Publications by authors named "Noriaki Wada"

38 Publications

Right entorhinal cortical thickness is associated with Mini-Mental State Examination scores from multi-country datasets using MRI.

Neuroradiology 2021 Jul 11. Epub 2021 Jul 11.

Department of Radiology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, 810-0065, Fukuoka, Japan.

Purpose: To discover common biomarkers correlating with the Mini-Mental State Examination (MMSE) scores from multi-country MRI datasets.

Methods: The first dataset comprised 112 subjects (49 men, 63 women; range, 46-94 years) at the National Hospital Organization Kyushu Medical Center. A second dataset comprised 300 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (177 men, 123 women; range, 57-91 years). Three-dimensional T1-weighted MR images were collected from both datasets. In total, 14 deep gray matter volumes and 70 cortical thicknesses were obtained from MR images using FreeSurfer software. Total hippocampal volume and the ratio of hippocampus to cerebral volume were also calculated. Correlations between each variable and MMSE scores were assessed using Pearson's correlation coefficient. Parameters with moderate correlation coefficients (r > 0.3) from each dataset were determined as independent variables and evaluated using general linear model (GLM) analyses.

Results: In Pearson's correlation coefficient, total and bilateral hippocampal volumes, right amygdala volume, and right entorhinal cortex (ERC) thickness showed moderate correlation coefficients (r > 0.3) with MMSE scores from the first dataset. The ADNI dataset showed moderate correlations with MMSE scores in more variables, including bilateral ERC thickness and hippocampal volume. GLM analysis revealed that right ERC thickness correlated significantly with MMSE score in both datasets. Cortical thicknesses of the left parahippocampal gyrus, left inferior parietal lobe, and right fusiform gyrus also significantly correlated with MMSE score in the ADNI dataset (p < 0.05).

Conclusion: A positive correlation between right ERC thickness and MMSE score was identified from multi-country datasets.
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http://dx.doi.org/10.1007/s00234-021-02767-yDOI Listing
July 2021

Identification of predictors for mini-mental state examination and revised Hasegawa's Dementia Scale scores using MR-based brain morphometry.

Eur J Radiol Open 2021 24;8:100359. Epub 2021 May 24.

Department of Radiology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka, 810-0065, Japan.

Purpose: The early detection of cognitive function decline is crucial to help manage or slow the progression of symptoms. The Mini-Mental State Examination (MMSE) and revised Hasegawa's Dementia Scale (HDS-R) are widely used in screening for cognitive impairment. The purpose of this study was to explore common predictors of the two different cognitive testing systems using MR-based brain morphometry.

Materials And Methods: This retrospective study included 200 subjects with clinical suspicion of cognitive impairment who underwent 3D T1-weighted MRI at our institution between February 2019 and August 2020. Variables related to the volume of deep gray matter and 70 cortical thicknesses were obtained from the MR images using voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) and FreeSurfer software. The correlation between each variable including age and MMSE/HDS-R scores was evaluated using uni- and multi-variate logistic regression analyses.

Results: In univariate analysis, parameters include hippocampal volume and bilateral entorhinal cortex (ERC) thickness showed moderate correlation coefficients with both MMSE and HDS-R scores. Multivariate analysis demonstrated the right ERC thickness was the common parameter which significantly correlates with both MMSE and HDS-R scores (p < 0.05).

Conclusion: Right ERC thickness appears to offer a useful predictive biomarker for both MMSE and HDS-R scores.
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http://dx.doi.org/10.1016/j.ejro.2021.100359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167144PMC
May 2021

A practical system that enables physicians to respond expeditiously to significant unexpected findings (SUFs) in radiological reports.

Jpn J Radiol 2021 May 1;39(5):424-432. Epub 2021 Jan 1.

The Director of the hospital, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka City, Fukuoka Province, Japan.

Purpose: To demonstrate effectiveness of our present radiological report check flowchart enabling physicians to respond to significant unexpected findings (SUFs), by comparing the response periods from the examination date to the action date on untreated SUFs between the previous and present versions of our flowchart.

Methods: In the flowchart's previous version used February-October 2019, SUFs, which were notified by email, were audited every month. The physician received a phone call and was asked to act on the untreated SUF. In the flowchart's present version used from November 2019 to May 2020, SUFs were audited every 2 weeks. The physician and his/her chief were asked to return a written response to the untreated SUF. We evaluated the difference in the response periods between the previous and present versions of the flowchart.

Results: With the previous flowchart's use, untreated SUFs were 43 of 229 SUFs (18.8%) with the present flowchart untreated SUFs were 22 of 130 SUFs (16.9%). All SUFs in both periods were eventually responded. The present flowchart (median/range, 25/11-70 days) significantly had shorter response periods than the previous flowchart (70/16-290 days) (p < 0.0001).

Conclusion: The present flowchart employing a shortened primary audit interval, a written response, and the department chief's intervention, helped reduce the response periods.
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http://dx.doi.org/10.1007/s11604-020-01077-2DOI Listing
May 2021

Endovascular repair of a Clostridium perfringens infected pseudoaneurysm presenting as an intramural air pocket.

IDCases 2020 25;21:e00841. Epub 2020 May 25.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

An infected aneurysm (IA) is a relatively rare but complex and life-threatening disease. We report a 78-year-old man with an IA in the common iliac artery (CIA) due to . An initial computed tomography (CT) revealed an air pocket in the left CIA, and a pseudoaneurysm was seen on the CT taken the next day, in the area where the air pocket was initially observed. Due to the patient's high surgical risk, emergent endovascular aneurysm repair (EVAR) was performed. No indolent infection was found 1.5 years after the surgery. Because of its high risk of expansion and rupture, accurate diagnosis and immediate treatment is required for managing IAs. The case emphasizes that air density in an arterial wall could be an early radiologic feature of an IA, and EVAR could be a treatment option for IA.
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http://dx.doi.org/10.1016/j.idcr.2020.e00841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260675PMC
May 2020

The Japanese Breast Cancer Society clinical practice guidelines for surgical treatment of breast cancer, 2018 edition.

Breast Cancer 2020 Jan 12;27(1):4-8. Epub 2019 Dec 12.

Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.

We have prepared the Japanese Breast Cancer Society clinical practice guidelines (CPGs) for surgical treatment of breast cancer, 2018 update after a systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. The CPG committee for surgical treatment of breast cancer, composed of breast surgeons and plastic surgeons treating breast cancer, has developed the CPGs. Eight clinical questions (CQs) were selected and divided roughly into the following five categories: (1) breast surgery in initial therapy (CQs 1-3); (2) axillary surgery in initial therapy (CQs 4-5); (3) breast reconstruction in initial therapy (CQ 6); (4) surgical treatment for recurrent and metastatic breast cancer (CQs 7-8); and (5) others. Recommendations for these CQs were decided by the GRADE grid method. In addition, 4 outlines, 14 background questions (BQs), and 12 future research questions (FQs) were also selected. Statements for these BQs and FQs are provided. We developed the updated CPGs for surgical treatment of breast cancer, 2018, which include 8 CQs and recommendations. As a decision-making tool for the understanding and treatment of breast cancer, these guidelines will help surgical oncologists dealing with breast cancer, medical staff, and patients, along with their family members.
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http://dx.doi.org/10.1007/s12282-019-01030-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134293PMC
January 2020

Successful treatment of esophagopleural fistula following pulmonary resection for primary lung cancer: a case report.

Surg Case Rep 2019 May 14;5(1):78. Epub 2019 May 14.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, 5-11-13 Sugano, Ichikawa, Chiba, 272-8513, Japan.

Background: We report a rare case of esophagopleural fistula (EPF) developing during the postoperative period after pulmonary resection for primary lung cancer.

Case Presentation: A 71-year-old male who underwent video-assisted thoracoscopic right lower lobectomy with lymph node dissection for primary lung cancer developed severe stabbing pain in his right shoulder and high fever 3 days after the operation. The fever persisted, the cough became more productive, and a plain chest X-ray showed slight a few infiltrative opacities in the right lung field. Intravenous antibiotic therapy was initiated. The patient developed a right pneumothorax 5 days after the operation, and contaminated discharge from the right chest tube was noted. A chest computed tomography showed right-sided empyema, while bronchoscopic examination revealed no evidence of a bronchopleural fistula. Open-window thoracostomy (OWT) was performed. Finally, 2 days after the OWT, the patient was diagnosed as having an EPF, because the right chest cavity was found to be contaminated with food materials. Ample purification of the right chest cavity was achieved by repeated dressing changes, and the EPF was finally closed by omentopexy. The post-surgical course was uneventful. Five weeks after the omentopexy, an esophagogram revealed no leakage of the contrast medium from the esophageal wall. The patient was discharged 13 weeks after the omentopexy.

Conclusion: While EPF following pulmonary resection is a rare complication, it can lead to critical situations and the diagnosis is difficult. Prompt OWT and omentopexy were found to be effective treatment procedures for EPF following lung surgery.
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http://dx.doi.org/10.1186/s40792-019-0638-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517458PMC
May 2019

Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach.

Int J Mol Sci 2019 Jan 19;20(2). Epub 2019 Jan 19.

Division of Functional Imaging, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan.

The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach for developing a more efficient SLN biopsy procedure, we reported a two-stage imaging method combining lymphoscintigraphy and near-infrared (NIR) fluorescence imaging to depict metastatic cancer cells in SLNs in vivo. Furthermore, the theranostic potential of the combined procedure was examined by cell culture and xenograft mouse model. Anti-HER2 and anti-epidermal growth factor receptor (EGFR) affibody probes were used for NIR fluorescence imaging. Strong NIR fluorescence signal intensity of the anti-EGFR affibody probe was observed in SAS cells (EGFR positive). Radioactivity in the SLNs was clearly observed in the in vivo studies. High anti-EGFR affibody NIR fluorescence intensity was observed in the metastatic lymph nodes in mice. The addition of the IR700-conjugated anti-EGFR affibody to the culture medium decreased the proliferation of SAS cells. Decreased proliferation was shown in Ki-67 immunohistochemistry in xenograft tumors. Our data suggest that a two-stage combined imaging method using lymphoscintigraphy and affibody probes may offer the direct visualization of metastatic lymph nodes as an easily applied technique in SLN biopsy. Although further animal studies are required to assess the effect of treating lymphatic metastasis in this approach, our study results provide a foundation for the further development of this promising imaging and treatment strategy for earlier lymph node metastasis detection and treatment.
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http://dx.doi.org/10.3390/ijms20020427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359136PMC
January 2019

Calcium pyrophosphate dihydrate crystal deposition disease of the spinal dura mater: a case report.

BJR Case Rep 2018 7;4(1):20170049. Epub 2017 Oct 7.

Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University Hospital, Fukuoka, Japan.

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by the accumulation of CPPD crystal in articular and periarticular tissues, but CPPD crystal deposition along the spinal dura mater has not been previously reported. We report a 54-year-old male presenting with progressive neck pain and numbness of the extremities. CT showed diffuse dorsal epidural calcification from C3-T6 which resulted in spinal canal stenosis. On MR imaging, the lesion was hypointense on both and weighted images. From these findings, CPPD crystal deposition in the ligamentum flavum was suspected preoperatively. Biopsy at the level of C5-6 were performed to confirm the diagnosis. Perioperative and histopathological findings revealed that CPPD crystals were deposited along the dorsal dura mater, not in the ligamentum flavum. We firstly report the CT and MR imaging features of a possible new concept in the differential diagnosis of CPPD crystal deposition disease.
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http://dx.doi.org/10.1259/bjrcr.20170049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159146PMC
October 2017

Long-term influence of adjuvant breast radiotherapy on cognitive function in breast cancer patients treated with conservation therapy.

Int J Clin Oncol 2019 Jan 30;24(1):68-77. Epub 2018 Aug 30.

Innovation Center for Supportive, Palliative, and Psychosocial Care, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The mechanisms underlying cognitive decline after radiotherapy not directed at brain areas remains unclear. We previously suggested that adjuvant breast radiotherapy in breast conservation therapy could lower memory function soon after therapy, and that the process might be partially mediated by plasma interleukin (IL)-6 levels. The present study investigated how that relationship changes longitudinally.

Methods: We performed the Wechsler Memory Scale-Revised (WMS-R) test and measured plasma IL-6 levels for 47 breast cancer surgical patients within 1 year after the initial therapy (study 1) and more than 2 years after study 1 (study 2). We also performed 2 × 2 mixed [the radiotherapy group (n = 25) or the no-radiotherapy group (n = 22) × study 1 or study 2] analysis of covariance on the WMS-R indices and plasma IL-6 levels. The association between changes in plasma IL-6 levels and changes in the WMS-R indices between the two studies was evaluated using Pearson's correlation coefficient.

Results: The Immediate Verbal Memory Index was significantly higher in study 2. The Delayed Recall Index was significantly higher in study 2 and significantly lower in the radiotherapy group only in study 1. There was a significant correlation between changes in plasma IL-6 levels and changes only in the Delayed Recall Index of the WMS-R.

Conclusions: Memory decline in breast cancer patients soon after adjuvant breast radiotherapy was restored approximately 3 years after treatment, and decreased plasma IL-6 levels might be involved in the recovery process.
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http://dx.doi.org/10.1007/s10147-018-1330-3DOI Listing
January 2019

Improved overall survival over recent decades in patients with hormone-receptor-positive, HER2-negative breast cancer: a single-center retrospective analysis of prognostic factors.

Jpn J Clin Oncol 2018 Mar;48(3):248-254

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

Background: Hormone receptor (HR)-positive HER2-negative breast cancer (BC) rates and associated mortality have been increasing among Japanese women. It is unclear whether the prognosis of these patients has improved.

Methods: We retrospectively analyzed 1806 Japanese women with operable invasive HR-positive HER2-negative BC, who underwent complete resection at the National Cancer Center Hospital East between July 1992 and December 2010. We investigated whether overall survival (OS) and recurrence-free survival (RFS) had improved by comparing the 4-year periods 1992-96, 1997-2001, 2002-06, and 2007-10. The prognostic factors were evaluated using uni- and multivariate analyses.

Results: The number of ER- and PgR-positive cancers had increased over the years (P < 0.001). Tumor sizes and numbers of involved lymph nodes both gradually decreased (P < 0.001 for both). OS and RFS of all patients significantly improved in each of the periods analyzed: 5-year OS was 92.6%, 94.8%, 95.4% and 97.6% (P < 0.001, Log-rank), and 5-year RFS was 82.1%, 82.8%, 88.6% and 94.5% (P < 0.001) in 1992-96, 1997-2001, 2002-06 and 2007-10, respectively. In multivariate analysis, the history of adjuvant AI and that of TAM had positive-correlation with RFS.

Conclusions: The prognosis for HR-positive HER2-negative BC patients after surgical therapy has improved, resulting in longer OS and RFS across the study periods. These changes could be associated with early detection of tumor and history of hormone therapy.
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http://dx.doi.org/10.1093/jjco/hyy001DOI Listing
March 2018

Contribution of arterial spin-labelling MRI in a case with immune reconstitution inflammatory syndrome.

BMJ Case Rep 2017 Jul 6;2017. Epub 2017 Jul 6.

Department of Radiology, Kokuritsu Kokusai Iryo Center Byoin, Shinjuku-ku, Tokyo, Japan.

Central nervous system immune reconstitution inflammatory syndrome (CNS-IRIS), which occurs most often in HIV-infected patients, is an exacerbation of inflammatory reactions related to opportunistic infections as well as primary CNS malignancies both of which mostly occur in HIV-infected patients. However, differential diagnoses are challenging both clinically and radiologically. We describe a patient with CNS-IRIS due to toxoplasmosis whose C-methionine uptake suggested lymphoma but whose arterial spin-labelling MRI led to the correct diagnosis.
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http://dx.doi.org/10.1136/bcr-2017-219860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534855PMC
July 2017

Trends in axillary treatment for breast cancer patients undergoing sentinel lymph node biopsy as determined by a questionnaire from the Japanese Breast Cancer Society.

Breast Cancer 2017 May 23;24(3):427-432. Epub 2016 Aug 23.

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

Background: Sentinel lymph node biopsy (SLNB) alone has been compared with SLNB followed by axillary lymph node dissection (ALND) in sentinel lymph node (SLN)-positive breast cancer patients in randomized phase III trials: the addition of ALND did not further improve the patient's outcome. However, there is still some controversy, regarding the clinical application of SLNB alone. To identify the optimal axillary treatment in the era of SLNB, the Japanese Breast Cancer Society conducted a group study of SLNB in 2014.

Methods: A questionnaire on axillary surgery and radiation therapy was sent to 432 Japanese institutes in December 2014, and 309 (72 %) completed the questionnaire.

Results: SLNB was performed at 98 % of the institutes, and 77 % offered irradiation for cancer treatment. Regarding breast-conserving surgery (BCS), SLNB alone was indicated at 41 % of the institutes in the cases of SLN with micrometastases. However, in the cases of SLN with macrometastases, ALND was performed at 64 %. The proportion of ALND seemed to be higher in total mastectomy than in BCS regardless of the SLN-positive status. In the cases of SLN with micrometastases, the radiation field was localized in the conserved breast at about half of the institutes. On the other hand, in the cases of SLN with macrometastases, it was extended to axillary and/or supraclavicular lesions beyond the conserved breast at about 70 % of the institutes.

Conclusions: Japanese breast physicians were conservative with respect to the omission of ALND in SLN-positive breast cancer, especially in the cases of SLN with macrometastases.
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http://dx.doi.org/10.1007/s12282-016-0721-4DOI Listing
May 2017

The Japanese Breast Cancer Society clinical practice guideline for surgical treatment of breast cancer, 2015 edition.

Breast Cancer 2016 May 26;23(3):367-77. Epub 2016 Feb 26.

Department of General and Breast Surgery, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan.

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http://dx.doi.org/10.1007/s12282-016-0671-xDOI Listing
May 2016

Survival outcome and reduction rate of Ki-67 between pre- and post-neoadjuvant chemotherapy in breast cancer patients with non-pCR.

Breast Cancer Res Treat 2014 Aug 9;147(1):95-102. Epub 2014 Aug 9.

Department of Breast and Medical Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan,

The research question of this investigation is whether the reduction rate of Ki-67 after neoadjuvant chemotherapy (NAC) could indicate a survival in patients with non-pCR. A total of 455 patients had received NAC, and subsequent surgery was analyzed retrospectively. Patients with non-pCR were divided into three subgroups according to Ki-67 change: High-reduction (the absolute value of Ki-67 was reduced by >80 % compared with that prior to NAC), Low-reduction (the absolute value of Ki-67 was reduced by 0-80 % compared with that prior to NAC), and Increase group (the absolute value of Ki-67 was increased compared with that prior to NAC). The relapse-free survival (RFS) rates were compared among subgroups. pCR was achieved in 93 patients (20.4 %). In patients with non-pCR, the median reduction rate of Ki-67 was 60 %. A total of 15 % of patients were in the High-reduction, 63 % in the Low-reduction, and 22 % in the Increase group. The median follow-up period was 64.5 months. The 5-year RFS rates among the three groups were significantly different (p < 0.0001), and the differences were also observed in the HER2 (p = 0.033), triple-negative (p = 0.034), and luminal-like subtypes (p = 0.001). Patients in the High-reduction group showed comparable RFS to that of patients with pCR (p = 0.363). In patients with non-pCR, the reduction rate of Ki-67 after NAC significantly predicted RFS regardless of cancer subtypes. Therefore, patients who are non-pCR but who achieve a high reduction of Ki-67 can be expected to have a favorable prognosis similar to that of patients with pCR.
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http://dx.doi.org/10.1007/s10549-014-3084-6DOI Listing
August 2014

Japan Breast Cancer Society clinical practice guideline for surgical treatment of breast cancer.

Breast Cancer 2015 Jan 5;22(1):37-48. Epub 2014 Aug 5.

Section of Breast and Endocrine Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Onohigashi, Osakasayama, Osaka, 589-8511, Japan,

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http://dx.doi.org/10.1007/s12282-014-0558-7DOI Listing
January 2015

Observational study of axilla treatment for breast cancer patients with 1-3 positive micrometastases or macrometastases in sentinel lymph nodes.

Jpn J Clin Oncol 2014 Sep 16;44(9):876-9. Epub 2014 Jul 16.

Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Sentinel node biopsy is a standard procedure in clinically node-negative breast cancer patients. It has eliminated unnecessary axillary lymph node dissection in more than half of the early breast cancers. However, one of the unresolved issues in sentinel node biopsy is how to manage axilla surgery for sentinel node-positive patients and clinically node-negative patients. To evaluate the outcome of no axillary lymph node dissection in sentinel node-positive breast cancer, a prospective cohort study registering early breast cancer patients with positive sentinel nodes has been conducted (UMIN 000011782). Patients with 1-3 positive micrometastases or macrometastases in sentinel lymph nodes are eligible for the study. The primary endpoint is the recurrence rate of regional lymph nodes in patients treated with sentinel node biopsy. Patients treated with sentinel node biopsy followed by axillary lymph node dissection are also registered simultaneously to compare the prognosis. The propensity score matching is used to make the distributions of baseline risk factors comparable.
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http://dx.doi.org/10.1093/jjco/hyu090DOI Listing
September 2014

Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy.

Cancer Med 2014 Jun 23;3(3):702-9. Epub 2014 Apr 23.

Department of Stress Sciences and Psychosomatic Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Although protracted cognitive impairment has been reported to occur after radiotherapy even when such therapy is not directed to brain areas, the mechanism remains unclear. This study investigated whether breast cancer patients exposed to local radiotherapy showed lower cognitive function mediated by higher plasma interleukin (IL)-6 levels than those unexposed. We performed the Wechsler Memory Scale-Revised (WMS-R) and measured plasma IL-6 levels for 105 breast cancer surgical patients within 1 year after the initial therapy. The group differences in each of the indices of WMS-R were investigated between cancer patients exposed to adjuvant regional radiotherapy (n = 51) and those unexposed (n = 54) using analysis of covariance. We further investigated a mediation effect by plasma IL-6 levels on the relationship between radiotherapy and the indices of WMS-R using the bootstrapping method. The radiotherapy group showed significantly lower Immediate Verbal Memory Index and Delayed Recall Index (P = 0.001, P = 0.008, respectively). Radiotherapy exerted an indirect effect on the lower Delayed Recall Index of WMS-R through elevation of plasma IL-6 levels (bootstrap 95% confidence interval = -2.6626 to -0.0402). This study showed that breast cancer patients exposed to adjuvant regional radiotherapy in conservation therapy might have cognitive impairment even several months after their treatment. The relationship between the therapy and the cognitive impairment could be partially mediated by elevation of plasma IL-6 levels.
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http://dx.doi.org/10.1002/cam4.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101762PMC
June 2014

Use of the neo-adjuvant exemestane in post-menopausal estrogen receptor-positive breast cancer: a randomized phase II trial (PTEX46) to investigate the optimal duration of preoperative endocrine therapy.

Breast 2013 Jun 12;22(3):263-7. Epub 2013 Apr 12.

Department of Breast Surgery, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo, Japan.

Purpose: The optimal treatment duration time and the causal relationship between neoadjuvant endocrine therapy and clinical response are not clear. Therefore, we conducted the present study to investigate the potential benefits of neoadjuvant exemestane therapy with the goal of identifying the optimal treatment duration.

Methods: This study was conducted at three hospitals, as a multicenter, randomized phase II trial(UMIN000005668) of pre-operative exemestane treatment in post-menopausal women with untreated primary breast cancer. Fifty-one post-menopausal women with ER-positive and/or PgR-positive invasive breast cancer were randomly assigned to exemestane for 4 months or 6 months. Clinical response, pathological response, and decisions regarding breast-conserving surgery were the main outcome measures.

Results: Of the 52 patients that enrolled, 51 patients underwent surgery. Of those, 26 and 25 patients had been treated with exemestane for 4 and 6 months, respectively. Treatments were performed at 3 hospitals in Japan between April 2008 and August 2010. The response rates as assessed by clinical examination were 42.3% and 48.0% for 4 and 6 months of treatment, respectively. Pathological responses (minimal response or better) were observed in 19.2% and 32.0% of patients, and breast-conserving surgery was performed on 50.0% and 48.0% of patients from the 4 and 6 month treatment groups, respectively.

Conclusion: The results of this study demonstrate that responses were equal to 4 or 6 months of exemestane treatment. Therefore, we propose that the rates of breast-conserving surgery could be maximized by 4 months of treatment. Furthermore, in addition to using exemestane as a preoperative treatment in post-menopausal women with ER-positive breast cancer, we envision administering the drug over the long term under careful clinical supervision.
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http://dx.doi.org/10.1016/j.breast.2013.03.002DOI Listing
June 2013

Retrospective analysis of risk factors for central nervous system metastases in operable breast cancer: effects of biologic subtype and Ki67 overexpression on survival.

Oncology 2013 11;84(3):135-40. Epub 2012 Dec 11.

Divisions of Oncology/Hematology, National Cancer Center Hospital East, Kashiwa, Japan. mishihara @ clin.medic.mie-u.ac.jp

Objective: Identifying factors that predispose patients to central nervous system (CNS) metastases may hasten disease detection and improve treatment outcomes.

Methods: We reviewed the records of patients who were diagnosed with clinical stage I-III primary breast cancer at the National Cancer Center Hospital East from 2003 to 2005. Cox proportional hazard models were fitted to reveal risk factors for CNS metastases.

Results: The median follow-up period after the operation was 53.5 months. Among the 591 identified patients with breast cancer, 76 experienced a relapse. Seventeen patients developed CNS metastases. Multivariate analysis indicated that the triple negative (TN) subtype (hazard ratio = 5.5) and a high Ki67 labeling index (LI; hazard ratio = 3.9) were associated with a higher risk for CNS metastases. At 4 years, the TN subtype was associated with significantly worse overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with hormone receptor-positive/ human epidermal growth factor receptor-2-negative tumors. Breast cancers with a Ki67 LI ≥30% were also associated with lower overall and disease-free survival rates and a higher cumulative incidence of CNS metastases compared with cancers with a Ki67 LI <30%.

Conclusion: TN or Ki67-overexpressing breast cancer produced earlier CNS metastases and lower disease-free and overall survival rates.
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http://dx.doi.org/10.1159/000345321DOI Listing
March 2013

Different prognostic significance of Ki-67 change between pre- and post-neoadjuvant chemotherapy in various subtypes of breast cancer.

Breast Cancer Res Treat 2013 Jan 27;137(1):203-12. Epub 2012 Nov 27.

Department of Oncology and Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa city, Chiba 277-8577, Japan.

In a neoadjuvant setting, three parameters for Ki-67 could be obtained: pre-treatment Ki-67, post-treatment Ki-67 and Ki-67 change between pre- and post-treatments. It is uncertain which of the three parameters has the greatest prognostic significance, and whether this parameter has significance in each subtype of breast cancer. A total of 385 patients who received neoadjuvant anthracycline followed by taxane chemotherapy and subsequent surgery for breast cancer were analyzed retrospectively. By immunohistochemistry (IHC), patients were divided into four subtypes (Luminal A, Luminal B, Triple negative, and HER2). Ki-67 was examined by IHC in pre-treatment core needle samples and post-treatment surgical excision specimens. The relapse-free survival (RFS) rate was compared among each subtype. The median follow-up period was 56 months. The rate of pathological complete response was higher for HER2 (34.8 %) and Triple negative (24.3 %) subtypes than for Luminal B (8.3 %) and Luminal A (3.8 %) subtypes (p < 0.0001). A reduction in Ki-67 was observed in 58.5, 83.4, 70.2, and 74.2 % of patients in the Luminal A, Luminal B, Triple negative, and HER2 subtypes, respectively. Ki-67 change between pre- and post-treatments was an independent prognostic factor, but pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis. The RFS was significantly different between patients whose Ki-67 was reduced and those not reduced for Luminal B (81.4 vs. 50.0 %, p = 0.006), Triple negative (74.8 vs. 43.5 %, p = 0.006) and HER2 (82.7 vs. 59.0 %, p = 0.009). However, for Luminal A, the difference in RFS was not associated with changes of Ki-67 (78.8 vs. 75.3 %, p = 0.193). Ki-67 change between pre- and post-neoadjuvant chemotherapy is an independent prognostic factor in patients of Luminal B, Triple negative, and HER2 subtypes. Pre-treatment Ki-67 and post-treatment Ki-67 were not independent prognostic factors in a multivariate analysis.
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http://dx.doi.org/10.1007/s10549-012-2344-6DOI Listing
January 2013

Radiofrequency ablation of early breast cancer followed by delayed surgical resection--a promising alternative to breast-conserving surgery.

Breast 2011 Oct 8;20(5):431-6. Epub 2011 Jun 8.

Department of Breast Surgery, Hiroshima City Hospital, and Department of Pathology, Graduate School of Biomedical Sciences, Hiroshima University, 7-33 Moto-machi, Naka-ku, Hiroshima 730-8518, Japan.

To examine the radiofrequency ablation (RFA) reliability in early breast cancer, we performed RFA followed by delayed surgical resection on 41 patients with invasive or non-invasive breast carcinoma less than 2 cm. MRI scans were obtained before ablation and resection. Excised specimens were examined pathologically by haematoxylin-eosin and nicotinamide adenine dinucleotide-diaphorase staining. 40 patients completed 1 RFA session, which was sufficient to achieve complete tumour cell death. Overall complete ablation rate was 87.8% (36/41). There were no treatment-related complications other than that of a superficial burn in 1 case. After RFA, the tumour was no longer enhanced on MRI in 25/26 (96.2%) cases. Residual cancer, which was suspected on MRI in 1 case, was confirmed pathologically. MRI could be an applicable modality to evaluate therapeutic effect. RFA could be an alternate local treatment option to breast-conserving surgery for early breast cancer.
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http://dx.doi.org/10.1016/j.breast.2011.04.007DOI Listing
October 2011

E-cadherin expression on human carcinoma cell affects trastuzumab-mediated antibody-dependent cellular cytotoxicity through killer cell lectin-like receptor G1 on natural killer cells.

Int J Cancer 2011 May;128(9):2125-37

Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Trastuzumab is a recombinant antibody drug that is widely used for the treatment of HER2-overexpressing breast carcinoma. Despite encouraging clinical results, many HER2-overexpressing carcinomas are primarily resistant to trastuzumab. We attempted to explain trastuzumab resistance and search for solutions. Since the killer cell lectin-like receptor G1 (KLRG1), an inhibitory receptor expressed on subsets of natural killer (NK) cells recognizes E-cadherin as ligands and may inhibit immune responses by regulating the effector function of NK cells, we used HER2-overexpressing carcinoma cells which were expressing E-cadherin to investigate the role of antibody-dependent cellular cytotoxicity (ADCC) through KLRG1 on NK cells in vitro and vivo. The results indicated that HER2-overexpressing carcinoma cells were killed by trastuzumab-mediated ADCC and the ADCC activity was reflected the degree of E-cadherin expression on carcinoma cells. We found that expression of E-cadherin was shown to be a predictor of response to trastuzumab-based treatment for HER2-overexpressing carcinomas, furthermore, trastuzumab-mediated ADCC was markedly enhanced by KLRG1-negative peripheral blood mononuclear cells (PBMCs(KLRG1(-))).
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http://dx.doi.org/10.1002/ijc.25803DOI Listing
May 2011

Feasibility study on radiofrequency ablation followed by partial mastectomy for stage I breast cancer patients.

Breast 2009 Apr 26;18(2):130-4. Epub 2009 Mar 26.

Department of Breast Surgery, School of Medicine, Kyorin University, Mitaka, Tokyo, Japan.

To evaluate the safety and reliability of thermal ablation therapy instead of breast-conserving surgery (BCS), we performed radiofrequency ablation (RFA) for clinical stage I breast cancer patients. Subjects were T1N0 breast cancer patients with no extensive intraductal components. Under general anesthesia, sentinel node biopsy was performed, followed by RFA and BCS. Resected specimens were examined at 5-mm intervals by hematoxylin-eosin (H&E) staining and nicotinamide adenine dinucleotide (NADH) diaphorase staining. Thirty of the 34 eligible patients were enrolled. RFA-related adverse events were observed in nine patients: two with skin burn and seven with muscle burn. Twenty-six patients (87%) showed pathological degenerative changes in tumor specimens with H&E staining. In 24 of the 26 cases (92%) examined by NADH diaphorase staining, tumor cell viability was diagnosed as negative. RFA proved to be reliable and feasible in clinical stage I breast cancer, with no extensive intraductal components. Randomized clinical trials are needed to compare RFA with BCS.
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http://dx.doi.org/10.1016/j.breast.2009.02.008DOI Listing
April 2009

Histopathologic factors significantly associated with initial organ-specific metastasis by invasive ductal carcinoma of the breast: a prospective study.

Hum Pathol 2008 May 10;39(5):681-93. Epub 2008 Mar 10.

Surgical Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital East, Kashiwa, Chiba 277-0882, Japan.

The purpose of this study was to identify histologic factors significantly associated with initial organ-specific metastasis by 1044 invasive ductal carcinomas (IDCs) of the breast with and without adjuvant therapy, separately, according to nodal status and pathologic TNM stage status. The following histologic factors were prospectively analyzed by multivariate analyses for distant organ metastasis and bone metastasis in patients with IDC who did not receive adjuvant therapy, and for distant organ metastasis, bone metastasis, liver metastasis, and lung metastasis in patients with IDC who received adjuvant therapy: (1) invasive tumor size, (2) histologic grade, (3) tumor necrosis, (4) fibrotic focus (FF), (5) lymphatic invasion, (6) blood vessel invasion, (7) adipose tissue invasion, (8) skin invasion, (9) muscle invasion, (10) age, (11) estrogen (ER)/progesterone (PR) status, and (12) nodal status. The results showed that FF diameter greater than 8 mm and FF fibrosis grade 1 were the factors that most accurately predicted distant organ metastasis and bone metastasis in patients with IDC who did not receive adjuvant therapy. In patients with IDC who received adjuvant therapy, FF diameter greater than 8 mm was the factor that most accurately predicted bone metastasis, and the presence of tumor necrosis and ER-/PR- were very important predictive factors for metastasis to the lung. Ten or more nodal metastases (N3) were the factor that most accurately predicted liver metastasis. Based on these findings, FF characteristics can be concluded to be the most important histologic factors for predicting metastasis to the bone, the presence of tumor necrosis and ER-/PR- for predicting metastasis to the lung, and N3 for predicting metastasis to the liver.
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http://dx.doi.org/10.1016/j.humpath.2007.09.012DOI Listing
May 2008

Clinical evidence of breast cancer micrometastasis in the era of sentinel node biopsy.

Int J Clin Oncol 2008 Feb 29;13(1):24-32. Epub 2008 Feb 29.

National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan.

Sentinel node biopsy for early-stage breast cancer has been established as an excellent surgical and staging procedure developed to enhance the detection of minimal lymph node involvement such as micrometastases. Multisection and the proper use of immunohistochemical staining have led to the increased detection of micrometastases, and this has given rise to new questions about the treatment to be employed concerning micrometastasis. That is whether complete axillary lymph node dissection (ALND) and adjuvant systemic therapy are really required for patients with micrometastasis because of the low prevalence of nonsentinel lymph node metastasis. Some currently published case studies report that selected patients with micrometastases without further ALND would not suffer from a high incidence of regional recurrence. However, the long-term prognostic risk of systemic recurrence and local failure associated with residual axillary disease in the sentinel lymph node-positive patient electing for no further axillary surgery has not been defined. Numerous studies have investigated the impact of occult metastases, which may be regarded as micrometastases or a small tumor deposit. Although data from randomized controlled trials are lacking, these studies suggest that the prognosis of breast cancer patients with micrometastases should not be considered the same as that in truly node-negative patients. Patients with micrometastases should have some adjuvant systemic therapy. Ongoing randomized trials will provide prospective answers to the question of the optimal treatment for micrometastasis.
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http://dx.doi.org/10.1007/s10147-007-0736-0DOI Listing
February 2008

Grading system for lymph vessel tumor emboli for prediction of the outcome of invasive ductal carcinoma of the breast.

Hum Pathol 2008 Mar;39(3):427-36

Clinical Laboratory Division, National Cancer Center Hospital East, Kashiwa, 277-0882 Chiba, Japan.

There are no suitable histologic diagnostic clues for determining the true biological malignancy of invasive ductal carcinomas associated with lymph vessel tumor emboli. The purpose of this study was to devise a grading system for lymph vessel tumor emboli in invasive ductal carcinomas that would allow accurate prediction of the outcome of invasive ductal carcinoma patients with lymph vessel invasion. We classified 393 invasive ductal carcinomas into the following 4 grades according to the number of mitotic and apoptotic figures in tumor cells in lymph vessels at 1 high-power field: grade 0, no lymph vessel invasion; grade 1, absence of mitotic and apoptotic figures, presence of any number of mitotic figures and absence of apoptotic figures, or absence of mitotic figures and presence of any number of apoptotic figures; grade 2, 1 to 4 mitotic figures and 1 or more of apoptotic figures, or 1 or more of mitotic figures and 1 to 6 apoptotic figures; and grade 3, more than 4 mitotic figures and more than 6 apoptotic figures. The mortality rate increased with the grade, and the mortality rate of patients with grade 3 lymph vessel tumor emboli was more than 70%. Multivariate analyses with well-known prognostic factors demonstrated that grade 3 lymph vessel tumor emboli significantly increased the hazard rates for tumor recurrence, and tumor death independent of adjuvant therapy status, nodal status, or invasive tumor size. The grading system for lymph vessel tumor emboli is the best histologic grading system for accurately predicting the outcome of patients with invasive ductal carcinoma of the breast.
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http://dx.doi.org/10.1016/j.humpath.2007.07.016DOI Listing
March 2008

Invasive apocrine carcinoma of the breast: clinicopathologic features of 57 patients.

Breast J 2008 Mar-Apr;14(2):164-8. Epub 2008 Jan 31.

Breast Surgery Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Apocrine carcinoma is a rare, unique, and morphologically distinctive type of invasive ductal carcinoma (IDC). The features of invasive apocrine carcinoma (IAC) and their possible prognostic implications have not been fully investigated. To this end, we examined the clinicopathologic characteristics and outcome of patients with IAC and compared these factors with those of patients with IDC. Out of 2,055 breast cancer patients who had undergone breast surgery between 1995 and 2005, 57 patients of IAC and 1,583 patients of IDC were analyzed. The mean ages of the patients with IAC and of those with IDC were 58.5 +/- 10.9 years and 54.4 +/- 11 years, respectively (p = 0.006). The percentages of patients with axillary nodal metastasis and lymphatic invasion were significantly lower in the IAC group than in the IDC group (p = 0.03 and 0.02, respectively). The percentage of estrogen and progesterone receptor negativity was higher in the IAC group than in the IDC group (p < 0.001). After a median follow-up period of 49 months (range, 1-133 months), seven (12%) patients with IAC and 244 (15%) patients with IDC had experienced recurrences. Three (5%) patients with IAC and 125 (8%) patients with IDC died of recurrent breast cancer. No significant differences in the relapse-free survival (p = 0.83) and overall survival (p = 0.75) rates were observed between the two groups. Although IAC and IDC have different clinicopathologic characteristics, the prognoses of patients with these diseases are similar.
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http://dx.doi.org/10.1111/j.1524-4741.2007.00548.xDOI Listing
April 2008

Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy.

Cancer 2007 Jan;109(1):146-56

Psycho-Oncology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba, Japan.

Background: Previous studies have shown cognitive impairment in breast cancer survivors who were exposed to adjuvant chemotherapy. Neural damage by chemotherapy might have played some part in these findings. The current study explored the regional brain volume difference between breast cancer survivors exposed to adjuvant chemotherapy (C+) and those unexposed (C-).

Methods: High-resolution 1.5-tesla brain magnetic resonance imaging (MRI) databases of breast cancer survivors and healthy controls were used. Brain images were preprocessed for optimal voxel-based morphometry. Comparisons of gray matter and white matter were performed between the C+ and the C- groups, by using MRI scans from within 1 year (the 1-year study, n = 51 and n = 55, respectively) or 3 years after their cancer surgery (the 3-year study, n = 73 and n = 59, respectively). As exploratory analyses, correlation analyses were performed between indices of the Wechsler Memory Scale-Revised and regional brain volume where the volume were significantly smaller. As a reference, MRI scans of cancer survivors were compared with those of healthy controls (n = 55 for the 1-year study and n = 37 for the 3-year study).

Results: The C+ patients had smaller gray matter and white matter including prefrontal, parahippocampal, and cingulate gyrus, and precuneus in the 1-year study. However, no difference was observed in the 3-year study. The volumes of the prefrontal, parahippocampal gyrus, and precuneus were significantly correlated with indices of attention/concentration and/or visual memory. Comparisons with healthy controls did not show any significant differences.

Conclusions: Adjuvant chemotherapy might have an influence on brain structure, which may account for previously observed cognitive impairments.
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http://dx.doi.org/10.1002/cncr.22368DOI Listing
January 2007

Accurate assessment of lymph vessel tumor emboli in invasive ductal carcinoma of the breast according to tumor areas, and their prognostic significance.

Hum Pathol 2007 Feb 23;38(2):247-59. Epub 2006 Oct 23.

Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba, 277-0882, Japan.

Lymph vessel tumor emboli (LVTEs) within tumors are difficult to distinguish from stroma-invasive tumor foci. The purpose of this study was to evaluate staining of LVTEs with hematoxylin-eosin (HE) and with D2-40 to determine whether LVTEs identified by HE staining alone are D2-40-positive LVTE and whether the presence of LVTE identified by HE or D2-40 staining is an accurate predictor of outcome in 151 patients with invasive ductal carcinoma (IDC) of the breast. We first attempted to identify LVTE in the stroma-invasive tumor area (intratumor area), the advance area, and the nontumor area by HE staining alone, and then LVTE identified by HE staining was confirmed by D2-40 staining. The number of LVTE identified by HE staining and D2-40 staining successively increased from the intratumor area to the nontumor area. Although D2-40 staining detected larger numbers of LVTE than HE staining in all tumor areas, the highest positive predictive value of LVTE was observed in the intratumor area, and the next was in the advance area, and then the nontumor area, and significant correlations were found between the numbers of LVTE stained by HE and D2-40 in the same tumor areas. LVTE identified by HE staining or D2-40 staining in the intratumor area or nontumor area significantly increased the risk for tumor recurrence or death of patients with IDC, independent of hormone receptor status or nodal status. The results of this study demonstrate that the existence of intratumoral LVTE and that the presence of intratumoral LVTE identified by HE staining or D2-40 staining are accurate predictors of the outcome of patients with IDC of the breast.
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http://dx.doi.org/10.1016/j.humpath.2006.07.017DOI Listing
February 2007
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