Sadanori Matsuo

Aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin enhances liver damage in bile duct-ligated mice

The environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHR-target genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/1a2(-/-) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.

Primary Hyperparathyroidism with Thyroid Hemiagenesis

Thyroid hemiagenesis is a very rare anomaly. We herein report a case with right thyroid lobe agenesis, which was incidentally found during the assessment of primary hyperparathyroidism. A 42-year-old male presenting with urinary lithiasis was suspected of having primary hyperparathyroidism, and had elevated levels of both serum calcium and intact parathyroid hormone. Both computed tomography and ultrasonography demonstrated the absence of right thyroid lobe and a mass of 1 cm in diameter at the left lower pole of the thyroid. The patient underwent lower left parathyroidectomy, which confirmed the right thyroid hemiagenesis, as well as the absence of both upper and lower right parathyroid glands. The resected left lower parathyroid gland was pathologically diagnosed as adenoma. The postoperative course was favourable and he was discharged on the 2nd day after surgery, without complications.

CYP3A4 expression to predict treatment response to docetaxel for metastasis and recurrence of primary breast cancer

PurposeTumors expressing high levels of CYP3A4 are likely to have a poor treatment response to docetaxel (DOC), which is metabolized by CYP3A4. Tissue samples of recurrent breast cancer are sometimes hard to obtain just before treatment because the tumor is often difficult to access. Using immunohistochemistry, we measured CYP3A4 expression in primary lesions and compared their treatment responses to DOC with those of recurrent breast cancer lesions.MethodsThe subjects of this study were 42 patients who had undergone surgery for breast cancer, and had metastasis or recurrence treated by DOC (60 mg/m2 every 3 weeks). Tumor samples resected at surgery were immunostained for CYP3A4 and its expression levels were compared with the response rate to ongoing DOC treatment.ResultsPatients with CYP3A4-negative tumors (n = 19) showed a significantly higher response rate (63.2%) to DOC treatment than did those with CYP3A4-positive tumors (n = 23) (26.1%). The predictive value, negative predictive value, and diagnostic accuracy of CYP3A4 expression in the prediction response to DOC were 63.2%, 73.9%, and 68.6%, respectively.ConclusionsMeasuring CYP3A4 expression immunohistochemically in the primary breast cancer lesion was useful for predicting the treatment response to DOC of tumors that recurred after a long interval.

Menstruation recovery after chemotherapy and luteinizing hormone-releasing hormone agonist plus tamoxifen therapy for premenopausal patients with breast cancer.

PurposeLittle is known about the period required for menstruation recovery after long-term luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen therapy following chemotherapy. In this study we investigated the period required for menstruation recovery after the therapy.MethodsThe subjects comprised 105 premenopausal breast cancer patients who had undergone surgery. All patients were administered an LH-RH agonist for 24 months and tamoxifen for 5 years following the postoperative adjuvant chemotherapy, and the status of menstruation recovery was examined.ResultsMenstruation resumed in 16 cases (15.2%) after the last LH-RH agonist treatment session. The mean period from the last LH-RH agonist treatment to the recovery of menstruation was 6.9 months. The rate of menstruation recovery was 35.5% in patients aged 40 years or younger and 8.0% in those aged 41 years or older, and it was significantly higher in those aged 40 years or younger. The period until menstruation recovery tended to be longer in older patients at the end of treatment.ConclusionThis study showed that menstruation resumed after treatment at higher rates in younger patients. However, because it is highly likely that ovarian function will be destroyed by the treatment even in young patients, it is considered necessary to explain the risk to patients and obtain informed consent before introducing this treatment modality.

Atypical medullary carcinoma of the breast.

A 57-year-old woman was seen in our department for pain in the left breast, which had been noticed two months earlier. Her family history and past medical history were unremarkable. On arrival, a movable tumor 2 cm in diameter was palpated in the upper-outer-quadrant of the left breast. The ipsilateral axillary lymph nodes were not palpable. Blood chemistry results, including tumor markers, were normal. Mammography revealed a mass that had ill-defined borders and a higher central density with some spiculations in the left breast. The diagnosis was category 5 (Fig. 1). The tumor was seen by breast ultrasonography (Aplio, Toshiba, Tokyo, Japan) as a low echoic mass, 28 9 27 mm, with ill-defined borders, irregular margins, and internal heterogeneity. The anterior border was disrupted by tumor invasion (Fig. 2). Power Doppler US showed rich blood flow in the tumor (Fig. 3). Contrast-enhanced magnetic resonance imaging (MRI) showed the tumor as highly enhanced with irregular margins (Fig. 4). The time–intensity curve was an early peak and plateau pattern, suggesting malignancy. Pathological findings from a core needle biopsy revealed an infiltrating ductal carcinoma of the breast. Estrogen receptor (ER) and progesterone receptor (PgR) were positive, and the HER-2 score was 2?. No metastases were seen in the brain, lungs, liver, bones, abdominal cavity lymph nodes, infraclavicular lymph nodes, and axillary lymph nodes by computed tomography (CT) and bone scintigram. With a diagnosis of left breast cancer (T2N0M0 = Stage IIA), left quadrantectomy and biopsy of sentinel lymph nodes were performed. According to the intra-operative rapid pathological diagnosis, the sentinel lymph nodes were negative for metastasis. However, an intraductal carcinoma was noted at the resection margin on the papillary side of the resected breast tissue. Therefore, a pectoral muscle-sparing mastectomy was performed. The final pathological diagnosis was atypical medullary carcinoma (Fig. 5).