Publications by authors named "Kentaro Tamaki"

43 Publications

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

Breast 2021 Apr 16;56:70-77. Epub 2021 Feb 16.

Division of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan.

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G).

Patients And Methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors.

Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant.

Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.
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http://dx.doi.org/10.1016/j.breast.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907535PMC
April 2021

Physician's knowledge, attitudes and practice pattern for breast cancer diagnosed during pregnancy: a survey among breast care specialists in Japan.

Breast Cancer 2020 Sep 26;27(5):796-802. Epub 2020 Jun 26.

Department of Breast Surgical Oncology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.

Background: Breast cancer diagnosed during pregnancy (BCP) is uncommon, and thus there is limited evidence on its treatment. However, the incidence of BCP is increasing probably due to women having children at an older age. We aimed to clarify the practice patterns and limitations in treatment for BCP in Japan.

Methods: A cross-sectional survey was developed for board-certified Japanese breast cancer specialists (n = 1583) to evaluate their knowledge, attitude, experience, and practice patterns regarding BCP. Survey items also included questions regarding potential barriers of practice toward patients diagnosed during pregnancy and respondents' background.

Results: In March 2018, 492 (31.1%) breast oncologists responded to the survey. Among them, 234 (48%) respondents had the experience of treating at least one case of BCP. The accuracy of knowledge about BCP was evaluated by three items regarding BCP treatment from the latest Japanese Breast Cancer Society treatment guideline, and 265 (54%) were categorized to have "appropriate knowledge". Majority of the physicians (89%) have responded that patients should be treated in a center where both a cancer-treating team and obstetrician exist, and 48% responded that treating patients by the collaboration of cancer-treating team and obstetric team in different institutes is an alternative reasonable option.

Conclusions: Interest, knowledge, and awareness of the guidelines appear to influence physician attitude, and thus it is urgently important to lay out educational materials and learning opportunities regarding BCP for breast specialists. A regional network of oncologists, obstetricians, and pediatricians to support the BCP patients should be developed.
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http://dx.doi.org/10.1007/s12282-020-01118-8DOI Listing
September 2020

Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer.

Virchows Arch 2020 May 23;476(5):701-709. Epub 2019 Dec 23.

Department of Pathology and Oncology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm (range, 123-8101/mm). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P < 0.0001). In analyses using receiver operating characteristic curves, a threshold TIL density of 2420/mm best discriminated pCR from non-pCR. In multivariate analysis, high TIL density (> 2420/mm) was significantly associated with pCR (P < 0.0001). Our results indicate that DIA can assess TIL density quantitatively, machine learning-based classification algorithm allowing determination of TIL density as the number of TILs per unit area, and TIL density established by this method appears to be an independent predictor of pCR in HER2-positive breast cancer.
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http://dx.doi.org/10.1007/s00428-019-02730-6DOI Listing
May 2020

Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy.

Breast Cancer Res Treat 2019 Jan 10;173(2):275-288. Epub 2018 Oct 10.

Tohoku University, Sendai, Japan.

Purpose: Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms.

Methods: We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC.

Results: The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients.

Conclusion: KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.
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http://dx.doi.org/10.1007/s10549-018-4985-6DOI Listing
January 2019

Randomized trial of aromatherapy versus conventional care for breast cancer patients during perioperative periods.

Breast Cancer Res Treat 2017 04 8;162(3):523-531. Epub 2017 Feb 8.

Department of Pathology, Tohoku University Hospital, Sendai, Japan. 1-1 Seiryo-machi Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Purpose: Several studies focused on the effect of aromatherapy on mood, quality of life (QOL), and physical symptoms in patients with cancer. We compared the effects on QOL, vital signs, and sleep quality between aromatherapy and conventional therapy during perioperative periods of the breast cancer patients in this study.

Methods: Patients were randomly assigned in a 2:1 ratio to receive aromatherapy or usual care. The primary endpoint was QOL, which was assessed using the quality of life questionnaire QLQ-C30, Version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC) Study Group on quality of life. Secondary endpoints included the necessity of hypnotics, vital signs including blood pressure and heart rate and adverse events. In addition, we also summarized the patients' perception of the experience from a free description-type questionnaire.

Results: A total of 249 patients had breast cancer surgery and 162 patients gave physician consent and were recruited; 110 were randomly assigned to aromatherapy group (eight patients showed incomplete EORTC QLQ-C30) and 52 to control group (one patient showed incomplete EORTC QLQ-C30). There were no statistically significant differences between the aromatherapy group and control group in the EORTC QLQ-C30 at the surgery day. As for the results of the post-operation day 1, trends for differentiations of physical functioning and role functioning were detected between aromatherapy group and control group, but the differences did not reach statistical significance (p = 0.08 and 0.09). There were no significant differences of systolic and diastolic blood pressures between aromatherapy group and control group (p = 0.82 and 0.68). There was no statistically significant difference in heart rates between aromatherapy group (70.6 ± 11.0 bpm) and control group (71.2 ± 9.8 bpm) (p = 0.73). Likewise, the rate of hypnotic use was not statistically significant (p = 0.10). No adverse events were reported after aromatherapy and all impressions from aromatherapy group were positive with descriptors such as relaxed, comfortable, and enjoyable being common.

Conclusion: The results showed no effects of aromatherapy on QOL, sleep quality, and vital sign. However, there was not any harm or adverse event for using aromatherapy. All impressions from self-reporting were positive such as relaxed, comfortable, and enjoyable by the aromatherapy group. Therefore, we can use aromatherapy during perioperative periods in order to meet the expectations of the patients.
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http://dx.doi.org/10.1007/s10549-017-4134-7DOI Listing
April 2017

[Selection of goal-directed information triggers removal of irrelevant information from working memory].

Shinrigaku Kenkyu 2017 02;87(6):600-10

This study investigated the triggers for removing irrelevant information from working memory. Based on the perspective that removal is a unique process of updating working memory (Ecker et al., 2010), we hypothesized that the removal process begins after selection of task-relevant information. To test this hypothesis, we employed a modified Sternberg task that reflects the time-course for the removal of information. In a standard procedure of this task, the removal process is thought to be completed in approximately 1,500 ms after directing relevant information. If selection induces removal, removal might not end within 1,500 ms when selection requires more time. To increase the time for selection, we created a circumstance with high interference. Experiment 1 showed that removal was incomplete within 2,000 ms after directing relevant information. Experiment 2 showed that removal could be completed given more time. These results support the hypothesis that the trigger for the removal process is the completion of selection. This is in consistent with recent frameworks concerning executive functions.
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http://dx.doi.org/10.4992/jjpsy.87.15062DOI Listing
February 2017

Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

Breast Cancer Res Treat 2016 Feb 4;156(1):45-55. Epub 2016 Mar 4.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi Aoba-ku, Sendai, Japan.

The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17β-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17βHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17βHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.
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http://dx.doi.org/10.1007/s10549-016-3739-6DOI Listing
February 2016

Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

Breast Cancer Res Treat 2016 Jan 29;155(1):65-75. Epub 2015 Dec 29.

Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.
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http://dx.doi.org/10.1007/s10549-015-3668-9DOI Listing
January 2016

Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study.

Breast Cancer Res 2015 Sep 4;17:124. Epub 2015 Sep 4.

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Introduction: The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC).

Methods: One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8(+) TIL and FOXP3(+) TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8(+) TIL and FOXP3(+) TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated.

Results: TNBC patients with high CD8(+) TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8(+) TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537-6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029-4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8(+) TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499-9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8(+) TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively).

Conclusions: This is the first study to demonstrate that high CD8(+) TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.
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http://dx.doi.org/10.1186/s13058-015-0632-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560879PMC
September 2015

Can we improve breast cancer mortality in Okinawa? Consensus of the 7th Okinawa Breast Oncology Meeting.

Tohoku J Exp Med 2015 02;235(2):111-5

Okinawa Breast Oncology Meeting Group; Department of Breast Surgery, Nahanishi Clinic, Naha, Japan.

The rate of breast cancer mortality in Okinawa has gradually been increasing up to 2010. Now Okinawa has the second worst mortality rate in Japan, in part due to the enormous dietary changes resulting from the post-World War II US military occupation, high incidence of obesity, high non-optimal treatment rate, and low breast-cancer screening rate. To reduce breast cancer mortality in Okinawa, we established the Okinawa Breast Oncology Meeting (OBOM) in 2012. At the 7th OBOM held on January 10th, 2014, we discussed the breast cancer mortality in Okinawa focusing on lifestyle, breast cancer screening and optimal treatments. The Okinawan women who were overweight and/or obese during premenopausal and postmenopausal ages had a statistically significant higher risk of breast cancer development compared to those with non-overweight and/or obese women. The traditional diet of Okinawa consists of foods low in calories but rich in nutritional value. Therefore, we recommend Okinawan people not to forget the Okinawan traditional lifestyle, and to reduce their bodyweight to prevent breast cancer. One of the main goals of the OBOM is to raise breast cancer screening attendance rates to 50% (29.2% in 2010). We should standardize the quality control for breast cancer screening in Okinawa. It is important to continue enlightening the Okinawan population to receive optimal treatment. In addition, we are striving to establish systematic medical cooperation between the hospitals specializing in breast cancer treatment with rural hospitals. The OBOM group endeavors to contribute to the improvement of breast cancer mortality in Okinawa.
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http://dx.doi.org/10.1620/tjem.235.111DOI Listing
February 2015

Androgen receptor and enzymes in lymph node metastasis and cancer reoccurrence in triple-negative breast cancer.

Int J Biol Markers 2015 May 26;30(2):e184-9. Epub 2015 May 26.

1 Department of Pathology, Tohoku University School of Medicine, Sendai - Japan.

Background: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor, progesterone receptor and HER2. TNBCs are a diverse subgroup, but one promising marker and therapeutic target of this breast cancer is the androgen receptor (AR). Previously we demonstrated that AR and cognate intracrine pathways are associated with decreased proliferation in invasive ductal carcinoma with their decrease also detected between organ-confined and invasive diseases. Therefore, in this study, we examined the status of AR and androgen-producing enzymes during the process of metastasis to lymph nodes and cancer recurrence.

Materials And Methods: We studied 2 series of patients with TNBC, one from Kumamoto University Hospital composed of 16 matched cases of primary and locally or distal recurrences and the other from Tohoku University Hospital examining 46 lymph node metastasis from 23 patients. In addition to studying concordance in AR expression, we also examined the interactions between AR and Ki-67 labeling index and AR and site of distal metastasis.

Results: In both series, AR status was concordant between primary and recurrent/metastatic disease, but coordinated expression of AR and androgenic enzymes was lost during the process. The inverse association between AR and Ki-67, previously reported in invasive ductal carcinoma (IDC), was markedly potentiated in both lymph node and recurrent cancers. In addition, AR expression appeared to have little effect on visceral metastasis but was associated directly with bone metastasis and inversely with brain metastasis.

Conclusions: The results of our present study demonstrated that AR remained in the majority of metastatic samples from AR-positive primary TNBCs and that AR manipulation could be exploited in the metastatic settings of TNBC.
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http://dx.doi.org/10.5301/jbm.5000132DOI Listing
May 2015

Clinical significance of subtype classification in metastatic lymph nodes of breast cancer patients undergoing neoadjuvant chemotherapy.

Int J Biol Markers 2015 May 26;30(2):e174-83. Epub 2015 May 26.

1 Division of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi - Japan.

Background: Neoadjuvant chemotherapy has been increasingly utilized in the treatment of breast cancer patients. However, there are no established surrogate markers predicting the response to subsequent adjuvant therapy and clinical outcome of patients. In particular, whether primary or lymph nodes metastasis should be evaluated for these analyses has remained unknown. Therefore, in this study, we first evaluated the differences in biomarkers between primary and metastatic cancer tissues in the patients undergoing neoadjuvant chemotherapy. We then correlated the findings with the clinical outcomes of these patients.

Methods: We examined 49 patients receiving neoadjuvant chemotherapy and subsequent surgery with lymph node metastasis. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 were all immunohistochemically evaluated in core needle biopsy samples from primary and metastatic tumors following chemotherapy.

Results: No statistically significant differences in these markers were detected between the primary tumor and metastatic lymph nodes following therapy, but the Ki-67 labeling index was significantly higher in metastatic lymph nodes than in primary tumor (p = 0.017). The patients associated with luminal A type carcinoma in their lymph nodes following chemotherapy demonstrated significantly better clinical outcomes (disease-free survival: p = 0.0045, overall survival: p = 0.0006) than those who were not.

Conclusion: These data indicate that subtype classification following chemotherapy, in the metastatic lymph nodes rather than primary tumor could predict long-term outcomes of patients undergoing neoadjuvant chemotherapy.
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http://dx.doi.org/10.5301/jbm.5000128DOI Listing
May 2015

[Observing grasping action from egocentric perspective modulates observer's visual attention].

Shinrigaku Kenkyu 2014 Oct;85(4):398-403

Previous studies demonstrated that observing another person's grasp action modulated the observer's attention to the object in a manner congruent with another person's action goal. These studies suggest that this grasp-cueing effect results from representation of the observer's understanding of action intention in the mirror neuron system. This system serves as the neural mechanism underlying action-oriented goals, regardless of whether they are those of the observer or others. The present study examined whether the grasp-cueing effect emerged even when a grasp action was observed from an egocentric (observer's own) perspective. Reaction times were faster when the target was presented over the object that was congruent with the action goal implied by the size of the hand aperture. This indicated that the grasp cueing effect occurred when the stimulus was observed from an egocentric perspective, consistent with the view that this effect resulted from the observer's understanding of action intention as represented in the mirror neuron system.
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http://dx.doi.org/10.4992/jjpsy.85.13320DOI Listing
October 2014

Tumor-infiltrating CD8+ and FOXP3+ lymphocytes in triple-negative breast cancer: its correlation with pathological complete response to neoadjuvant chemotherapy.

Breast Cancer Res Treat 2014 Dec 14;148(3):525-34. Epub 2014 Nov 14.

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan,

The anti-tumor immune response was recently reported to play a critical role in the chemotherapeutic sensitivity of breast cancer. Therefore, we investigated the correlation between CD8+ and FOXP3+ tumor-infiltrating lymphocytes and the pathological complete response (pCR) following neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC), in conjunction with neoangiogenesis, basal and proliferation markers. CD8+ and FOXP3+ lymphocytes were assessed in biopsy specimens by double-staining immunohistochemistry, in combination with immunostaining of vasohibin-1, CD31, EGFR, CK5/6, and Ki-67. Earlier age, pre-menopausal status, smaller tumor size, and high Ki-67 were significantly associated with pCR, as in high CD8+, high CD8+/FOXP3+ ratio, and low vasohibin-1 positive ratio. Multivariate analysis did reveal that a high CD8+/FOXP3+ ratio was a strong predictor of pCR with an odds ratio of 5.32 (P = 0.005). High Ki-67 was also significantly associated with pCR (P = 0.002). TNBCs with a high CD8+/FOXP3+ ratio and high Ki-67 had the highest pCR rate (70%) following NAC. However, the pCR rate of the patients with low CD8+/FOXP3+ ratio and low Ki-67 was only 5%. The pCR rates of a high CD8+/FOXP3+ ratio and low Ki-67 patients and those with a low CD8+/FOXP3+ ratio and high Ki-67 were 24 and 21%, respectively. TNBCs with a high CD8+/FOXP3+ ratio were more sensitive to anthracycline and taxane-based chemotherapeutic regimens, and the CD8+/FOXP3+ ratio in conjunction with Ki-67 could predict pCR following NAC in TNBC. This predictor may represent a new surrogate for testing the efficacy of investigational agents in the neoadjuvant setting.
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http://dx.doi.org/10.1007/s10549-014-3197-yDOI Listing
December 2014

The correlation between body mass index and breast cancer risk or estrogen receptor status in Okinawan women.

Tohoku J Exp Med 2014 11;234(3):169-74

Department of Breast Surgery, Nahanishi Clinic.

Dietary changes resulting from the post-World War II occupation of Okinawa by the US military have been largely deleterious, resulting in a marked increase of obesity among Okinawan residents. In this study, we examined the association between BMI and the risk of developing breast cancer according to the menstruation status and age, and the correlation between BMI and expression of estrogen receptor (ER). Breast cancer cases were 3,431 females without any personal or family history of breast cancer. Control subjects were 5,575 women drawn from the clinical files of Nahanishi Clinic. We found that women, who were overweight or obese, regardless of menopausal stage, had a higher risk of breast cancer compared to women with normal weight and this difference was statistically significant (p < 0.001, respectively). This risk was especially apparent in older (> 40 years) overweight or obese women. The women who were overweight or obese during postmenopausal ages were at higher risk of ER-positive breast cancer compared to women with normal weight. Results of our present study clearly indicate that increased BMI was associated with increased risk of developing breast cancer in Okinawan women, regardless of menopausal status. In addition, there was statistically significant correlation between BMI and ER expression in the postmenopausal period. Given the obesity epidemic associated with the extreme sociological and dietary changes brought about by the post-war occupation of Okinawa, the present study provides essential guidelines on the management, treatment and future breast cancer risk in Okinawa.
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http://dx.doi.org/10.1620/tjem.234.169DOI Listing
November 2014

Intratumoral androgen metabolism and actions in invasive lobular carcinoma of the breast.

Cancer Sci 2014 Nov 7;105(11):1503-9. Epub 2014 Nov 7.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai.

Invasive lobular carcinoma (ILC) accounts for approximately 10% of all breast carcinomas and is characterized by higher levels of androgen receptor (AR) compared to invasive ductal carcinoma (IDC). Despite this potentially androgen-responsive environment, the combined importance of AR and androgen metabolism in non-neoplastic lobules and lobular carcinoma remains unknown. Therefore, in this study, we evaluated the status of pivotal androgen-producing enzymes 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) and 5α-reductase type 1 (5αRed1) in 178 cases of ILC and surrounding histologically non-neoplastic lobular tissue using immunohistochemistry. Androgen receptor prevalence was higher but androgenic enzymes lower in ILC than non-neoplastic lobules. In ILC cases the status of 5αRed1 and 17βHSD5 was inversely correlated with tumor size (P = 0.0053) and nuclear grade (P = 0.0290), and significantly associated with better overall survival of the patients (P = 0.0059). Based on these findings, we hypothesized that androgen signaling could act as a tumor suppressor. As previous studies suggested that androgens might partially act by increasing levels of the estrogen inactivating enzyme 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) in IDC tissues, this was reasonably considered a potential mechanism of androgen actions. Significantly positive correlation was detected between the status of androgenic enzymes and 17βHSD2 (P < 0.0001) and intratumoral 17βHSD2 was inversely correlated with tumor size in ILC (P = 0.0075). These correlations suggest one protective mode of androgen action could be through modulation of estrogen metabolism. Results of our present study indicated that androgen-producing enzymes could play pivotal protective roles in AR-enriched ILC cases.
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http://dx.doi.org/10.1111/cas.12535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462384PMC
November 2014

Correlation of tumor-infiltrative lymphocyte subtypes alteration with neoangiogenesis before and after neoadjuvant chemotherapy treatment in breast cancer patients.

Int J Biol Markers 2014 Sep 30;29(3):e193-203. Epub 2014 Sep 30.

Department of Pathology, Tohoku University School of Medicine of Medicine, Sendai - Japan.

The two most important factors in tumor-stromal interactions are tumor-infiltrating lymphocytes (TIL) and neoangiogenesis (NAng). While changes of these parameters in responders of neoadjuvant chemotherapy (NCTx) have been reported, their correlation with pathological response in breast cancer (BC) patients treated with NCTx have not been described. We therefore evaluated alterations of the TIL subtypes ratio and alterations of NAng using the vasohibin-1-positive ratio (VPR) in BC patients during the course of NCTx. To this aim we used: (i) double immunohistochemistry of CD8 cytotoxic T cells and T regulatory cells (Treg) with Foxp3, determining the CD8+/Foxp3 ratio; (ii) immunostaining of CD31 and vasohibin-1, yielding the VPR, which reflects the NAng status. Changes between the CD8+/Foxp3 ratio and VPR before and after therapy were then correlated with the pathological response of the patients. A concomitant significant decrement of Foxp3 and NAng, represented by VPR, were detected only in NCTx pathological responders (p<0.001 and p=0.044, respectively). The CD8+/Foxp3 ratio increased in both responders and non-responders, but to greater extent in responders (p=0.02). The changes of VPR in the NCTx-treated group differed from those recorded for the patients treated with aromatase inhibitors and shown in our earlier study; this indicates that the reactions of the tumor-stromal interaction to therapy were different among different treatments in BC patients. Changes in Foxp3 and VPR in responders may reflect the dynamic activity of tumor stroma and host immune response to tumor antigens in the tumor microenvironment in response to the NCTx. VPR can be a potential surrogate marker in BC specimens for predicting the response to NCTx, incorporating both features of carcinoma and stromal cells.
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http://dx.doi.org/10.5301/jbm.5000082DOI Listing
September 2014

Assessment of the Ki67 labeling index: a Japanese validation ring study.

Breast Cancer 2016 Jan 3;23(1):92-100. Epub 2014 May 3.

Study Group of Standard Measurement of Ki67, The Japanese Society of Breast Cancer, Tokyo, Japan.

Background: A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples.

Patients And Methods: This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study.

Results: For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (ρ: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of <13.25 % and in those with a Ki67 labeling index of >13.25 % (κ = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining.

Conclusion: The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.
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http://dx.doi.org/10.1007/s12282-014-0536-0DOI Listing
January 2016

Androgenic pathways in the progression of triple-negative breast carcinoma: a comparison between aggressive and non-aggressive subtypes.

Breast Cancer Res Treat 2014 Jun 9;145(2):281-93. Epub 2014 Apr 9.

Department of Pathology, Tohoku University School of Medicine, Sendai, Japan,

One of the active intracellular pathways/networks in triple-negative breast carcinoma (TNBC) is that of the androgen receptor (AR). In this study, we examined AR and androgen-metabolising enzyme immunoreactivity in subcategories of TNBC to further elucidate the roles of androgenic pathways in TNBC. We utilised formalin-fixed paraffin-embedded breast cancer samples from ductal carcinoma in situ (DCIS) and invasive ductal carcinoma patient cohorts. We then used immunohistochemistry to classify these samples into basal-like and non-basal samples and to assess interactions between AR, androgen-metabolising enzymes and proliferation. To further substantiate our hypothesis and provide mechanistic insights, we also looked at the expression and regulation of these factors in publically available microarray data and in a panel of TNBC AR-positive cell lines. DCIS was associated with higher levels of AR and enzymes (p < 0.02), although a similar difference was not noticed in basal and non-basal samples. AR and enzymes were correlated in all states. In TNBC cell lines (MDA-MD-453, MFM-223 and SUM185-PE), we found that DHT treatment up-regulated 5αR1 and 17βHSD5 suggesting a mechanistic explanation for the correlations observed in the histological samples. Publicly available microarray data in TNBC cases suggested similar patterns to those observed in histological samples. In the majority of settings, including publically available microarray data, an inverse association between AR and proliferation was detected. These findings suggest that decreases in AR and androgen-metabolising enzymes may be involved in the increased biological aggressiveness in TNBC development.
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http://dx.doi.org/10.1007/s10549-014-2942-6DOI Listing
June 2014

Angiogenesis and vascular maturation in neuroendocrine tumors.

Hum Pathol 2014 Apr 8;45(4):866-74. Epub 2014 Jan 8.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Pathology, Tohoku University Hospital, Sendai 980-8575, Japan.

Neuroendocrine tumors (NETs) are highly vascularized, but the process of proliferation and maturation of vascular structures during tumor development and progression has remained unknown. We examined the structural alterations of intratumoral blood vessels in human gastroenteropancreatic NET. Microvessel density was evaluated using the endothelial cell markers vasohibin-1 (VASH-1), CD31, and endoglin in 135 cases. Double immunohistochemistry staining was performed to localize endothelium and pericytes on the same vessels using the pericyte marker nestin. The ratio of Ki-67/CD31 was significantly correlated with that of VASH-1/CD31 positivity (P<.001), indicating that the ratio of VASH-1/CD31 also reflects the status of neovascularization in NET. This ratio was higher in NET than in its nonneoplastic counterpart (P=.10) and tended to increase according to World Health Organization (WHO) grade, although the differences were not statistically significant (P=.32). The ratio of VASH-1/nestin-positive vessels, representing the maturation of neovessels, was also significantly higher in NET than in its nonneoplastic counterparts (P=.003). Among WHO grades, the ratio increased from grade 1 to grade 2 (P=.36) and decreased in neuroendocrine carcinoma (P=.34). Our results demonstrated that VASH-1/CD31 can be an ideal immunohistochemical marker for characterizing neovascularization in NET. The VASH-1/CD31 content increased with WHO grade, and the vessels covered by pericytes decreased in higher grades. These structural changes in the vessels are considered to play an important role in inducing tumor-cell proliferation.
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http://dx.doi.org/10.1016/j.humpath.2013.09.024DOI Listing
April 2014

Non-invasive evaluation of axillary lymph node status in breast cancer patients using shear wave elastography.

Tohoku J Exp Med 2013 11;231(3):211-6

Department of Breast Surgery, Nahanishi Clinic Okinawa.

Less invasive procedures are currently required to examine the axillary lymph node status. Shear wave elastography with acoustic radiation force impulse provides objective and reproducible quantification of the intrinsic property of the soft tissue. In this study, we measured shear wave velocity of the axillary lymph nodes of patients with breast cancer using Virtual Touch Tissue Quantification (VTTQ). The degree of lymph node metastasis was evaluated by measuring the expression level of cytokeratin 19 (CK19) mRNA, a specific marker for breast cancer cells. The one-step nucleic acid amplification (OSNA) was used to determine the copy number of CK19 mRNA in 149 lymph node specimens of 149 primary breast cancer patients. Axillary lymph node status according to OSNA (copy number/μl) were categorized as 0-249 copies (-), 250-5,000 copies (+), and copy number > 5,000 (++). A category (-) represents no metastasis in the axillary lymph node. There were 121 patients with OSNA-, 9 with OSNA+ and 19 with OSNA++. The average velocities according to OSNA categories were 1.64 ± 0.42 m/second for OSNA-, 2.25 ± 0.78 m/second for OSNA+, and 2.79 ± 0.98 m/second for OSNA++. There were significant differences in the shear wave velocity between OSNA- and OSNA+ (P = 0.040) or OSNA++ (P < 0.001). The most optimal cutoff velocity to distinguish benign from metastasis is 1.44 m/second, as determined using the receiver operating characteristic method. The shear wave velocity measured with VTTQ could provide clinically useful information about axillary lymph node metastasis in patients with primary breast cancer.
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http://dx.doi.org/10.1620/tjem.231.211DOI Listing
November 2013

A non-invasive modality: the US virtual touch tissue quantification (VTTQ) for evaluation of breast cancer.

Jpn J Clin Oncol 2013 Sep 2;43(9):889-95. Epub 2013 Aug 2.

Department of Breast Surgery, Nahanishi Clinic, Naha, Okinawa, Japan.

Objective: We evaluated the biologic features of breast tissues using a newly developed non-invasive diagnostic system, named virtual touch tissue quantification.

Methods: A total of 180 patients including 115 invasive ductal carcinoma, 30 ductal carcinoma in situ, 4 mucinous carcinoma, 7 invasive lobular carcinoma, 8 fibroadenoma, 12 fibrocystic change and 4 intraductal papilloma were studied at Nahanishi Clinic, Okinawa. We first compared the results of virtual touch tissue quantification according to each histologic subtype and determined the optimal cutoff values for virtual touch tissue quantification to distinguish benign from malignant tissues, using the receiver operating characteristic method. In addition, we also examined the correlation between virtual touch tissue quantification velocities and Ki-67, estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 in cases of invasive ductal carcinoma using linear regression analyses and Student's t-test.

Results: Virtual touch tissue quantification velocities were statistically higher in malignant cases than in benign cases (P < 0.05, respectively) and the best cutoff value for the virtual touch tissue quantification velocity which could differentiate benign from malignant cases was 2.89 m/s. There were statistically significant correlations between the virtual touch tissue quantification velocity and the Ki-67 labeling index (r = 0.338, r(2) = 0.114 and P < 0.001) and significant inverse correlations between virtual touch tissue quantification and the estrogen receptor (r = -0.311, r(2) = 0.097 and P < 0.001) or progesterone receptor (r = -0.361, r(2) = 0.131 and P < 0.001) status of invasive ductal carcinoma. There were also significant differences of the average velocities between human epidermal growth factor receptor 2-positive (6.39 ± 1.44 m/s) and -negative (4.43 ± 1.41 m/s) cases (P < 0.001).

Conclusion: Virtual touch tissue quantification could be a valuable clinical tool for estimating breast cancer pathology in a non-invasive fashion.
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http://dx.doi.org/10.1093/jjco/hyt098DOI Listing
September 2013

Hexokinase II in breast carcinoma: a potent prognostic factor associated with hypoxia-inducible factor-1α and Ki-67.

Cancer Sci 2013 Oct 21;104(10):1380-8. Epub 2013 Aug 21.

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Hypoxia-inducible factor-1α (HIF-1α) mediates adaptive responses to changes under tissue hypoxia in carcinoma cells by controlling the expression of various target genes. Previous studies have demonstrated that HIF-1α is associated with adverse clinical outcome in breast carcinoma patients, but details of HIF-1α's role have remained largely unknown. Therefore, in this study, we examined the expression profiles of HIF-1α-induced genes in 10 breast carcinoma cases using microarray data. As a result, we demonstrated that the status of hexokinase II (HKII) was associated with carcinoma recurrence in patients with these genes. The enzyme HKII is involved in the first, and rate-limiting, step of glycolysis, but its clinical significance has not yet been examined in breast carcinoma. Therefore, we immunolocalized HKII in 118 breast carcinomas, and HKII immunoreactivity was detected in 44% of the cases. It is significantly associated with histological grade, Ki-67 labeling index and HIF-1α immunoreactivity. Also, HKII status is significantly associated with increased risk of recurrence and adverse clinical outcome in breast cancer patients. Subsequent multivariate analysis demonstrated that HKII status was an independent prognostic factor for disease-free survival of patients. These results all suggest that HKII is induced by HIF-1α and plays important roles in the proliferation and/or progression of breast carcinoma possibly through increased glycolytic activity. The status of HKII is therefore considered a potent prognostic factor in human breast cancer patients.
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http://dx.doi.org/10.1111/cas.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656546PMC
October 2013

The clinical significance of breast MRI in the management of ductal carcinoma in situ diagnosed on needle biopsy.

Jpn J Clin Oncol 2013 Jun 16;43(6):654-63. Epub 2013 Apr 16.

Department of Surgery and Breast Surgery, Nihonkai General Hospital, 30 Akiho-cho, Sakata 998-8501, Japan.

Objective: To identify the factors associated with invasive disease in ductal carcinoma in situ diagnosed on needle biopsy by analyzing breast magnetic resonance imaging findings with the histopathological factors of biopsy specimens.

Methods: This was an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study. Seventy-five ductal carcinoma in situ patients diagnosed by needle biopsy who underwent preoperative magnetic resonance imaging were retrospectively reviewed. The magnetic resonance imaging and histopathological variables were assessed between pure ductal carcinoma in situ and invasive breast cancer diagnosed on surgical specimens. Multivariable analyses were performed to determine the independent factors for invasion using a logistic-regression model.

Results: The median age of patients was 55 (34-76) years. On dynamic magnetic resonance imaging, 60 cases out of 75 (80%) were classified as non-mass-like enhancement type and 15/75 (20%) were Mass type. In non-mass-like enhancement, 11/60 (18%) were ultimately diagnosed as invasive breast cancer. Lesion size (P = 0.027), signal intensity ratios (calculated as the signal intensity of detected lesions divided by the signal intensity of surrounding normal breast tissue; P = 0.032) on magnetic resonance imaging and the number of biopsy-cores containing cancer nests (P = 0.012) were each independently associated with invasion. Furthermore, each signal intensity ratio of invasive and non-invasive components of invasive breast cancer represented a value significantly higher than that of 49 pure ductal carcinoma in situ classified as non-mass-like enhancement (P = 0.001 and P = 0.034, respectively). Conversely, there were no significant magnetic resonance imaging findings to distinguish seven invasive breast cancer from among Mass type.

Conclusions: Needle-biopsy-proven ductal carcinoma in situ cases with non-mass-like enhancement type might be sufficiently managed using breast magnetic resonance imaging features such as enhanced lesion size and signal intensity, incorporating the number of cancer-cores at needle biopsy specimen in the clinical setting.
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http://dx.doi.org/10.1093/jjco/hyt055DOI Listing
June 2013

Proliferation and maturation of intratumoral blood vessels in non-small cell lung cancer.

Hum Pathol 2013 Aug 19;44(8):1586-96. Epub 2013 Mar 19.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.

Non-small cell lung carcinoma is one of the most common leading causes of cancer mortality, and studying the features of intratumoral vessels, especially their generation and maturation, has become more important because of the recent application of antiangiogenic therapy. Vasohibin-1 has been recently considered one of the immunohistochemical markers for identifying neovascularization in archival materials. In addition, the functional maturation of blood vessels is considered to be related to pericyte formation around endothelial cells. Therefore, in this study, we evaluated the status of angiogenesis and maturation of intratumoral blood vessels in 93 patients with non-small cell lung carcinoma (50 with adenocarcinoma and 43 with squamous cell carcinoma) using immunohistochemistry of vasohibin-1, endoglin, CD31, and nestin. The vasohibin-1/CD31-positive ratio was significantly (P = .03) correlated with the Ki-67/CD31 ratio, confirming that the vasohibin-1/CD31-positive ratio represented the status of neovascularization in lung cancer. There were no statistically significant differences in vasohibin-1/CD31 ratios between adenocarcinoma and squamous cell carcinoma in both inner (P = .39) and outer areas (P = .36) of the tumor. The vasohibin-1/nestin-positive ratio, which represents the degrees of vascular maturation in proliferative vessels, was significantly lower in inner areas of adenocarcinoma (0.4 ± 0.1) than those in squamous cell carcinoma (0.8 ± 0.1) (P = .02). These results demonstrated that the degrees of maturation in newly formed blood vessels were less developed in inner areas of squamous cell carcinoma than adenocarcinoma, which may account partly for the complications of antivascular endothelial growth factor therapy more frequently detected in patients with squamous cell carcinoma.
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http://dx.doi.org/10.1016/j.humpath.2013.01.004DOI Listing
August 2013

Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation.

Cancer Sci 2013 May 15;104(5):639-46. Epub 2013 Mar 15.

Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.

Triple negative breast cancer (TNBC) is defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negativity. Patients with TNBC frequently undergo an aggressive clinical course due to the unavailability of specific targeted therapies. Androgen receptor (AR) was reported to be expressed in up to 60% of TNBC cases but there have been controversies as to the roles of androgen signaling through AR in TNBC. Therefore, in this study, we analyzed the status of AR in combination with androgen synthesizing enzymes (5α-reductase type 1 (5αR1) and 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5)] in order to further understand androgenic actions in TNBC. Androgen receptor, 5αR1, and 17βHSD5 were immunolocalized in a cohort of 203 TNBC patients from Thailand and Japan. We then correlated the findings with clinicopathological characteristics (age, stage, tumor diameter, lymph node invasion, metastatic spread, Ki-67 labeling index, disease-free survival, and overall survival) of the patients. Univariate analysis revealed that AR+/enzyme+ cases were associated with a significantly lower Ki-67 labeling index than AR-/enzyme- samples. Multivariate analysis indicated the presence of significant positive correlations between AR and enzyme status in tumor cells, and between tumor diameter, lymph node invasion, and distant metastasis. Significant negative correlations were also detected between Ki-67 labeling index and AR status (P = 0.04) or 5αR1 (P < 0.001). Cox proportional hazards analysis showed that Ki-67 labeling index and stage were the only factors predicting disease-free and overall survival of the patients, although univariate Kaplan-Meier analysis revealed AR/5αR1 negativity suggested a more adverse clinical course up to 80 months after surgery. These results suggest that the presence of androgen synthesizing pathways in addition to AR expression in tumor cells could confer a better clinical outcome through suppression of cell proliferation.
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http://dx.doi.org/10.1111/cas.12121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657136PMC
May 2013

The challenge to reduce breast cancer mortality in Okinawa: consensus of the first Okinawa breast oncology meeting.

Jpn J Clin Oncol 2013 Feb 3;43(2):208-13. Epub 2013 Jan 3.

2-1-9 Akamine, Naha, Okinawa 901-0154, Japan.

Breast cancer mortality is gradually increasing in Okinawa. The 1st Okinawa Breast Oncology Meeting was held on 6 July 2012 and discussions on how to curb the rising trend were focused on breast cancer screening, adjuvant treatment, socioeconomic and geographic issues, and the problem of complementary and alternative medicine. The consensus of the 1st Okinawa Breast Oncology Meeting was that ultrasonography screening is an acceptable screening system for Okinawan women because of the geographic disadvantage of having many small islands and rural areas. Educational and economic support is needed for women in rural areas to get correct information, for access to urban areas and to be treated by evidence-based optimal therapy for breast cancer. In addition, new approaches are needed for Okinawan people to successfully educate patients to correctly interpret evidence-based information.
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http://dx.doi.org/10.1093/jjco/hys217DOI Listing
February 2013

Clinical significance following breast conservation therapy with or without irradiation in breast cancer patients.

Jpn J Clin Oncol 2013 Mar 30;43(3):251-7. Epub 2012 Dec 30.

Department of Breast Surgery, Nahanishi Clinic, 2-1-9 Akamine, Naha, Okinawa, Japan.

Background: We retrospectively examined the clinical outcome of irradiated versus non-irradiated groups of Japanese breast cancer patients according to their clinical and histopathological characteristics following breast-conserving therapy.

Methods: We retrospectively evaluated a total of 1197 Japanese female breast cancer patients (598 irradiated and 599 non-irradiated) who received breast-conserving therapy. The median age of the patients was 54 years (range: 24-99 years). We retrospectively examined the local recurrence-free survival rates in those with or without post-operative irradiation according to age, surgical margin status and histopathological characteristics including histological grade, estrogen receptor expression and HER2 status.

Results: Local recurrence-free survival rates in the irradiated group were significantly higher than those in the non-irradiated group, especially in surgical margin-positive [hazard ratio (HR): 0.334, 95% confidence interval: 0.14-0.79, P = 0.001], estrogen receptor-positive (HR: 0.249, 95% confidence interval: 0.11-0.54, P < 0.001), HER2-negative (HR: 0.382, 95% confidence interval: 0.21-0.69, P = 0.001) and non-triple-negative (HR: 0.382, 95% confidence interval: 0.21-0.69, P = 0.001) breast cancer patients.

Conclusion: The results indicated that irradiation after breast-conserving therapy is strongly recommended in Japanese breast cancer patients, especially those with surgically positive margins, estrogen receptor-positive tumors and HER2-negative invasive breast cancers.
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http://dx.doi.org/10.1093/jjco/hys214DOI Listing
March 2013

Analysis of clinically relevant values of Ki-67 labeling index in Japanese breast cancer patients.

Breast Cancer 2014 May 11;21(3):325-33. Epub 2012 Jul 11.

Department of Breast Surgery, Nahanishi Clinic, 2-1-9 Akamine, Naha, Okinawa, 901-0154, Japan,

Background: It has become important to standardize the methods of Ki-67 evaluation in breast cancer patients, especially those used in the interpretation and scoring of immunoreactivity. Therefore, in this study, we examined the Ki-67 immunoreactivity of breast cancer surgical specimens processed and stained in the same manner in one single Japanese institution by counting nuclear immunoreactivity in the same fashion.

Methods: We examined 408 Japanese breast cancers with invasive ductal carcinoma and studied the correlation between Ki-67 labeling index and ER/HER2 status and histological grade of breast cancer. We also analyzed overall survival (OS) and disease-free survival (DFS) of these patients according to individual Ki-67 labeling index.

Results: There were statistically significant differences of Ki-67 labeling index between ER positive/HER2 negative and ER positive/HER2 positive, ER negative/HER2 positive or ER negative/HER2 negative, and ER positive/HER2 positive and ER negative/HER2 negative groups (all P < 0.001). There were also statistically significant differences of Ki-67 labeling index among each histological grade (P < 0.001, respectively). As for multivariate analyses, Ki-67 labeling index was strongly associated with OS (HR 39.12, P = 0.031) and DFS (HR 10.85, P = 0.011) in ER positive and HER2 negative breast cancer patients. In addition, a statistically significant difference was noted between classical luminal A group and "20 % luminal A" in DFS (P = 0.039) but not between classical luminal A group and "25 % luminal A" (P = 0.105).

Conclusions: A significant positive correlation was detected between Ki-67 labeling index and ER/HER2 status and histological grades of the cases examined in our study. The suggested optimal cutoff point of Ki-67 labeling index is between 20 and 25 % in ER positive and HER2 negative breast cancer patients.
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http://dx.doi.org/10.1007/s12282-012-0387-5DOI Listing
May 2014