Publications by authors named "Noriaki Ohuchi"

231 Publications

TP53 signature diagnostic system using multiplex reverse transcription-polymerase chain reaction system enables prediction of prognosis of breast cancer patients.

Breast Cancer 2021 Jul 24. Epub 2021 Jul 24.

Department of Medical Oncology, Tohoku University Hospital, 1-1, Seiryomachi, Aoba-ku, 4-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.

Background: TP53 status based on TP53 signature, a gene expression profile to determine the presence or absence of TP53 mutation, is an independent prognostic factor of breast cancer. The purpose of this study was to develop a simple diagnostic system for TP53 signature status.

Methods: We developed a multiplex reverse transcription-polymerase chain reaction system to determine TP53 status. Based on this system, prospectively collected 189 patients with stage I and II breast cancer were determined to have TP53 mutant signature or TP53 wild-type signature. The prognostic significance of the TP53 signature by the diagnostic system was analyzed.

Results: The diagnostic accuracy of TP53 status and reproducibility of this diagnosis system was confirmed. Using the diagnostic system, 89 patients were classified as TP53 mutant signature and the remaining 100 cases were classified as TP53 wild-type signature. Recurrence-free survival (RFS) among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature. On univariate and multivariate analyses, the TP53 signature status was an independent predictor of RFS. RFS among patients with TP53 mutant signature was significantly shorter than that among those with TP53 wild-type signature in a cohort of estrogen receptor-positive breast cancer. Although a difference was not significant, no recurrent cases was observed in TP53 wild-type signature group in triple negative breast cancer.

Conclusion: This simple and precise diagnostic system to determine TP53 signature status may help in prognostic assessment, therapeutic decision-making, and treatment optimization in patients with breast cancer.
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http://dx.doi.org/10.1007/s12282-021-01250-zDOI Listing
July 2021

Application of Large Electronic Medical Database for Detecting Undiagnosed Patients in the General Population.

Tohoku J Exp Med 2019 10;249(2):113-119

Department of Surgery, Tohoku University Graduate School of Medicine.

Clinical application of accumulated medical big data is a hot topic in medical informatics. Not only for suggesting possible diagnoses in each individual, large medical database can be possibly used for detecting undiagnosed patients in the general population. In this study, we tried to develop a computerized system of detecting overlooked undiagnosed patients with rare chronic diseases in the community population by utilizing the uniformed national medical insurance record database. A cumulative total of 489,823 hospital visits at one tertiary medical center were collected for this project. As the target disease, we selected esophagogastric junction outflow obstruction (EGJOO), including achalasia, which is known to be easily overlooked without performing a barium swallow test. Patient selection software automatically picked out 17,814 individuals with the given suspected diagnoses that could be misdiagnosed in patients with the target disease, from which the software further picked out 526 individuals who underwent upper endoscopy but did not undergo barium swallow test. Of them, the hospital medical records suggested that 39 people still suffered from prolonged symptoms lasting for more than 6 months after the first hospital visit. Among them, 16 individuals agreed to undergo the barium swallow test. One of them was confirmed to suffer from EGJOO, possibly based on some undiagnosed connective tissue diseases. An automated computerized detection system with uniform big medical data would realize more efficient and less expensive screening system for undiagnosed chronic diseases in the general population based on symptoms and previously performed examinations in each individual.
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http://dx.doi.org/10.1620/tjem.249.113DOI Listing
October 2019

The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer.

Oncotarget 2019 Aug 6;10(47):4907-4918. Epub 2019 Aug 6.

Department of Molecular and Functional Dynamics, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Although cyclin-dependent kinase (CDK) 4/6 inhibitors have exhibited remarkable results for patients with estrogen receptor (ER)-positive breast cancer in clinical trials, the mechanism of CDK4/6 inhibitor resistance remains unclear. Thus, this study aimed to investigate the mechanism of CDK4/6 inhibitor resistance using two CDK4/6 inhibitor resistant breast cancer cell lines. We established CDK6 overexpressed cell lines (MCF7-C6) from MCF-7 cells using the stably transfected CDK6 expression vector. Additionally, acquired ribociclib-resistant (RIBR) cell lines were created using ER-positive hormone-resistant cell lines by long-term exposure to ribociclib. CDK6 overexpression and the knockdown of CDK4 experiments highlight the significance of high levels of CDK4 and low levels of CDK6 in CDK4/6 inhibitor sensitivity. Moreover, RIBR cell lines did not exhibit incremental CDK6 compared with ER-positive hormone-resistant cell lines. In MCF7-C6 and RIBR cell lines, p21 levels decreased, and p21 levels were proportional to CDK4/6 inhibitor sensitivity. This study suggests that overexpression of CDK6 is one of the many possible mechanisms of resistance to CDK4/6 inhibitors. Furthermore, p21 levels have the potential to serve as a marker for CDK4/6 inhibitors independent of the resistance mechanism.
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http://dx.doi.org/10.18632/oncotarget.27127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690670PMC
August 2019

Preoperative change of modified Glasgow prognostic score after stenting predicts the long-term outcomes of obstructive colorectal cancer.

Surg Today 2020 Mar 12;50(3):232-239. Epub 2019 Aug 12.

Department of Gastroenterological Surgery, Sendai City Medical Center Sendai Open Hospital, 5-22-1 Tsurugaya, Miyagino-ku, Sendai, 983-0824, Japan.

Purpose: Inflammation-based markers predict the long-term outcomes of various malignancies. We investigated the relationship between the modified Glasgow prognostic score (mGPS) and the long-term outcomes of obstructive colorectal cancer in patients who underwent self-expandable metallic colonic stent placement and subsequently received curative surgery.

Methods: We retrospectively analyzed 63 consecutive patients with pathological stage II and III obstructive colorectal cancer from 2013 to 2018. The mGPS was calculated before stenting and surgery, and the difference of the scores was defined as the d-mGPS.

Results: All d-mGPS = 2 patients were > 70 years of age (p = 0.01). Postoperative complications were more common in the preoperative mGPS = 2 group (p = 0.02). The postoperative hospital stay was significantly longer in the mGPS = 2 group (p = 0.007). Multivariate analyses revealed that d-mGPS was an independent prognostic factor for overall survival (OS) (hazard ratio [HR] = 9.18, p = 0.004) and cancer-specific survival (HR = 9.98, p = 0.01). Preoperative mGPS = 2 was significantly associated with poor OS (HR = 5.53, p = 0.04).

Conclusion: The results indicated that mGPS might serve as a valuable indicator of the immunonutritional status of preoperative patients, and a preoperative change of the status might affect the long-term outcomes of patients with obstructive colorectal cancer.
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http://dx.doi.org/10.1007/s00595-019-01862-1DOI Listing
March 2020

Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR/HER2 Breast Cancer.

Cancers (Basel) 2019 Apr 12;11(4). Epub 2019 Apr 12.

Department of Medical Physics, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8574, Japan.

In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ERα by IHC-PIDs in vitro, we developed "the nearest-neighbor method" to calculate the extranuclear ERα. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ERα, nuclear ERα, extranuclear ERα PIDs score, and ratio of extranuclear-to-nuclear ERα (ENR) were measured using the novel method. We demonstrate that quantification of ERα using IHC-PIDs exhibited strong correlations to real-time qRT-PCR ( = 0.94) and flow cytometry ( = 0.98). High ERα ENR was significantly associated with poor overall survival ( = 0.048) and disease-free survival (DFS) ( = 0.007). Multivariate analysis revealed that the ERα ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4-11.8; = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ERα. A high ERα ENR in HR/HER2 BC indicates decreased likelihood of benefiting from ET.
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http://dx.doi.org/10.3390/cancers11040526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520781PMC
April 2019

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

Do you know how to get the J-START quality assurance guideline?

Breast Cancer 2018 Jul 9;25(4):375-376. Epub 2018 May 9.

Japan Association of Breast Cancer Screening, Tokyo, Japan.

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http://dx.doi.org/10.1007/s12282-018-0867-3DOI Listing
July 2018

Newly-Developed Positron Emission Mammography (PEM) Device for the Detection of Small Breast Cancer.

Tohoku J Exp Med 2018 05;245(1):13-19

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

Positron emission mammography (PEM) has higher detection sensitivity for breast cancer compared with whole-body positron emission tomography (PET) due to higher spatial resolution. We have developed a new PEM device with high resolution over a wide field of view. This PEM device comprises novel scintillation crystals, praseodymium-doped lutetium aluminum garnet (Pr:LuAG). In the present study, the clinical use of the newly developed PEM for the detection of small breast cancer was compared with that of the conventional PET-computed tomography (PET/CT). Eighty-two patients with breast cancer less than 20 mm (UICC T1) participated in this study, including 23 patients with T1a or T1b breast cancer (less than 10 mm). Histologically-proved lesions were examined by PET/CT and PEM on the same day after injection of [F]fluoro-2-deoxy-2-fluoro-D-glucose ([F]FDG), a marker of glycolytic activity. The newly developed PEM showed better sensitivity of cancer detection compared with PET/CT especially in case of the small T1a or T1b lesions. Moreover, when the conventional PET/CT and new PEM were combined, the detection sensitivity with [F]FDG molecular imaging for T1 (N = 82) and T1a plus T1b breast cancer (N = 23) were 90% and 70%, respectively. The uptake of [F]FDG was proportional to the histological malignancy of breast cancer. Using the newly-developed PEM with [F]FDG, we are able to identify and characterize exactly the small breast tumors less than 10 mm in combination with the conventional PET/CT. These data indicate that PEM and PET/CT are synergic and complementary for the detection of small breast cancer.
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http://dx.doi.org/10.1620/tjem.245.13DOI Listing
May 2018

Increased centrosome number in BRCA-related breast cancer specimens determined by immunofluorescence analysis.

Cancer Sci 2018 Jun 15;109(6):2027-2035. Epub 2018 May 15.

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

BRCA-related breast carcinoma can be prevented through prophylactic surgery and an intensive follow-up regimen. However, BRCA genetic tests cannot be routinely performed, and some BRCA mutations could not be defined as deleterious mutations or normal variants. Therefore, an easy functional assay of BRCA will be useful to evaluate BRCA status. As it has been reported that BRCA functions in the regulation of centrosome number, we focused on centrosome number in cancer tissues. Here, 70 breast cancer specimens with known BRCA status were analyzed using immunofluorescence of γ-tubulin (a marker of centrosome) foci. The number of foci per cell was higher in cases with BRCA mutation compared to wild-type cases, that is, 1.9 (95% confidence interval [CI], 1.5-2.3) vs 0.5 (95% CI, 0.2-0.8) (P < .001). Specifically, foci numbers per cell in BRCA1 and BRCA2 mutation cases were 1.2 (95% CI, 0.6-1.8) and 2.2 (95% CI, 1.7-2.6), respectively, both higher than those in wild-type cases (P = .042 and P < .0001, respectively). The predictive value of γ-tubulin foci as determined by area under the curve (AUC = 0.86) for BRCA status was superior to BRCAPRO (AUC = 0.69), Myriad Table (AUC = 0.61), and KOHBRA BRCA risk calculator (AUC = 0.65) pretest values. The use of γ-tubulin foci to predict BRCA status had sensitivity = 83% (19/23), specificity = 89% (42/47), and positive predictive value = 77% (20/26). Thus, γ-tubulin immunofluorescence, a functional assessment of BRCA, can be used as a new prospective test of BRCA status.
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http://dx.doi.org/10.1111/cas.13595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989840PMC
June 2018

Molecular and clinical features of the signature gene expression profile in early-stage breast cancer.

Oncotarget 2018 Mar 8;9(18):14193-14206. Epub 2018 Feb 8.

Department of Clinical Oncology, Juntendo University Graduated School, Tokyo 113-8421, Japan.

Purpose: signature has a robust predictive performance for prognosis in early-stage breast cancer, but the experiment that reported this relied on public microarray data and fresh-frozen samples. Before signature can be used in a clinical setting, a simple and low-cost diagnostic system using formalin-fixed paraffin-embedded (FFPE) samples is needed. New treatments based on the biological characteristics of signature are expected to follow.

Experimental Design: signature was evaluated in 174 FFPE early breast cancer specimens using digital quantification via the nCounter technique (NanoString). Patients were classified as signature mutant type ( = 64) or wild type ( = 110). Predictive power of signature was compared with those of other gene expression signatures in 153 fresh-frozen samples of the same cohort by RNA-seq. The molecular features of signature were elucidated using TCGA omics data and RNA-seq data to explore new therapeutic strategies for patients with signature mutant type.

Results: signature was a strong predictor of prognosis and was also more accurate than other gene expression signatures and independent of other clinicopathological factors. TCGA data analysis showed that risk score of signature was an index of chromosomal and genomic instability and that signature mutant type was associated with higher PD-L1 expression, variation in copy numbers, and numbers of somatic mutations.

Conclusions: TP53 signature as diagnosed using the nCounter system is not only a robust predictor of prognosis but also a potential predictor of responsiveness to immune checkpoint inhibitors.
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http://dx.doi.org/10.18632/oncotarget.24447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865663PMC
March 2018

Effect of the normal mammary differentiation regulator ELF5 upon clinical outcomes of triple negative breast cancers patients.

Breast Cancer 2018 Jul 2;25(4):489-496. Epub 2018 Feb 2.

Department of Anatomical Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.

Background: Elf5 is a transcription factor previously shown to be involved in regulating cell differentiation in both normal and pathological breast tissues. Pertinently, Elf5 was reported to interact with the FOXA1 transcription factor, a pivotal regulatory factor in a subset of AR overexpressing triple negative cancer (TNBC) cases.

Methods: We examined the correlation among AR, FOXA1, and Elf5 expression in a series of TNBC cases. The cases were retrieved from surgical pathological files of Tohoku University Hospital Japan and consisted of 60 cases operated between the year 1999 and 2007. An additional cohort cases of 51 TNBC ductal carcinoma in situ was used to compare invasive and non-invasive TNBC.

Results: In our cohort, 47% of all carcinomas were positive for Elf5, with a significantly higher proportion of Elf5 positive cases occurring in the younger age groups (p = 0.0061). Elf5 immunoreactivity was not associated with any other clinicopathological factors examined in this study. However, Elf5 expression was associated with decreased overall and disease-free survival of the patients (Peto-Peto modification of Gehan-Wilcoxon test, OS p = 0.132, DFS p = 0.1 (LI cutoff 10%); OS p = 0.038, DFS p = 0.021 (LI cutoff 50%)). Of particular interest, its effects on survival were more pronounced in the EGFR-/CK5/6- (non-basal surrogate) than the EGFR+ and/or CK5/6+ (basal-surrogate) subtype of TNBC.

Conclusions: Elf5 is present in TNBC and its status was significantly correlated with overall survival of the patients. Further studies examining possible interactions between Elf5 and other factors in TNBC could contribute to disentangling TNBC biology.
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http://dx.doi.org/10.1007/s12282-018-0842-zDOI Listing
July 2018

Alcohol Consumption and Breast Cancer Risk According to Hormone Receptor Status in Japanese Women: A Case-Control Study.

Tohoku J Exp Med 2018 01;244(1):63-73

Division of Community Health, Tohoku University Graduate School of Medicine.

Alcohol consumption is a risk factor for breast cancer in Western countries, but few studies have evaluated the risk for Japanese women, who have a relatively low alcohol intake. This case-control study investigated the association of alcohol consumption with breast cancer risk according to estrogen-receptor and progesterone-receptor (ER/PgR) status in Japanese women. From female patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2011, 1,256 breast cancer cases (669 ER+/PgR+, 162 ER+/PgR-, 21 ER-/PgR+, 305 ER-/PgR-, and 99 missing) and 2,933 controls were selected. Alcohol-related measures were assessed using a self-administered questionnaire. Unconditional logistic regression analysis was performed. Alcohol-related measures were not associated with breast cancer risk among the women overall. Moreover, no association was observed between ever drinking and the risk of a concordant receptor subtype (ER+/PgR+ or ER-/PgR-). Conversely, ever drinking was inversely associated with the risk of discordant subtype (ER+/PgR-, odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.41-0.95; ER-/PgR+, OR = 0.44, 95% CI: 0.14-1.42). For ER+/PgR-, an inverse association with the amount of alcohol consumed per day was observed (P for trend = 0.04), and this inverse association was limited to premenopausal women. Alcohol consumption may have differential effects on concordant and discordant receptor subtypes of breast cancer. In view of the low frequency of discordant subtype in Japanese women and their relatively low alcohol intake, our findings may provide a clue for elucidating the etiology of breast cancer rather than for preventing discordant subtype.
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http://dx.doi.org/10.1620/tjem.244.63DOI Listing
January 2018

The Optimization of the Prevascularization Procedures for Improving Subcutaneous Islet Engraftment.

Transplantation 2018 03;102(3):387-395

Division of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Sendai, Japan.

Background: Subcutaneous islet transplantation is associated with minimal invasiveness, but poor vascularization. Thus, the optimization of the prevascularization procedures is crucial for improving the outcomes. Although the effectiveness of basic fibroblast growth factor (bFGF) was reported, the optimal procedures remain unclear. We sought to optimize the prevascularization procedures including the use of a novel scaffold, recombinant peptide (RCP).

Methods: Devices containing various amount of bFGF with/without heparin or RCP were implanted into the subcutaneous space of diabetic C57BL/6 mice. Syngeneic islets were transplanted into the prevascularized space. Blood glucose, intraperitoneal glucose tolerance, and immunohistochemistry were evaluated.

Results: The cure rates in all the device groups irrespective of bFGF doses were considerably higher than in the nondevice group. The cure rate in the bFGF0 group was unexpectedly higher than that in the subcutaneous islet transplant alone group (the None group) (57.1% vs 28.6%). Glucose tolerance was ameliorated in the bFGF10(-), 10(+) and 15(-) groups. The number of von Willebrand factor-positive vessels in the bFGF10(+) group was significantly higher than that in the None and bFGF0 groups (P < 0.01). Taken together, the bFGF10(+) group was considered to have received optimized procedures. In a marginal graft model, the efficiency in the RCP group was better than that in the bFGF10(+) group, furthermore, comparable to that in the intraportal transplantation group. Unlike bFGF, no bleeding and effusion were observed in the RCP group.

Conclusions: These results suggest that optimizing biomaterials to induce efficient prevascularization could be a novel strategy for improving subcutaneous islet transplantation.
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http://dx.doi.org/10.1097/TP.0000000000001970DOI Listing
March 2018

Effects of cytokines derived from cancer-associated fibroblasts on androgen synthetic enzymes in estrogen receptor-negative breast carcinoma.

Breast Cancer Res Treat 2017 Dec 22;166(3):709-723. Epub 2017 Aug 22.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-Ku, Sendai-shi, Miyagi, 980-8575, Japan.

Purpose: The tumor microenvironment plays pivotal roles in promotion of many malignancies. Cancer-associated fibroblasts (CAFs) have been well-known to promote proliferation, angiogenesis, and metastasis but mechanistic understanding of tumor-stroma interactions is not yet complete. Recently, estrogen synthetic enzymes were reported to be upregulated by co-culture with stromal cells in ER positive breast carcinoma (BC) but effects of co-culture on androgen metabolism have not been extensively examined. Therefore, we evaluated roles of CAFs on androgen metabolism in ER-negative AR-positive BC through co-culture with CAFs.

Methods: Concentrations of steroid hormone in supernatant of co-culture of MDA-MB-453 and primary CAFs were measured using GC-MS. Cytokines derived from CAFs were determined using Cytokine Array. Expressions of androgen synthetic enzymes were confirmed using RT-PCR and Western blotting. Correlations between CAFs and androgen synthetic enzymes were analyzed using triple-negative BC (TNBC) patient tissues by immunohistochemistry.

Results: CAFs were demonstrated to increase expressions and activities of 17βHSD2, 17βHSD5, and 5α-Reductase1. IL-6 and HGF that were selected as potential paracrine mediators using cytokine array induced 17βHSD2, 17βHSD5, and 5α-Reductase1 expression. Underlying mechanisms of IL-6 paracrine regulation of 17βHSD2 and 17βHSD5 could be partially dependent on phosphorylated STAT3, while phosphorylated ERK could be involved in HGF-mediated 5α-Reductase1 induction. α-SMA status was also demonstrated to be significantly correlated with 17βHSD2 and 17βHSD5 status in TNBC tissues, especially AR-positive cases.

Conclusions: Results of our present study suggest that both IL-6 and HGF derived from CAFs could contribute to the intratumoral androgen metabolism in ER-negative BC patients.
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http://dx.doi.org/10.1007/s10549-017-4464-5DOI Listing
December 2017

Quantitative diagnostic imaging of cancer tissues by using phosphor-integrated dots with ultra-high brightness.

Sci Rep 2017 08 8;7(1):7509. Epub 2017 Aug 8.

Department of Nano-Medical Science, Graduate School of Medicine, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.

The quantitative sensitivity and dynamic range of conventional immunohistochemistry (IHC) with 3,3'-diaminobenzidine (IHC-DAB) used in pathological diagnosis in hospitals are poor, because enzyme activity can affect the IHC-DAB chromogenic reaction. Although fluorescent IHC can effectively increase the quantitative sensitivity of conventional IHC, tissue autofluorescence interferes with the sensitivity. Here, we created new fluorescent nanoparticles called phosphor-integrated dots (PIDs). PIDs have 100-fold greater brightness and a more than 300-fold greater dynamic range than those of commercially available fluorescent nanoparticles, quantum dots, whose fluorescence intensity is comparable to tissue autofluorescence. Additionally, a newly developed image-processing method enabled the calculation of the PID particle number in the obtained image. To quantify the sensitivity of IHC using PIDs (IHC-PIDs), the IHC-PIDs method was compared with fluorescence-activated cell sorting (FACS), a method well suited for evaluating total protein amount, and the two values exhibited strong correlation (R = 0.94). We next applied IHC-PIDs to categorize the response to molecular target-based drug therapy in breast cancer patients. The results suggested that the PID particle number estimated by IHC-PIDs of breast cancer tissues obtained from biopsy before chemotherapy can provide a score for predicting the therapeutic effect of the human epidermal growth factor receptor 2-targeted drug trastuzumab.
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http://dx.doi.org/10.1038/s41598-017-06534-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548777PMC
August 2017

The Optimization of Short-Term Hepatocyte Preservation Before Transplantation.

Transplant Direct 2017 Jul 19;3(7):e176. Epub 2017 Jun 19.

Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: No optimal methods for short-term hepatocyte preservation have been established. We have recently developed a prominent oxygen-permeable bag (Tohoku Device [TD]) for pancreatic islet culture and transplantation. In this study, we investigated whether TD is also effective for hepatocyte preservation and tried to optimize other conditions.

Methods: Hepatocytes were preserved in the following conditions, and their outcomes were observed. First, the effectiveness of TD was investigated. Second, hepatocyte medium (HM) and organ preservation solutions with or without fetal bovine serum (FBS) were compared. Third, as supplementations, FBS and human serum albumin (HSA) were compared. Fourth, low, room and high temperature were compared. And finally, hepatocytes preserved in various conditions were transplanted into the subrenal capsule space of nonalbumin rats and engrafted areas were assessed.

Results: The survival rate of hepatocytes preserved in TD tended to be higher and their viability and function were maintained significantly greater than those of non-TD group. Irrespective of FBS supplementation, the survival rate of HM group was significantly higher than those of organ preservation solution group while viabilities and plating efficiency were similar among them. Although survival rates of groups without FBS were extremely low, results of HSA supplemented group were not inferior to FBS supplemented group. Hepatocytes preserved at high temperature had the worst results. The engrafted area of TD group tended to be higher than those of other groups.

Conclusions: TD is effective for short-term hepatocyte preservation. HSA is a useful substitute for FBS, and preserving in HM at low temperature is recommended.
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http://dx.doi.org/10.1097/TXD.0000000000000687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498017PMC
July 2017

Oral Steroid Use and Abdominal Aortic Aneurysm Expansion - Positive Association.

Circ J 2017 Nov 30;81(12):1774-1782. Epub 2017 Jun 30.

Department of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital.

Background: The maximum axial diameter (MAD) of a fusiform abdominal aortic aneurysm (AAA) is an indicator of the risk of expansion or rupture. Apart from smoking and MAD itself, few expansion risk factors have been reported. In this study, we investigated expansion risk factors for AAA.Methods and Results:This retrospective cohort study included 176 patients who attended Tohoku University Hospital with infrarenal fusiform AAA. AAA expansion rate was determined on multidetector computed tomography, and the correlations between expansion rate and the clinical data were analyzed. The median expansion rate was 2.405 mm/year. On univariate analysis, a significant positive correlation with expansion rate was observed for the initial MAD (P<0.001) and significant negative correlations for oral angiotensin receptor blocker usage (P=0.025), height (P=0.005), body weight (P=0.017), total cholesterol (P=0.007), low-density lipoprotein cholesterol (P=0.004), and HbA1c (P=0.037). On logistic regression analysis, significant positive associations with expansion rate were observed for initial MAD (P<0.001) and oral steroid usage (P=0.029) and a negative association for height (P=0.041).

Conclusions: Oral steroid usage is an important risk factor for AAA expansion, independent of other risk factors of atherosclerosis and MAD.
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http://dx.doi.org/10.1253/circj.CJ-16-0902DOI Listing
November 2017

Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment.

Breast Cancer Res 2017 06 19;19(1):70. Epub 2017 Jun 19.

Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.

Background: Breast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma-adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of cancer-associated adipocytes differ from those of normal ASCs. Therefore, we investigated an interaction between ASCs and carcinoma cell lines to identify genes associated with ASC invasion of carcinoma cells.

Methods: 3T3-L1 ASC-derived conditioned medium (CM) was treated to measure the proliferation rate of breast cancer cells. To further examine the effect of ASCs, breast cancer cells were cocultivated with either primary human or 3T3-L1 ASCs for migration assays, DNA microarrays, quantitative real-time polymerase chain reactions, and Western blotting experiments. Furthermore, immunoreactivity of S100A7, the most upregulated gene in MCF7, after coculture with ASCs was evaluated for 150 breast cancer tissues to statistically analyze its association with clinicopathological parameters.

Results: We first confirmed that ASC-derived CM treatment enhanced the cell proliferation rate of MCF7, T47D, SK-BR-3, and ZR-75-1 cell lines, whereas the migration rate of breast cancer cells was promoted by coculture with ASCs. We identified that a small calcium-binding protein, S100A7, was markedly upregulated (by 5.8-fold) in MCF7 cells after coculture with primary human ASCs. Knockdown of S100A7 significantly suppressed ASC-stimulated cell proliferation and migration rate, indicating a possible involvement of S100A7 in the carcinoma-ASC interaction in breast tumors. Furthermore, strong S100A7 immunoreactivity was detected at the invasive front of adipose stromal tissues compared with that at the intratumoral area. The status of S100A7 was also significantly correlated with adverse pathological parameters, and multivariate analysis revealed that S100A7 could be an independent prognostic marker for a poor relapse-free survival rate. Moreover, induction of oncostatin M was detected in cancer-stimulated ASCs, whereas the downstream S100A7 binding proteins/receptor for advanced glycation endproducts were significantly upregulated in correspondence with S100A7 expression in breast cancer cells after coculture with ASCs.

Conclusions: The results of our study suggest that paracrine production of cytokines from ASCs stimulates breast carcinoma cell growth via upregulation of S100A7 expression in breast cancer cell lines.
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http://dx.doi.org/10.1186/s13058-017-0863-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477117PMC
June 2017

Minimal impact of postmastectomy radiation therapy on locoregional recurrence for breast cancer patients with 1 to 3 positive lymph nodes in the modern treatment era.

Surg Oncol 2017 Jun 16;26(2):163-170. Epub 2017 Mar 16.

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

Introduction: Given modern treatment strategies, controversy remains regarding whether postmastectomy radiation therapy (PMRT) is necessary for breast cancer patients with 1-3 positive axillary lymph nodes (ALN). Our aim was to assess the significance of PMRT in the modern treatment era for these patients.

Material And Methods: We have conducted the retrospective multicenter study and identified 658 patients with 1-3 positive ALN who were treated with mastectomy and ALN dissection between 1999 and 2012. Propensity score weighting was used to minimize the influence of confounding factors between the PMRT and no-PMRT groups. The variables including tumor size, lymph nodes status, skin and/or muscle invasion, histological grade, lymphovascular invasion and ER positivity which were statistically unbalanced between the groups were used to define the propensity scores.

Results: The median follow-up time was 7.3 years. In the modern era (2006-2012), no significant difference in locoregional recurrence (LRR)-free survival was noted between the PMRT and no-PMRT groups (P = 0.3625). The 8-year LRR-free survival rates of the PMRT and no-PMRT groups were 98.2% and 95.3%, respectively. After matching patients by propensity scores, the PMRT group, compared to the no-PMRT group, exhibited significantly better locoregional control (P = 0.0366) in the entire cohort. The 10-year LRR-free survival rates were 97.8% and 88.4% in the PMRT and no-PMRT groups, respectively. In contrast, no significant difference in LRR-free survival was noted between the PMRT and no-PMRT groups in the modern era (P = 0.5298). The 8-year LRR-free survival rates of patients treated in the modern era were approximately the same between the groups (98.0% and 95.7% in the PMRT and no-PMRT groups, respectively). Particularly, LRR-free survival of HER2 positive breast cancer significantly improved in the modern treatment era, compared with that of the old treatment era (P = 0.0349).

Conclusion: PMRT had minimal impact on LRR for breast cancer patients with 1-3 positive ALN in the modern treatment era.
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http://dx.doi.org/10.1016/j.suronc.2017.03.003DOI Listing
June 2017

Arterial and biliary complications after living donor liver transplantation: a single-center retrospective study and literature review.

Surg Today 2018 Feb 24;48(2):131-139. Epub 2017 Apr 24.

Division of Transplantation, Reconstruction, and Endoscopic Surgery, Department of Surgery, Upper Digestive and Vascular Surgery, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Aim: The mortality of patients on the waiting list for deceased donor liver transplantation (DDLT) is high, especially in countries where donation rates are low. Thus, living donor liver transplantation (LDLT) is an attractive option. However, compared with DDLT, LDLT is associated with increased rates of arterial and biliary complications. We examined the rates of complications and risk factors following LDLT.

Methods: We retrospectively investigated and compared the rates of complications of DDLT and LDLT in our institute. We also performed univariate and multivariate analyses to identify the independent risk factors for these complications. The complications and specific disadvantages of LDLT were reviewed and discussed.

Results: The incidence rate of arterial complications in LDLT was 6.0%, compared with 3.2% (13/441) in DDLT. A multivariate analysis identified low body weight (P = 0.032) as the only independent risk factor for hepatic artery thrombosis. The rate of all biliary complications in LDLT was 17.3%, compared with 18.7% in DDLT. The risk factors for biliary stricture identified by the multivariate analysis were recurrent cholangitis and the number of bile ducts. The durations of hospital stay and overall survival rates were similar between the two groups.

Conclusion: Given the shortage of deceased donor organs, we believe that LDLT is acceptable in an attempt to meet demand.
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http://dx.doi.org/10.1007/s00595-017-1515-9DOI Listing
February 2018

Hassab's operation for Joubert syndrome with congenital hepatic fibrosis: A case report.

Int J Surg Case Rep 2017 28;34:134-138. Epub 2017 Mar 28.

Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Introduction: Joubert syndrome is characterized by psychomotor developmental delay, hypotonia, oculomotor abnormalities, occasional retinal dystrophy and cystic kidneys, and frequent and often, striking breathing abnormalities, especially in the neonatal period, with panting tachypnea followed by apnea. We report a case of Joubert syndrome with hepatic fibrosis, portal hypertension, and pancytopenia treated by Hassab's operation.

Presentation Of Case: Our patient was a 27-year-old woman with a history of tachypnea, muscle hypotonia, and psychomotor retardation shortly after birth and a diagnosis of Joubert syndrome at 2 years of age. At 19 years of age, she was diagnosed with progressive pancytopenia. At 27 years of age, she visited her local doctor for sudden-onset hematemesis. Endoscopy revealed esophageal varices exhibiting the red color sign and no evidence of recent bleeding. Splenomegaly and development of portal collateral circulation were observed on computed tomography scans. The patient was referred to our hospital, where she was diagnosed with Joubert syndrome and hepatic fibrosis, portal hypertension, and hypersplenism. After performing Hassab's operation, the pancytopenia improved, but anticoagulant therapy was required for splenic vein thrombosis. The patient was discharged on postoperative day 25. Two years following surgery, the gastroesophageal varices were controlled, and no progression of the splenic vein thrombosis or hepatic failure was evident.

Conclusion: This is the first case report of Hassab's operation for congenital hepatic fibrosis in a patient with Joubert syndrome, a rare congenital condition. We achieved a favorable clinical outcome.
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http://dx.doi.org/10.1016/j.ijscr.2017.03.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389103PMC
March 2017

Successful corticosteroid treatment for pleural effusion due to radiation-induced pleuritis after chemoradiotherapy in a patient with esophageal cancer.

Int Cancer Conf J 2017 Jul 11;6(3):138-143. Epub 2017 Apr 11.

1Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Concurrent chemoradiotherapy (CRT) is one of the therapies with curative intent used to treat esophageal squamous cell carcinoma (ESCC), and overall survival of patients with esophageal carcinoma treated with CRT has improved. As the number of long-term survivors treated with concurrent CRT has increased, more patients experience late toxicities. A delayed adverse event, such as pleural effusion, is sometimes fatal, but little is known about its treatment. A 72-year-old man diagnosed with ESCC was treated with definitive CRT. He had a complete response to CRT, and 4 years later he complained of dyspnea, caused by pleural effusion. Diuretic agents and drainage of pleural effusion were not sufficiently effective in this case. After oral administration of 30 mg prednisolone, re-accumulation of fluid in the pleural space was controlled and the prednisolone dose was gradually tapered. Corticosteroids could be effective treatment for delayed pleural effusion after radiotherapy, and should be considered an option for treatment-refractory pleural effusion.
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http://dx.doi.org/10.1007/s13691-017-0293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498221PMC
July 2017

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

Bilateral approach for thoracoscopic esophagectomy with lymph node dissection in the dorsal area of the thoracic aorta in patients with esophageal cancer: A report of two cases.

Int J Surg Case Rep 2017 19;31:154-158. Epub 2017 Jan 19.

Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan.

Introduction: The incidence of lymph node metastasis in the dorsal area of the thoracic aorta (DTA) is relatively low in patients with esophageal cancer. It is difficult to approach the DTA using surgical procedures, such as an open thoracotomy and thoracoscopy in the left decubitus position.

Case Presentation: Case 1: A 70-year-old man with esophageal cancer underwent thoracoscopic esophagectomy with mediastinal lymph node dissection via a right thoracoscopic approach, followed by lymphadenectomy in the DTA via left thoracoscopy in the prone position. Microscopic findings revealed two metastatic lymph nodes in the DTA. The definitive diagnosis was squamous cell carcinoma of the esophagus, and the pathological stage was T2N3M0 (Union for International Cancer Control [UICC], 7th edition). The patient showed lung metastasis 8 months after the surgery. Case 2: A 72-year-old man with esophageal cancer underwent esophagectomy via a bilateral approach in the prone position, using a similar procedure as in case 1. The definitive diagnosis was squamous cell carcinoma of the esophagus, and the pathological stage was T3N2M0. The patient showed a metastatic mediastinal lymph node 4 months after the surgery.

Conclusion: Bilateral thoracoscopic esophagectomy in the prone position can be safely performed, and it might be an alternative curative surgery for esophageal cancer. However, both our cases showed metastasis in the early postoperative period. The long-term outcome and significance of dissection of lymph nodes in the DTA in patients with esophageal cancer remains controversial. Further studies are required to establish the indications and efficacy of this therapeutic approach.
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http://dx.doi.org/10.1016/j.ijscr.2017.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293718PMC
January 2017

Thoracoscopic esophageal repair with barbed suture material in a case of Boerhaave's syndrome.

J Thorac Dis 2016 Dec;8(12):E1576-E1580

Division of Advanced Surgical Science and Technology, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

A 53-year-old man was referred to our hospital with Boerhaave's syndrome. Thirty hours after onset, a left thoracoscopic operation was performed, with carbon dioxide pneumothorax and the patient in right semi-prone position. The thoracic cavity was copiously irrigated with physiological saline and a 4-cm longitudinal rupture was identified on the left side of the lower esophagus. The esophageal injury was repaired in 2 layers by using barbed absorbable suture material. The patient was allowed oral feeds after contrast esophagography confirmed the absence of contrast leak at the sutured site on postoperative day 7, and discharged by day 28. Suturing of the ruptured esophagus under thoracoscopic guidance is considered to be difficult and requires expertise. This case report demonstrates that the use of a barbed suture material simplifies thoracoscopic esophageal repair and also highlights the importance of pneumothorax and patient position in improving access to the esophagus.
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http://dx.doi.org/10.21037/jtd.2016.12.46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227234PMC
December 2016

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Mod Pathol 2017 05 20;30(5):660-671. Epub 2017 Jan 20.

Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.
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http://dx.doi.org/10.1038/modpathol.2016.222DOI Listing
May 2017

Thoracoscopic surgery in the prone position for esophageal cancer in patients with situs inversus totalis: A report of two cases.

Int J Surg Case Rep 2017 6;31:43-46. Epub 2017 Jan 6.

Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.

Introduction: Situs inversus totalis (SIT) is a rare congenital condition characterized by a complete transposition of thoracic and abdominal organs. Here, we present two successful cases of left thoracoscopic esophagectomy in the prone position for SIT-associated esophageal cancer.

Presentation Of Case: Our first case was of an 82-year-old man who underwent a left thoracoscopic esophagectomy in the prone position, followed by hand-assisted laparoscopic gastric mobilization. Surgical duration and blood loss were 661min and 165g, respectively. His postoperative course was uneventful. The second case was of a 66-year-old man who underwent a left thoracoscopic esophagectomy in the prone position, followed by gastric mobilization via laparotomy owing to a concomitant intestinal malrotation and polysplenia. Surgical duration and blood loss were 637min and 220g, respectively. We trained for the surgical procedures preoperatively using left-inverted and right-inverted thoracoscopic surgical videos of patients with normal anatomy.

Discussion: Surgical procedures in SIT patients are challenging owing to their mirrored anatomy. Recognition of their variations is thus important to avoid intraoperative accidental injuries. Left-inverted and right-inverted thoracoscopic surgical videos of patients with normal anatomy were found to be useful for image training prior to the actual surgery.

Conclusion: Thoracoscopic surgical treatment for esophageal cancer associated with SIT in the prone position can be performed safely, similar to the manner performed for thoracoscopic surgery in the right decubitus position, or surgery via an open thoracotomy. Gastric mobilization via laparotomy should be considered in patients associated other anatomic variations.
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http://dx.doi.org/10.1016/j.ijscr.2017.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241577PMC
January 2017

A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells.

JCI Insight 2017 01 12;2(1):e86492. Epub 2017 Jan 12.

Department of Reproductive Biology, Centre for Regenerative Medicine, National Research Institute for Child Health and Development, Tokyo, Japan.

Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions. The stem cell-derived gut organoids produced here were found to contain distinct types of intestinal cells, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, that were derived from all 3 germ layers; moreover, they demonstrated intestinal functions, including peptide absorption, and showed innervated bowel movements in response to stimulation with histamine and anticholinergic drugs. Importantly, the gut organoids obtained using this xenogeneic-free system could be stably maintained in culture for prolonged periods and were successfully engrafted in vivo. Our xenogeneic-free approach for generating gut organoids from hPSCs provides a platform for studying human intestinal diseases and for pharmacological testing.
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http://dx.doi.org/10.1172/jci.insight.86492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214546PMC
January 2017

Associations of obesity and physical activity with serum and intratumoral sex steroid hormone levels among postmenopausal women with breast cancer: analysis of paired serum and tumor tissue samples.

Breast Cancer Res Treat 2017 02 2;162(1):115-125. Epub 2017 Jan 2.

Division of Community Health, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Purpose: It has been hypothesized that intratumoral estrogens may play important roles in the growth of breast cancer. However, few studies have investigated such intratumoral hormones, or their association with risk factors of breast cancer.

Methods: In this cross-sectional study, hormone levels in paired serum and tumor tissue samples from 146 postmenopausal women with breast cancer were measured by liquid chromatography-tandem mass spectrometry and compared between estrogen/progesterone (ER/PgR) subtypes. The associations of risk factors including body mass index (BMI) and other lifestyle factors with these hormone levels were investigated using analysis of covariance.

Results: The level of estradiol (E2) in tumor tissue was extremely high in women with ER+ (geometric mean 95.6 pg/g) relative to women with ER-/PgR- (8.9 pg/g), whereas serum E2 level did not differ much between the two groups (3.1 and 2.8 pg/ml, respectively). Serum levels of precursors for E2, including testosterone (T) and androstenedione (Adione), and tissue Adione level, were high among women with ER+. After adjustment for confounding variables, BMI was found to be positively associated with tissue levels of E2, estrone (E1), T, and Adione among women with ER+ (P  < 0.0001 for E2; 0.0016 for E1; 0.0002 for T; and 0.03 for Adione).

Conclusion: The data suggest that tissue E2 is related to the growth of receptor-positive breast cancer and that risk factors such as BMI affect tissue levels of E2 and its precursors. Understanding of hormonal environments within tumor tissue may be important for elucidating hormonal etiology of breast cancer and improving the prognosis of patients.
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http://dx.doi.org/10.1007/s10549-016-4094-3DOI Listing
February 2017

Aryl hydrocarbon receptor induced intratumoral aromatase in breast cancer.

Breast Cancer Res Treat 2017 02 30;161(3):399-407. Epub 2016 Nov 30.

Department of Pathology, Tohoku University School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Purpose: Aryl hydrocarbon receptor (AhR) inhibits estrogen receptor (ER) pathway, which may suppress estrogen-dependent cell proliferation. However, the correlation between AhR stimulation and intratumoral estrogen synthesis, especially through aromatase, has not been reported to date. In the present study, we examined this correlation in breast cancer cells.

Methods: We examined AhR and aromatase immunoreactivity in 29 patients with invasive ductal carcinoma. We performed in vitro studies using three breast carcinoma cell lines, MCF-7, T47D, and MDA-MB-231.

Results: AhR stimulation induced the mRNA expression of the aromatase gene in vitro in three breast carcinoma cell lines, and increased estrogen synthesis in MCF-7 cell line. Results of microarray analysis showed that AhR-induced aromatase expression was associated with BRCA1 induction. Analysis of patients with breast cancer showed a significant positive correlation between intratumoral AhR and aromatase status. We also compared the effects of AhR stimulation on the induction of intratumoral estrogen synthesis and inhibition of the ER signaling pathway, because AhR exerts contradictory effects on estrogen action in breast carcinoma cells. AhR-induced aromatase expression persisted for a significantly longer duration than AhR-induced ER pathway inhibition. Moreover, breast carcinoma cells treated with an AhR agonist tended to show earlier cell proliferation after removing the agonist than cells not treated with the AhR agonist.

Conclusion: The results of the present study suggest that AhR stimulates estrogen-dependent progression of breast carcinoma by inducing aromatase expression under some conditions. These results provide new insights on the possible roles of environmental toxins in breast cancer development.
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http://dx.doi.org/10.1007/s10549-016-4063-xDOI Listing
February 2017
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