Chemical shift-encoded MRI with compressed sensing combined with parallel imaging for proton density fat fraction measurement of the lumbar vertebral bone marrow.

We aimed to investigate the accuracy of proton density fat fraction (PDFF) measurement of the lumbar vertebral bone marrow using chemical shift-encoded magnetic resonance imaging (CSE-MRI) with compressed sensing combined with parallel imaging (CSPI). This study recruited a commercially available phantom, and 43 patients. Fully sampled data without CSPI and under-sampled data with CSPI acceleration factors of 2.4, 3.6, and 4.8 were acquired using a 1.5T imaging system. The relationships between PDFF measurements obtained with the no-CSPI acquisition and those obtained with each CSPI acquisition were assessed using Pearson correlation coefficient (r), linear regression analyses, and Bland-Altman analysis. The intra- and inter-observer variabilities of the PDFF measurements were evaluated using the intraclass correlation coefficient. PDFF measurements obtained with all acquisitions showed a significant correlation and strong agreement with the reference PDFF measurement of the phantom. PDFF measurements obtained using CSE-MRI with and without CSPI were positively correlated (all acquisitions: r = 0.99; P < .001). The mean bias was -0.31% to -0.17% with 95% limits of agreement within ±2.02%. The intra- and inter-observer agreements were excellent (intraclass correlation coefficient: 0.988 and 0.981, respectively). A strong agreement and positive correlation were observed between the PDFF measurements obtained using CSE-MRI with and without CSPI. PDFF measurement of the lumbar vertebral bone marrow using CSE-MRI with CSPI can be acquired with a maximum reduction of approximately 75% in the acquisition time compared with a fully sampled acquisition.

Chemical Shift-Encoded MRI of the Lumbar Vertebral Bone Marrow for Detecting Osteoporosis With Low Trabecular Bone Quality in Patients With Breast Cancer Receiving Aromatase Inhibitors.

BACKGROUND: Osteoporosis with low trabecular bone quality (OLB) in patients with breast cancer receiving aromatase inhibitor (AI) therapy is associated with an increased risk of vertebral fractures. The capability of chemical shift-encoded MRI (CSE-MRI) in detecting OLB needs to be investigated. PURPOSE: To assess the diagnostic performance of proton density fat fraction (PDFF) and R2* measurements from CSE-MRI for detecting OLB in postmenopausal women with breast cancer undergoing AI therapy. STUDY TYPE: Prospective. POPULATION: 126 postmenopausal females (mean age: 69.5 ± 8.8 years) receiving AIs (average period: 41.6 ± 26.5 months) after breast cancer surgery. FIELD STRENGTH/SEQUENCE: 1.5-T, three-dimensional CSE-MRI (six echoes), T1-weighted Dixon, short tau inversion recovery, and diffusion-weighted images. ASSESSMENT: Both CSE-MRI and dual-energy x-ray absorptiometry were performed on the same day. Measurements included averaged PDFF, R2*, bone mineral density (BMD), and trabecular bone score (TBS) from L1 to L4 vertebrae. A T-score ≤ -2.5 from BMD measurements indicated osteoporosis, whereas T-scores of ≤ - 2.5 plus TBS ≤-3.7 indicated OLB. The diagnostic performance of PDFF, R2*, and the combination of PDFF and R2* for identifying osteoporosis or OLB was assessed. STATISTICAL TESTS: Student's t-test; Mann-Whitney U test; χ2 or Fisher exact tests; Pearson correlation; multivariate analysis; Receiver operating characteristic (ROC) analysis with the area under the curve (AUC); logistic regression model; intraclass correlation coefficient. A P-value <0.05 was considered statistically significant. RESULTS: For detecting osteoporosis, AUC values were 0.59 (PDFF), 0.66 (R2*), and 0.65 (combined PDFF and R2*). Significant mean differences were noted between patients with and without OLB for PDFF (66.11 ± 5.36 vs. 57.49 ± 6.43) and R2* (46.62 ± 9.24 vs. 63.36 ± 12.44). AUC values for detecting OLB were 0.75 (PDFF), 0.82 (R2*), and 0.84 (combined PDFF and R2*). DATA CONCLUSION: R2* may perform better than PDFF for identifying OLB in patients with breast cancer receiving AIs. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 4.

New insights into patterns of first metastatic sites influencing survival of patients with hormone receptor-positive, HER2-negative breast cancer: a multicenter study of 271 patients.

BACKGROUND: The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. METHODS: We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. RESULTS: Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence. CONCLUSIONS: Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.

Carcinosarcoma of the breast: A case of breast conservation surgery and breast reconstruction.

Breast carcinosarcoma is an extremely rare, clinically aggressive tumor, and no standard treatment has been established. We report about a 34-year-old woman presenting with a 2.5-cm-sized carcinosarcoma in her right breast. She presented to our hospital for examination of this mass. Ultrasonography showed a hypoechoic mass with partially irregular margins. Fine-needle aspiration cytology indicated malignancy. No enlarged lymph nodes or distant metastases were detected. We diagnosed right breast cancer and performed partial mastectomy, sentinel lymph node biopsy, and latissimus dorsi muscle flap transfer. Histological findings revealed that the tumor consisted of a mixture of an epithelial component and a mesenchymal component. The final diagnosis was carcinosarcoma. After undergoing adjuvant chemotherapy and radiotherapy, the patient has had no recurrence, and her cosmesis is maintained. Clinical data of carcinosarcoma are insufficient. Breast conservation and reconstruction for carcinosarcoma may be suitable as local treatments; however, the most appropriate treatment method has not been established.

PI3K/Akt/mTOR signalling pathway activation in patients with ER-positive, metachronous, contralateral breast cancer treated with hormone therapy.

Oestrogen receptor (ER)-positive, metachronous, contralateral breast cancer (MCBC) sometimes develops during or soon after completion of hormone therapy (HT), but it is uncertain whether it is HT-resistant. We examined the association between ER-positive second cancer and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which are associated with HT resistance. We examined the treatment-free interval (time after completion of HT for initial cancer) in 41 patients with ER-positive MCBC with a history of adjuvant HT for initial cancer (HT group), and initial-to-second period duration (time after operation of initial cancer to onset of second cancer) in 17 patients with ER-positive MCBC in whom adjuvant HT was not applied to the initial tumour (control group or no HT group). Phosphorylated S6 (pS6) and phosphorylated MAPK (pMAPK) were used as indicators of PI3K/Akt/mTOR and MAPK pathway activity, respectively. Tumours were classified as showing negative, positive or strongly positive staining, and the correlation between staining and treatment-free interval or initial-to-second period duration was evaluated using the Spearman's rank correlation coefficient (ρ). Treatment-free interval and pS6 staining showed a negative correlation (ρ=-0.5355; P=0.0003) in the HT group. There was no correlation between initial-to-second period duration and pS6 staining in the no HT group (ρ=-0.0814; P=0.756). There was no correlation between pMAPK signalling and the treatment-free interval in the HT group (ρ=-0.1560; P=0.330) or the initial-to-second period duration in the no HT group (ρ=-0.0116; P=0.965). Development of a second ER-positive cancer during or soon after completion of HT for the initial cancer may be associated with activation of the PI3K/Akt/mTOR pathway. Care should be taken during follow-up and when selecting adjuvant therapy for second cancer.

Response to First-line Recurrence Treatment Influences Survival in Hormone Receptor-positive, HER2-negative Breast Cancer: A Multicenter Study.

BACKGROUND/AIM: Little evidence is currently available on significant determinants of post-recurrence survival for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer. The objective of this study was to evaluate factors influencing post-recurrence survival in HR+/HER2-breast cancer. PATIENTS AND METHODS: A cohort of 236 patients with recurrent HR+/HER2- breast cancer was retrospectively analyzed to identify significant factors correlating with prognosis after recurrence. RESULTS: Multivariate analysis revealed independent prognostic factors of poor survival as follows: short intervals between recurrence and the end of adjuvant endocrine therapy (ET; p=0.046); short disease-free intervals (p=0.019); liver metastasis (p=0.007) or multiple metastases (p<0.001) at recurrence; and a poor response to first-line treatment (p<0.001). A poor first-line treatment response was significantly associated with a shorter response to a subsequent treatment line (p=0.007). Logistic regression analysis indicated that liver metastasis significantly increased the risk of a poor first-line-ET response (p=0.009). CONCLUSION: The first-line treatment response was the key to post-recurrence survival in patients with HR+/HER2- breast cancer. Particularly poor responses led to subsequent unfavorable prognostic outcomes.

One-step nucleic acid amplification assay for intraoperative prediction of advanced axillary lymph node metastases in breast cancer patients with sentinel lymph node metastasis.

The one-step nucleic acid amplification (OSNA) assay is used to semiquantitatively measure the cytokeratin (CK)19 mRNA copy numbers of each sentinel lymph node (SLN) in breast cancer patients. The aim of the present study was to evaluate whether the diagnosis of ≥4 LN metastases is possible using the OSNA assay intraoperatively. Between May, 2010 and December, 2014, a total of 134 patients who underwent axillary lymph node dissection (ALND) of positive SLNs were analyzed. The total tumor load (TTL) was defined as the total CK19 mRNA copies of all positive SLNs. The correlation between TTL and ≥4 LN metastases was evaluated. Of the 134 patients, 31 (23.1%) had ≥4 LN metastases. TTL ≥5.4×104 copies/µl evaluated by receiver operator characteristic curve analysis was examined along with other clinicopathological variables. In the multivariate analysis, only TTL ≥5.4×104 copies/µl was correlated with ≥4 LN metastases (odds ratio = 2.95, 95% confidence interval: 1.17-7.97, P=0.022). Therefore, TTL assessed by the OSNA assay has the potential to be a predictor of ≥4 LN metastases and it may be useful for the selection of patients with positive SLNs in whom ALND may be safely omitted.

O6-methylguanine-DNA methyltransferase as a prognostic and predictive marker for basal-like breast cancer treated with cyclophosphamide-based chemotherapy.

The O6-methylguanine-DNA methyltransferase (MGMT) protein protects cells from alkylating agents by removing alkyl groups from the O6-position of guanine. However, its effect on DNA damage induced by cyclophosphamide (CPM) is unclear. The present study investigated whether MGMT expression was correlated with prognosis in patients with breast cancer that was managed according to a common therapeutic protocol or treated with CPM-based chemotherapy. The intrinsic subtypes and MGMT protein expression levels were assessed in 635 consecutive patients with breast cancer using immunohistochemistry. In total, 425 (67%) luminal A, 95 (15%) luminal B, 47 (7%) human epidermal growth factor receptor-2+/estrogen receptor- (HER2+/ER-) and 48 (8%) basal-like subtypes were identified. Of these, MGMT positivity was identified in 398 (63%) of 635 breast cancers; 68% of luminal A, 67% of luminal B, 30% of HER2+/ER- and 46% of basal-like subtypes were positive. The overall survival (OS) and disease-free survival (DFS) rates did not significantly differ according to the MGMT status among patients with luminal A, luminal B or HER2+/ER- subtypes, and patients with MGMT-negative basal-like cancers tended to have a longer DFS, but not a significantly longer OS time. CPM-containing chemotherapy was administered to 26%, 40%, 47% and 31% of patients with luminal A, luminal B, HER2+/ER- and basal-like tumors, respectively. Although the MGMT status and clinical outcomes of patients with the luminal A, luminal B or HER2+/ER- subtypes treated with CPM were not significantly correlated, the patients with MGMT-negative basal-like tumors who received CPM exhibited significantly improved DFS and OS compared with the CPM-treated patients with MGMT-positive tumors. MGMT may be a useful prognostic and predictive marker for CPM-containing chemotherapy in basal-like breast cancer.

Relationship between thymidylate synthase (TYMS) gene polymorphism and TYMS protein levels in patients with high-risk breast cancer.

The thymidylate synthase gene (TYMS) has three functional polymorphisms which are associated with TYMS expression. To explore the predictability of TYMS polymorphisms for the sensitivity and toxicity of 5-fluorouracil (5-FU) in breast cancer patients, this study investigated the association between TYMS polymorphisms and TYMS protein expression in normal and tumour tissue specimens from 49 lymph node-positive breast cancer patients. An analysis of the TYMS 3'-UTR polymorphism showed that level of TYMS protein in normal tissue with the +6 bp/+6 bp genotype was significantly higher than that for the -6 bp/+6 bp genotype. Tumour tissue with the +6 bp/+6 bp genotype had a significantly higher TYMS protein expression than did those with other genotypes. These findings suggest that breast cancer patients with the TYMS 3'-UTR +6 bp/+6 bp polymorphism whose tumours show a 6 bp deletion within TYMS 3'-UTR represent a group that may derive the most benefit from 5-FU chemotherapy.

Hematoma-directed and ultrasound-guided breast-conserving surgery for nonpalpable breast cancer after Mammotome biopsy.

Stereotactic vacuum-assisted (Mammotome) breast biopsy is a powerful diagnostic tool for detecting microcalcifications on mammography, but it is difficult to remove the targeted lesion precisely when subsequent breast-conserving surgery is to be carried out. We achieved satisfactory results by performing hematoma-directed breast-conserving surgery after stereotactic Mammotome biopsy in seven patients. To identify the exact location of the Mammotome biopsy during the breast-conserving surgery, we created an iatrogenic hematoma in the biopsy cavity using patient's blood. This hematoma was detected easily on intraoperative ultrasonography in all patients, and was palpable as a soft mass in five of the seven patients. The microcalcifications were completely removed in all patients, and no cancer cells were found in the margin surfaces after breast-conserving surgery. There were no complications during the injection of the patient's blood into the biopsy cavity or during the hematoma-directed surgery. We describe this new procedure of hematoma-directed breast-conserving surgery following Mammotome biopsy for nonpalpable cancer with microcalcifications.

An Activated Germanium Metal-Promoted, Highly Diastereoselective Reformatsky Reaction.

Activated germanium metal, prepared by the reduction of germanium(II) iodide with potassium metal, was found to promote the Reformatsky reaction effectively under mild conditions. In the presence of activated germanium metal, the reactions of alpha-bromo ketones 2a and 2b and alpha-bromo imides 2e and 2f with benzaldehyde (1a) proceeded smoothly to give the corresponding beta-hydroxy carbonyl compounds 3a, 3b, 3e and 3f, respectively, in good yields and with good syn diastereoselectivity. The activated germanium metal-promoted, asymmetric Reformatsky reaction of enantiomerically pure-oxazolidinone derivatives 2g-j with various aldehydes 1a-d was also examined; the highest diastereoselectivity was achieved when (1S,2R)-2-amino-1,2-diphenylethanol-derived 2j was used as the Reformatsky donor. The excellent diastereoselectivity could be explained in terms of the formation of a chairlike, six-membered transition state between the aldehyde and enolate as in the Zimmerman-Traxler model. A single recrystallization of the Reformatsky adducts, followed by hydrolysis and subsequent esterification, led to enantiomerically pure methyl 3-hydroxy-2-methylalkanoates 10j-m, with almost quantitative recovery of the enantiomerically pure 2-oxazolidinone 14.

Highly Stereoselective Cationic Cyclization Assisted by a Sulfenyl Group. Scope, Limitation, and Mechanism.

When 8-acetoxy-2-methyl-9-(phenylthio)-2-nonene (1a) was treated with an acid, followed by a base, alkylative cyclization proceeded to give a mixture of 1,2-disubstituted cyclohexanes: 2a, 3a, and 4a. The stereochemistry of the reaction was only slightly affected by the leaving group and the reaction conditions, such as the temperature, solvent, and acid. However, the bulkiness of the sulfenyl group had a great effect on the stereochemical course of the reaction. High trans selectivity was attained when 1c (a derivative of 1a with a bulkier sulfenyl group) was used as a substrate. On the other hand, the length and rigidity of the carbon chain of the substrate also had a major effect on the stereochemistry of the reaction; a high cis selectivity was observed when 10a (a one-carbon-fewer analog of 1a) or 15a (a derivative with one more double bond in the carbon chain than in 1a) was used as the substrate. The reaction proceeded via a 6,5- or 5,5-fused-ring intermediate. The sulfenyl-group-assisted reaction could be a useful method for the stereoselective cyclization of acetates of alpha-sulfenylated secondary alcohols.