Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Inflammatory myofibroblastic tumors of the breast with simultaneous intracranial, lung, and pancreas involvement: ultrasonographic findings and a review of the literature.

We encountered a case of inflammatory myofibroblastic tumor (IMT) of the breast with simultaneous intracranial, lung, and pancreas involvement. Here, we present the clinical imaging results and report the significance of sonographic findings of breast IMT along with a review of the literature. A 16-year-old girl with a history of subarachnoidal hemorrhage was admitted to our hospital due to tonic-clonic seizure. Computed tomography (CT) and magnetic resonance imaging (MRI) showed multiple intracranial, lung, and pancreas mass lesions and a solitary mass lesion in the right breast. Breast ultrasonography showed a circumscribed oval-shaped hypoechoic mass with a central hyperechoic region. Power Doppler sonography revealed an unusual spiral-shaped flow signal. Breast tumorectomy was performed for definitive diagnosis, and pathological analysis indicated IMT. A literature review indicated that ultrasonographic findings of IMT of the breast are nonspecific, as in other systems or organs. It would be difficult to make a diagnosis of IMT of the breast preoperatively due to its rarity and the lack of specificity of clinical imaging findings. In addition, it is better to consider the possibility of IMT of the breast especially in younger patients without an obvious family history of hereditary breast cancer.

Long-Term Follow-Up of Node-Negative Breast Cancer Patients Evaluated via Sentinel Node Biopsy After Neoadjuvant Chemotherapy.

BACKGROUND: Sentinel node biopsy (SNB) is used to accurately assess axillary lymph node status in patients with node-negative breast cancer. However, its use after neoadjuvant chemotherapy (NAC) is controversial. We retrospectively assessed the usefulness of SNB after NAC by comparing axillary recurrence rates and other parameters in patients with clinically node-negative breast cancer who underwent SNB after NAC or without NAC. PATIENTS AND METHODS: At our hospital, 1179 patients with clinically node-negative breast cancer underwent SNB from April 2007 to December 2013. The clinicopathological and survival data of patients who underwent SNB after NAC (the NAC group) and those who underwent SNB without NAC (the control group) were compared. Patients with a metastatic sentinel node underwent axillary lymph node dissection. RESULTS: The number of patients in the NAC and control groups was 183 (15.5%) and 996 (84.5%), respectively. At diagnosis, tumors were significantly larger in the NAC group (P < .0001). Sentinel nodes were identified in almost all patients in both groups (99.5% in the NAC group vs. 99.8% in the control group). They were nonmetastatic in 147 (80.8%) patients in the NAC group and 849 (85.5%) patients in the control group. At the median follow-up time of 51.1 months, 6 patients (0.6%) in the control group had axillary lymph node recurrence compared with no patients in the NAC group. CONCLUSION: SNB after NAC was as accurate as SNB without NAC in patients with clinically node-negative breast cancer. Axillary recurrence-free survival rates were excellent regardless of whether NAC was performed before SNB.

Primary ectopic breast cancer of the vulva, treated with local excision of the vulva and sentinel lymph node biopsy: a case report.

Primary breast cancer fairly infrequently occurs in ectopic breast tissue, and primary ectopic breast cancer of the vulva is particularly rare. Only 26 cases have been published in the English-language literature, and there has been no report of primary breast carcinoma of the vulva in Japan. We report a rare case of primary ectopic breast cancer of the vulva that was treated with local excision of the vulva and sentinel lymph node biopsy (SLNB). The patient was a 72-year-old woman who had noticed a right vulvar tumor 10 years earlier. The tumor was excised by the Department of Plastic Surgery of our hospital. The histology of the vulvar tumor revealed an invasive ductal carcinoma of the breast, and immunohistochemical staining of the vulvar specimen showed the tumor cells to be 100% estrogen-receptor-positive and 100% progesterone-receptor-positive. All margins of resection were positive for neoplastic involvement. An additional local excision of the vulva and right inguinal SLNB were performed in our department. The intraoperative frozen section was negative for metastasis, and lymph node dissection was not performed. The final pathology was negative for residual disease, and a partially normal ductal component was present. Adjuvant hormonal therapy with an aromatase inhibitor was indicated post-operatively. The patient was asymptomatic and free of detectable disease at a 6-month follow-up. Due to the rarity of this diagnosis, there are no established guidelines for treatment. Although cases in which SLNB was performed are rare, we consider SLNB to be an effective alternative to inguinal node dissection for ectopic primary breast cancer of the vulva.

Nonrecurrent inferior laryngeal nerves and anatomical findings during thyroid surgery: report of three cases.

A nonrecurrent inferior laryngeal nerve (NRILN) is found more frequently on the right side than on the left, and it is closely associated with an aberrant right subclavian artery. The presence of the aberrant right subclavian artery on preoperative computed tomography (CT) scan suggests NRILN; however, different types of branching locations and pathways exist. Here, we report three NRILN cases with different pathways where the vagus nerve arises more medial than usual and a review of the literature. Case 1: A 30-year-old Japanese female presented with papillary thyroid carcinoma. Preoperative CT scan revealed an aberrant right subclavian artery, and an operation was performed under suspicion of NRILN. During the operation, the vagus nerve was found to arise more medially than usual and two NRILNs originated from it at the level of the cricoid cartilage and at a more caudal position; the two NRILNs were preserved. Case 2: A 33-year-old Japanese female with a thyroid nodule of increased size underwent surgery. Preoperative CT scan revealed an aberrant right subclavian artery, which suggested NRILN. During the operation, the vagus nerve was identified to run more medially than usual and NRILN was found to originate at the level of the cricoid cartilage; NRILN was preserved. Case 3: A 78-year-old Japanese female underwent an operation with a diagnosis of papillary thyroid carcinoma. Preoperative CT scan showed an aberrant right subclavian artery. During the operation, NRILN was found to originate from the vagus nerve at the level of the lower pole of the thyroid gland, and the vagus nerve ran medial to the common carotid artery at the caudal level.

Intraoperative 99mTc-MIBI-guided detection of ectopic glands in secondary hyperparathyroidism.

99mTc-MIBI-guided detection of abnormal parathyroid glands in primary hyperparathyroidism (1-HPT) has become a popular and effective technique, but its efficacy for detecting the ectopic glands of secondary hyperparathyroidism (2-HPT) is still controversial. Of the 2-HPT cases from 2000 to 2004, 14 ectopic parathyroid glands in 11 patients were resected using intraoperative 99mTc-MIBI scintigraphy. We evaluated and compared the results of radioguided surgery with the preoperative findings from ultrasonography (US), computed tomography (CT), and scintigraphy. The overall results for intraoperative 99mTc-MIBI-guided detection of ectopic parathyroid glands were sensitivity of 100% (14/14) and accuracy of 84.2% (16/19) compared with 42.9% (6/14) and 31.6% (6/19), respectively, for preoperative US and 50.0% (6/12) and 42.9% (6/14), respectively, for preoperative 99mTc-MIBI scintigraphy. Using intraoperative 99mTc-MIBI-guided surgery in cases of 2-HPT will ensure all ectopic parathyroid glands are detected, making the surgery easier to perform and the outcome more successful.

Alpha-catenin is essential in intestinal adenoma formation.

A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line19-Apc(580D/+)) showed a remarkably reduced incidence of intestinal adenomas (<5% compared with other lines). Extensive genetic analysis identified a deletion in the alpha-catenin (Ctnna1) gene as the cause of this suppression. Notably, the suppression only occurred when the Ctnna1 deletion was in cis-configuration with the Apc580D mutation. In all adenomas generated in line19-Apc(580D/+), somatic recombination between the Apc and Ctnna1 loci retained the wild-type Ctnna1 allele. These data strongly indicate that simultaneous inactivation of alpha-catenin and Apc during tumor initiation suppresses adenoma formation in line19-Apc(580D/+), suggesting that alpha-catenin plays an essential role in the initiation of intestinal adenomas. Although accumulating evidence obtained from human colon tumors with invasive or metastatic potential has established a tumor-suppressive role for alpha-catenin in late-stage tumorigenesis, the role of alpha-catenin in the initiation of intestinal tumorigenesis is not well documented, especially compared with that of beta-catenin. A mouse model used in this study focused on the early stage of tumor initiation and clearly indicated an essential role for alpha-catenin. Thus, alpha-catenin has dual roles in intestinal tumorigenesis, a supporting role in tumor initiation, and a suppressive role in tumor progression.

Cytological and histological diagnoses of recurrent thyroid carcinoma with monoclonal antibody JT-95, which can detect modified fibronectin.

Although fine needle aspiration (FNA) cytology has increasingly gained importance as a tool in thyroid diagnosis over the recent years, up to 20% of thyroid carcinomas, in particular follicular tumors and follicular variant tumors, are inconclusive by FNA. The monoclonal antibody (MoAb) JT-95 detects the modified fibronectin, expressed in most thyroid carcinomas. Consequently, it has been applied to FNA and tissue section specimens obtained from thyroid tumors during surgery. For FNA specimens of 57 thyroid tumors followed-up for more than 10 years postoperatively and stained with both the Papanicolaou and the immunoperoxidase technique using MoAb JT-95, we retrospectively compared the sensitivity, specificity, and diagnostic accuracy of the two procedures. Histological specimens stained with HE and investigated by JT-95 were also re-evaluated. The pathological results of aspirated specimens, after a change in diagnosis following recurrence, revealed that 43 of 47 malignant lesions were positive, while nine of 10 benign tumors remained unreactive using MoAb JT-95. Sensitivity was 91.4%, specificity 90.0%, and diagnostic accuracy 91.2% by JT-95 cytology. By contrast, sensitivity ascertained by the Papanicolaou technique was 78.1%, specificity 100%, and accuracy 82.4%. Of the six examples that recurred during the 10-12-year follow-up period, tissue sections of all six and aspirated materials of five of the six were stained by JT-95.

Malignant melanoma originating on the female nipple: a case report.

We report a very rare case of malignant melanoma arising on a female nipple. A 42-year-old housewife had suffered from a small dark brown nevus on her left nipple for about thirty years without any changes. Six months before her initial visit it had begun to enlarge and rapidly changed from dark brown to black. A small bleeding ulcer was also present in the center of the lesion. Malignant melanoma rather than mammary Paget's disease was suggested based on its clinical course. Excisional biopsy was performed to differentiate between mammary Paget's disease and malignant melanoma. The histopathological examination revealed malignant melanoma, about 4 mm in thickness. She then underwent wide excision with axillary lymph node dissection. The surgical margin was made in a 3 cm radius around the biopsy site. The excision included nipple, areola, and part of the underlying breast parenchyma, adipose tissue and corresponding superficial layer of fascia. Microscopy showed metastasis in one of 13 axillary lymph nodes. After the operation, the patient received adjuvant DAV-Ferron therapy. In such a case, conserving surgery based on correct diagnosis can achieve a good cosmetic result and optimal tumor control.

Breast-conserving surgery after chemotherapy: value of MDCT for determining tumor distribution and shrinkage pattern.

OBJECTIVE: For this study, we investigated the usefulness of MDCT in assessing the extent of residual breast cancer after neoadjuvant chemotherapy. To ensure the success of breast-conserving surgery, we evaluated the usefulness of determining the tumor distribution before neoadjuvant chemotherapy and the shrinkage pattern after neoadjuvant chemotherapy. SUBJECTS AND METHODS: MDCT before and after neoadjuvant chemotherapy was performed in 46 consecutive patients with 47 locally advanced breast cancers. The distribution pattern of contrast enhancement on MDCT before neoadjuvant chemotherapy was classified into five categories: solitary lesion, grouped lesion (localized lesion with linear, spotty, or linear and spotty enhancement), separated lesion (multiple foci of contrast enhancement), mixed lesion (grouped lesion with multiple foci), and replaced lesion (diffuse contrast enhancement in whole quadrants). RESULTS: There was agreement between the MDCT assessment and pathologic findings in 44 (94%) of the 47 tumors. In the partial response group with nonreplaced lesions, MDCT revealed three shrinkage patterns: pattern 1a, concentric shrinkage without surrounding lesions; pattern 1b, concentric shrinkage with surrounding lesions; and pattern 2, shrinkage with residual multinodular lesions. Breast-conserving surgery was performed successfully in 14 patients including complete response cases that were detected on the basis of MDCT findings and partial response cases that were detected on the basis of observation of pattern 1 shrinkage. In all five patients with pattern 2 shrinkage, CT underestimated the residual tumor extent by more than 2 cm. CONCLUSION: MDCT classification of tumor distribution before neoadjuvant chemotherapy and of shrinkage patterns after neoadjuvant chemotherapy is important in the preoperative evaluation of patients undergoing breast-conserving surgery.

Successful combination therapy with trastuzumab and Paclitaxel for adriamycin- and docetaxel-resistant inflammatory breast cancer.

We present a case of adriamycin-and docetaxel-resistant inflammatory breast cancer (IBC) in which partial response was achieved with combination therapy using trastuzumab and paclitaxel. A 48-year old woman noticed a lump in her right breast. She was diagnosed with IBC and the disease was staged as T4d N1 M0, stage III B. The patient was started on neoadjuvant chemotherapy with adriamycin (50 mg/m2) and docetaxel (60 mg/m2) administered every three weeks. Six courses were performed and the response was evaluated as no change. After one month, contralateral breast swelling indicated bilateral IBC. Bilatera1 mastectomy using the Halsted method was performed. The immunohistochemical results of the Hercep Test was strongly positive (3+). After the mastectomy, right pleural effusion appeared, and cytological examination revealed the cells to be classV(adenocarcinoma). To treat the clinically advanced breast cancer, combination therapy with trastuzumab (initially 4 mg/kg followed by two or more cycles of 2 mg/kg) and paclitaxel (80 mg/m2) were given intravenously every week for eight cycles and then every two weeks thereafter. A total of 32 courses of therapy were performed, the pleural effusion completely disappeared and partial response was maintained for a duration of 482 days. The adverse reactions were mild, and it was possible for her to be treated as an outpatient with high quality of life. This report suggests that weekly combination therapy of trastuzumab and paclitaxel was useful for treatment of adriamycin-and docetaxel-resistant metastatic breast cancer.

Histologic breast cancer extent after neoadjuvant chemotherapy: comparison with multidetector-row CT and dynamic MRI.

PURPOSE: To evaluate the efficacy of dynamic multidetector-row CT (MDCT) in assessing residual cancer extent after neoadjuvant chemotherapy (NAC), and to compare MDCT results with those derived from dynamic three-dimensional MRI using the volumetric interpolated breath-hold examination (VIBE) sequence. MATERIALS AND METHODS: MDCT before and after NAC was performed in 19 consecutive patients with breast cancer. MRI was also performed before surgery. The early phase of MDCT and MRI was started 60 sec after commencing contrast injection. The late phase was started at a 4-min delay from the injection. The injection rate was 3 mL/sec. The distribution pattern of contrast enhancement (CE) by CT before NAC was classified into two groups: replaced lesion (diffuse CE in whole quadrants) and non-replaced lesion (localized CE). RESULTS: Pathological complete response (pCR) was obtained in one case. In replaced lesions, accuracy for the detection of tumor extent with a deviation of less than 2 cm in length was 0% (0/7) with early-phase CT/MRI and 100% (7/7) with late-phase CT/MRI. In non-replaced lesions, accuracy was 55% (6/11) with early-phase CT/MRI and 82% (9/11) with late-phase CT/MRI. One case of ductal carcinoma in situ (DCIS) could be detected only with late phase MRI. CONCLUSION: Late-phase images obtained by MDCT and MRI may be accurate in the diagnosis of residual cancer extent after NAC. The tumor distribution determined by MDCT before NAC is thought to be useful in the evaluation of shrinkage pattern following NAC.

Usefulness of radio-guided surgery using technetium-99m methoxyisobutylisonitrile for primary and secondary hyperparathyroidism.

The efficacy of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI)-guided surgery for detecting abnormal parathyroid glands in patients with secondary hyperparathyroidism (2-HPT) was evaluated and compared with the results from the same examination in patients with primary hyperparathyroidism (1-HPT). The results were also compared with those found by ultrasonography (US) and preoperative 99mTc-MIBI scintigraphy was also made. At operation 99mTc-MIBI accumulated in 64 nodules of 15 cases of 2-HPT, and all of 60 parathyroid swellings were detected (true-positives 60, sensitivity 100%, accuracy 94%). In the cases of 1-HPT, 99mTc-MIBI revealed 11 hot nodules in 10 cases, and the evaluation was true-positive 10, sensitivity 100%, and accuracy 91%. US and preoperative 99mTc-MIBI scintigraphy in patients with 2-HPT had a sensitivity of 75% and 67% and an accuracy of 70% and 66%, respectively. The usefulness of 99mTc-MIBI-guided surgery for detecting abnormal parathyroid tissue in 2-HPT patients was similar to that in 1-HPT patients but was superior to US and preoperative 99mTc-MIBI scintigraphy. Intraoperative 9mTc-MIBI for patients with 2-HPT is effective and makes the surgery easier, especially when the parathyroid glands are ectopic or when a few glands are markedly enlarged but the other glands are atrophied.

p73beta is regulated by protein kinase Cdelta catalytic fragment generated in the apoptotic response to DNA damage.

Protein kinase C (PKC) delta is cleaved by caspase-3 to a kinase-active catalytic fragment (PKCdeltaCF) in the apoptotic response of cells to DNA damage. Expression of PKCdeltaCF contributes to the induction of apoptosis by mechanisms that are presently unknown. Here we demonstrate that PKCdeltaCF associates with p73beta, a structural and functional homologue of the p53 tumor suppressor. The results show that PKCdeltaCF phosphorylates the p73beta transactivation and DNA-binding domains. One PKCdeltaCF-phosphorylation site has been mapped to Ser-289 in the p73beta DNA-binding domain. PKCdeltaCF-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation. By contrast, PKCdeltaCF-induced activation of p73beta is attenuated by mutating Ser-289 to Ala (S289A). The results also demonstrate that PKCdeltaCF stimulates p73beta-mediated apoptosis and that this response is attenuated with the p73beta(S289A) mutant. These findings demonstrate that cleavage of PKCdelta to PKCdeltaCF induces apoptosis by a mechanism in part dependent on PKCdeltaCF-mediated phosphorylation of the p73beta Ser-289 site.