Language：Japanese   Publisher：(一社)日本外科学会  

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Rationale: The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity often precludes conclusions on function. Methods: We combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. The significance of the findings was then evaluated in a cohort of tumors (N=75) from breast cancer patients using immunohistochemistry analysis. Results: Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFβ-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-β signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-β signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-β inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFβ immunosuppressive function. Histological analysis of 75 breast cancer samples confirmed that high EMILIN1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. Conclusion: Our data show that correlating TGF-β signaling to a CAF subpopulation is not enough because proteins with TGF-β-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.

DOI： 10.7150/thno.90627

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This study aimed to identify microRNAs associated with histological grade using comprehensive microRNA analysis data obtained by next-generation sequencing from early-stage invasive breast cancer. RNA-seq data from normal breast and breast cancer samples were compared to identify candidate microRNAs with differential expression using bioinformatics. A total of 108 microRNAs were significantly differentially expressed in normal breast and breast cancer tissues. Using clinicopathological information and microRNA sequencing data of 430 patients with breast cancer from The Cancer Genome Atlas (TCGA), the differences in candidate microRNAs between low- and high-grade tumors were identified. Comparing the expression of the 108 microRNAs between low- and high-grade cases, 25 and 18 microRNAs were significantly upregulated and downregulated, respectively, in high-grade cases. Clustering analysis of the TCGA cohort using these 43 microRNAs identified two groups strongly predictive of histological grade. miR-3677 is a microRNA upregulated in high-grade breast cancer. The outcome analysis revealed that patients with high miR-3677 expression had significantly worse prognosis than those with low miR-3677 expression. This study shows that microRNAs are associated with histological grade in early-stage invasive breast cancer. These findings contribute to the elucidation of a new mechanism of breast cancer growth regulated by specific microRNAs.

DOI： 10.3390/ijms25010035

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BACKGROUND/AIM: In patients with breast cancer, the expression of stathmin1 (STMN1) has been significantly related to a poor prognosis, cancer aggressiveness, and expression of cancer stem cell markers. The STMN1 protein is closely regulated by phosphorylation in four sites. However, few studies have investigated the relationship between the expression of phosphorylated STMN1 (pSTMN1) and clinicopathological findings, including tumor-aggressive biomarkers, in patients with breast cancer. MATERIALS AND METHODS: The expression levels of four pSTMN1 (Ser16, Ser25, Ser38, and Ser63) were immunohistochemically analyzed in 213 breast cancer cases. The clinicopathological factors evaluated included epithelial-mesenchymal transition (EMT) markers and cancer stem cell markers. RESULTS: The cytoplasmic expression of pSTMN1 (Ser16, Ser25, Ser38, and Ser63) in normal breast tissues was low. The positive expression ratios of Ser25 (54.5%) and Ser38 (39.0%) were high compared to those of Ser16 (25.8%) and Ser63 (23.9%). The overexpression of pSTMN1 (Ser38) was associated with tumor-aggressive characteristics, such as triple-negative breast cancer (TNBC) phenotypes, high mesenchymal marker, and expression of cancer stem cell markers. CONCLUSION: STMN1 phosphorylation might be associated with clinicopathological factors, breast cancer subtypes, and expression of mesenchymal markers and breast cancer stem cell markers through the regulation of STMN1 function. Ser38 phosphorylation of STMN1 may be a novel biomarker for high-grade TNBC associated with mesenchymal marker expression and cancer stemness.

DOI： 10.21873/anticanres.16737

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：日本肺高血圧・肺循環学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16-7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35-8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.

DOI： 10.1038/s41598-022-06615-8

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Language：Japanese   Publisher：日本画像医学会  

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Language：Japanese   Publisher：日本画像医学会  

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Tumor-infiltrating lymphocytes (TILs) are a significant prognostic factor in triple-negative breast cancer. However, the clinicopathological significance of TILs in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer remains unclear. The purpose of the present study was to evaluate the role of TILs in the prognosis of ER-positive and HER2-negative breast cancer. A total of 65 consecutive patients with ER-positive and HER2-negative breast cancer were examined. TILs in stromal tissue (str-TILs) were graded using the International TILs Working Group criteria. The association between several clinicopathological factors and TIL grade were investigated, and the prognostic impact of TILs was compared between luminal A-like and luminal B-like breast cancer. A total of 51 patients (78.5%) had low-grade (0-10%), 11 (16.9%) had intermediate (10-40%) and 3 (4.6%) had high-grade (40-90%) str-TIL levels. There was a significant association between high levels of Ki67 expression and a high str-TIL count. Relapse-free survival was significantly worse in patients with luminal B-like cancer compared with that in patients with luminal A-like cancer. Patients with an intermediate or high str-TIL count had a better prognosis compared with those with a low str-TIL count. All patients with luminal B-like cancer and intermediate or high str-TIL levels developed no recurrence during follow-up. In conclusion, there was a significant correlation between high-grade str-TIL levels and high tumor cell proliferation rate, as well as high levels of Ki67 expression.

DOI： 10.3892/mco.2021.2414

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

DOI： 10.21873/anticanres.15185

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Language：English   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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OBJECTIVE: The morphological features of nuclei in cytological and histological specimens were compared and examined for the presence of BRAFV600E mutation and the appearance rate of intranuclear cytoplasmic inclusions (NI). METHODS: BRAFV600E mutation was identified using a mutation-specific antibody (clone; VE1) in 103 thyroid papillary carcinoma cases at Gunma University Hospital. The nuclear area, perimeter, and roundness of the corresponding cytological specimens and haematoxylin and eosin-stained specimens were analysed using image analysis software, and the appearance rate of NI was calculated and compared. RESULTS: BRAFV600E mutation was detected in 71 (69%) cases. The appearance rate of NI was significantly higher in the BRAFV600E mutation-positive group in cytological and histological specimens (P = .0070 and .0184, respectively). Significant differences were observed between the BRAFV600E mutation-negative and -positive groups in the average nuclear area and average nuclear perimeter in cytological specimens (P = .0137 and .0152, respectively). In addition, nuclear enlargement was correlated with the appearance rate of NI regardless of the presence of BRAFV600E mutation in cytological specimens. In the BRAFV600E mutation-negative group, the nuclear area and perimeter were significantly smaller in the lymph node metastasis-positive cases (P = .0182 and .0260, respectively). CONCLUSION: This study found that the appearance rate of NI was positively correlated with the nuclear area and perimeter and negatively correlated with nuclear roundness in cytological specimens. Furthermore, these results were observed regardless of the existence of BRAFV600E mutation. These results have never been previously reported and clearly demonstrate the usefulness of cytological specimens in computer-assisted image analysis.

DOI： 10.1111/cyt.13022

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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BACKGROUND: Immediate breast reconstruction with skin-sparing (SSM) or nipple-sparing mastectomy (NSM) has become a common procedure. In this study, we evaluated the distance between breast tumor and skin in a series of patients undergoing IBR as it relates to oncologic safety, namely, the incidence of recurrence. METHODS: The distance of the tumor to the dermis, rather than the outer layer of skin, was the key parameter of our preoperative ultrasound measurements. Our data set comprised the cases of 171 patients and 181 breasts with breast cancer that had undergone two-stage breast reconstruction by expander. The median age of the patients was 47 years (25-75 years). The overall median follow-up period was 47.1 months (8.8-125.3 months). Eighty-five breasts underwent IBR with SSM/NSM; the others underwent conventional mastectomy. RESULTS: Among the total of 181 reconstructed breast mounds, the locoregional recurrence rate was 1.1% (2 breasts) with no cases of skin flap recurrence or skin flap necrosis. The tumor-to-dermis distance of cases with skin preservation (NSM/SSM) was significantly less than that of cases with conventional mastectomy (3.8 ± 2.7 mm vs 5.2 ± 2.4 mm). In cases with invasive carcinoma, all cases whose tumor-to-dermis distance was less than 2 mm underwent resection of the skin immediately overlying the tumor. CONCLUSIONS: Our results suggested that a 2-mm distance between the dermis and tumor on ultrasound evaluation is sufficient for the use of this tissue as a skin flap in SSM/NSM procedures. Our study indicated that immediate breast reconstruction with SSM/NSM can be an oncologically safe surgical option for breast cancer. However, we recommend that resection of the skin overlying the tumor be performed in cases with invasive breast cancer in which the tumor-to-dermis distance is less than 2 mm. TRIAL REGISTRATION: Patients in this study were retrospectively registered. This study design was approved by our Clinical Ethics Committee (No 1297) ( http://ciru.dept.showa.gunma-u.ac.jp/guidance/storage-sample/list.html ).

DOI： 10.1186/s12957-021-02185-7

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BACKGROUND: Chemotherapy-induced alopecia (CIA) is a common and quite distressing adverse effects of chemotherapy. There are few detailed observational studies of CIA or of the impact of age on CIA. We performed a prospective observational study to investigate the prevalence and degree of CIA, including CIA of eyebrows, eyelashes, and body, and we examined patient's recovery from CIA, focusing on age-depending effects. METHODS: We analyzed 68 female Japanese patients with breast cancer (median age 53 years, range 29-76 years) who received perioperative adjuvant chemotherapy with fluorouracil/epirubicin/cyclophosphamide (FEC) and taxane. A questionnaire was administered at the point of chemotherapy completion and 6 and 12 months after chemotherapy completion. RESULTS: CIA occurred in all patients, with severe hair loss irrespective of age. CIA occurred mainly in the scalp but also in the eyebrows, eyelashes, and body for most of the patients. There were significant associations between the patient's age and the onset of hair regrowth in the eyebrows, eyelashes, and body. The onset of eyebrows, eyelash, and body hair growth were significantly shorter in the premenopausal patients. Any hair changes (e.g., thinned diameter, softer texture, curlier structure) were reported by 85.3% of the patients. CONCLUSIONS: Severe CIA occurred in all 68 patients who received FEC and taxane chemotherapy. The present findings provide the first data demonstrating that age was not associated with the degree or incidence of hair loss, but age affected the recovery from CIA. These results contribute more accurate information provision and insights regarding the proper treatment of CIA.

DOI： 10.1007/s12282-020-01161-5

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Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibody (Ab) is significantly associated with internal malignancies in adult patients with dermatomyositis (DM). Although pathogenesis of cancer-associated DM is unknown, TIF1γ overexpression in tumors has been considered to be critical for the development of DM. The objective of this study was to investigate clinical characteristics of patients with anti-TIF1γ Ab-positive DM and elucidate risk factors that are potentially associated with internal malignancy. In addition, we compared the expression of TIF1γ in tumor tissues of patients with anti-TIF1γ Ab-positive DM, anti-TIF1γ Ab-negative DM and without DM in order to investigate the pathogenesis of cancer-associated DM. We analyzed 77 Japanese patients with DM, and found 19 patients to be positive for anti-TIF1γ Ab. Patients with anti-TIF1γ Ab-positive DM were older and presented heliotrope rash and flagellate erythema more frequently than patients without anti-TIF1γ Ab (P < 0.05). Interstitial lung disease (ILD) and rapidly progressive ILD, as well as palmar violaceous erythema, were less frequent in patients with anti-TIF1γ Ab than in patients without. Furthermore, internal malignancy and dysphagia were significantly more frequent in the anti-TIF1γ Ab-positive group (P < 0.01). Male sex and dysphagia were significantly associated with internal malignancy in patients with anti-TIF1γ Ab-positive DM (P < 0.01 and <0.05, respectively). Using immunohistochemistry, we examined the TIF1γ expression in tumors of 11 patients with cancer-associated DM (anti-TIF1γ Ab-positive, nine; anti-TIF1γ Ab-negative, two) and 25 patients without DM. TIF1γ was highly expressed in all tumors, and there was no significant difference in TIF1γ expression between patients with and without DM. Furthermore, TIF1γ expressions in tumors were similar irrespective of the presence of anti-TIF1γ Ab. These results suggest that anti-TIF1γ antibody may not be simply induced by overexpression of TIF1γ in tumors in patients with DM, but that other mechanisms may exist.

DOI： 10.1111/1346-8138.15526

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BACKGROUND: S-1 and cyclophosphamide (CPA) can be given orally, and their combination may have great potential for treating metastatic breast cancer (MBC). A phase I study of sequential S-1 and CPA therapy was conducted in patients with MBC; the recommended doses that were determined for this regimen were 80 mg/m2/day for S-1 and 100 mg/m2/day for CPA. We then conducted a phase II study of this oral S-1 and CPA regimen. METHODS: This was a single-arm, open-label, single-center prospective phase II study to evaluate the efficacy of a sequential S-1 and CPA regimen for MBC. S-1 was administered orally 2×/day for 14 consecutive days, and then CPA was administered orally 2×/day for 14 consecutive days in a repeating 4-week cycle (S-1 for 2 weeks, CPA for 2 weeks). The primary endpoint was the overall response rate (ORR). Secondary endpoints included the overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR) and safety. RESULTS: Thirty-six patients were enrolled in this study. The overall response was complete response in 0 (0%), partial response in 12 (33.3%), stable disease in 12 (33.3%), and progressive disease in 11 (30.1%) patients. The ORR was 33.3% (12/36). The CBR was 66.7% (24/36). The median PFS was 9.5 months (95%CI: 7.8-12.6 months). The median OS was 20.2 months (95%CI: 15.0-25.4 months) Grade 3/4 adverse events included leukopenia in seven patients (19.4%). Dose reductions because of adverse events occurred in 12 patients (33.3%). There was no treatment-related mortality. CONCLUSION: The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC; however, further study is warranted to explore the efficacy of this therapy. TRIAL REGISTRATION: JRCT, JRCTs031180296 . Registered 2 December 2019 - Retrospectively registered.

DOI： 10.1186/s12885-020-07550-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

DOI： 10.1016/S0959-8049(20)30784-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

DOI： 10.1016/S0959-8049(20)30785-1

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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BACKGROUND: Invasive lobular carcinoma (ILC) accounts for 10-15% of primary breast cancers and is typically estrogen receptor alpha positive (ER+) and ERBB2 non-amplified. Somatic mutations in ERBB2/3 are emerging as a tractable mechanism underlying enhanced human epidermal growth factor 2 (HER2) activity. We tested the hypothesis that therapeutically targetable ERBB2/3 mutations in primary ILC of the breast associate with poor survival outcome in large public datasets. METHODS: We performed in silico comparison of ERBB2 non-amplified cases of ER+ stage I-III primary ILC (N = 279) and invasive ductal carcinoma (IDC, N = 1301) using METABRIC, TCGA, and MSK-IMPACT information. Activating mutations amenable to HER2-directed therapy with neratinib were identified using existing functional data from in vitro cell line and xenograft experiments. Multivariate analysis of 10-year overall survival (OS) with tumor size, grade, and lymph node status was performed using a Cox regression model. Differential gene expression analyses by ERBB2 mutation and amplification status was performed using weighted average differences and an in silico model of response to neratinib derived from breast cancer cell lines. RESULTS: ILC tumors comprised 17.7% of all cases in the dataset but accounted for 47.1% of ERBB2-mutated cases. Mutations in ERBB2 were enriched in ILC vs. IDC cases (5.7%, N = 16 vs. 1.4%, N = 18, p < 0.0001) and clustered in the tyrosine kinase domain of HER2. ERBB3 mutations were not enriched in ILC (1.1%, N = 3 vs. 1.8%, N = 23; p = 0.604). Median OS for patients with ERBB2-mutant ILC tumors was 66 months vs. 211 months for ERBB2 wild-type (p = 0.0001), and 159 vs. 166 months (p = 0.733) for IDC tumors. Targetable ERBB2 mutational status was an independent prognostic marker of 10-year OS-but only in ILC (hazard ratio, HR = 3.7, 95% CI 1.2-11.0; p = 0.021). Findings were validated using a novel ERBB2 mutation gene enrichment score (HR for 10-year OS in ILC = 2.3, 95% CI 1.04-5.05; p = 0.040). CONCLUSIONS: Targetable ERBB2 mutations are enriched in primary ILC and their detection represents an actionable strategy with the potential to improve patient outcomes. Biomarker-led clinical trials of adjuvant HER-targeted therapy are warranted for patients with ERBB2-mutated primary ILC.

DOI： 10.1186/s13058-020-01324-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

DOI： 10.21873/invivo.12003

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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DOI： 10.21873/invivo.11915

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BACKGROUND: High F18-fluorodeoxyglucose (FDG) uptake has been reported to be a predictor of poor prognosis in patients with breast cancer. We investigated the relationship between FDG uptake and immunological factors, including the data of programmed cell death-ligand 1 (PD-L1), CD8, and tumor-infiltrating lymphocytes (TILs). METHODS: Breast cancer tissues of 97 patients who underwent surgery without preoperative therapy were examined. The grade of stromal TILs was immunohistochemically evaluated using the criteria of the International TILs Working Group in breast cancer. PD-L1 positivity and CD8 positivity were immunohistochemically evaluated. The FDG uptakes were evaluated based on the standardized uptake value max (SUVmax). The relationships between SUVmax and TIL grade and expression of PD-L1 and CD8 were investigated. RESULTS: Among the 97 patients, 41 (42.3%) had a high SUVmax in their primary tumor, based on the SUVmax cut-off value 3 yielded by receiver operating characteristic curves. PD-L1 was positive in 17 patients (17.5%). Our analyses revealed that large tumor size, high nuclear grade, high degree of TILs and positive expression of PD-L1 were significantly associated with high SUVmax in the primary tumor. There were significant associations between SUVmax and the degree of TILs (r = 0.428, p < 0.001) and between SUVmax and the PD-L1 positivity (r = 0.413, p < 0.001). All cases with a high degree of TILs showed high CD8 expression. CONCLUSION: Our results indicate that the FDG uptake may be predictive of immunological features including TILs and PD-L1 expression in breast cancer patients. Additional research is necessary to further evaluate FDG-PET as a biomarker of immune checkpoint therapy in breast cancer.

DOI： 10.1007/s10549-020-05619-0

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Biomarkers that can accurately predict treatment response are required for indicating optimal neoadjuvant treatments. The current study assessed the predictive value of secreted protein acidic and rich in cysteine (SPARC) mRNA expression for the response to neoadjuvant nab-paclitaxel (nab-PTX) therapy in patients with breast cancer. It was hypothesized that SPARC expression can affect the response to albumin-bound taxanes, including nab-PTX since SPARC binds albumin with a high affinity. Pre-therapeutic specimens of core needle biopsies were analyzed from 50 patients in a phase II trial of neoadjuvant nab-PTX and the factors that were associated with a pathological complete response (pCR) were assessed. The pre-therapeutic tumor mRNA levels of chemotherapy-related proteins were quantified, including SPARC, and the correlations with post-therapeutic clinicopathological factors were assessed, including with pCR. The results demonstrated that pre-therapeutic SPARC mRNA expression was significantly higher in non-pCR patients compared with patients with pCR (92.37±55.33 vs. 56.53±30.19; P=0.027). A cutoff point of 48.5 was determined using receiver operating characteristic (ROC) curve analysis (sensitivity, 83.3%; specificity, 50.0%), and patients were classified into low and high SPARC expression groups. High SPARC expression was associated with histological grade (P=0.035), estrogen receptor expression (P=0.037), and progesterone receptor expression (P=0.002) but not with HER2 (P=0.895), and Ki-67 LI (P=0.743) expression. The results of the current study indicated that a high SPARC mRNA expression was a negative predictor of pCR following neoadjuvant nab-PTX therapy regardless of breast cancer subtype. The phase II study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the National Hospital Organization Takasaki General Medical Center (Registration nos. H23-9 and H23-33).

DOI： 10.3892/ol.2020.11354

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

Sarcopenia is characterized by skeletal muscle mass (SMM) depletion and decreased muscle power. In two-stage breast reconstruction using a tissue expander, obesity is the main risk factor for postoperative complications. Obese patients with breast cancer and sarcopenia have a hidden lower SMM with a larger body mass index (BMI). This study aimed to investigate the impact of decreased SMM on complications after tissue expander surgery. In this nonrandomized, retrospective cohort study, 157 patients underwent 169 expander indwelling surgeries. Cross-sectional areas (cm2) of skeletal muscles at the third lumbar vertebra were measured on computed tomography (CT) and normalized for height (cm2/m2) to determine the skeletal muscle index (SMI). Subcutaneous and visceral adipose tissue areas were measured in the same slice and normalized for height (cm2/m2) to determine the total adipose tissue index (TATI). The SMI/TATI ratio was calculated as an index of sarcopenic obesity. Postoperative complications occurred in 40 cases (23.7%). In multivariate analysis, a lower SMI/TATI ratio was identified as a significant independent risk factor for complications (P < 0.001, adjusted odds ratio (OR) = 2.28 per 10% decrease). Delayed wound healing was significantly associated with lower SMI/TATI ratio (P = 0.003, OR = 6.33 per 10% decrease) and diabetes (P = 0.044, OR = 7.36). Seroma was significantly associated with high BMI (P < 0.001, OR = 8.00 per 5-kg/m2 increase) and blood loss (P = 0.003, OR = 1.18 per 10 g increase). These results show that patients with a large adipose tissue volume and lower SMM (sarcopenic obesity) have more complications after expander surgery than those with high BMI, or TATI alone.

DOI： 10.1016/j.bjps.2020.02.006

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PURPOSE: The epithelial-mesenchymal transition (EMT) plays a key role in breast cancer progression and metastasis. Lipocalin 2 (LCN2) is involved in the regulation of EMT. The aim of this study was to investigate the clinicopathological significance of LCN2 expression in breast cancer. METHODS: The expression of LCN2 protein was immunohistochemically assessed in two well-characterised annotated cohorts of breast cancer (discovery cohort, n = 612; validation cohort, n = 1363). The relationship of LCN2 expression and subcellular location with the clinicopathological factors and outcomes of patients was analysed. RESULTS: Absent or reduced nuclear LCN2 expression was associated with features of aggressive behaviour, including high histological grade, high Nottingham Prognostic Index, high Ki67 labelling index, hormone receptor negativity and human epidermal growth factor receptor 2 positivity. The high cytoplasmic expression of LCN2 was correlated with lymph node positivity. The nuclear downregulation of LCN2 was correlated with the overexpression of EMT associated proteins (N-cadherin and Twist-related protein 2) and basal biomarkers (cytokeratin 5/6 and epidermal growth factor receptor). Unlike the cytoplasmic expression of LCN2, the loss of nuclear expression was a significant predictor of poor outcome. The combinatorial expression tumours with high cytoplasmic and low nuclear expression were associated with the worst prognosis. CONCLUSIONS: Tumour cell expression of LCN2 plays a role in breast cancer progression with loss of its nuclear expression which is associated with aggressive features and poor outcome. Further functional analysis is warranted to confirm the relationship between the subcellular localisation LCN2 and behaviour of breast cancer.

DOI： 10.1007/s10549-019-05488-2

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Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA-dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA-sequencing of breast cancer (BrCa) clinical specimens to identify tumor-suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor-suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre-miRNA were downregulated in BrCa tissues (e.g. miR-99a-5p/-3p, miR-101-5p/-3p, miR-126-5p/-3p, miR-143-5p/-3p, and miR-144-5p/-3p). Among these miRNA, we focused on miR-101-5p, the passenger strand of pre-miR-101, and investigated its tumor-suppressive roles and oncogenic targets in BrCa cells. Low expression of miR-101-5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR-101-5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine-Rich Splicing Factor Kinase 1, Vang-like protein 1, and Mago Homolog B) regulated by miR-101-5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor-suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

DOI： 10.1002/1878-0261.12602

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/invivo.12082

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Publishing type：Research paper (scientific journal)   Publisher：Anticancer Research USA Inc.  

DOI： 10.21873/invivo.12188

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

DOI： 10.21873/invivo.11858

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Several ongoing clinical trials are investigating the use of immuno-targeting therapy with programmed cell death protein-1 and programmed death-ligand 1 (PD-L1) inhibitors for triple-negative breast cancer. However, the role of PD-L1 expression in HER2-positive breast cancer remains unclear. We investigated the clinicopathological utility of PD-L1 expression in HER2-positive breast cancer. Cohort A included 248 patients with invasive breast cancer (all subtypes). Cohort B included 126 HER2-positive patients who received neoadjuvant chemotherapy (NAC) concomitant with trastuzumab. The relationship of PD-L1 expression on the cancer cells with clinicopathological factors including pathological complete response (pCR) and prognosis was investigated. In cohort A, 8.1% patients were PD-L1-positive; PD-L1 positivity showed a correlation with high degree of tumor-infiltrating lymphocytes (TILs), estrogen receptor negativity, progesterone receptor negativity, and high histological grade. In cohort B, 17.5% patients were PD-L1-positive; PD-L1 positivity showed a significant correlation with high degree of TILs and high abundance of CD8-positive TILs. The pCR rates were related to TILs and PD-L1 expression. Among PD-L1-negative patients, high CD8-positive TILs were associated with significantly better prognosis. In conclusion, 17.5% of HER2-positive type patients were PD-L1-positive. PD-L1 expression was associated with response to NAC with trastuzumab in patients with HER2-positive breast cancer.

DOI： 10.1038/s41598-019-52944-6

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：北関東医学会  

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Ulcerative colitis (UC) is thought to be associated with precancerous lesions that can ultimately lead to colon cancer. Therefore, diagnostic markers for colorectal dysplasia and cancer are urgently needed for patients with UC. Stathmin 1 (STMN1) is a novel cancer biomarker that is also a novel target for treatment in several cancers, including colon cancer. However, few studies have investigated the relationship between STMN1 expression and clinical features in colorectal dysplasia and cancer in patients with UC. The present study examined the clinical significance of STMN1 expression in colorectal dysplasia and cancer with UC. The present study performed an immunohistochemical analysis of 31 clinical colorectal samples from eight patients with colorectal dysplasia and/or cancer to assess the relationships between STMN1 expression and clinicopathological features including mismatch repair protein expression, rate of Ki-67 positivity, differentiation level, TNM stage, and UC duration. STNM1 expression was detected in 95.7% of dysplastic and cancerous lesions, whereas p53, the current diagnostic marker, was not expressed in 39.1% of dysplastic and cancerous lesions. Furthermore, STMN1 expression was associated with a high rate of positivity for Ki-67, a proliferation marker. Our data suggest that STMN1 in the colonic mucosa of UC patients may be useful as an early diagnostic marker of dysplasia and colitic cancer.

DOI： 10.3892/ol.2019.10814

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PURPOSE: Antitumor immunity plays an important role in the progression of breast cancer. β2-adrenergic receptor (β2AR) was found to regulate the antitumor immune response and breast cancer progression in preclinical studies. To understand the clinical role of β2AR in cancer progression, we investigated the clinicopathological and prognostic significance of β2AR expression in invasive breast cancer. METHODS: β2AR levels in breast tumors were evaluated by immunohistochemistry in a well-characterized patient cohort with long-term follow-up (n = 278). We evaluated the relationship of β2AR expression to patient survival and clinicopathological factors, including immune biomarkers such as tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. Breast cancer-specific survival was compared between high- and low-β2AR expression groups. RESULTS: Although β2AR was not related to clinicopathological factors across the whole cohort, high β2AR was significantly related to PD-L1 negativity in estrogen receptor (ER)-negative patients. Tumors with high β2AR tended to have low TIL grade, and high β2AR was an independent prognostic factor for reduced survival in ER-negative patients. CONCLUSIONS: β2AR is an independent poor prognostic factor in ER-negative breast cancer. The findings suggest that tumor β2AR regulates immune checkpoint activity, which may have therapeutic implications for patients with ER-negative breast cancer.

DOI： 10.1007/s10549-019-05341-6

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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DOI： 10.1007/s12282-018-00942-3

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PURPOSE: Androgen receptor (AR) and AR signaling pathways are thought to play a role in breast cancer (BC) and are potentially related to treatment responses and outcomes. Ankyrin 3 (ANK3) is associated with AR stability in cancer cells. In the present study, we investigated the clinicopathological utility of ANK3 expression with emphasis on AR and its associated signalling pathway at transcriptomic and proteomic phases. PATIENTS AND METHODS: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1980) and The Cancer Genome Atlas (TCGA) dataset (n = 1039) were used to assess the expression and significance of ANK3 mRNA and other AR signalling pathway-associated gene signature. Using immunohistochemistry, ANK3 protein expression was evaluated in large (n = 982) cohort of early-stage BC with long-term follow-up and compared with clinicopathological characteristics and its prognostic value in the whole cohort and the subgroups stratified by AR protein expression. RESULTS: An AR-related gene signature was developed, comprising 20 genes, which included ANK3. This AR-related gene signature was significantly associated with AR mRNA expression, oestrogen receptor, human epidermal growth factor receptor 2 (HER2) status and the patients' outcomes. In tumours with high AR protein expression (n = 614), high ANK3 protein expression was significantly associated with progesterone receptor positivity and it was independently associated with the good outcomes (p = 0.025). CONCLUSIONS: This study indicates that ANK3 is related to AR signalling pathway and is associated with BC prognosis.

DOI： 10.1007/s10549-019-05216-w

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BACKGROUND: Lymphovascular invasion (LVI) is associated with the development of metastasis in invasive breast cancer (BC). However, the complex molecular mechanisms of LVI, which overlap with other oncogenic pathways, remain unclear. This study, using available large transcriptomic datasets, aims to identify genes associated with LVI in early-stage BC patients. METHODS: Gene expression data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1565) was used as a discovery dataset, and The Cancer Genome Atlas (TCGA; n = 854) cohort was used as a validation dataset. Key genes were identified on the basis of differential mRNA expression with respect to LVI status as characterised by histological review. The relationships among LVI-associated genomic subtype, clinicopathological features and patient outcomes were explored. RESULTS: A 99-gene set was identified that demonstrated significantly different expression between LVI-positive and LVI-negative cases. Clustering analysis with this gene set further divided cases into two molecular subtypes (subtypes 1 and 2), which were significantly associated with pathology-determined LVI status in both cohorts. The 10-year overall survival of subtype 2 was significantly worse than that of subtype 1. CONCLUSION: This study demonstrates that LVI in BC is associated with a specific transcriptomic profile with potential prognostic value.

DOI： 10.1038/s41416-019-0486-6

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The human epidermal growth factor receptor (HER) family plays a vital role in the development of resistance to treatments in estrogen receptor (ER)-positive breast cancer. This study investigated the correlation between protein and mRNA expressions of the HER family in ER-positive breast cancer. We dissected regions of invasive cancer from the frozen tissues of 34 patients with ER-positive breast cancer using laser-capture microdissection, followed by evaluation of the mRNA levels of the ER and HER family (EGFR, HER2, HER3, and HER4) using the quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. In addition, we assessed the protein expressions of the ER and HER family using an immunohistochemical (IHC) assay. A significant correlation was observed between the ER protein and mRNA expressions. For HER2, HER3, and HER4, protein expressions significantly correlated with mRNA levels. We established significant correlations of the mRNA level between EGFR versus HER2, as well as EGFR versus HER3. Furthermore, a significant correlation of the mRNA level between HER2 and HER3 was illustrated. In conclusion, IHC evaluation may be reliable and representable for mRNA. Hence, this study established a marked correlation between the mRNA expressions of HER family members in patients with ER-positive breast cancer.

DOI： 10.1007/s00795-018-0206-y

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Language：Japanese   Publisher：(一社)日本内分泌外科学会  

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Using whole transcriptome analysis and a lentiviral short hairpin RNA screening library, carboxypeptidase A4 (CPA4) was identified as a novel marker in breast cancer and a therapeutic target in triple‑negative breast cancer (TNBC) in the present study. Immunohistochemistry was used to evaluate the presence of CPA4, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki67, epidermal growth factor receptor, cytokeratin 5/6, aldehyde dehydrogenase 1, cluster of differentiation (CD)44, CD24, claudins, E‑cadherin, vimentin and androgen receptor in 221 cases of breast cancer, including 68 TNBC cases. The effects of CPA4 on the viability and migration ability of TNBC cells were analyzed using RNA interference methods. Increased CPA4 expression, specifically in the cytoplasm of cancer tissue cells, was detected. Furthermore, high CPA4 expression in TNBC cases was associated with low expression of E‑cadherin and with the expression of cancer stem cell markers (high CD44/low CD24). Patients with TNBC and high levels of CPA4 expression had a significantly poorer prognosis compared with those with low CPA4 expression. Notably, viability and migration were reduced, but E‑cadherin expression was upregulated in CPA4‑suppressed TNBC cells. The present data suggested that CPA4 may be a novel inducer for epithelial‑mesenchymal transition, which is characterized by the downregulation of E‑cadherin and mesenchymal phenotypes. To conclude, CPA4 may be a marker for poor prognosis and a promising therapeutic target in TNBC with aggressive phenotypes.

DOI： 10.3892/ijo.2019.4675

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Tumour-infiltrating lymphocytes (TILs) are regarded as significant prognostic markers in patients with breast cancer. However, the prognostic utility of TIL expression based on the intrinsic subtypes has just been identified. The present study investigated the relationship between TIL grades and prognosis in 294 Japanese paitents with breast cancer stratified based on the intrinsic subtypes and clinicopathological characteristics. Stromal TIL status was evaluated using haematoxylin and eosin staining, and TIL grades were categorised into low (<10%), intermediate (≥10 and ≤40%) and high (>40%) groups. The relationship between TIL expression and the intrinsic subtypes, clinicopathological characteristics and patient prognosis was analyzed. It was revealed that high TIL expression was correlated with negative oestrogen receptor (ER) expression and high histological grade (P<0.001). Among the ER-negative patients, the relapse-free survival (RFS) rate of the high-grade TIL group was significantly higher than that of the low-grade TIL group (P=0.04). Among the ER-negative patients without lymph node metastasis, RFS and cancer-specific survival (CSS) rates of patients with high-grade TILs were significantly higher than the RFS and CSS rates of patients with low-grade TILs (P=0.01). However, among ER-positive patients, RFS was significantly higher in the low-grade TIL group than in the high-grade TIL group (P=0.02). In conclusion, TIL expression correlated with ER status and tumour proliferation. High TIL expression was a poor prognostic marker in ER-positive patients but was a good prognostic marker in ER-negative patients. Therefore, the biological association between TILs and primary breast tumours may differ between ER-positive and ER-negative breast cancer.

DOI： 10.3892/ol.2019.9938

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Predictive utility of tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancer patients receiving neoadjuvant chemotherapy (NAC) with concurrent trastuzumab remains unclear. We examined TILs grades of pretreatment cancer tissue specimens and residual tumors after NAC with trastuzumab and determined the predictive utility of the TILs grade in pathological complete response (pCR) and the prognostic power of TILs in HER2-positive breast cancer. This cohort study included 128 HER2-positive breast cancer who received NAC with trastuzumab. TILs grading of the tumor stroma in pretreatment biopsy specimens and residual tumors after NAC with trastuzumab was categorized as low, intermediate, and high based on the criteria of the International Working Group. In current study, the pCR rate was 64.8%, and the Relapse-free survival (RFS) was significantly worse in the non-pCR group than in the pCR group. The pCR rate correlated with the TILs grade in pretreatment tumors. In 45 non-pCR patients, TILs grade was higher in the residual tumors than in the pretreatment tumors. The RFS was significantly better in residual tumors with high TILs grade than those with low TILs grade (p = 0.033). In conclusion, assessment of the TILs grade in residual tumors after NAC with trastuzumab might be necessary to determine patients with good prognosis among those who do not achieve pCR.

DOI： 10.1038/s41598-018-38272-1

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Nipple sparing mastectomy (NSM) for breast cancer preserves the nipple-areola complex (NAC) and has limited the extent of the scar, giving good cosmetic results. However, NAC malposition may occur. The aim of this study is to evaluate NAC malposition after NSM and to determine factors associated with malposition in two-stage reconstruction. METHODS: The subjects were 46 patients who underwent unilateral NSM, without contralateral mastopexy or reduction surgery, in two-stage reconstruction using an expander with implant or flap replacement. Vertical and horizontal NAC malposition and predictors of malposition were evaluated before and more than 1 year after reconstruction surgery. RESULTS: The total amount of saline injected into the expander and aging were significant predictors of increased superior malposition of NAC before and more than 1 year after reconstruction or implant surgery. In contrast, the amount of saline injected into the expander until 2 weeks after expander insertion was a significant predictor of decreased superior NAC malposition. BMI was also a statistically significant predictor of decreased superior NAC malposition, but this result was likely to have been due to the measurement method. Autologous reconstruction was a significant negative predictor of superior malposition at more than 1 year after surgery. Superior NAC malposition resulting from full expansion of the expander improved by a mean vertical angle of 4.5° after autologous reconstruction, but hardly improved after implant use. In autologous reconstruction, NAC tended to move slightly to the lateral side after autologous reconstruction, compared to implant use. CONCLUSIONS: Until 2 weeks after expander insertion, as much saline as possible should be injected to prevent superior NAC malposition. At full expansion, superior malposition of vertical angle > 4.5° may require repositioning surgery.

DOI： 10.1007/s12282-018-0890-4

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In this study, we investigated the relationships of pathological response after neoadjuvant chemo-endocrine therapy with alterations in the Ki67 labeling index (LI), expression of cyclin D1 (CCND1) and progesterone receptor (PgR), and estrogen receptor (ER) activity in breast cancer. A total of 43 Japanese post-menopausal ER-positive and human epidermal growth factor receptor 2-negative invasive breast cancer patients with tumors >2 cm or positive lymph nodes were enrolled. Exemestane alone was administered for 2 months. Neoadjuvant chemo-endocrine therapy included four cycles of doxorubicin plus paclitaxel followed by weekly paclitaxel. The immunohistochemical expression of Ki67 LI, CCND1, and PgR, and ER activity were evaluated using core needle biopsy samples at the pretreatment and post-exemestane alone stages. ER activity was evaluated through transfection of an adenovirus vector carrying an estrogen-response element-green fluorescent protein gene. In current study, marked pathological responses (including 4.7% with pathological complete response) were obtained in 34.9% of patients. Ki67 LI and PgR expression were significantly decreased after treatment. High Ki67 LI at pretreatment was a significant predictive factor of marked pathological response. At the stage of post-exemestane alone, Ki67 LI was not significantly associated with pathological response; however, high CCND1 expression was significantly correlated with high Ki67 LI. Moreover, low-level ER activity at the post-exemestane alone stage was significantly associated with marked pathological response. In conclusions, pretreatment Ki67 LI was a predictor of response to neoadjuvant chemo-endocrine therapy. CCND1 expression and ER activity at the post-endocrine therapy alone stage may be useful in determining further treatments.

DOI： 10.1371/journal.pone.0217279

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Triple-negative breast cancer (TNBC) is an aggressive type of cancer associated with a poor prognosis. Identification of novel therapeutic targets in TNBC is urgently needed. Here, we investigated the microRNA (miRNA) expression signature of TNBC using clinical specimens. In total, 104 miRNAs (56 upregulated and 48 downregulated) were significantly dysregulated in TNBC tissues; miR-204-5p showed the most dramatic downregulation. We then examined the antitumor roles of miR-204-5p in breast cancer (BC) cells. Notably, cancer cell migration and invasion were significantly reduced by ectopic expression of miR-204-5p in BC cells. Genome-wide gene expression analysis and in silico database search revealed that 32 genes were putative miR-204-5p targets. High expression of AP1S3, RACGAP1, ELOVL6, and LRRC59 was significantly associated with poor prognosis in patients with BC, and adaptor-related protein complex 1 sigma 3 subunit (AP1S3) was directly regulated by miR-204-5p, as demonstrated by luciferase reporter assays. AP1S3 overexpression was detected in TNBC clinical specimens and enhanced cancer cell aggressiveness. We further analyzed downstream RNA networks regulated by AP1S3 in BC cells. Overall, this miRNA signature is expected to be an effective tool for identification of miRNA-mediated molecular mechanisms of TNBC pathogenesis.

DOI： 10.1038/s10038-018-0510-3

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BACKGROUND: Ras association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and, therefore, may play a key role in carcinogenesis and metastasis. We, herein, investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts. METHODS: The clinicopathological and prognostic significance of RAPH1 was assessed at the genomic and transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039) and the results were validated using the Molecular taxonomy of breast cancer international consortium (METABRIC) cohort (n = 1980). RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n = 1040). RESULTS: In both the TCGA and METABRIC cohorts, RAPH1 mRNA expression and RAPH1 copy number alteration were strongly correlated. RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. RAPH1 mRNA overexpression was a significant predictor of a poor prognosis (Hazard ratio 3.88; p = 0.049). High RAPH1 protein expression was associated with higher grade tumours with high proliferation index, triple negative phenotype and high E-cadherin expression. High RAPH1 protein expression was an independent predictor of shorter survival (Hazard ratio 4.37; p = 0.037). CONCLUSIONS: High RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.

DOI： 10.1007/s10549-018-4891-y

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BACKGROUND: 18F-Fluorodeoxyglucose-positron-emission tomography (FDG-PET) is used to evaluate the glucose metabolic rates of tumors. Several studies have reported that high FDG uptake is predictive of poor prognosis and aggressive features in patients with breast cancer. FDG uptake is influenced by many factors, including inflammation. In this study, the relationship between FDG uptake and neutrophil/lymphocyte ratio (NLR), which is an indicator of systemic inflammation, was investigated. PATIENTS AND METHODS: A retrospective investigation of the cases of 143 consecutive patients with invasive ductal carcinoma who had undergone surgery and FDG-PET preoperatively. PET was evaluated using standardized uptake value max (SUVmax). The median SUVmax was 2.5 (range=0-10.5). The cases were divided into two groups based on the value of SUVmax: low (<2.5) and high (≥2.5). The relationships between SUVmax and clinicopathological features, including NLR, were investigated. RESULTS: Among the 143 patients, 73 (51.0%) had high SUVmax in the primary tumor. The analysis revealed that large tumor size (p<0.001), high nuclear grade (p<0.001), the presence of lymphovascular invasion (p<0.001), high C-reactive protein (p=0.046) and high NLR (p<0.001) were significantly associated with high SUVmax in the primary tumor. SUVmax and NLR were significantly positively correlated (r=0.323, p<0.001). Among the 70 cases with low SUVmax, there was no recurrent disease, while out of the 73 cases with high SUVmax had disease recurrence. It is interesting to note that the group with high SUVmax and low NLR had no recurrent disease. CONCLUSION: The present study demonstrated that the finding of high preoperative FDG uptake in breast cancer may be reflective of poor prognosis and that a high NLR may be predictive of aggressive features among patients with breast cancer. On the other hand, among patients with breast cancer with high SUVmax in the primary tumor, it will be useful to identify those with a low NLR in order to improve prognostic accuracy.

DOI： 10.21873/anticanres.12809

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PURPOSE: To evaluate the biological effects of proton beams as part of daily clinical routine, fast and accurate calculation of dose-averaged linear energy transfer (LETd ) is required. In this study, we have developed the analytical LETd calculation method based on the pencil-beam algorithm (PBA) considering the off-axis enhancement by secondary protons. This algorithm (PBA-dLET) was then validated using Monte Carlo simulation (MCS) results. METHODS: In PBA-dLET, LET values were assigned separately for each individual dose kernel based on the PBA. For the dose kernel, we employed a triple Gaussian model which consists of the primary component (protons that undergo the multiple Coulomb scattering) and the halo component (protons that undergo inelastic, nonelastic and elastic nuclear reaction); the primary and halo components were represented by a single Gaussian and the sum of two Gaussian distributions, respectively. Although the previous analytical approaches assumed a constant LETd value for the lateral distribution of a pencil beam, the actual LETd increases away from the beam axis, because there are more scattered and therefore lower energy protons with higher stopping powers. To reflect this LETd behavior, we have assumed that the LETs of primary and halo components can take different values (LETp and LEThalo ), which vary only along the depth direction. The values of dual-LET kernels were determined such that the PBA-dLET reproduced the MCS-generated LETd distribution in both small and large fields. These values were generated at intervals of 1 mm in depth for 96 energies from 70.2 to 220 MeV and collected in the look-up table. Finally, we compared the LETd distributions and mean LETd (LETd,mean ) values of targets and organs at risk between PBA-dLET and MCS. Both homogeneous phantom and patient geometries (prostate, liver, and lung cases) were used to validate the present method. RESULTS: In the homogeneous phantom, the LETd profiles obtained by the dual-LET kernels agree well with the MCS results except for the low-dose region in the lateral penumbra, where the actual dose was below 10% of the maximum dose. In the patient geometry, the LETd profiles calculated with the developed method reproduces MCS with the similar accuracy as in the homogeneous phantom. The maximum differences in LETd,mean for each structure between the PBA-dLET and the MCS were 0.06 keV/μm in homogeneous phantoms and 0.08 keV/μm in patient geometries under all tested conditions, respectively. CONCLUSIONS: We confirmed that the dual-LET-kernel model well reproduced the MCS, not only in the homogeneous phantom but also in complex patient geometries. The accuracy of the LETd was largely improved from the single-LET-kernel model, especially at the lateral penumbra. The model is expected to be useful, especially for proper recognition of the risk of side effects when the target is next to critical organs.

DOI： 10.1002/mp.12991

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Language：Japanese   Publisher：(一社)日本病理学会  

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The preoperative endocrine prognostic index (PEPI) predicts survival after neoadjuvant endocrine therapy (NAE) using aromatase inhibitors (AIs) for women with postmenopausal estrogen receptor (ER)-positive breast cancer irrespective of the human epidermal growth factor receptor 2 (HER2) status. Although the progesterone receptor (PgR) is also a prognostic factor for ER-positive breast cancer, the PgR status was not considered a prognostic factor in the original PEPI scoring system. In this study, we investigated the utility of a modified PEPI including the PgR status (PEPI-P) as a prognostic factor after NAE for postmenopausal patients with ER-positive and HER2-negative breast cancer. We enrolled 107 patients with invasive ER-positive and HER2-negative breast cancer treated with exemestane for ≥4 months as NAE. We initially assessed PEPI and compared survival between the groups. Additionally, we obtained an effective cutoff for PgR through survival analysis. Then, we assessed the survival significance of PEPI-P. A PgR staining rate of 50% was the most significant cutoff for predicting recurrence-free survival (RFS) and cancer-specific survival (CSS). PEPI was a significant prognostic factor; moreover, PEPI-P was the most significant prognostic indicator for RFS and CSS. PEPI-P is a potent prognostic indicator of survival after NAE using AIs for postmenopausal patients with ER-positive and HER2-negative breast cancer. This modified PEPI may be useful for therapeutic decision-making regarding postmenopausal ER-positive and HER2-negative breast cancer after NAE.

DOI： 10.1371/journal.pone.0201846

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In a surgical operation requiring endoscopy, it is essential to obtain a clear endoscopic view. However, it is often disturbed by the contamination on the lens during the surgery. No device can clean the lens surface simply and completely. Many surgeons are hampered by the impaired view and the distraction by the repeated cleaning of the lens. Therefore, we developed a novel endoscope cleaning device to address this problem. The device was made of 3D-printed rubber-like plastic. It contains a syringe filled with saline and an aspiration system. It would be used intraoperatively to wash the lens surface in a few seconds with rapid flow of water and air. The cleaning ability of the device was evaluated using mayonnaise with adenosine triphosphate (ATP) as a model contaminant. The gauze-wiping maneuver was selected as control. After each maneuver, the clarity of the endoscopic view was evaluated, and residual contaminants were assessed quantitatively with ATP assay. The cleaning device obtained a crisp and clear view and eliminated the contaminant on the lens every time after a single cleaning maneuver. The gauze-wiping maneuver required for the lens to be wiped at least three times to obtain a clear view, and even then, some contaminants remained. Repeated contamination and cleaning using gauze led to accumulation of contaminants on the lens, which resulted in difficulty in cleaning the lens as the operation proceeded. The cleaning device did not show such accumulation. Our novel cleaning device with air and water flow has been shown to wash out the lens contaminants completely and immediately in a simple manner. It is expected to improve the safety and cost-effectiveness of endoscopic surgery.

DOI： 10.1371/journal.pone.0200749

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DOI： 10.3892/mco.2017.1304

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DOI： 10.1093/jrr/rrx020

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DOI： 10.1016/j.ijrobp.2016.09.027

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DOI： 10.5348/ijcri-2017102-CR-10841

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DOI： 10.2116/analsci.33.395

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DOI： 10.3892/mco.2016.958

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DOI： 10.5348/ijcri-201656-CR-10644

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DOI： 10.5348/ijcri-201505-CR-10466

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DOI： 10.1128/AEM.00084-12

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DOI： 10.1093/pcp/pcq195

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DOI： 10.1161/ATVBAHA.109.201111

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DOI： 10.1152/ajpheart.00015.2009

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DOI： 10.1007/s00595-008-3938-9

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DOI： 10.1152/ajpheart.01006.2005

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DOI： 10.1161/01.RES.0000197842.38758.45

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DOI： 10.1128/AEM.71.2.741-745.2005

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DOI： 10.1007/bf02967581

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：北関東医学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：Springer New York LLC  

DOI： 10.1007/s10549-018-4777-z

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：(株)メジカルビュー社  

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English   Publisher：International Institute of Anticancer Research  

DOI： 10.21873/anticanres.12301

Scopus

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Language：English  

DOI： 10.3892/ol.2017.6768

Web of Science

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Language：English   Publishing type：Book review, literature introduction, etc.  

DOI： 10.1007/s00795-017-0170-y

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：北関東医学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(NPO)日本乳癌検診学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：English  

DOI： 10.21873/anticanres.11921

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Language：Japanese   Publisher：(株)医学書院  

DOI： 10.11477/mf.1407211728

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2017359359

Language：Japanese   Publisher：(一社)日本乳癌学会  

J-GLOBAL

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：乳癌基礎研究会  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Language：Japanese   Publisher：北関東医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J03107&link_issn=&doc_id=20161202460058&doc_link_id=http%3A%2F%2Fhdl.handle.net%2F10087%2F10670&url=http%3A%2F%2Fhdl.handle.net%2F10087%2F10670&type=%8CQ%94n%8C%A7%92n%88%E6%8B%A4%93%AF%83%8A%83%7C%83W%83g%83%8A_AKAGI&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80146_3.gif

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English  

DOI： 10.21873/anticanres.11129

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：English  

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：English  

DOI： 10.1007/s12282-015-0622-y

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Language：English  

DOI： 10.1002/jso.24255

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Language：Japanese   Publisher：(一社)日本消化器外科学会  

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Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1118/1.4956326

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Language：English   Publishing type：Research paper, summary (international conference)  

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：English  

DOI： 10.1111/cas.12872

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Language：English  

DOI： 10.1002/jso.24114

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DOI： 10.9738/INTSURG-D-14-00281.1

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DOI： 10.1007/s11626-015-9944-5

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DOI： 10.9738/INTSURG-D-14-00280.1

Web of Science

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Language：English  

Web of Science

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Language：Japanese   Publisher：日本臨床外科学会  

DOI： 10.3919/jjsa.76.809

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：English   Publisher：日本癌学会  

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Language：Japanese   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：北関東医学会  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2016004919

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Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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Web of Science

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Language：Japanese   Publisher：日本外科系連合学会  

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Web of Science

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DOI： 10.5754/hge12423

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DOI： 10.5754/hge13238

Web of Science

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Language：Japanese   Publisher：(一社)日本外科学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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DOI： 10.5754/hge12320

Web of Science

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Language：English  

DOI： 10.1093/carcin/bgu242

Web of Science

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Language：Japanese   Publisher：北関東医学会  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2015308005

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

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DOI： 10.1245/s10434-014-3941-x

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DOI： 10.3892/mco.2015.538

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BACKGROUND/AIMS: Reduced port laparoscopic surgery has recently emerged as a method to improve the cosmetic results of conventional laparoscopic surgery. We reported our technique of reduced port laparoscopic colectomy using 3-port and short-time outcomes. METHODOLOGY: Between 2005 and 2012, we performed 161 reduced port laparoscopic colectomies using the 3-port technique. Data analyzed in-cluded age, gender, body mass index (BMI), duration of surgery, number of harvested lymph nodes, and duration of hospital stay. RESULTS: All of the cases were successfully performed using the 3-port procedure. The median durations of surgery and postoperative hospital stay were 140 mm (range 75-463 mm) and 9 days (range 5-38 days), respectively. No mortality was associated with this technique. CONCLUSION: Reduced port laparoscopic colectomy is feasible and may have advantages over conventional laparoscopic colectomy.

PubMed

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Language：Japanese   Publisher：日本臨床外科学会  

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DOI： 10.1186/1477-7819-12-309

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Language：Japanese   Publisher：日本臨床外科学会  

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Language：Japanese   Publisher：(一社)日本内視鏡外科学会  

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Language：Japanese   Publisher：日本内分泌外科学会・日本甲状腺外科学会  

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BACKGROUND: Hepatic resection of metastatic colorectal cancer (CRC) has become the treatment of choice for patients after resection of the primary CRC. However, some patients do not benefit from immediate resection because of rapidly progressive disease. The aim of this study was to examine the prognostic value of extracapsular invasion (ECI) of lymph node (LN) metastasis of CRC with liver metastases following liver resection. METHODS: All patients who underwent resection for CRC with liver metastases between 1995 and 2011 were reviewed. All of those with metastasis from primary CRC were included in this study. Preoperative, intraoperative, and postoperative data, including primary tumor pathology results, were retrospectively reviewed. All resected LNs from primary CRC were re-examined to assess ECI. Associations between clinicopathologic factors, survival, and the nodal findings were evaluated. RESULTS: ECI was identified in 47 (48%) patients. ECI was correlated with the number of positive LNs (p = 0.0022), timing of liver metastasis (p = 0.0238), and number of liver metastases (p = 0.0001). Univariate analysis indicated that the number of positive LNs (p = 0.0014), ECI (p = 0.0203), and adjuvant chemotherapy (p = 0.0423) were significant prognostic factors. Patients with ECI had a significantly worse survival (p = 0.0024) after liver resection than patients with LN-negative and ECI-negative groups. CONCLUSIONS: In patients with hepatic CRC metastases, ECI in regional LNs reflects a particularly aggressive behavior, such as a greater number of liver metastases. In CRC patients with liver metastases, ECI in regional LNs might be correlated with poor prognosis following liver resection.

DOI： 10.1007/s00268-014-2488-0

PubMed

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Language：Japanese   Publisher：北関東医学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2014&ichushi_jid=J03107&link_issn=&doc_id=20140822320082&doc_link_id=%2Fde3kitak%2F2014%2Fs06403%2F081%2F0288-0288%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fde3kitak%2F2014%2Fs06403%2F081%2F0288-0288%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本乳癌学会  

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Language：Japanese   Publisher：(一社)日本消化器外科学会