Neuroendocrine tumor of the breast showing invasive micropapillary features and multiple lymph node metastases.

BACKGROUND: Herein, for the first time, we present a case with mixed invasive micropapillary and neuroendocrine mammary neoplasm. CASE: The patient, a 65-year-old postmenopausal woman, had become aware of a tumor in her right breast 11 months prior to presentation at our hospital. The cut surface of the mastectomy specimen contained a well-circumscribed, multinodular, red-brown tumor, measuring 15x15x15 cm. Histopathologically, this solid cystic lesion consisted of medullary growth of cancer cells accompanied by a well-developed vascular network as well as conspicuous hemorrhage. Cancer cell nests of various sizes displayed an "inside-out" structure surrounded by empty spaces. Most cancer cells were polygonal, though a few were short fusiform-shaped, and possessed finely granular, eosinophilic cytoplasm and ovoid, fine-granular nuclei. Eighteen mitotic figures were observed in 10 high-power fields. Macrometastases, up to 13x8 mm in size, with the same morphological features as the original tumor site, were identified in 3 of 15 dissected right axillary nodes. Immunohistochemically, primary and metastatic cancer cells were diffusely positive for chromogranin A and the estrogen receptor (Allred's total score: 8) and focally reactive for synaptophysin and the progesterone receptor (total score: 5). HER2 and cytokeratin 5/6 were negative, and the MIB-1 labelling index was 36.2%. MUC1 and EMA lined the stroma-facing surfaces of the cell membranes, indicating reversed polarity. CONCLUSION: Our current patient, who had an invasive breast carcinoma with concomitant neuroendocrine and micropapillary features, developed multiple nodal metastases in association with a large-diameter tumor showing a luminal B-like immuno-profile. Accordingly, meticulous clinical follow-up remains essential for this uncommon case.

A case of Turner's syndrome with Graves' disease and primary hyperparathyroidism.

We report a 21-year-old woman with Turner's syndrome, Graves' disease and primary hyperparathyroidism. At 12 years of age, she was of short stature, and was diagnosed with Turner's syndrome and treated with growth hormone. At the age of 17 years, she was diagnosed with Graves' disease. On treatment with methimazole, her laboratory findings normalized. At the age of 20 years, her serum calcium and intact parathyroid hormone levels were high. The upper left parathyroid gland showed swelling and was resected, and adenoma was diagnosed pathologically. Then, primary hyperparathyroidism induced by the adenoma was diagnosed. After the parathyroidectomy, the patient's serum calcium and intact parathyroid hormone levels normalized. Is likely that Turner's syndrome and Graves' disease were not associated with primary hyperparathyroidism. Multiple endocrine neoplasia type 1 was unlikely considering the clinical, laboratory, ultrasonographic, and scintigraphic findings.

A Real-World Retrospective Cohort Study of Combined Therapy with Bevacizumab and Paclitaxel in Japanese Patients with Metastatic Breast Cancer.

OBJECTIVE: Combined therapy with bevacizumab and paclitaxel (BP regimen) as a first-line treatment has proven highly effective with good tolerance for patients with metastatic breast cancer (MBC). The objective of this study was to examine the efficacy and safety of the BP regimen for Japanese patients with MBC in real-world clinical settings. METHODS: From June 2012 through May 2014, we recruited 94 patients at 10 medical institutions. The primary endpoint was time to treatment failure (TTF), and the secondary endpoints were overall survival (OS) and safety. Objective response was assessed according to the Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0-Japan Clinical Oncology Group. RESULTS: Nighty patients with MBC (mean 58 years, range: 34-80 years) were enrolled, and 60 (66.6%) and 52 (57.7%) had undergone prior chemotherapy as adjuvant treatment and treatment for MBC, respectively. Median TTF was 6.2 months (95% confidence interval [CI], 4.2-8.3 months), and median OS was 15.4 months (95% CI, 12.0-18.9 months). The overall response rate was 67.8% (95% CI: 57.1-77.2%). A total of 28 patients (31.1%) required a dose reduction of paclitaxel. Forty-five, 42, and 3 patients received the initial doses of 90, 80, and 60 mg/m2, respectively. Among patients who received the initial doses of 90 mg/m2, 13 patients (28.9%) unexpectedly required a dose reduction of ≥20 mg/m2. The BP regimen was discontinued for 66 (73.3%) of the 90 patients, 52 (57.7%) of whom experienced "disease progression." Grade 3/4 hematologic AEs developed in 51 patients (56.6%), with leukopenia and neutropenia in 16 patients (17.8%) and 21 patients (23.3%), respectively. Grade 3 nonhematologic AEs developed in 8 patients (8.9%), with the most common nonhematologic AE of peripheral neuropathy in 4 patients (4.4%). No Grade 4 nonhematologic AEs developed. Peripheral neuropathy [56 patients (62.2%) ], nail discoloration [53 patients (58.9%) ], and fatigue [51 patients (56.7%) ] were the most predominant AEs-the known AEs of paclitaxel. CONCLUSIONS: The BP regimen was active and well tolerated in the real-world clinical settings. As many as 28.9% of patients who received the initial dose of 90 mg/m2 required a dose reduction of paclitaxel by 20 mg/m2. Therefore, there is a need to find a therapeutic regimen that is less likely to result in dose reductions for patients with MBC who undergo a BP regimen using the initial paclitaxel dose of 90 mg/m2.

[Two cases of unresectable advanced gastric cancer treated with S-1, CDDP and trastuzumab].

We report two cases of unresectable advanced gastric cancer treated with S-1, CDDP and trastuzumab. A significant reduction of tumors was observed in these cases. A 77-year-old man was diagnosed as unresectable gastric cancer. The pathological diagnosis was tub2 and human epidermal growth factor receptor 2(HER2)positive(3+IHC method). We started chemotherapy(S-1+CDDP+trastuzumab). After 2 courses of S-1+CDDP, the findings of upper gastrointestinal endoscopy and CT were much improved to PR. But after 6 courses of S-1+CDDP, they worsened to PD. The regimen of chemotherapy was changed to weekly paclitaxel. The other patient, a 68-year-old woman, was diagnosed as far advanced gastric cancer. The pathological diagnosis was tub2=por2 and HER2 positive(3+IHC method). We started chemotherapy(S- 1+CDDP+trastuzumab). After 3 courses of S-1+CDDP, the tumor reduced significantly to PR. We continued this regimen. From the result of the ToGA trial, addition of trastuzumab to chemotherapy(capecitabine+CDDP or fluorouracil+CDDP) has been recommended as a new standard first-line regimen for HER2-positive advanced gastric cancer. But there is no evidence that trastuzumab added to the other regimen improved survival in patients with advanced gastric cancer. It is necessary to conduct a clinical trial to evaluate the treatment effect of this chemotherapy.

A large deletion in the succinate dehydrogenase B gene (SDHB) in a Japanese patient with abdominal paraganglioma and concomitant metastasis.

Recently, mutations in nuclear genes encoding two mitochondrial complex II subunit proteins, Succinate dehydrogenase D (SDHD) and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that the mutation of SDHB is highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma). In the present study, we used multiplex ligation dependent probe amplification (MLPA) analysis to identify a large heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, in addition to exon 1 and exon 2 malignant paraganglioma patient in whom previously characterized SDHB mutations were undetectable. This is the first Japanese case report of malignant paraganglioma, with a large SDHB deletions. Our present findings strongly support the notion that large deletions in the SDHB gene should be considered in patients lacking characterized SDHB mutations.

Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy.

CONTEXT: About 10% of pheochromocytomas are malignant. Exact survival has not been reported, nor has an analysis of the efficacy of chemotherapy on survival time. OBJECTIVE: The aim of this study was to analyze the survival curves and survival times of patients with malignant pheochromocytoma and to determine the efficacy of chemotherapy on prolongation of life. DESIGN: An inception cohort and Kaplan-Meier survival analysis was conducted. PATIENTS AND OUTCOME MEASURES: Thirty-two patients with metastasized malignant pheochromocytoma were analyzed for survival. Twenty-five patients had undergone excision of their primary tumors. Survival curves were compared among the 16 patients in this group treated with combined chemotherapy using cyclophosphamide, vincristine and dacarbazine (CVD) and the nine patients not treated with chemotherapy. RESULTS: The survival curve of the 32 patients declined continuously and linearly to at least 20 yr after the diagnosis of pheochromocytoma. The 50% survival rate was estimated to be 14.7 yr. In the 25 patients whose primary tumor was excised, patients who already had metastases at the time of pheochromocytoma diagnosis had better survival than those whose metastases were found later. The survival rate after diagnosis of metastasis was worse in the CVD group than in controls. When the effects of CVD were examined after stratifying several factors, female gender and adrenal origin of tumor were found to be negative prognostic factors for CVD chemotherapy. CONCLUSION: The present study revealed a long survival time. CVD chemotherapy was not shown to extend survival, especially for women and patients with adrenal gland-derived primary tumors.

Differential diagnosis and appropriate treatment of four thyrotoxic patients with Graves' disease required to take amiodarone due to life-threatening arrhythmia.

We report the treatment of four thyrotoxic patients. Two were cases of type I amiodarone-induced thyrotoxicosis (AIT) treated with methimazole. The third Graves' disease patient, who became hypothyroid 25 years after subtotal thyroidectomy, developed type II AIT. Furthermore, one case with heart failure and ventricular tachycardia, who developed an adverse reaction to antithyroid agents and was prescribed amiodarone, underwent total thyroidectomy. The clinical course was uneventful, and the patient is doing well. Since amiodarone contains a large amount of iodine, it is frequently difficult to make a differential diagnosis. Surgical treatment of Graves' disease patients is recommended when immediate control of hyperthyroidism and heart failure is required.

Water-clear cell parathyroid adenoma causing primary hyperparathyroidism in a patient with neurofibromatosis type 1: report of a case.

Water-clear cell parathyroid adenoma is an exceedingly rare tumor, composed exclusively of tumor cells with abundant foamy cytoplasm. A combination of hyperparathyroidism and neurofibromatosis type 1 (NF1) is also a rare phenomenon. We report an 18-year-old woman with primary hyperparathyroidism caused by water-clear cell parathyroid adenoma in association with NF1. She had renal stones, hypercalcemia, and an elevated plasma level of intact parathyroid hormone. Physical examination revealed a palpable tumor in the right neck, and café-au-lait spots distributed over her entire body. An ultrasound examination showed an isoechoic mass in the right thyroid lobe. Thallium-technetium subtraction scintigraphy showed high thallium accumulation in the right thyroid lobe area. A surgical exploration revealed the palpable mass to be a parathyroid tumor. The pathological features were consistent with water-clear parathyroid adenoma. This is the first reported case of water-clear cell parathyroid adenoma associated with NF1.

Phonatory function of the elderly determined by intensity-loading test: a comparison with the young.

OBJECTIVE: The goal was to test the hypothesis that the elderly have diminished laryngeal regulation capability, so we investigated phonatory function in the elderly and young using a sound pressure-loading test. STUDY DESIGN AND SETTING: In 36 healthy men (17 in their 20s, 19 in their 70s) and 45 healthy women (22 in their 20s, 23 in their 70s), fundamental frequency, sound pressure level, mean flow rate (MFR), and expiratory lung pressure (EP) were determined from phonatory function testing. Subjects phonated at a comfortable level and at high intensity, without changing vocal pitch. RESULTS: MFR, EP, and airway resistance increased with high-intensity phonation in the young; however, only MFR and EP increased in the elderly. CONCLUSIONS: The findings supported our hypothesis: with high-intensity phonation, the elderly undergo unchanged laryngeal regulation but a greater degree of expiratory regulation. SIGNIFICANCE: The elderly are likely to become tired due to the effort required for phonation.

Probability of axillary lymph node metastasis when sentinel lymph node biopsy is negative in women with clinically node negative breast cancer: a Bayesian approach.

BACKGROUND: Although sentinel lymph node biopsy(SLNB)is highly accurate in predicting axillary nodal status in patients with breast cancer, it has been shown that the procedure is associated with a few false negative results. The risk of leaving metastatic nodes behind in the axillary basin when SLNB is negative should be estimated for an individual patient if SLNB is performed to avoid conventional axillary lymph node dissection(ALND). METHODS: A retrospective analysis of 512 women with T1-3N0M0 breast cancer was conducted to derive a prevalence of nodal metastasis by T category as a pre-test(i.e., before SLNB)probability and to examine potential confounders on the relationship between T category and axillary nodal involvement. Probability of nodal metastasis when SLNB was negative was estimated by means of Bayes' theorem which incorporated the pre-test probability and sensitivity and specificity of SLNB. RESULTS: Axillary nodal metastasis was observed in 6.1% of T1a-b, 25.1% of T1c, 28.7% of T2, 35.0% of T3 tumors. Point estimates for the probability of nodal involvement when SLNB was negative ranged from 0.3-1.3% for T1a-b, 1.6-6.3% for T1c, 2.0-7.5% for T2, and 2.6-9.7% for T3 tumors with representative sensitivities of 80%, 85%, 90% and 95%, respectively. The risk may be higher when the tumor involves the upper outer quadrant of the breast, while it may be lower for an underweight woman. CONCLUSIONS: The probability of axillary lymph node metastasis when SLNB is negative can be estimated using a Bayesian approach. Presenting the probability to the patient may guide the decision of surgery without conventional ALND.

Adrenal-preserving laparoscopic surgery in selected patients with bilateral adrenal tumors.

BACKGROUND: There have been few reports of laparoscopic adrenal-sparing surgery for bilateral adrenal tumors. We review our experience with this type of surgery with the aim of evaluating its feasibility and safety. METHODS: Over a 4-year period, we treated 9 patients with bilateral benign adrenal tumors. Seven patients had bilateral pheochromocytomas (MEN 2: 5, VHL: 1, sporadic: 1), and 2 patients had Cushing's syndrome caused by bilateral adrenocortical adenomas. Laparoscopic procedures were performed by a flank approach. The mean diameter of the tumors was 3.7 cm (range, 2.0-8.5 cm). RESULTS: All the tumors were removed laparoscopically. Four patients with hereditary pheochromocytomas underwent bilateral total adrenalectomy because of the large tumor size and multiplicity. The other 5 patients were treated successfully with preservation of adrenocortical function. In 4 of these 5 patients, the adrenal tumors were 3 cm or less in diameter. None of the patients experienced surgical complications. At a mean follow-up of 16 months (range, 4-40 months), none of the 5 patients who were treated by adrenal-sparing surgery required corticosteroid replacement. CONCLUSION: Laparoscopic surgery is feasible for the treatment of bilateral adrenal tumors. Adrenal-preserving laparoscopic surgery may be practicable for the removal of these tumors, if the tumor on either side is 3 cm or less in diameter; however, our follow up is short (mean, 16 months).