Shino Nakagawa

Relationship between microvessel density and thermographic hot areas in breast cancer.

Abstract.Purpose: This study was conducted to evaluate the validity of thermography in breast examination. Methods: We performed contact thermography and measured the direct temperature by inserting a needle-type thermometer into the tissue. The core temperature of the tumor (dTt) and the temperature of the tissue surrounding the tumor (dTs) were compared with normal tissue. The microvessel density (MVD) and the MIB-1 labeling index (MIB-1 LI) of the tumor were examined immunohistochemically. The subjects were 48 women with primary invasive ductal carcinoma. The area of the tumor was diagnosed pathologically, and the hot area was measured using thermography. Results: The dTt was significantly higher than the dTs. Both the dTt and dTs were significantly higher when the thermographical hot area was positive, or when more than four lymph node metastases were found. The dTs was correlated with MVD. A correlation between MVD and tumor temperature measured directly was also confirmed. A higher dTs was related to the dissociated wide area of the thermogram. Conclusion: These findings suggested a relationship between dTs and the high-risk group of breast cancer. We also found that abnormalities in temperature were reflected in thermography and that a higher dTs was related to the dissociated wide area of the thermogram.

FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes is associated with breast cancer prognosis

The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3+ tumor cells and as being highly infiltrated by FOXP3+ lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3+ lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P<0.001), with a high infiltration of FOXP3+ lymphocytes accompanied by a cytoplasmic FOXP3+ tumor being the most detrimental phenotype. These findings indicated that FOXP3 expression in lymphocytes as well as in tumor cells may be a prognostic marker for breast cancer. FOXP3 in tumor cells may have distinct biological activities and prognostic values according to its localization, which may help establish appropriate cancer treatments.

Cell growth inhibition by all‐trans retinoic acid in SKBR‐3 breast cancer cells: Involvement of protein kinase Cα and extracellular signal‐regulated kinase mitogen‐activated protein kinase

All‐trans retinoic acid (ATRA), a synthetic derivative of vitamin A, inhibits the growth of breast cancer cells. To elucidate the mechanism by which ATRA causes cell growth inhibition, we examined changes in cell cycle and intracellular signaling pathways, focusing on protein kinase C (PKC) and mitogen‐activated protein kinase (MAPK). Using the estrogen receptor‐negative, retinoid receptor–positive breast cancer cell line SKRB‐3, we found that treatment with ATRA significantly decreased the expression of PKCα, as well as reducing ERK MAPK phosphorylation. ATRA treatment leads to dephosphorylation of Rb, and consequently to G1 arrest. Marked changes in the expression of cyclins (particularly cyclins A and E) were observed in SKBR‐3 cells treated with ATRA. Using a series of pharmacological and molecular approaches, we found evidence that ATRA‐induced SKBR‐3 cell growth inhibition involves the deregulation of the PKCα‐MAPK pathway. These data suggest that retinoids interfered with signal transduction pathways that are crucial for cell cycle progression, and highlight the complexities of the biological effects of retinoid derivatives.

Axillary Lymph Node Recurrence of Papillary Thyroid Microcarcinoma: Report of a Case

We report a case of axillary lymph node recurrence of thyroid papillary microcarcinoma (PMC) in a 51-year-old woman who had undergone thyroidectomy with lymph node dissection 5 years earlier. We performed residual thyroid resection with cervical and bilateral axillary lymph node dissection, and pathological examination revealed well-differentiated papillary carcinoma, with partial poor differentiation. Postoperative radioiodine therapy was ineffective, and the patient died of systemic dissemination of the recurrence 8 months after her second operation. The positive cell rates of proliferating cell nuclear antigen and Ki-67 were clearly higher in the recurrent lymph nodes than in the primary thyroid tumor, suggesting increased cell proliferation in the recurrent lymph nodes. Thyroid papillary carcinoma rarely recurs in the axillary lymph nodes, but its possibility must be kept in mind, especially in patients with remarkable cervical lymph node metastasis and those who undergo extensive lymph node dissection.

Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer

We have investigated protein kinase C (PKC) signaling, a putative differentiation-related and metastasis suppressor gene Cap43/NDRG1/Drg-1, and Y-box binding protein-1 (YB-1) to identify new molecular targeting for breast cancer. PKC is a family of serine/threonine kinases that is involved in the regulation of cell growth. We have demonstrated that PKC caused G1 arrest in a breast cancer cell line through a mechanism involving a PKC–ERK MAPK–JNK–Rb protein signaling pathway. We have also characterized a novel mechanism through which all-trans retinoic acid (ATRA) and antineoplaston, anticancer drug, caused cell growth inhibition in breast cancer cells through effects on intracellular pathways. ATRA decreased the expression of PKCα, as well as reduced ERK MAPK phosphorylation, and consequently caused G1 arrest. Antineoplaston caused the down-regulation of PKCα protein expression, resulting in inhibition of ERK MAPK phosphorylation, with resultant inhibition of Rb phosphorylation leading to G1 arrest. PKC signaling represents a promising target for development of novel therapeutic agents. Cap43 is known as N-myc downstream-regulated gene 1 (NDRG1). Treatment with estradiol (E2) significantly decreased the expression of Cap43 in ER-α-positive breast cancer cell lines. Co-administration of tamoxifen abrogated the E2-induced downregulation of Cap43 in ER-α-positive cell lines. These results suggested that Cap43 may hold the potential of being a molecular marker to determine the therapeutic efficacy of anti-estrogenic anticancer agents in breast cancer. YB-1 is a member of the cold shock domain protein family. The expression of nuclear YB-1 was correlated with HER2 positively in clinical specimens of human breast cancer. Immunostaining studies showed that nuclear YB-1 expression was an independent prognostic factor of overall survival. Expression of nuclear YB-1 played an essential role in acquirement of malignant characteristics through HER2-dependent pathways in breast cancer patients. PKC, Cap43 and YB-1 may be useful in new molecular-targeting diagnosis and therapeutics in breast cancer.

Breast ultrasound elastography and magnetic resonance imaging of fibrotic changes of breast disease: correlations between elastography findings and pathologic and short Tau inversion recovery imaging results, including the enhancement ratio and apparent diffusion coefficient.

Purpose Ultrasound (US) elastography provides information regarding tissue hardness and is expected to become a novel diagnostic tool for breast disease. In contrast, magnetic resonance (MR) images reflect the tissue characteristics. Fibrosis of the stroma of breast diseases may affect their hardness. We investigated the correlation among elasticity score (ES) and signal intensity of short Tau inversion recovery MR images, enhancement ratio, apparent diffusion coefficient (ADC), and the fibrosis in the breast lesions. Materials and Methods We reviewed the findings of US elastography and MR imaging from 41 consecutive patients with breast lesions (25 invasive ductal carcinoma, 3 fibroadenoma, 1 phyllodes tumor, 2 ductal hyperplasia, 2 primary malignant lymphoma, 3 mastopathy, 1 metastasis, 1 tubular adenoma, 1 ductal carcinoma in situ, 1 diabetic mastopathy, and 1 intraductal papilloma). In each patient, elastography images were classified based on Tsukuba ES. We calculated the ratio of signal intensity of the lesion to the muscle on short Tau inversion recovery images (L/M ratio), enhancement ratio of early to precontrast and early to delayed images, and ADC for each lesion. The ES and MR findings were correlated with the degree of fibrosis (based on Masson trichrome stain). Results The ES significantly correlated with the L/M ratio (P = 0.0306) and the ADC (P = 0.0256). The stromal fibrosis also correlated with ES (P = 0.0023), the L/M ratio (P = 0.0344), and enhancement ratio of the early-to-delayed images (P = 0.049). Conclusions The ES and L/M ratio are correlated significantly with each other, and they are correlated with the fibrosis. These results suggest that they will provide the information on the fibrosis and may help the diagnosis of breast lesions.

Usefulness of endoscopic breast-conserving surgery for breast cancer

PurposeWe compared the safety, invasiveness and cosmetic outcomes between endoscopic breast-conserving surgery (endoscopic group) and surgery under direct vision (direct vision group) for treating breast cancer.MethodsWe compared 100 cases of endoscopic surgery with 150 cases of direct vision surgery. The safety was evaluated in terms of the blood loss, length of the operation and presence or absence of complications, whereas the degree of invasiveness was assessed using preoperative and postoperative leukocyte counts, neutrophil counts, interleukin (IL-6) levels and fever. The cosmetic outcome was assessed on the basis of a breast evaluation by the medical staff and the patient’s subjective satisfaction.ResultsIn both groups, serious postoperative complications were absent. No significant differences were observed in the leukocyte counts, neutrophil counts, IL-6 level or fever between the groups. An evaluation of the cosmetic outcomes by the staff showed a more favorable breast size, breast shape and scar condition in the endoscopic group. A significantly higher level of patient satisfaction was also observed in the endoscopic group. Postoperative local recurrence was absent.ConclusionsThe endoscopic approach showed comparable safety and invasiveness, and provided better postoperative cosmetic outcomes than direct vision surgery. Our results suggest that endoscopic breast-conserving surgery is a potentially useful surgical method for the treatment of breast cancer.

Adenomyoepithelioma of the breast diagnosed by a mammotome biopsy: Report of a case

Adenomyoepithelioma is an uncommon primary breast tumor. It is conspicuous for two elements of the tumor, namely, ductal and myoepithelial components. Recently, a Mammotome biopsy, or stereotactic vacuum-assisted biopsy has become popular and various benign or borderline lesions are obtained. We report an adenomyoepithelioma of the breast in a 56-year-old woman. She was pointed out to have a cluster of some microcalcifications on mammography and a 9-mm hypoechoic mass lesion was detected by ultrasound. A Mammotome biopsy revealed a well-defined lesion. Histologically, the tumor demonstrated a thick and bi-cellular growth pattern consisting of ducts and myoepithelium. Immunohistochemically, epithelial cells were positive for cytokeratin AE1/AE3 and cytokeratin, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA), negative for alpha-smooth muscle actin (alpha-SMA). In addition, myoepithelial cells were positive for alpha-SMA and CEA, which were scatterly positive for cytokeratin AE1/AE3, and negative for EMA. In examinations of non-palpable lesions found on mammography and ultrasound, a Mammotome biopsy is useful for making diagnosis, however, and adenomyoepithelioma is rarely found. In diagnosing such a rare disease from the limited information obtained from a needle biopsy, an immunohistochemical study was thus found to be useful for making a differential diagnosis.

Lung adenocarcinoma metastasis to the male breast: a case report.

We report the case of a 60-year-old male patient who was diagnosed with metastasis from primary lung cancer to the breast. The patient presented with a mass in the right breast. Mammography, ultrasound, and magnetic-resonance imaging each suggested primary breast cancer. A core-needle biopsy of the right breast mass indicated poorly differentiated adenocarcinoma. A basic chest X-ray showed a shadow in the left upper lung. Thoraco-abdominal computed tomography revealed a mass with a diameter of 90 mm in the left superior region, the shape of which was indicative of primary lung cancer. A lung biopsy confirmed poorly differentiated adenocarcinoma. We diagnosed primary lung cancer with metastases to the bone, brain and right breast (cT2N3M1, stage IV) by imaging and histopathology. He was administered carboplatin (area under the curve 6 mg / ml) and paclitaxel (200 mg / m(2)) tri-weekly, and underwent gamma-knife treatment for the brain metastasis. The treatments reduced the primary tumor and the metastases. However, after completion of the fifth treatment cycle, he developed disseminated intravascular coagulation from septic shock, and died on the eleventh day after completing the fifth cycle of treatment. Although metastasis to the mammary gland is uncommon, especially among males, metastasis to the mammary gland should be considered when a mammary mass does not exhibit the typical characteristics of breast cancer. A correct diagnosis of metastasis to the mammary gland from lung cancer makes it possible to select the most appropriate treatment method.

Case report of a dose-volume histogram analysis of rib fracture after accelerated partial breast irradiation: interim analysis of a Japanese prospective multi-institutional feasibility study

We initiated the first multi-institutional prospective study of accelerated partial breast irradiation for early breast cancer in Japan. Our early clinical results showed that the treatment methods were technically reproducible between institutions and showed excellent disease control at a median follow-up of 26 months in our previous report. At present, total 46 patients from six institutions underwent the treatment regimen from October 2009 to December 2011, and the median follow-up time was 60 months (range, 57-67 months). In 46 patients, we experienced one patient who had rib fracture as a late complication. The dose-volume histogram (DVH) result of this patient was analyzed. The D0.01cc, D0.1cc, and D1cc values of the patient were 913, 817, and 664 cGy per fraction, respectively. These values were the highest values in 46 patients. The average D0.01cc, D0.1cc, and D1cc values of the other 45 patients were 546, 500, and 419, respectively, cGy per fraction. From this result, DVH values showing high-dose irradiated volume (D0.01cc, D0.1cc, and D1cc) seem to be a good predictive factor of rib fracture for accelerated partial breast irradiation. However, further investigation is necessary because of the small number of patients investigated.