigned to the high- (n=245) or low- (n=209) LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly lower serum albumin level (median 4.1 vs. 3.9 g/dL, P <0.0001), lower platelet count (median 14.0 vs. 12.0 ×10/μL, P=0.0468), lower prothrombin time (median 93.2 vs. 89.6 %, P=0.0006), and larger tumor size (median 2.3 vs. 2.5 cm, P=0.0056). Patients with low-LCR status had significantly worse outcomes of overall survival and disease-free survival than patients with high-LCR status (P=0.0003 and P=0.0069, respectively). Low-LCR status was significantly associated with worse overall survival in multivariate analysis (hazard ratio 1.57, 95% confidence interval 1.14-2.17, P=0.0058).

Conclusions: Low-LCR status may predict worse outcomes in patients with HCC. Measurement of LCR is routine and can easily be applied for risk stratification in the assessment of patients with HCC.
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http://dx.doi.org/10.1007/s11605-021-05085-zDOI Listing
July 2021

Does short-term cessation of smoking before lung resections reduce the risk of complications?

J Thorac Dis 2020 Dec;12(12):7127-7134

Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Smoking cessation is a highly important preparation before thoracic surgery. We examined the effects of short-term smoking cessation intervention before pulmonary resection on postoperative pulmonary complications (PPCs).

Methods: A retrospective analysis of prospectively collected data was performed for 753 patients who underwent curative surgical resection for thoracic malignancy at 3 institutions. Patients with a smoking history were instructed to quit smoking. After confirming smoking cessation by at least four weeks before surgery, surgical resection was performed. Subjects were classified into three groups based on their smoking status: abstainers (anyone who had stopped smoking for at least 4 weeks but less than 2 months), former smokers (anyone who had abstained from smoking for more than two months prior to surgery), and never smokers (those who had never smoked). We examined the relationship between the preoperative smoking status and PPCs.

Results: Surgery was performed for 660 primary lung cancers and 93 metastatic lung tumors. The smoking statuses were classified as follows: abstainers (n=105, 14%), former smokers (n=361; 48%) and never smokers (n=287, 38%). The incidence of PPCs among abstainers, former smokers and never smokers was 15%, 8% and 6%, respectively (P=0.01). The mean duration of post-operative chest tube drainage among abstainers, former smokers and never smokers was 3.2, 2.2 and 2.2 days, respectively (P=0.04). The mean post-operative hospital stay among abstainers, former smokers and never smokers was 12.1, 10.6 and 10.2 days, respectively (P=0.07). There was no 30-day mortality in the cohort.

Conclusions: Short-term smoking cessation intervention did not enough reduce the PPCs as much as in former or never smokers.
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http://dx.doi.org/10.21037/jtd-20-2574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797847PMC
December 2020

A case of perforation of Meckel's diverticulum with enterolith.

Surg Case Rep 2020 Jul 6;6(1):161. Epub 2020 Jul 6.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, 1-9-6 Senda-machi, Naka-ku, Hiroshima, 730-8619, Japan.

Background: Perforation of Meckel's diverticulum with enteroliths is a rare complication. Here, we report a case of perforation of Meckel's diverticulum with one enterolith, which could not be accurately diagnosed by preoperative computed tomography.

Case Presentation: A 16-year-old male patient with acute onset of severe abdominal pain and a localized muscle guarding in the right hypochondrium had a solitary stone detected in the right abdomen by radiography. Abdominal computed tomography revealed a saclike outpouching of the small intestine, which contained fluid levels and an enterolith, with a mesenteric inflammatory change in the right paraumbilical area. He was diagnosed with peritonitis due to appendicitis or Meckel's diverticulitis with enterolith, and emergency operation was indicated. The perforated Meckel's diverticulum was identified approximately 30 cm proximal to the ileocecal valve. The diverticulum was transected at the base and removed. The patient's postoperative course was uneventful.

Conclusions: It is crucial for clinicians to thoroughly examine patients and appropriately request investigations that consider perforation of Meckel's diverticulum as a possible diagnosis to facilitate prompt treatment.
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http://dx.doi.org/10.1186/s40792-020-00926-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338335PMC
July 2020

The Influence of Clinical T Factor on Predicting Pathologic N Factor in Resected Lung Cancer.

Ann Thorac Surg 2019 10 16;108(4):1080-1086. Epub 2019 May 16.

Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.

Background: We investigated the utility of the clinical T factor of the 8th edition of the TNM classification, which newly defines the consolidation size of the tumor, as a valuable predictor of pathologic lymph node metastasis (pN+) and the prognosis.

Methods: We retrospectively reviewed 825 patients with surgically resected cN0 M0 non-small cell lung cancer of any T stage, focusing on the tumor's total size (7th edition) and consolidation size (8th edition) and examined pN+ and the prognosis.

Results: No pN+ cases in the 7th or 8th edition groups had a tumor size of less than 1 cm, and in those sized 1 to 3 cm, the frequency of pN+ in the 7th and 8th edition groups was 10.3% and 13.4%, respectively. The frequency of pN+ in tumors without ground glass opacity (GGO-) was 5.5-times higher than that of tumors with GGO (GGO+). The frequency of pN+ in the GGO+ 8th edition group was twice that in the GGO+ 7th edition group. The frequency of pN+ in the GGO- 7th edition group was 4-times higher than that of the GGO+ 7th edition group. A multivariate analysis revealed that total size exceeding 2 cm, consolidation size exceeding 2 cm, and GGO- were significant predictors of a pN+ status, indicating that a consolidation size of more than 2 cm was a stronger predictor than a total size of more than 2 cm.

Conclusions: A consolidation size of more than 2 cm and GGO- were predictors of pN+, and the clinical T factor of the 8th Edition was a stronger predictor of the pN+ status than that of the 7th edition.
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http://dx.doi.org/10.1016/j.athoracsur.2019.04.026DOI Listing
October 2019

Pneumonectomy after induction chemoradiotherapy for locally advanced non-small cell lung cancer: should curative intent pulmonary resection be avoided?

Surg Today 2019 Mar 4;49(3):197-205. Epub 2019 Jan 4.

Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka City, 811-1395, Japan.

Purpose: We conducted a retrospective analysis to assess the practicality of pneumonectomy, especially after concurrent induction chemoradiotherapy (i-CRT), for locally advanced non-small cell lung cancer (LA-NSCLC). The operative risks vs. the survival benefit of this procedure for such patients is a subject of controversy.

Methods: The subjects of this retrospective study were 71 consecutive LA-NSCLC patients with cStage IIIA-C NSCLC, who underwent i-CRT followed by curative intent pulmonary resection between February, 2001 and March, 2013.

Results: Thirty-two patients underwent pneumonectomy (group P) and 39 patients underwent lobectomy (group L). In group P, 17 (54.8%) patients underwent right pneumonectomy. There was no 30-day postoperative mortality in either group and no significant difference in 90-day postoperative mortality between the groups (3.1% vs. 2.6% in groups P and L, respectively). The 5-year overall survival (OS) rate was 58.7% (95% CI: 41.5-75.9%) in group P and 57.3% (95% CI 41.2-73.4%) in group L, without a significant difference between the groups.

Conclusion: Our findings suggest that i-CRT followed by pneumonectomy is feasible, with a similar survival benefit to lobectomy. Thus, pneumonectomy after i-CRT should not be avoided as it is a potentially curative intent strategy for carefully selected patients.
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http://dx.doi.org/10.1007/s00595-018-1751-7DOI Listing
March 2019

Acute median arcuate ligament syndrome after pancreaticoduodenectomy.

Surg Case Rep 2018 Nov 26;4(1):137. Epub 2018 Nov 26.

Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, 1-9-6, Sendamachi, Naka-ku, Hiroshima City, Hiroshima, 730-0052, Japan.

Background: Median arcuate ligament syndrome (MALS) can cause severe complications after pancreaticoduodenectomy (PD). Most of the reported cases of MALS have been diagnosed perioperatively and can be treated efficiently by interventional radiology or division of the median acute ligament (MAL) fibers.

Case Report: A 69-year-old woman underwent PD with resection of the SMV for pancreatic head cancer. Intraoperative exploration showed normal anatomy of the celiac trunk. Intraoperative digital palpation revealed normal pulsation of the common hepatic artery after resection of the gastroduodenal artery. On postoperative day (POD) 3, her liver function tests were abnormal, and bloody fluids were found in the drain. Abdominal CT showed necrosis of the pancreatic body and ischemia in the liver secondary to MALS which was not detected in the preoperative CT. Interventional radiology was tried first but failed. Division of the MAL fibers markedly increased the blood flow in the hepatic artery. Resection of the remnant pancreas and spleen was also performed simultaneously. Abdominal CT on POD 20 showed re-occlusion of the celiac artery. She experienced rupture of the gastrojejunostomy site, severe hepatic cytolysis, and choledochojejunostomy stricture thereafter.

Conclusions: This is the third case of MALS that has developed acutely after PD. MALS can cause refractory complications even after MAL release.
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http://dx.doi.org/10.1186/s40792-018-0545-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261092PMC
November 2018

The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells.

PLoS One 2018 2;13(7):e0194160. Epub 2018 Jul 2.

Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Aberrant Wnt/β-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/β-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/β-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/β-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/β-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194160PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028230PMC
December 2018

A case of different mutations in surgically resected synchronous triple lung cancer.

J Thorac Dis 2018 Apr;10(4):E255-E259

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka 811-1395, Japan.

We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases. At eight months after surgery, a new lesion emerged in the right lower lobe. Given that the most advanced tumor had an EGFR del-19 mutation, the patient was orally administered afatinib. Since then, the treatment response of the patient has been assessed as stable disease (SD) for about two years. This is a very rare case of resected triple synchronous primary lung cancer on the same lung side in which the lesions all had a different mutation status, and this report highlights the clinical utility of surgical resection of multifocal lung nodules without lymph node metastasis or distant metastasis in order to optimize therapy for patients with known driver mutations.
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http://dx.doi.org/10.21037/jtd.2018.03.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949472PMC
April 2018

A typical carcinoid tumor of the lung presenting with pure persistent ground-glass opacity on high-resolution computed tomography: a case report.

Surg Case Rep 2017 Oct 4;3(1):108. Epub 2017 Oct 4.

Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1, Notame, Minami-ku, Fukuoka, 811-1395, Japan.

Pure ground-glass opacity nodules (p-GGN) on high-resolution computed tomography (HRCT) generally have been considering typically associated with adenocarcinoma with less invasive nature. We herein reported a patient presenting focal p-GGN on middle lobe of the right lung who underwent surgical resection with its pathological diagnosis turned out to be typical carcinoid tumor.
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http://dx.doi.org/10.1186/s40792-017-0382-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628087PMC
October 2017

Surgical resection of a well-differentiated inflammatory liposarcoma of the middle mediastinum: a case report.

J Thorac Dis 2017 Aug;9(8):E689-E693

Department of Thoracic Oncology, Institute for Clinical Research, National Kyushu Cancer Center, Fukuoka, Japan.

Liposarcomas are the most common type of mesenchymal neoplasm in soft tissue sarcomas. Although they frequently develop at the lower limbs or retroperitoneum, cases arising from the mediastinum are rare. Furthermore, the incidence of the inflammatory subtype of well-differentiated liposarcoma is known to be low. We experienced a case of a middle mediastinal liposarcoma in a 68-year-old woman. The tumor, which was completely resected, was 92 mm in diameter. The tumor consisted of two different imaging components that showed different growth and which were diagnosed as the lipoma-like subtype and inflammatory subtype of well-differentiated liposarcoma. To the best of our knowledge, this is the first report of a well-differentiated inflammatory liposarcoma arising from the middle mediastinum.
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http://dx.doi.org/10.21037/jtd.2017.07.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594142PMC
August 2017

Evaluation of erlotinib for the treatment of patients with non-small cell lung cancer with epidermal growth factor receptor wild type.

Oncol Lett 2017 Jul 4;14(1):306-312. Epub 2017 May 4.

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka 811-1395, Japan.

Erlotinib is one of the treatment choices for patients with advanced non-small cell lung cancer (NSCLC), regardless of the epidermal growth factor receptor () mutation status. However, its efficacy for the treatment of patients with NSCLC with wild type or who are beyond the usage of gefitinib remains controversial. The present study therefore retrospectively assessed the efficacy of erlotinib in patients with wild type who had previously undergone gefitinib therapy. A total of 222 patients with NSCLC who received chemotherapeutic treatment with erlotinib between July 2007 and February 2013 were evaluated. The background variables, response rates, progression-free survival (PFS) and overall survival rates were retrospectively analyzed. The male/female ratio of patients was 103/119, and patients had a median age of 63 years (range, 33-95 years). A total of 10 of the 222 patients had clinical stages IIIB/IV, 191 had adenocarcinoma, 5 had large cell carcinoma, 10 had squamous cell carcinoma and 6 had NSCLC of a variety not otherwise specified. The mutation was positive, wild type or unknown in 95, 52 and 75 patients, respectively. In the 52 patients with wild type, there were 3 partial responders, 25 with stable disease and 24 with progressive disease, for a response rate of 6% [95% confidence interval (CI), 1.3-15%]. The median PFS of wild type and positive were 1.1 months (95% CI, 1.04-1.16 months) and 5.42 months (95% CI, 5.43-5.68 months), respectively. The results of the study demonstrated that erlotinib is not sufficiently effective for patients with NSCLC who possess the wild type status.
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http://dx.doi.org/10.3892/ol.2017.6118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494899PMC
July 2017

Uncommon features of surgically resected ALK-positive cavitary lung adenocarcinoma: a case report.

Surg Case Rep 2017 Dec 20;3(1):46. Epub 2017 Mar 20.

Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, 811-1395, Japan.

Some features found on chest computed tomography (CT), such as central tumor location, large pleural effusion, and the absence of a pleural tail, and a patient age of less than 60 years, have been suggested to be useful in predicting anaplastic lymphoma kinase (ALK) rearrangement in patients with non-small cell lung cancer (NSCLC).A 68-year-old female patient with a history of gynecological treatment was found to have a cavitary mass in the right lower lobe on an annual chest roentgenogram. The tumor was located in the peripheral area with a pleural tail showing no pleural effusion. In addition, two pure ground-glass-opacity nodules (p-GGNs) in the right upper lobe of the lung were detected on consecutive chest CT scans. The patient underwent right lower lobectomy, partial resection of the right upper lobe, and hilar mediastinal lymph node dissection for complete resection of each tumor. The pathological diagnosis was invasive mucinous adenocarcinoma with signet-ring cells for the cavitary mass in the right lower lobe and invasive adenocarcinoma for the rest of the p-GGNs; subcarinal lymph node metastasis was also detected. The ALK rearrangement was detected by fluorescence in situ hybridization from the cavitary mass. The patient underwent four cycles of cisplatin and vinorelbine chemotherapy as standard adjuvant chemotherapy for pStage III NSCLC. The ALK fusion gene status of NSCLC with atypical CT features should also be investigated.
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http://dx.doi.org/10.1186/s40792-017-0322-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359261PMC
December 2017

The Controlling Nutritional Status Score Is a Significant Independent Predictor of Poor Prognosis in Patients With Malignant Pleural Mesothelioma.

Clin Lung Cancer 2017 07 2;18(4):e303-e313. Epub 2017 Feb 2.

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.

Introduction: Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM.

Methods: The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut-off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups.

Results: Fifty-two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease- or progression-free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively.

Conclusions: The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment.
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http://dx.doi.org/10.1016/j.cllc.2017.01.008DOI Listing
July 2017

Pulmonary Resection for Synchronous M1b-cStage IV Non-Small Cell Lung Cancer Patients.

Ann Thorac Surg 2017 May 15;103(5):1594-1599. Epub 2016 Nov 15.

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.

Background: We wanted to assess the efficacy of curative intent pulmonary resection for non-small cell lung cancer (NSCLC) patients with synchronous M1b-distant metastases in a single organ or lesion.

Methods: Between 1995 and 2015, 23 consecutive synchronous M1b-cStage IV NSCLC patients who underwent any treatment for metastases and curative intent pulmonary resection were retrospectively analyzed.

Results: Sixteen patients were men and 7 were women, with a median age of 56 years (range: 41 to 76 years). There were 17 adenocarcinoma, 4 large-cell carcinoma, 1 large-cell neuroendocrine cancer, and 1 carcinosarcoma. Thirteen patients had no lymph node metastasis. Fourteen patients received preoperative chemotherapy, and 10 received postoperative chemotherapy. The metastatic sites were the brain in 13 patients; bone in 3 patients; adrenal glands and extrathoracic lymph nodes in 2 patients each; and the liver, small intestine, and subcutaneous tissue in 1 patient each. Nineteen patients underwent lobectomy, and the other 4 patients underwent pneumonectomy. Seventeen patients experienced recurrence as follows: local recurrence in 3 patients, distant recurrence in 13 patients, and both in 1 patient. The 5-year progression-free survival rates in the 23 patients was14.5% (95% confidence interval: 0% to 30.6%), and the 5-year overall survival rate was 41.7% (95% confidence interval: 19.6% to 63.8%).

Conclusions: Some M1b-cStage IV NSCLC patients achieved longer survival than others with the same stage disease by using local treatment for distant metastases and curative intent pulmonary resection. Oligometastatic patients might have been inadvertently included in the present cohort. However, at present, the optimum method for patient selection remains unclear.
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http://dx.doi.org/10.1016/j.athoracsur.2016.08.098DOI Listing
May 2017

The Prognostic Impact of Jumonji Domain-containing 2B in Patients with Resected Lung Adenocarcinoma.

Anticancer Res 2016 09;36(9):4841-6

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.

Background: Jumonji domain-containing 2B, JMJD2B, has been shown to play an important role in the pathogenesis of lung cancer cells. However, the significance of JMJD2B in patients with lung cancer remains to be elucidated.

Patients And Methods: Seventy-eight patients with resected adenocarcinoma, whose data regarding oncogenic drivers in lung cancer were available, were included in the study. Immunohistochemical analysis was performed with a specific antibody for JMJD2B to investigate JMJD2B expression and the significance of JMJD2B expression in survival after surgery was evaluated.

Results: Among the 78 patients, 50 (64%) exhibited JMJD2B immunopositivity. The overall survival (OS) of the 50 JMJD2B-positive patients after surgery was significantly inferior to that of the JMJD2B-negative patients (five-year survival=56.7% vs. 92.6%; log-rank: p=0.01). Multivariate analysis showed that JMJD2B positivity was an independent prognostic factor.

Conclusion: JMJD2B may be a novel prognostic factor for resected lung adenocarcinoma.
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http://dx.doi.org/10.21873/anticanres.11046DOI Listing
September 2016

mutation-positive advanced thymic carcinoma successfully treated as a mediastinal gastrointestinal stromal tumor: A case report.

Mol Clin Oncol 2016 Apr 28;4(4):527-529. Epub 2016 Jan 28.

Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Fukuoka 811-1395, Japan.

Thymic carcinoma is an exceptionally rare tumor, which has a very poor prognosis, differing from thymoma. Although cytotoxic chemotherapy is commonly used to treat advanced thymic carcinoma, its effectiveness has not been found to be sufficient. There are several reports that thymic carcinoma also harbors an oncogenic driver mutation, similar to lung cancer. A patient with a mutation-positive thymic carcinoma received imatinib followed by sunitinib consecutively, which are both c-Kit inhibitors. Although the patient had achieved long-term disease control for 21 months, the primary lesion and pulmonary metastases had increased in size by November, 2014. Following failure of imatinib treatment, the patient received sunitinib, a multiple kinase inhibitor, initiated in December, 2014. Following administration of sunitinib, a computed tomography scan revealed a partial response and the disease was effectively controlled with continued sunitinib treatment for 6 months, up to June, 2015. The patient achieved long-term disease control (~27 months) with imatinib followed by sunitinib. The efficacy of consecutive molecular-targeted therapy for thymic carcinoma was demonstrated in this case. Therefore, thymic carcinoma with oncogenic driver mutations should be treated with molecular-targeted agents rather than with cytotoxic drugs, and it may be suitable to treat mutation-positive thymic carcinoma as a mediastinal gastrointestinal stromal tumor.
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http://dx.doi.org/10.3892/mco.2016.752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812268PMC
April 2016

How should we manage small focal pure ground-glass opacity nodules on high-resolution computed tomography? A single institute experience.

Surg Oncol 2015 Sep 13;24(3):258-63. Epub 2015 Aug 13.

Department of Thoracic Oncology, National Kyushu Cancer Center, Japan.

Background: Although the detection of pure ground-glass opacity (p-GGO) nodules on high-resolution chest computed tomography (HRCT) often implies a diagnosis of lung adenocarcinoma, the management of p-GGO nodules remains under discussion.

Objective: To assess the correlation between the radiological and pathological diagnoses of small p-GGO on HRCT.

Patients And Methods: This is a single-institution retrospective study. We analyzed 89 consecutive patients, including 33 patients with resected p-GGO nodule(s) equal or less than 20 mm in maximal diameter on axial images of HRCT.

Results: Thirty-nine patients underwent locoregional treatment (Treatment group), including surgical resection in 33 and stereotactic body radiation therapy in six. The remaining 50 patients were observed (Observation group) using periodic chest HRCT. The median follow-up time was 30.4 (4.9-102.5) months in the Treatment group and 44.8 (0.4-1125.8) months in the Observation group. During the follow-up period, the p-GGO nodules increased in size in eight patients over a median of 20.6 (12.1-50.6) months, with increased attenuation in three patients over a median of 20.6 (12.1-50.6) months, and either decreased in size or disappeared in four patients over a median of 6.9 (2.0-11.2) months. Thirty-three patients with 47 nodules underwent surgical resection, including 41 adenocarcinomas, one neuroendocrine tumor, three cases of atypical adenomatous hyperplasia and two benign lesions. The frequency of invasive adenocarcinoma was higher among the larger p-GGO nodules.

Conclusions: Careful observation and decision making with respect to the timing of intervention in cases of p-GGO nodules are warranted.
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http://dx.doi.org/10.1016/j.suronc.2015.08.004DOI Listing
September 2015

Role of activating transcription factor 3 (ATF3) in endoplasmic reticulum (ER) stress-induced sensitization of p53-deficient human colon cancer cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis through up-regulation of death receptor 5 (DR5) by zerumbone and celecoxib.

J Biol Chem 2014 Aug 17;289(31):21544-61. Epub 2014 Jun 17.

From the Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan,

Death receptor 5 (DR5) is a death domain-containing transmembrane receptor that triggers cell death upon binding to its ligand, TNF-related apoptosis-inducing ligand (TRAIL), and a combination of TRAIL and agents that increase the expression of DR5 is expected to be a novel anticancer therapy. In this report, we demonstrate that the stress response gene ATF3 is required for endoplasmic reticulum stress-mediated DR5 induction upon zerumbone (ZER) and celecoxib (CCB) in human p53-deficient colorectal cancer cells. Both agents activated PERK-eIF2α kinases and induced the expression of activating transcription factor 4 (ATF4)-CCAAT enhancer-binding protein (C/EBP) homologous protein, which were remarkably suppressed by reactive oxygen species scavengers. In the absence of ATF3, the induction of DR5 mRNA and protein was abrogated significantly, and this was associated with reduced cell death by cotreatment of TRAIL with ZER or CCB. By contrast, exogenous expression of ATF3 caused a more rapid and elevated expression of DR5, resulting in enhanced sensitivity to apoptotic cell death by TRAIL/ZER or TRAIL/CCB. A reporter assay demonstrated that at least two ATF/cAMP response element motifs as well as C/EBP homologous protein motif at the proximal region of the human DR5 gene promoter were required for ZER-induced DR5 gene transcription. Taken together, our results provide novel insights into the role of ATF3 as an essential transcription factor for p53-independent DR5 induction upon both ZER and CCB treatment, and this may be a useful biomarker for TRAIL-based anticancer therapy.
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http://dx.doi.org/10.1074/jbc.M114.558890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118115PMC
August 2014

Role of ATF3 in synergistic cancer cell killing by a combination of HDAC inhibitors and agonistic anti-DR5 antibody through ER stress in human colon cancer cells.

Biochem Biophys Res Commun 2014 Mar 12;445(2):320-6. Epub 2014 Feb 12.

Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address:

Histone deacetylase inhibitors (HDACIs) are promising agents for cancer therapy. However, the mechanism(s) responsible for the efficacy of HDACIs have not yet to be fully elucidated. Death receptor 5 (DR5) is a transmembrane receptor containing death domain that triggers cell death upon binding to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) or agonistic anti-DR5 monoclonal antibody, and the combination of TRAIL/agonistic anti-DR5 monoclonal antibody and agents that increase the expression of DR5 is expected as a novel anticancer therapeutic strategy. Here we report that six different HDACIs activated endoplasmic reticulum (ER) stress sensor PERK and eIF2α and induced the ATF4/ATF3/CHOP pathway in p53-deficient human colon cancer cells. This resulted in an increased expression of DR5 on the cell surface and sensitized cells to apoptosis by agonistic anti-DR5 monoclonal antibody. Stress response gene ATF3 was required for efficient DR5 induction by HDACIs, and DR5 reporter assay showed that ATF3 play crucial role for the HDACIs-induced activation of DR5 gene transcription. These provide important mechanistic insight into how HDACIs exhibit pro-apoptotic activity in clinical anti-cancer treatments when they are used in combination with other therapeutic strategies.
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http://dx.doi.org/10.1016/j.bbrc.2014.01.184DOI Listing
March 2014
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