[Effectiveness of Lenvatinib for Thyroid Cancer with Lung Metastases - Report of a Case].

A 73-year-old woman visited our hospital 1 year 4 months ago because of multiple lung masses that were incidentally detected on CT. We subsequently conducted a whole body examination. Ultrasonography revealed multiple masses in her thyroid. We performed fine needle aspiration biopsy cytology(ABC), and the cytological diagnosis was papillary carcinoma. Total thyroidectomy and modified radical neck dissection were performed. Two months after the operation, cervical lymph nodes were enlarged, and she received I -131 radioisotope therapy. However, the lung masses became enlarged. Five months after operation, she was stared on lenvatinib therapy. The lung lesions did not progress during the 10 months after starting this therapy. In this case, lenvatinib was effective against metastatic thyroid cancer.

[Indoleamine 2,3-Dioxygenase Activity during Fulvestrant Therapy for Aromatase Inhibitor-Resistant Metastatic Breast Cancer].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) during fulvestrant therapy for aromatase inhibitor (AI)-resistant metastatic breast cancer. IDO activity can be measured by the tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured with high performance liquid chromatography (HPLC). Patients with AI resistant metastatic breast cancer had a 28.6% response rate to fulvestrant therapy, and the clinical benefit rate was 76.2%. AI-resistant metastatic breast cancer patients with distant metastases had a lower serum Trp/Kyn level than patients who had local recurrences. During fulvestrant therapy, IDO activity significantly decreased in the fulvestrant responder group compared to that in the fulvestrant non-responder group. During fulvestrant therapy, the IDO activity correlated with the number of metastatic lesions. These results suggest that measuring the Trp/Kyn ratio is useful for evaluating immunological metastatic status during endocrine therapy.

[PSK decreased FOLFOX4-induced peripheral neuropathy and bone marrow suppression in patients with metastatic colorectal cancer].

FOLFOX4 has been proven to be effective for metastatic colorectal cancer and is now used as a postoperative adjuvant therapy. However, adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common, and this may necessitate a change of chemotherapy regimen even though FOLFOX is effective. PSK, a polysaccharide derived from mushrooms, has been developed in Japan as an immune-enhancing agent, and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy. FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, po) were given to 25 patients with metastatic (19 hepatic, 3 pulmonary and 3 peritoneal) colorectal cancer. There was no CR (0%), while PR, SD and PD were 48, 36 and 16%, respectively. The response rate was 48%, and the disease control rate was 84%. There were significantly lower frequencies of adverse effects in comparison with published data. Grades 1 and 3 neutropenia occurred in 48 and 24%, respectively, of the patients; grades 1 and 3 nausea in 48 and 4%; and grades 1, 2 and 3 sensory neurotoxicity in 52, 4 and 0%. No patient dropped out due to adverse effect in this study. PSK plus FOLFOX4 seemed to be as effective as FOLFOX4 monotherapy as has been published, and significantly less toxic. These results suggest that this combination therapy may be more effective than FOLFOX4 monotherapy when given over a longer period, with a lower incidence of adverse effects.

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

PURPOSE: Tumors 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. METHODS: The subjects of this study were 42 patients who had undergone surgery for breast cancer, and had metastasis or recurrence treated by DOC (60 mg/m(2) 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. RESULTS: Patients 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. CONCLUSIONS: Measuring 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.

PURPOSE: Little 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. METHODS: The 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. RESULTS: Menstruation 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. CONCLUSION: This 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.

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-1ß, 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.

[A case of advanced breast cancer with skin ulceration successfully treated with paclitaxel and toremifene therapy].

We report a case of advanced breast cancer with skin ulceration and bleeding (T4bN3bM0, Stage IIIC) achieving a significant improvement of QOL by paclitaxel (PTX) and toremifene (TOR) therapy. The patient was a 31-year-old woman who had ulcerative breast lump with skin ulcer. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. She received 4 courses of tri-weekly CEF (C: 500 mg, E: 60 mg, F: 500 mg/m2/tri-weekly) and 4 courses of weekly PTX (80 mg/m2) with TOR (120 mg/day). The bleeding from the tumor disappeared after CEF chemotherapy. The response for breast tumor after PTX and TOR therapy was evaluated as partial response, and the infraclavicular, subpectoral, and interpectoral lymph nodes metastasis disappeared. Muscle-preserving radical mastectomy (Bt+Ax: Auchincloss) without skin transplantation were performed. She had no recurrence during one year after operation. PTX and TOR therapy were effective for advanced breast tumor, and can improve patient QOL and the clinical outcomes in Stage IIIC advanced breast cancer.

[Indoleamine 2,3-dioxygenase activity during chemotherapy in patients with breast cancer].

We evaluated the significance of indoleamine 2, 3-dioxygenase (IDO) in recurrent breast cancer during chemotherapy. IDO activity can be measured by tryptophan (Trp)/kynurenine (Kyn) ratio. Trp and Kyn were measured by high performance liquid chromatography (HPLC). The correlations among age and Trp/Kyn ratio or immunosuppressive acidic protein (IAP) value in pre-chemotherapies or post-chemotherapies were studied. In under 35-year-old patients, there were no correlations between pre-chemotherapy and post-chemotherapy in IAP values and Trp/Kyn ratio. But in over 36-year-old patients, both Trp/Kyn ratio and IAP value in post-chemotherapy were higher than in pre-chemotherapy. These results suggest that the immunological damages for the patients during chemotherapy may depend on the age of patients.

[The combined effect of paclitaxel and toremifene therapy for metastatic breast cancer].

A comparison of paclitaxel (PTX) alone with PTX+toremifene (TOR) in hormone receptor negative metastatic breast cancer (MBC) patients was conducted to determine the therapeutic value of adding TOR to a PTX regimen. Eight MBC patients received 80 mg/m2 PTX weekly (PTX group) and six MBC patients received the same weekly dose of PTX plus 120 mg/day TOR daily (PTX+TOR group). Patients were repeatedly treated with a combination of PTX and TOR as long as a disease progression or unmanageable severe adverse events were defined. The PTX group was compared with the PTX+TOR group with respect to best overall response, response rate, clinical benefit rate, time to progression, adverse events and toxic profile of PTX and TOR. No significant difference in response rate was observed between the PTX group and the PTX+TOR group. However, a clinical benefit rate and time to progression improved significantly in the PTX+TOR group in comparison with the PTX group. TOR did not significantly enhance the adverse events of PTX. These results suggested that the combined treatment of PTX and TOR for MBC patients improved a patient response over PTX alone.

[Treatment strategy of breast carcinoma in the elderly patient-surgery, hormone therapy, and chemotherapy].

We report an elderly breast carcinoma patient with complication. The patient was a 91-year-old woman who had breast lump. The tumor was 3 cm in diameter. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and positive for HER2/neu protein expression. She received tumorectomy. After operation, she was administered aromatase inhibitor. After six months from operation, metastases of lymph nodes and lung were observed. Although she had administered another aromatase inhibitor, the metastases were rapidly growing. Eight months after operation, she died from carcinomatous lymphangitis. Even the less invasive operation by local anesthesia can progress metastases rapidly in elderly breast cancer patients. This case suggested that a treatment strategy for elderly breast cancer patients should have been determined carefully.

Vitamin D3 modulates the expression of bile acid regulatory genes and represses inflammation in bile duct-ligated mice.

Vitamin D receptor (VDR), a nuclear receptor that regulates calcium homeostasis, has been found to function as a receptor for secondary bile acids. Because the in vivo role of VDR in bile acid metabolism remains unknown, we investigated the effect of VDR activation in a mouse model of cholestasis. We treated mice with 1alpha-hydroxyvitamin D(3) [1alpha(OH)D(3)] after bile duct ligation (BDL) and examined mRNA expression and cytokine levels. 1alpha(OH)D(3) treatment altered the expression of genes involved in bile acid synthesis and transport in the liver, kidney, and intestine but did not decrease bile acid levels in the plasma and liver of BDL mice. 1alpha(OH)D(3) treatment suppressed mRNA expression of proinflammatory cytokines in the liver and strongly decreased the plasma levels of proinflammatory cytokines in BDL mice. These findings indicate that 1alpha(OH)D(3) regulates a network of bile acid metabolic genes and represses proinflammatory cytokine expression in BDL mice. VDR ligands have the potential to prevent the cholestasis-induced inflammatory response.

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.

[A case of advanced breast cancer with meningeal carcinomas and orbital metastasis successfully treated with multi-disciplinary therapy].

We report a case of advanced breast cancer with meningeal metastasis and orbital metastasis (T4bN3cM1, Stage IV) achieving a significant improvement in QOL by multi-disciplinary therapy. The patient was a 51-year-old woman who had headaches and an ulcerative breast lump with meningeal metastasis and orbital metastasis. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for HER2/neu protein expression. She received 9 cycles of weekly trastuzumab and radiation therapy for meningeal metastasis and orbital metastasis. Although the size of breast tumor, orbital metastasis lesion, and meningeal metastasis lesion exhibited no change, clinical symptoms were improved. One year later, she received paclitaxel so that the sensitivity of HER2/neu dropped. However, the tumor markers relapsed and we then changed paclitaxel to TS-1. Eighteen-months later, she had no neurological symptoms. Multi disciplinary therapy can improve patient's QOL and the clinical outcomes in Stage IV advanced breast cancer.

[A case of breast cancer detected by MRI mammography after Hollywood syndrome].

A-64-year-old woman, who had been treated with augmentation mammaplasty 40 years ago, came to our hospital complaining of left breast pain. The mass was ill-defined, located in the upper outer quadrant area of her breast, and was 2 cm in diameter. MRI examination showed that the tumor had a spiculation and an irregular edge. There were no regional lymph nodes in her axilla and supra-subscapular. The diagnosis was Class IV by the fine needle aspiration biopsy cytology. We diagnosed the left breast cancer being in T2N0M0, Stage IIA, then we carried out Bt (Auchincloss method) and Sentinel lymph node biopsy (SLNB). There were metastatic cancer cells in the sentinel lymph node. So, we added level II lymph nodes dissection. The histological diagnosis was papillotubular carcinoma, f+, n+ (8/11). The endocrine receptor status of the tumor was ER+, PgR+ and the HER2/neu score was 0. There was paraffinoma in the non-cancer area. We dosed 6 cycles of FEC chemotherapy (CPA 800 mg, EPI 80 mg, 5-FU 750 mg/body x 1 cycle). We recognized no side effects of the chemotherapy for the patient.

[A case of advanced breast cancer with multiple lung and liver metastases successfully treated with multi-disciplinary therapy].

We report a case of advanced breast cancer with multiple lung and liver metastases (T4bN1M1) achieving a significant improvement of QOL by multi-disciplinary therapy. The patient was a 63-year-old woman with slight jaundice who had ascites and an ulcerative breast lump with multiple lung and liver metastases. A core needle biopsy for breast tumor led to a diagnosis of an invasive ductal carcinoma positive for HER2/neu protein expression. She received 6 cycles of tri-weekly docetaxel (60 mg/m2) and weekly trastuzumab. Although the ascites and the jaundice disappeared after chemotherapy, the response for breast tumor, metastatic sites in the lung and the liver were less satisfactory. Fifteen-months later, she received radiation therapy so that metastasis in the brain was recognized. But she had no neurological symptoms. Multi-disciplinary therapy can improve patient's QOL and the clinical outcomes in Stage IV advanced breast cancer.

[Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer].

We evaluated the clinical significance of indoleamine 2,3-dioxygenase (IDO) in breast cancer. Operative specimens obtained from 30 patients with breast cancer were investigated by semiquantitative RT-PCR with specific primers against IDO. The correlations among IDO expression, clinicopathologic factors and prognosis were studied. The expression of IDO was observed in 100%, both of the cancer specimens and the non-cancer specimens. The IDO expression of the cancer specimens was higher than the non-cancer specimens. The expression of IDO did not correlate to histologic classification, tumor size, lymphatic invasion, venous invasion and lymph nodes metastasis, but correlated to clinical stage and the serum level of immunosuppressive acidic protein (IAP). There were no correlations for a survival rate after surgery between the high IDO level group and the one. The serum IDO levels of cancer patients were higher than that of a healthy volunteer measured by semiquantitative RT-PCR and HPLC. It is suggested that the expression of IDO in breast cancer patients may play a critical role for immunosuppression in those patients.