Survival impact of FDG-PET metabolic response Kaplan-Meier survival analysis demonstrated that metabolic responders (n = 18) as measured by serial FDG-PET/CT scans with a cut-off value of 20% reduction of SUVmax, had a favorable outcome of overall survival compared to non-responders (n = 10) (log-rank test, p = 0.1). Multivariate analysis using the COX regression model demonstrated hormonal receptor negativity (HR 7.6, 95%CI 1.0-57.2, p = 0.04) as an independent predictor of poor survival when compared to PET non-responders (HR 7.2, 95%CI 0.9-57.6, p = 0.06) and distant metastasis (HR 2.5, 95%CI 0.4-14.9, p = 0.3).

Baseline relations between FDG, FMISO, and metabolic response: Scatter diagrams show the relationship between FDG and FMISO in both luminal breast cancer (A) (r = 0.54; 95% CI, 0.13-0.79; p = 0.01) and triple-negative breast cancer (B) (r = 0.61; 95% CI â^'0.25-0.93; p = 0.1). Open circles are metabolic responders and filled circles are non-responders.

The measurement of hemoglobin (Hb) concentrations in breast cancer by near-infrared spectroscopy is useful for the assessment of responses to neoadjuvant chemotherapy (NAC). However, the chest wall muscles may affect this measurement. We corrected Hb concentrations based on the skin-to-chest wall distance. Corrected Hb was compared with uncorrected Hb as a marker of treatment responses in breast cancer patients.

We report the case of a patient who presented with a hypoglycemic attack associated with a Phyllodes tumor and the presence of high-molecular-weight Insulin-like Growth Factor II (IGF-II). A 42-year-old premenopausal woman, who had had a palpable mass in her left breast for several months, was found unconscious at her home by a family member early in the morning. She was emergently transported to our hospital. Her clinical examination revealed an approximately 15-cm mass in the entire left breast. Her blood glucose level was 33 mg/dL, resulting in hypoglycemia, and a 50% glucose injection immediately improved her awareness level. Thoracoabdominal computed tomography demonstrated a large, lobulated left breast tumor showing heterogeneous internal echotexture without enlargement of the lymph nodes (axillary, supraclavicular, cervical, and mediastinum) or distant metastasis. We performed a vacuum-assisted needle biopsy of the breast lesion that showed a Phyllodes tumor. We performed mastectomy, including the tumor, and the patient recovered from the hypoglycemic episode. The histological examination revealed a borderline Phyllodes tumor. Immunohistochemical examinations revealed neoplastic cells diffusely positive for IGF-II. Moreover, Western blot analysis demonstrated large amounts of highmolecular-weight IGF-II in the resected tumor. No relapse of a hypoglycemic attack and tumor recurrence has been reported post-surgery.

This study reports data from three clinical studies using the time-resolved diffuse optical spectroscopy (TRS) system among breast cancer patients. The parameters of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb), and oxygen saturation (SO2) were evaluated using TRS, and its efficacy was tested in three trials. In trial 1, we recruited 118 patients with primary breast cancer to estimate the tumor detection rate. The cumulative detection rate was 62.7%, while that in T stage 0 was 31.3% and in T stage 1 was 44.7%. These were lower than those of T stage 2 (78.9%) and T stage 3 (100%). Next, we used TRS to monitor tumor hemodynamic response to neoadjuvant chemotherapy (n = 100) and found that pathological complete response (pCR) tumors had significantly lower tumor tHb than non-pCR tumors; a similar result was observed in estrogen receptor (ER)-negative tumors, but not in ER-positive tumors. The third trial monitored hemodynamic response to antiangiogenic therapy, bevacizumab (n = 28), and we demonstrated that sequential optical measurement of tumor SO2 might be useful for detecting acute hypoxia 1–3 days after bevacizumab initiation. Next, response monitoring of neoadjuvant endocrine therapy (n = 30) suggested that changes in tumor tHb during treatment can predict and distinguish between responsive and non-responsive tumors early in letrozole therapy. In conclusion, our results show that hemodynamic monitoring of tumors by TRS could pair the unique features of tumor physiology to drug therapy and contribute to patient-tailored medicine. We recently established a platform for performing TRS in patients with breast cancer.

Hypoxia is a key driver of cancer progression. We evaluated the prognostic impact of 18F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer.

A 77-year-old woman with left breast cancer received F-FDG PET/CT for initial staging, and F-FDG-avid lymph nodes were observed in the bilateral axillae. As estrogen receptor (ER) status of primary lesion was positive, the patient also received F-fluoroestradiol (F-FES) PET/CT. Unlike primary lesion, no remarkable F-FES uptakes in the lymph nodes were observed. F-FDG uptakes in the nodes were finally interpreted as inflammation. F-FES PET that can noninvasively evaluate the ER status may have a potential to reveal the pathology of the false-positive lesion observed in F-FDG PET for patients with ER-positive breast cancer.

After the publication of this article [1], we noticed that in Fig. 2, the survival curve images (C and D, lower panel) were incorrect. The corrected Fig. 2 is presented below. The correction does not affect in any our results and conclusions.

乳腺血管肉腫は稀な難治性疾患であるが，ジェムシタビン（GEM）+パクリタキセル（PTX）が奏効した症例を経験した．症例:29歳の女性，乳腺血管肉腫と診断．初期治療として胸筋合併乳房切除術+広背筋皮弁術+分層植皮術を施行した後，補助化学療法としてエピルビシン+シクロホスファミドおよびドセタキセルを逐次投与した．術後13カ月目で肺，肝，骨転移を認めた．一次治療としてGEM-PTXを開始した．20コース継続して治療効果は部分奏効であったが，治療開始後14カ月で肺転移の増大，新規病変を認め，病勢進行となった．二次治療，三次治療ともに効果なく術後2年8カ月で死亡した．再発・転移性血管肉腫に対してはアンスラサイクリン系やタキサン系抗がん剤による治療法が基軸となるが，既治療例に対しGEM+PTXは有効な選択肢となりうると考えられた．

Abstract Purpose: Bevacizumab, an antibody against endothelial growth factor, is a key but controversial drug in the treatment of metastatic breast cancer. We, therefore, aimed to determine the intrinsic resistance to bevacizumab at the physiologic and molecular levels in advanced breast cancer using PET, dynamic contrast-enhanced MRI, diffuse optical spectroscopic imaging (DOSI), and multiplex cytokine assays. Experimental Design: In total, 28 patients diagnosed with advanced stage III/IV breast cancer receiving single-agent bevacizumab for 1 week followed by paclitaxel combined with bevacizumab underwent 18F-fluorodeoxyglucose (FDG)-PET, 18F-fluoromisonidazole (FMISO)-PET, and MRI at both baseline and two courses after treatment initiation. Hemodynamic measurement using DOSI and blood sample collection were performed at baseline and multiple times during the first week after the initiation of single-agent bevacizumab. We distinguished nonresponders from responders by serial FDG-PET based on their glycolytic changes to chemotherapy. Results: Nonresponders showed significantly higher hypoxic activity on FMISO-PET and less tumor shrinkage than responders. Hemodynamic parameters showed higher tumor blood volume and a remarkable decrease in the tissue oxygen level in nonresponders compared with responders after the infusion of single-agent bevacizumab. Multiplex cytokine assays revealed increased plasma levels of both proangiogenic and hypoxia-related inflammatory cytokines in nonresponders and decreased levels in responders. Conclusions: Nonresponders exhibited a higher degree of angiogenesis with more severe hypoxia than responders during bevacizumab treatment. These findings demonstrated that the addition of bevacizumab to paclitaxel treatment under hypoxic conditions could be ineffective and may result in acute hypoxia and increased cytokine secretion associated with cancer progression. Clin Cancer Res; 23(19); 5769–78. ©2017 AACR.

We present our initial experience with a novel method of functional hypoxia imaging. 18F-fluoromisonidazole-positron emission tomography/computed tomography and diffuse optical spectroscopic imaging were used to noninvasively evaluate the biological effects induced by eribulin monotherapy in a patient treated for recurrent breast cancer with acquired resistance to endocrine therapy. Eribulin monotherapy clearly induced reoxygenation, indicated by the markedly reduced 18F-fluoromisonidazole uptake and enhanced oxygen saturation levels in the lesion. These observations suggest that the reversal of hypoxia can be captured utilizing 18F-fluoromisonidazole positron emission tomography/computed tomography and diffuse optical spectroscopic imaging.

Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor‐associated macrophage (CD68, CD163 or CD204‐positive) infiltration or whether the presence of tumor‐associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68‐, CD163‐ or CD204‐positive tumor‐associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204‐positive tumor‐associated macrophage infiltration clearly demonstrated that CD204‐positive tumor‐associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204‐positive tumor‐associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast.

Purpose: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To understand the mechanism of vascular remodeling of eribulin, we compared optical hemodynamic and blood biomarker changes between eribulin and bevacizumab. Methods: Patients with advanced breast cancer with stage III/IV were eligible for the study. Patients were assigned to receive either eribulin or single-agent bevacizumab. Diffuse optical spectroscopic imaging (DOSI) measured tissue concentrations of oxy-hemoglobin (O2Hb), deoxy-hemoglobin (HHb), total hemoglobin (tHb) and oxygen saturation (SO2) of breast tumors before and day 7 after the first infusion. Peripheral blood samples were obtained from the patients to measure plasma concentration of VEGF, bFGF, FLT-3L, EGF, G-CSF, TNFα, IL1b, IL4, IL6, IL8, IL10, IL12p40, and TGF-β1. Results: Baseline DOSI measurement of all 29 patients (eribulin, n = 14 and bevacizumab, n = 15) revealed significantly higher tumor concentrations of O2Hb, HHb, and tHb than that in the normal breast tissue. Eribulin significantly decreased in HHb concentration and increased SO2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O2Hb and tHb. The blood biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin suppressed the plasma concentration of TGF-β1. Conclusions: Optical imaging technology revealed that eribulin, but not bevacizumab, induced tumor reoxygenation after the start of infusion. Eribulin had a potent anti-angiogenic properties as well as bevacizumab, while suppression of TGF-β1 observed by only eribulin could be associated with remodeling of the microvasculature through suppression of activated stromal cells. Citation Format: Ueda S, Saeki TS, Takeuchi H, Shigekawa T, Yamane T, Kuji I, Osaki A. Eribulin induces vascular remodeling and reoxygenation in advanced breast cancer patients: A comparative study with bevacizumab [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-01.

This phase II neoadjuvant study evaluated the efficacy and safety of a triweekly regimen of docetaxel and carboplatin in combination with trastuzumab (TCbH) in Japanese women with human epidermal growth factor receptor type2 (HER2)-positive primary breast cancer.

Background: Eribulin mesylate (eribulin) is a first-in-class halichondrin B-based microtubule dynamics inhibitor. To compare the anti-angiogenic activity of eribulin to that of bevacizumab, we compared tumour vessel remodelling and reoxygenation between the two agents. Methods: Patients with advanced breast cancer with stage III/IV were eligible for the study. Patients were assigned to receive either eribulin or single-agent bevacizumab. Tissue concentrations of oxyhaemoglobin (O 2 Hb) and deoxyhaemoglobin (HHb), and oxygen saturation (SO 2 ) of breast tumours before and day 7 after the first infusion were repeatedly measured using diffuse optical spectroscopic imaging (DOSI). A pair of blood samples was collected for multiplex biomarker studies. Results: Baseline DOSI measurement of all 29 patients (eribulin, n =14 and bevacizumab, n =15) revealed significantly higher tumour concentrations of O 2 Hb and HHb than that in the normal breast tissue. After eribulin treatment, DOSI revealed a significant decrease in HHb concentration and increased SO 2 during the observation period. This trend was not observed for bevacizumab. Instead, bevacizumab significantly decreased the concentration of O 2 Hb. The multiplex biomarker study revealed that both eribulin and bevacizumab decreased plasma concentrations of VEGF and bFGF, but only eribulin treatment suppressed the plasma concentration of TGF- β 1. Conclusions: Eribulin, but not bevacizumab, treatment increased tumour SO 2 . Suppression of TGF- β 1 by eribulin could have a favourable anti-angiogenic effect. Our results suggest that differences in vascular remodelling between these two agents may account for their different effects on tumour reoxygenation.

BACKGROUND Trastuzumab, used to treat breast cancer overexpressing human epidermal growth factor receptor 2, may be cardiotoxic. Cardiac magnetic resonance (CMR) imaging with myocardial strain studies has been used to evaluate subclinical biventricular myocardial changes, however, its clinical utility during chemotherapy has not been evaluated. METHODS The clinical outcomes, CMR and cardiac biomarkers of 9 women aged 62.3 ± 12.6 years with early or locally advanced breast cancer were evaluated at baseline, and at 3, 6 and 12 months after the initiation of trastuzumab. RESULTS None of the patients developed heart failure or elevated serum cardiac biomarkers. Global left ventricular (LV) peak systolic longitudinal and circumferential strains were significantly decreased at 6 months (longitudinal strains, -21.1 ± 1.7% [baseline] vs. -19.5 ± 1.0% [6 months], p = 0.039, and circumferential strains, -23.4 ± 1.8% [baseline] vs. -21.6 ± 2.5% [6 months], p = 0.036). These changes were analogous to those observed in the LV ejection fraction. Right ventricular (RV) free wall peak systolic circumferential strains were decreased at 6 months (-20.9% ± 2.4% [baseline] vs. -19.1% ± 2.3% [6 months], p = 0.049), whereas RV longitudinal strains and ejection fraction remained unchanged. The LV longitudinal strain was the most reproducible of the 4 peak strain parameters. CONCLUSIONS The LV longitudinal and circumferential strains measured by CMR decreased during trastuzumab therapy, although their predictive value for later heart failure or association with RV parameters was not determined. These techniques may be a useful means of diagnosing and monitoring trastuzumab-related cardiotoxicity.