Pilot Study of Irinotecan and S-1 (IRIS) for Advanced and Metastatic Breast Cancer.

BACKGROUND/AIM: Irinotecan is rarely used on the metastatic breast cancer (MBC) setting. S-1 is an oral mixture of tegafur, gimeracil and oteracil. We conducted this pilot study to assess efficacy and safty of chemotherapy with combined irinotecan and S-1 (IRIS). PATIENTS AND METHODS: Irinotecan was given intravenously at 80 mg/m2 on days 1 and 8 and S-1 was given orally at 80-120 mg/day depending on body surface area for 2 weeks, repeating the cycle every 3 weeks. RESULTS: Twenty-two patients were enrolled in the study. Median age was 50.5 years (range=26-72). Nineteen patients were evaluable for response. Median overall survival and progression-free survival were 672 days (95% CI=420-967) and 166 days (95% CI=76-814), respectively. CONCLUSION: The IRIS regimen has an acceptable safety profile and modest efficacy against MBC in patients previously heavily treated with chemotherapy. This regimen has potential to treat MBC.

Effects of breast structure on high-intensity focused ultrasound focal error.

BACKGROUND: The development of imaging technologies and breast cancer screening allowed early detection of breast cancers. High-intensity focused ultrasound (HIFU) is a non-invasive cancer treatment, but the success of HIFU ablation was depending on the system type, imaging technique, ablation protocol, and patient selection. Therefore, we aimed to determine the relationship between breast tissue structure and focal error during breast cancer HIFU treatment. METHODS: Numerical simulations of the breast cancer HIFU ablation were performed using digital breast phantoms constructed using the magnetic resonance imaging data obtained from 12 patients. RESULTS: The focal shapes were distorted despite breast tissue representing soft tissue. Focal errors are caused by the complex distribution of fibroglandular tissue, and they depend on the target position and the arrangement of the transducer. We demonstrated that the focusing ratio increases with the decrease in the local acoustic inhomogeneity, implying that it may be used as an indicator to reduce the HIFU focal error depending on the breast structure. CONCLUSIONS: The obtained results demonstrated that the focal error observed during the breast cancer HIFU treatment is highly dependent on the structure of fibroglandular tissue. The optimal arrangement of the transducer to the target can be obtained by minimizing the local acoustic inhomogeneity before the breast cancer HIFU treatment.

Influence of human serum albumin on the bile acid-mediated inhibition of liver microsomal type 1 11beta-hydroxysteroid dehydrogenase

The influence of human serum albumin (HSA) on the bile acid-mediated inhibition of liver microsomal type 1 11β-hydroxysteroid dehydrogenase (11β-HSD1) was studied in vitro. A rat liver microsomal fraction was prepared, and the 11β-HSD1 enzyme activity in the presence of various concentrations of bile acids and HSA was determined using hydrocortisone as the substrate. The products of the reaction were extracted and analyzed using high-performance liquid chromatography. The magnitude of the inhibition decreased with the addition of HSA in a dose-dependent manner. Four percent human albumin decreased the inhibitory effects of 100 μM chenodeoxycholic acid and lithocholic acid from 89.9 ± 5.6 to 54.5 ± 6.1 % and from 83.8 ± 4.8 to 20.8 ± 4.2 %, respectively. In contrast, ursodeoxycholic acid and deoxycholic acid showed no inhibitory effect on the enzyme activity in the presence of 4 % human serum albumin, and the addition of 1 % γ-globulin to the assay mixture in the presence of bile acids did not affect the enzyme activity. Our in vitro study showed that the addition of HSA ameliorated the inhibition of 11β-HSD1 and that the magnitude of the change is dependent on the species of bile acid, presumably based on the numbers of hydroxyl groups. These results suggest that HSA seems to protect the bile acid-mediated inhibition of 11β-HSD1 in the healthy subject. On the other hand, in the patients with obstructive biliary diseases, not only elevated serum bile acid but also the accompanying hypoalbuminemia is important to evaluate the pathophysiology of the bile acid-mediated inhibition of 11β-HSD1 of the disease

Influence of human serum albumin on the bile acid-mediated inhibition of liver microsomal type 1 11ß-hydroxysteroid dehydrogenase.

The influence of human serum albumin (HSA) on the bile acid-mediated inhibition of liver microsomal type 1 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) was studied in vitro. A rat liver microsomal fraction was prepared, and the 11ß-HSD1 enzyme activity in the presence of various concentrations of bile acids and HSA was determined using hydrocortisone as the substrate. The products of the reaction were extracted and analyzed using high-performance liquid chromatography. The magnitude of the inhibition decreased with the addition of HSA in a dose-dependent manner. Four percent human albumin decreased the inhibitory effects of 100 µM chenodeoxycholic acid and lithocholic acid from 89.9 ± 5.6 to 54.5 ± 6.1% and from 83.8 ± 4.8 to 20.8 ± 4.2%, respectively. In contrast, ursodeoxycholic acid and deoxycholic acid showed no inhibitory effect on the enzyme activity in the presence of 4% human serum albumin, and the addition of 1% γ-globulin to the assay mixture in the presence of bile acids did not affect the enzyme activity. Our in vitro study showed that the addition of HSA ameliorated the inhibition of 11ß-HSD1 and that the magnitude of the change is dependent on the species of bile acid, presumably based on the numbers of hydroxyl groups. These results suggest that HSA seems to protect the bile acid-mediated inhibition of 11ß-HSD1 in the healthy subject. On the other hand, in the patients with obstructive biliary diseases, not only elevated serum bile acid but also the accompanying hypoalbuminemia is important to evaluate the pathophysiology of the bile acid-mediated inhibition of 11ß-HSD1 of the disease.

Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer.

PURPOSE: Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5'-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC). MATERIALS AND METHODS: Patients received capecitabine 828 mg/m(2) twice daily with cyclophosphamide 33 mg/m(2) twice daily, days 1-14 every 3 weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1 months. ORR was 44.4% and stable disease (≥24 weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3 months (95% confidence interval: 8.9-18.9 months). Median PFS was 10.7 months in triple-negative disease and 13.2 months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome. CONCLUSIONS: Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.

MR and US imaging for breast cancer patients who underwent conservation surgery after neoadjuvant chemotherapy: comparison of triple negative breast cancer and other intrinsic subtypes.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is commonly utilized to treat operable breast cancer. The purpose of this study was to review the findings of ultrasonography (US) and magnetic resonance (MR) imaging in patients treated with breast conservation surgery (BCS) after NAC with a focus on intrinsic subtypes. METHODS: Eighty-six patients underwent BCS after NAC. The tumors were classified into four subgroups by receptor status. US and MR were performed before and after NAC. The tumor diameters in US and MR after NAC were examined for correlations with pathological tumor distances in the specimens from BCS after NAC. RESULTS: The correlation coefficient (r) of US to pathological tumor size was 0.3 in all tumors, 0.6 in HER2-type tumors, and 0.7 in triple negative breast cancers (TNBC). The correlation coefficient of tumor size in MR to pathological tumor size was 0.9 in TNBC, and other correlations were not statistically significant. CONCLUSIONS: The correlation between tumor size in MR and pathological tumor size in triple negative breast cancers corresponded best. This information is one of the clues to selecting patients for BCS after NAC.

The relevance of intrinsic subtype to clinicopathological features and prognosis in 4,266 Japanese women with breast cancer.

BACKGROUND: Estrogen receptor (ER), progesterone receptor (PgR), and HER2 expression status in breast cancer function as prognostic and predictive factors that enable individualized treatment. Intrinsic subtype classification has also been performed based on these and other biological and prognostic characteristics. However, clinical analysis of such subtypes in a large number of Japanese breast cancer patients has not yet been reported. METHODS: Between January 2003 and December 2007, 4,266 patients with primary breast cancer were registered. Four subtypes based on immunohistochemically evaluated ER/PgR/HER2 status, clinicopathological features, and prognosis were analyzed retrospectively. RESULTS: The following subtype distribution was observed: luminal A type (ER+ and/or PgR+, HER2-), 3,046 cases (71%); luminal B type (ER+ and/or PgR+, HER2+), 321 cases (8%); HER2 type (ER-, PgR-, HER2+), 398 cases (9%); and triple negative (TN) type (ER-, PgR-, HER2-), 501 cases (12%). The HER2+ subtypes (luminal B and HER2 types) had a significantly higher incidence of lymph node metastasis and lymphatic permeation, while the hormone receptor negative subtypes (HER2 and TN types) showed a significantly higher nuclear grade. Overall, patients with HER2-type and TN-type disease had a significantly poorer prognosis than other subtypes. CONCLUSION: Intrinsic breast cancer subtypes are associated with clinicopathological features and prognosis in Japanese women. Long-term clinical observation of the relationship between each subtype and therapies used should provide useful information for selecting appropriately tailored treatments.

Clinicopathological study of invasive ductal carcinoma with large central acellular zone: special reference to magnetic resonance imaging findings.

Invasive ductal carcinoma (IDC) with central acellular zone is sometimes encountered, but its clinicopathological features have not yet been fully investigated. The clinicopathological features of 10 resected cases of IDC with a large central acellular zone were investigated. The tumor size ranged from 6 to 28 mm with a mean of 14.3 +/- 6.9 mm. Contrast-enhanced magnetic resonance imaging (MRI) showed a ring-like appearance in the tumor. Sagittal fat-suppressed T2-weighted MRI had very high to intermediate signal intensity in a central area. Histologically, cancer tissue was located in the periphery of the tumor with a ring-like pattern and a large central area was occupied by acellular amorphous tissue that was strongly stained by alcian blue. Lymph vessel permeation was seen in eight cases. Among the tumors with focal enhancement in the central areas >1 cm in diameter on contrast MRI, marked increase of microvessel was observed in the enhanced spot. The mean of p53 and Ki-67 labeling indices was 56.2% and 36.3%, respectively. IDC with a large central acellular zone presenting with characteristic MRI should be noted as a new morphological entity.

The evolving non-surgical ablation of breast cancer: MR guided focused ultrasound (MRgFUS).

MRgFUS (MR guided Focused Ultrasound) being one of the non-surgical ablation techniques. We have already achieved favorable results in the past clinical study of MRgFUS to local treatment. New twenty one cases of invasive/noninvasive ductal carcinoma of the breast were treated by MRgFUS. Core needle biopsy led to the definitive diagnosis. All the patients were positioned prone in the treatment, using the therapeutic apparatus such as Signa Excite 1.5 T for MRI and ExAblate 2000 version 2.6/4.1 for FUS. Irradiation was not applied to all the 21 cases after MRgFUS. Axillary lymph node metastases were examined by dissection or sentinel lymph node biopsy. Recurrence or abnormal area of residual cancer was treated with Re-MRgFUS or ablated by usual surgery. All the 21 cases were from women patients. Median age is 54 years (range: 34-72). Median diameter of tumor is 15 mm (range: 5-50). As for the numbers of treatment, 17 patients were treated once, and 4 patients twice. Median period of observation is 14 months (range: 3-26). One case of recurrence of pure mucinous carcinoma was experienced. No evidences of recurrence were obtained through MRI for the rest of 20 cases. Skin burns were found in 2 cases. The patient had dimple on the skin immediately above tumor. In conclusion, MRgFUS is a good mean as local control of breast cancer, but the indicated case must be selected strictly. And it needs to observe longer the patients who ware treated by MRgFUS alone.

Magnetic resonance-guided focused ultrasound surgery of breast cancer: reliability and effectiveness.

BACKGROUND: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive technique that has been shown to coagulate benign and malignant tumors. The purpose of this study was to evaluate MRgFUS safety and effectiveness for the ablation of breast carcinomas. STUDY DESIGN: Thirty women with biopsy-proved breast cancer underwent MRgFUS treatment. Gadolinium-enhanced MR images were used for treatment planning and posttreatment radiologic assessment of treated tissue, and temperature-sensitive MR images provided real-time treatment monitoring. After MRgFUS, all 30 women underwent wide excision or mastectomy. The extent of thermal ablation was assessed with tumor histology. RESULTS: Treatment was well tolerated, with a minimum of adverse effects, especially when performed under local anesthesia. On pathologic examination, mean (+/-SD) necrosis of the targeted breast tumors was 96.9 +/- 4% (median 100%, range 78% to 100%) of tumor volume. Fifteen (53.5%) of 28 evaluable patients had 100% necrosis of the ablated tumor; only 3 patients (10.7%) had less than 95% necrosis. In 28 (93.3%) patients, 100% of the malignancy was within the treatment field, and 98% and 95% of tumor lay within the treatment field in 2 remaining patients. Retrospective analysis in two patients with residual tumor showed treatment was not delivered to the full recommended area, reaffirming the need for precise localization and the value of contrast-enhanced images for treatment planning. CONCLUSIONS: MRgFUS has great potential to become a viable noninvasive replacement for lumpectomy. Additional studies focusing on posttreatment image-based evaluation are needed.

Breast focused ultrasound surgery with magnetic resonance guidance.

This paper will review the experience and current applications of magnetic resonance-guided focused ultrasound surgery (MRgFUS) for treatment of breast tumors. Because of the efficient screening mammography programs, most of the breast cancers diagnosed today in the United States and European Union are in early stage and are treated with limited surgery. The MRgFUS may offer an alternative treatment option to conventional surgical lumpectomy with the advantage of being a noninvasive procedure and potentially achieving a better cosmetic outcome. Selection of appropriate patients is of paramount importance. Additional studies are needed to determine the effectiveness of the MRgFUS tumor ablation and define its role as a replacement for surgical lumpectomy.

A comparison of MR imaging, galactography and ultrasonography in patients with nipple discharge.

BACKGROUND: The aim of this study is to assess the usefulness of three-dimensional contrast-enhanced magnetic resonance (MR) imaging, compared with galactography and ultrasonography(US). METHODS: Fifty-five patients with bloody nipple discharge were investigated retrospectively. All patients were examined by galactography, ultrasonography and MR imaging. These three sets of findings were compared with the histopathological results from 16 intraductal biopsies, 3 excisional biopsies, 24 microdochectomies and 12 mastectomies. RESULTS: Contrast enhanced MR imaging demonstrated all malignant lesions including ductal carcinoma in situ (DCIS). Four cases of DCIS were not visualized by ultrasonography and three malignant lesions were missed by galactography. In the MR study, segmental clumped enhancement (positive predictive value =100 %), and focal mass with smooth border (negative predictive value =87.5 %) were the statistically significant predictive factors. CONCLUSIONS: Among the three modalities, contrast-enhanced three-dimensional MR imaging demonstrated the location and distribution of the lesions most clearly, especially in cases of ductal carcinoma in situ. It has the potential to be a useful diagnostic tool for patients with nipple discharge.

Accumulation of 4- and 5-ene steroid sulfates in human breast cyst fluids.

Gross cystic disease of the breast is one of the most common diseases of adult females. Breast cyst fluid contains various steroid hormones. In order to obtain more information about the concentrations of 4- and 5-ene steroids in human breast cyst fluids, levels of pregnenolone sulfate (PREGS), pregnenolone (PREG), dehydroepiandrosterone sulfate (DHEAS) and dehydroepiandrosterone (DHEA) were determined by high-performance liquid chromatography (HPLC). A total of 35 human breast cyst fluid samples, obtained from 35 patients (28-54 years old) were analyzed. Cyst fluid electrolytes were simultaneously determined. Levels of PREGS (mean+/-S.D.) were 26.9+/-20.0 micromol/l (N=35) and of PREG were <0.1 micromol/l. Levels of DHEAS and DHEA were 89.1+/-111.7 micromol/l (N=35) and 0.3+/-0.2 micromol/l (N=35), respectively. Cyst fluids were divided into two groups (types I and II) according to their electrolyte ratio (K(+)/Na(+)). The cysts of the type I group (K(+)/Na(+) >1.5) contained significantly higher levels of PREGS (39.9+/-21.1 micromol/l) and DHEAS (133.2+/-87.9 micromol/l) than those of the type II group (K(+)/Na(+) <1.5), the mean levels of which were 19.8+/-16.2 micromol/dl for PREGS, and 36.3+/-29.0 micromol/dl for DHEAS (P<0.05). PREGS and DHEAS levels in the cysts were significantly correlated (r=0.49; P<0.01). Human breast cyst fluids contain high concentration of DHEAS and PREGS, especially in the cyst fluids containing high K(+)/Na(+) ratios.

Extension of breast cancer: comparison of CT and MRI.

PURPOSE: To compare three-dimensional (3D) helical CT with 3D MRI in the evaluation of intraductal spread of breast cancer. METHODS: Fifty patients with breast cancer were examined. Tumor size ranged from Tis to T2. The whole breast was scanned by both breath-holding helical CT and MRI with contrast media. Linear or segmental enhancement, and spotty enhancement around the main tumor were considered to indicate ductal carcinoma in situ (DCIS) or ductal spread. These findings were compared with thin section histopathologic data. RESULTS: Seventeen of 35 patients had intraductal spread with invasive cancer and 15 patients had DCIS. The sensitivity, specificity, and accuracy of 3D CT in detecting intraductal spread or DCIS were 71.9%, 83.3%, and 76.0%, respectively, and those of 3D MRI were 87.5%, 61.1%, and 78.0%. Overestimations numbered three (6.0%) on CT and seven (14.0%) on MRI, and underestimations numbered nine (18.0%) on CT and four (8.0%) on MRI. CONCLUSION: 3D helical CT can provide good information about the spread of breast cancer and could be an alternative to 3D MRI for preoperative examination of breast cancer.