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The current study proposed and evaluated "residual squeeze and excitation attention gate" (rSEAG), a novel network that can improve image quality by reducing distortion attributed to artifacts. This method was established by modifying the Cycle Generative Adversarial Network (cycleGAN)-based generator network using projection data for pre-reconstruction processing in digital breast tomosynthesis. Residual squeeze and excitation were installed in the bridge of the generator network, and the attention gate was installed in the skip connection between the encoder and decoder. Based on the radiation dose index (exposure index and division index) incident on the detector, the cases approved by the ethics committee and used for the study were classified as reference (675 projection images) and object (675 projection images). For the cases, unsupervised data containing a mixture of cases with and without masses were used. The cases were trained using cycleGAN with rSEAG and the conventional networks (ResUNet and U-Net). For testing, predictive processing was performed on cases (60 projection images) that were not used for learning. Images were generated using filtered backprojection reconstruction (kernel: Ramachandran and Lakshminarayanan) from projection data for testing data and without pre-reconstruction processing data (evaluation: in-focus plane). The distortion was evaluated using perception-based image quality evaluation (PIQE) analysis, texture analysis (feature: "Homogeneity" and "Contrast"), and a statistical model with a Gumbel distribution. PIQE has a low rSEAG value. Texture analysis showed that rSEAG and a network without cycleGAN were similar in terms of the "Contrast" feature. In dense breasts, ResUNet had the lowest "Contrast" feature and U-Net had differences between cases. The maximal variations in the Gumbel plot, rSEAG reduced the high-frequency ripple artifacts. In this study, rSEAG could improve distortion and reduce ripple artifacts.

In some cases of human epidermal growth factor 2 (HER2)-negative breast cancer, including triple-negative breast cancer, HER2 expression is sporadically and strongly upregulated, a condition known as HER2 heterogeneity. We investigated the clinicopathological features of patients with HER2 heterogeneity in triple-negative breast cancers treated with neoadjuvant chemotherapy. Thirty-nine patients with triple-negative breast cancer who had undergone preoperative chemotherapy participated in this study. To assess for HER2 heterogeneity, we used dual in situ hybridization slides. We evaluated the association between HER2 heterogeneity and clinicopathological factors such as rates of pathologic complete response (pCR) and of recurrence-free survival. Of the 39 patients, 15 (38.5%) had cancers with HER2 heterogeneity. The pCR rates were 13.3% among patients with HER2 heterogeneity and 20.8% among those with HER2 nonheterogeneity, but the difference was not significant. The recurrence-free survival rate was significantly lower in patients with HER2 heterogeneity than in those without (P = 0.025). HER2 heterogeneity is a significant predictor of poor prognosis in patients with triple-negative breast cancer treated with neoadjuvant chemotherapy., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: NK105 is a paclitaxel (PTX)-incorporating "core-shell-type" polymeric micellar nanoparticle formulation composed of block copolymers (polyethylene glycol and a polyamino acid). The efficacy and safety of NK105 and paclitaxel in advanced or recurrent breast cancer have never been compared at equivalent dose levels., Patients and Methods: Patients were randomly assigned to either NK105 or PTX in a 1:1 ratio. The study drug was administered on Day 1, 8, and 15 of a 28-day cycle with 80 mg/m 2 . The primary endpoint was overall response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events., Results: A total of 123 patients (NK105, n=62; PTX, n=61) received one of the two drugs. There was no significant difference in ORR, the median PFS, or OS (NK105 group: 41.9%, 9.1, and 27.5 months, respectively; PTX group: 45.9%, 7.8, and 32.4 months, respectively). Neutropenia occurred more frequently in the NK105 group, but most patients did not require granulocyte-colony stimulating factor or dose-reduction. The median time to onset of peripheral sensory neuropathy (PSN) in the NK105 group was significantly longer than that in the PTX group (p=0.001), and PSN (≥ grade 3) was not observed in the NK105 group., Conclusion: Weekly NK105 administration was well-tolerated. Efficacy was similar in both groups. The PSN profile was better in the NK105 group., Competing Interests: Y.K. reports having received honoraria from Chugai, AstraZeneca, Eisai, Pfizer, Kyowa Kirin, Novartis, Taiho, and Nippon Kayaku; and financial support from Nippon Kayaku for attending meetings. T.S. reports having received grants from Eisai, Kyowa Kirin, Taiho, Chugai, Nippon Kayaku, AstraZeneca, NRG Oncology Japan, Sawai, JBCRG, Daiichi Sankyo, Novartis, and West Japan Oncology Group; honoraria from Aska, AstraZeneca, Eisai, Ono, Taiho, Takeda, Chugai, Eli Lilly, Nippon Kayaku, Novartis, Pfizer, MiRTeL, and Meiji; and financial support from Nippon Kayaku for attending meetings. T.T. reports having received grants from Chugai, Daiichi Sankyo, Ono, MSD, and Eisai, and honoraria from Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Celltrion Healthcare. T.A. reports having received honoraria and support for attending meetings from Pfizer, Chugai, AstraZeneca, Eli Lilly, Eisai, Daiichi Sankyo, MSD, Taiho, Celltrion, Nihon Medi-Physics, Kirin, Konica Minolta REALM, and Nippon Kayaku. T.Y. reports having received grants from Chugai, Taiho, Kyowa Kirin, and Nippon Kayaku; honoraria from Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Novartis Pharma, Taiho, AstraZeneca, Pfizer Japan, and Nippon Kayaku; and support for attending meetings from Nippon Kayaku. N.M. reports having received grants from AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Sanofi, Chugai, Eisai, Kyowa Kirin, Novartis, Pfizer, and Nippon Kayaku; honoraria from AstraZeneca, Chugai, Eisai, Eli Lilly, Pfizer, and Nippon Kayaku; and board memberships from the Japanese Breast Cancer Society and the Japan Breast Cancer Research Group Association. Y.K. reports having received honoraria and support for attending meetings from Nippon Kayaku. A. O. reports having received grants from AstraZeneca, Eisai, Kyowa Kirin, Taiho, Chugai, Nippon Kayaku, Covance Japan, Maruho, Bayer, Sanofi, Eli Lilly, MSD, Takeda, Sawai, Daiichi Sankyo, Pfizer, and West Japan Oncology Group; honoraria from AstraZeneca, Eisai, Daiichi Sankyo, Chugai, Nippon Kayaku, Pfizer, Shionogi, and Eli Lilly; and financial support from Nippon Kayaku for attending meetings. J.W. reports having received grants and honoraria from AstraZeneca, Eisai, MSD, Gilead, Daiichi Sankyo, and Eli Lilly; honoraria from Chugai, Pfizer, Taiho, Novartis, Takeda, and Nippon Kayaku; and support for attending meetings from Nippon Kayaku. R.S. is an employee of Nippon Kayaku Co. Ltd. The authors report no other conflicts of interest in this work., (© 2022 Kosaka et al.)

In this study, we evaluated the improvement of image quality in digital breast tomosynthesis under low-radiation dose conditions of pre-reconstruction processing using conditional generative adversarial networks [cGAN (pix2pix)]. Pix2pix pre-reconstruction processing with filtered back projection (FBP) was compared with and without multiscale bilateral filtering (MSBF) during pre-reconstruction processing. Noise reduction and preserve contrast rates were compared using full width at half-maximum (FWHM), contrast-to-noise ratio (CNR), peak signal-to-noise ratio (PSNR), and structural similarity (SSIM) in the in-focus plane using a BR3D phantom at various radiation doses [reference-dose (automatic exposure control reference dose: AECrd), 50% and 75% reduction of AECrd] and phantom thicknesses (40 mm, 50 mm, and 60 mm). The overall performance of pix2pix pre-reconstruction processing was effective in terms of FWHM, PSNR, and SSIM. At ~50% radiation-dose reduction, FWHM yielded good results independently of the microcalcification size used in the BR3D phantom, and good noise reduction and preserved contrast. PSNR results showed that pix2pix pre-reconstruction processing represented the minimum in the error with reference FBP images at an approximately 50% reduction in radiation-dose. SSIM analysis indicated that pix2pix pre-reconstruction processing yielded superior similarity when compared with and without MSBF pre-reconstruction processing at ~50% radiation-dose reduction, with features most similar to the reference FBP images. Thus, pix2pix pre-reconstruction processing is promising for reducing noise with preserve contrast and radiation-dose reduction in clinical practice.

Background/aim: This phase II trial evaluated the efficacy and safety of neoadjuvant nab-paclitaxel plus cyclophosphamide (CPA) plus trastuzumab (AbraC-HER) in patients with early HER2-positive breast cancer., Patients and Methods: This was a single-arm, open-label, single-center prospective phase II study. The primary endpoint was pathological complete response rate (pCR rate). The secondary endpoints were clinical antitumor efficacy and the frequency and severity of adverse events., Results: Fifty-nine patients were enrolled in this study. pCR (ypT0/is ypN0) was achieved in 29 patients (49%). The overall response rate was 88.1% (52/59) in all patients. Dose reductions because of adverse events occurred in 3 patients (5.1%) and relative dose intensity was 98%. Compared to Abra-HER, AbraC-HER induced fewer adverse effects., Conclusion: Treatment with nab-paclitaxel plus CPA plus trastuzumab was tolerable and effective with a high pCR rate. This AbraC-HER neoadjuvant therapy may be a feasible new treatment option for patients with early HER2-positive breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We evaluated the usefulness of topoisomerases (TOPs) expression as prognostic predictors in breast cancer., Patients and Methods: We retrospectively investigated sixty cases with primary breast cancer. We evaluated the tumor and non-tumor mRNA levels of TOP1 and TOP2α using quantitative reverse-transcription polymerase chain reaction. TOP1/TOP2α positivity was defined as the ratio of the mRNA expression of cancer/normal tissue of >1 for both TOP1 and TOP2α., Results: TOP1 and TOP2α were markedly overexpressed in breast cancer tissues compared to normal breast tissues. Of the 60 cases, 46 (76.7%) were positive for TOP1/TOP2α. The relapse-free survival was relatively shorter for patients with positive TOP1/TOP2α. There was no recurrent disease among the 14 patients who were negative for TOP1/TOP2α, whereas four of the 46 TOP1/TOP2α-positive patients had disease recurrence., Conclusion: Negative TOP1 or TOP2α expression may be useful for predicting better prognoses in breast cancer patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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)., (Copyright: © Nakazawa et al.)

Purpose: We evaluated the efficacies of the adaptive steepest descent projection onto convex sets (ASD-POCS), simultaneous algebraic reconstruction technique (SART), filtered back projection (FBP), and maximum likelihood expectation maximization (MLEM) total variation minimization iterative algorithms for reducing exposure doses during digital breast tomosynthesis for reduced projections., Methods: Reconstructions were evaluated using normal (15 projections) and half (i.e., thinned-out normal) projections (seven projections). The algorithms were assessed by determining the full width at half-maximum (FWHM), and the BR3D Phantom was used to evaluate the contrast-to-noise ratio (CNR) for the in-focus plane. A mean similarity measure of structural similarity (MSSIM) was also used to identify the preservation of contrast in clinical cases., Results: Spatial resolution tended to deteriorate in ASD-POCS algorithm reconstructions involving a reduced number of projections. However, the microcalcification size did not affect the rate of FWHM change. The ASD-POCS algorithm yielded a high CNR independently of the simulated mass lesion size and projection number. The ASD-POCS algorithm yielded a high MSSIM in reconstructions from reduced numbers of projections., Conclusions: The ASD-POCS algorithm can preserve contrast despite a reduced number of projections and could therefore be used to reduce radiation doses.

Aim: Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC., Patients and Methods: We conducted a single-arm, open-label, multicenter prospective phase II study to evaluate the efficacy of an S-1 plus trastuzumab regimen for HER2-positive MBC. S-1 was administered orally [80-120 mg, based on body surface area (BSA)] twice a day for 14 consecutive days in a 3-week cycle. Patients with BSA of <1.25 m 2 received a total of 80 mg of S-1, those with BSA ≥1.5 m 2 received 120 mg, and the remaining received 100 mg daily in two divided doses. Trastuzumab was administered intravenously at 8 mg/kg on day 1 of the first cycle and at 6 mg/kg on day 1 of subsequent cycles, i.e., every 3 weeks., Results: Between December 2008 and March 2013, 10 patients were enrolled and received a median of 17 (range=3-76) cycles of treatment. Overall response and clinical benefit rates were 60.0% and 90.0%, respectively. Progression-free survival was 15.8 (95% confidence interval=9.4-29.6) months and overall survival was 45.5 (95% confidence interval=37.1-62.2) months. Grade 3/4 adverse events included were neutropenia and hyperglycemia in one patient each (10.0%). There was no clinically significant cardiotoxicity., Conclusion: The combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this study. S-1 plus anti-HER2 therapy is a feasible treatment option for HER2-positive MBC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Following the Fukushima Dai-ichi Nuclear Power Station accident, regional road dust, heavily contaminated with radiocesium, now represents a potential source of radiocesium pollution in river water. To promote effective countermeasures for reducing the risk from radiocesium pollution, it is important to understand its sources. This study evaluated the utility of metals, including Al, Fe, and Zn as road dust tracers, and applied them to analyze sources of 137 Cs in rivers around Fukushima during wet weather. Concentrations of Zn in road dust were higher than agricultural and forest soils, whereas concentrations of Fe and Al were the opposite. Concentrations of Zn were weakly but significantly correlated with benzothiazole, a molecular marker of tires, indicating Zn represents an effective tracer of road dust. Al, Fe, and Zn were frequently detected in suspended solids in river water during wet weather. Distribution coefficients of these metals and 137 Cs exceeded 10 4 , suggesting sorptive behavior in water. Although concentrations of Al, Fe, Zn, and 137 Cs were higher in fine fractions of road dust and soils than in coarse fractions, use of ratios of 137 Cs to Al, Fe, or Zn showed smaller differences among size fractions. The results demonstrate that combinations of these metals and 137 Cs are useful for analyzing sources of radiocesium in water. These ratios in river water during wet weather were found to be comparable with or lower than during dry weather and were closer to soils than road dust, suggesting a limited contribution from road dust to radiocesium pollution in river water., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

After the 2011 nuclear accident in Fukushima, radiocesium was released from the Fukushima Dai-ichi Nuclear Power Plant and contaminated waters in urban areas near Tokyo. By intensive field monitoring during 3 years, this study investigated the temporal trends and the occurrence of radiocesium during dry and wet weather, and analyzed the variations in radiocesium during rainfall events and factors controlling them. Concentrations of particulate radiocesium decreased rapidly from May 2012 to March 2013 and reached an equilibrium in 2014. Concentrations of particulate (137)Cs during wet weather were almost double those during dry weather in the same period. In contrast to the small variations in (137)Cs concentrations in the particulate phase on a suspended solids (SS) weight basis during events, those in the dissolved phase on a liquid-volume basis fluctuated greatly, resulting in variations in the partition coefficient (apparent Kd). The apparent Kd of (137)Cs during wet weather ranged from 30,000 to 150,000 L kg(-1) and showed a significant negative correlation with SS concentrations during wet weather. Specific surface area in solids contributed to the variations in apparent Kd., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Context: Mutations of the KCNJ5 gene have recently been identified in patients with aldosterone-producing adenomas (APA)., Objective: Our objective was to investigate the expression and mutations of the KCNJ5 gene in Japanese patients with APA., Design and Patients: We sequenced KCNJ5 cDNA and measured KCNJ5 mRNA levels in 23 patients with APA operated on at Gunma University Hospital., Main Outcome Measures: Mutations and mRNA levels of the KCNJ5 gene were examined and compared to those in cortisol-producing adenomas (Cushing's syndrome) and pheochromocytomas., Results: Of the 23 patients with APA, 15 (65.2%) had two somatic mutations of the KCNJ5 gene: 12 cases of p.G151R (eight with c.451G>A, and four with c.451G>C) and three cases of p.L168R (c.503T>G). Levels of KCNJ5 mRNA were significantly higher in the APA with mutations than those without. Immunohistochemistry also showed a stronger staining of KCNJ5 on the cell membrane in the tumor with a mutation. Furthermore, a PCR-restriction fragment length polymorphism assay with c.503T>G revealed the mutant mRNA to be expressed at a similar level to the wild type. The level of KCNJ5 mRNA in cortisol-producing adenomas was approximately 30% of that in APA, and almost no expression was observed in pheochromocytomas., Conclusion: We found that: 1) a significant number of patients with APA had somatic mutations of the KCNJ5 gene; 2) KCNJ5 mRNA levels were higher in the APA with KCNJ5 mutations; and 3) the expression of KCNJ5 mRNA was significantly higher in APA than cortisol-producing adenomas and pheochromocytomas.

Although implantation of crude bone marrow cells has been applied in a small number of patients for fracture healing, transplantation of peripheral blood CD34(+) cells, the hematopoietic/endothelial progenitor cell-enriched population, in patients with fracture has never been reported. Here, we report the first case of tibial nonunion receiving autologous, granulocyte colony stimulating factor mobilized CD34(+) cells accompanied with autologous bone grafting. No serious adverse event occurred, and the novel therapy performed 9 months after the primary operation resulted in bone union 3 months later without any symptoms including pain and gait disturbance.

Estrogen is a key regulator of the proliferation and differentiation of breast cancer cells. In addition to the estrogen supply from the ovary, estrogen is produced locally from androgen by aromatase. However, the regulation of aromatase gene expression in breast cancer has not yet been fully clarified. Retinoic acid receptor-related orphan receptor (ROR) alpha plays an important role in the differentiation of many organs by regulating the transcription of target genes. Because aromatase and RORalpha are expressed in breast cancer, the effect of RORalpha on aromatase gene expression was studied. RORalpha significantly augmented the expression of aromatase mRNA, particularly those containing exon I.4, in MCF7 cells, and aromatase activities in T47D and MCF7 cells. RORalpha also stimulated the proliferation of these cells. Transient transfection-based reporter gene assays using the promoter at exon I.4 showed that RORalpha augmented the transcription. A series of truncated mutation studies revealed that RORalpha activated the transcription through -147 to +14 bp of the promoter I.4. Furthermore, RORalpha bound to the fragment containing -119 to -107 bp of the promoter in vitro, indicating that this region may contain a novel ROR response element. Chromatin immunoprecipitation assay showed that RORalpha bound to the region containing this site of the promoter I.4 in MCF7 cells. Moreover, we examined clinical samples and found a correlation between RORalpha and aromatase expression. These results suggest that RORalpha directly activates the aromatase expression to accelerate the local production of estrogen, which results in the proliferation of breast cancer cells.

A phase II clinical trial was conducted to examine the clinical and pathologic efficacy and safety of neoadjuvant paclitaxel with or without trastuzumab in women with advanced or metastatic breast cancer. A total of 49 patients with advanced or metastatic breast cancer (clinical stage IIB -IV) were included. Patients with HER2-negative tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break for 4 cycles. Patients with HER2-positive tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break and a trastuzumab 4 mg/kg loading dose, intravenously, followed by 2 mg/kg weekly for 4 cycles. The age of the patients was 51.6 +/- 1.6 years (mean +/- SE) and the size of their tumors was 5.8 +/- 0.4 cm (mean +/- SE). Thirty-two patients had HER2-negative tumors and 17 had HER2-positive tumors. Of 49 patients, 13 (26.5%) had a clinical complete response and 24 (49.0%) had a clinical partial response. Five (10.2%) patients had a pathological complete response (pCR) and three (6.1%) patients had a near pCR in the breast. A total of eight (16.3%) patients had a pCR or near pCR in the breast. The pCR or near pCR rate was 3.1% in the HER2-negative group and 41.2% in the HER2-positive group. With a median follow-up of 28 months (range, 1-45), the 3-year overall survival was 88%. Clinical responders showed a significantly better overall survival than non-responders (p < 0.01). Pathological responders showed a better overall survival than non-responders. There was no significant difference in overall survival between patients with HER2-positive and -negative tumors. In conclusion, combined neoadjuvant weekly paclitaxel and trastuzumab achieved high clinical and pathological response rates for HER2 -overexpressing breast cancers, despite the omission of an anthracycline.

A 54-year-old woman visited our hospital with a palpable tumor in her left breast, which was diagnosed as invasive ductal carcinoma. Breast-conserving surgery was performed, in association with a sentinel lymph node (SLN) biopsy and back-up dissection of the axillary lymph nodes. One dyed axillary lymph node with high radioactivity was defined as an SLN, and intraoperative frozen-section analysis of the SLN was negative for metastasis. The final pathological diagnosis of the tumor was invasive ductal carcinoma, and one small lymph node, located in the retromammary space, just under the tumor, was positive for metastasis. The backup axillary lymph nodes were not metastatic. This patient was diagnosed false-negative by SLN biopsy, despite being positive for retroMLN metastasis. It should be recognized that retroMLNs are difficult to detect preoperatively, or intra-operatively, using dye or radiocolloid, if they are located in the post-tumoral retro-mammary space. RetroMLNs may be a pitfall in SLN biopsies.

A dose-escalation study was conducted for patients with inoperable or recurrent breast cancer in order to determine the recommended dose (RD) of capecitabine combined with a fixed dose of weekly paclitaxel. Capecitabine was administered twice daily from day 1 through day 14 combined with paclitaxel given on days 1 and 8, every 21 days. Dose-limiting toxicities(DLT)were evaluated during the first two cycles. Three patients were recruited at one of two dose levels (capecitabine 1,255 mg/m2 or 1,657 mg/m2, paclitaxel 80 mg/m2). In this study, no DLT was seen in each level, and the RD of capecitabine was determined to be 1,657 mg/m2.

The estrogen receptor (ER) is a key regulator of proliferation and differentiation in breast cancer cells. In the present study, the effect of steroid and xenobiotic receptor (SXR) on 17/beta-estradiol (E2)-induced transcription through ERalpha was studied. SXR augmented ER-mediated transcription in the presence of E2 in MCF-7 breast cancer-derived cells and CV-1 fibroblast-derived cells. On the other hand, SXR alone did not affect the estrogen response element (ERE)-containing promoter activity in CV-1 cells. SXR did not directly bind to ERalpha or ERE in vitro, indicating that SXR may affect ER-mediated transcription by altering cofactor binding to ER. Although SXR did not alter the binding between ERalpha and p300/CBP interacting protein (p/CIP), it decreased the binding of a specific corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT) to liganded ERalpha as assessed by mammalian two-hybrid, glutathione S-transferase pull-down, immunoprecipitation and newly developed Liquid Chemiluminescent DNA Pull-Down Assays. These results indicate that SXR augmented ER-mediated transcription by dissociating SMRT from ERalpha. Thus, the expression of SXR in breast cancer cells may alter the ER signaling, which may play crucial role for growth and differentiation of breast cancer cells.

Tamoxifen has significantly improved mortality of both pre- and postmenopausal women with hormone receptor-positive breast cancer. Recent clinical trials have demonstrated benefits of aromatase inhibitor therapy in adjuvant regimens for postmenopausal women. Tamoxifen is now expected to demonstrate potential benefits for bone health during endocrine treatment such as switching therapy with aromatase inhibitors because aromatase inhibitors are associated with a reduction in bone mineral density. In premenopausal women, although tamoxifen remains the standard of care, combination treatment of tamoxifen and an LH-RH agonist is recommended.

B9L/BCL9-2, a novel beta-catenin-interacting protein, plays an important role in colorectal carcinogenesis by translocating beta-catenin to the nucleus and enhancing beta-catenin-T-cell factor-mediated transcription. To elucidate the role of B9L in breast cancers, we studied B9L expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of the breast immunohistochemically and compared it to the immunohistochemical expression of known proteins involved in breast carcinogenesis. In breast tissues, B9L immunoreactivity was present exclusively in the nuclei of normal and neoplastic ductal cells. In DCIS, immunohistochemical B9L expression was significantly associated with the tumor nuclear grade, comedo necrosis and the expression of ErbB2/HER-2, c-myc and p53. In IDC, B9L expression was correlated with ErbB2/HER-2 expression and tumor nuclear grade only. In both DCIS and IDC, immunohistochemical B9L expression was not related to the expression of cytoplasmic beta-catenin. We demonstrated that nuclear B9L expression was closely associated with the high nuclear grade cancer phenotype and the expression of ErbB2/HER-2 in breast cancers.

Background: Adrenocortical carcinoma (ACC) is a rare tumor usually diagnosed at an advanced stage on invasion of or adherence to adjacent organs. We report surgical outcome of stage III and IV ACCs., Methods: ACCs from seven patients at clinical stage II (n = 1), III (n = 4), or IV (n = 2) were resected. Combined resection of the liver and inferior vena cava was performed in six patients. Morbidity, mortality, recurrence and survival were analyzed., Results: The pathological stage was stage III in five patients and stage IV in two patients. The mortality was zero and the morbidity was two of seven (29%) patients. The estimated 3-year disease-free and overall survivals for stage III were 20% and 40%, respectively, with a median follow-up of 32 months (range, 11-58). The mean disease-free survival was 21.0 +/- 9.0 months (95% CI: 3.3-38.7). The 3-year disease-free and overall survivals for stage III and IV were 14.3% and 28.6%, respectively. The mean disease-free survival time was 18.6 +/- 6.7 months (95% CI: 5.4-31.8). The most frequent site of metastasis was the lungs, seen in four patients, and liver in three patients. Loco-regional, intra-abdominal lymph node, peritoneum, bone, brain recurrences were also seen in one patient each. The mean survival after recurrence was 19.0 +/- 3.3 months (95% CI: 12.6-25.5), and the 50% survival was 18.4 months with mitotan and cytotoxic drug therapy., Conclusions: Resection for stage III, IV ACCs affords the possibility of negative margins, acceptable peri-operative morbidity and mortality, and prolongs survival in selected patients.

Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy, usually diagnosed at an advanced stage when it has invaded or adhered to adjacent organs. We report our experience of performing combined liver and inferior vena cava (IVC) resection for ACC., Methods: Six patients with clinical stage III (n = 4) or IV (n = 2) ACC underwent combined resection of the liver and IVC. Two patients underwent extended right hepatectomy, and four underwent segmentectomy. In four patients, the IVC was resected segmentally: it was replaced with expanded polytetrafluoroethylene (ePTFE) in three of these patients, and not reconstructed in one. In two patients, the IVC was partially resected and closed directly., Results: Perioperative mortality was zero, and morbidity was 33.3%, with temporary liver failure in two patients and renal failure in one patient. Recurrence was found within 8.1 months in three (50%) of the six patients. The mean recurrence-free survival period was 20.1 +/- 7.7 months (95% confidence interval [CI]: 5.1-35.4), and the median survival time was 6.1 +/- 9.8 months (95% CI: 00-25.3). The 5-year disease-free survival rate was 16.7%., Conclusions: Patients with ACC involving both the liver and IVC are candidates for partial hepatectomy and segmental IVC resection. Resection affords the possibility of negative margins, acceptable perioperative morbidity and mortality, and prolonged survival in some patients.

Cytochrome P450 monooxygenase 3A4 (CYP3A4) and P-glycoprotein, encoded by multidrug resistance 1 (MDR1) gene, are responsible for the metabolism of endogenous steroids, prescribed drugs, and xenobiotics. Both genes are regulated by steroid and xenobiotic receptor (SXR), a member of nuclear hormone receptors. Various endogenous steroids and drugs function as ligands of SXR. Although CYP3A4, MDR1, and SXR are expressed mainly in the liver and the small intestine, these gene products are also expressed in breast cancer cells. Because tamoxifen (TAM) is known to be metabolized by CYP3A4 and P-glycoprotein, we investigated the effect of TAM on these SXR-targeted genes in breast cancer cells. Transient transfection-based reporter gene assays showed 4-hydroxy TAM activated the SXR-mediated transcription through CYP3A4 and MDR1 promoters in a ligand- and receptor concentration-dependent manner. We confirmed the binding of 4-hydroxy TAM to SXR by ligand binding assay. Moreover, semiquantitative RT-PCR studies revealed that 4-hydroxy TAM activated the expression of CYP3A4 and MDR1 mRNA in MCF-7 cells. These results suggest that TAM induces CYP3A4 and MDR1 gene expression through SXR, which may affect TAM metabolic pathway in breast cancer cells.