Activation of transcription factor HIF inhibits IL-1ß-induced NO production in primary cultured rat hepatocytes.

Roxadustat and other hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have recently been approved for the treatment of chronic renal anemia. In macrophages and monocytes, the activation of HIF-1 by pro-inflammatory cytokines induces iNOS expression and activity through the NF-κB pathway to produce nitric oxide (NO), which causes liver injury when excessively produced. Few studies have reported a relationship between HIF activity and iNOS induction in hepatocytes. We investigated the effect of drug- and hypoxia-induced HIF activations on NO production in primary cultured rat hepatocytes. Roxadustat treatment and hypoxic conditions activated HIF. Contrary to expectations, HIF-PHI treatment and hypoxia inhibited IL-1ß-induced NO production. RNA-Seq analysis of mRNA expression in rat hepatocytes showed that roxadustat treatment decreased the expression of genes related to inflammation, and genes in the NF-κB signaling pathway were induced by IL-1ß. Moreover, roxadustat suppressed IL-1ß-activated signaling pathways in an HIF-dependent manner. GalN/LPS-treated rats were used as in vivo models of hepatic injury, and roxadustat treatment showed a tendency to suppress the death of rats. Therefore, exogenous HIF-1 activation, including HIF-PHI and hypoxia exposures, suppressed IL-1ß-induced iNOS mRNA expression and subsequent NO production in hepatocytes, by suppressing the NF-κB signaling pathway. Roxadustat treatment suppresses the expression of pro-inflammatory genes by activating HIF, and thus may exhibit hepatoprotective effects.

[Radiation-Induced Breast Angiosarcoma after Conservative Surgery for Breast Cancer].

We present the case of an 88-year-old woman who had undergone breast conserving surgery for left breast cancer 8 years ago.She received postoperative radiotherapy(total dose of 60 G/30 Fr)to the residual breast together with endocrine therapy.She underwent skin biopsy after having had a red skin tumor in the left breast.Angiosarcoma was diagnosed and chemotherapy and radiotherapy were initiated.The patient is alive without recurrence 8 months after chemotherapy.

[The Approach of Breast Reconstruction for Breast Cancer in Our Hospital].

The demand for breast reconstruction is expected to increase with the currently observed increase in the number of breast cancer patients. Among the 70 patients included in the study, 59 received tissue expanders, 1 received implant, and 10 received deep inferior epigastric perforator flaps. Complications were noted in is 11 patients who received tissue expanders. In this study, age>50 years and smoking were associated with higher rates of complication. Choosing an appropriate method for breast reconstruction is important. In addition with plastic surgery, an approach to reduce complications will be necessary in future.

[A Case of Pulmonary Tumor Thrombotic Microangiopathy(PTTM)Diagnosed During Chemotherapy for Metastatic Breast Cancer].

A 46-year-old woman with metastatic breast cancer developed dyspnea that progressed relatively rapidly during chemotherapy. Chest-abdominal CT revealed wedge-shaped infiltration shadow, and cardiac catheterization revealed elevated pulmonary artery pressure. Aspiration cytology of pulmonary arterial blood was performed and malignant cells were confirmed. Chemotherapy was difficult to continue because of deterioration in general condition, and she died 7 days after diagnosis. This time, we report a case of PTTM for which pulmonary arterial blood cytology was useful for diagnosis.

[A Case of Ductal Carcinoma In Situ(DCIS)Diagnosed by Excisional Biopsy with Benign Cytology Findings of Fine-Needle Aspiration].

Nipple discharge is a common symptom and frequently results from benign tumors. However, there is a 5-30% risk of malignancy. A 65-year-old woman presented at the hospital because of bloody nipple discharge in her right breast. She had noticed an abnormal nipple discharge for several months. Mammography showed focal asymmetric densities without calcification in the middle outer quadrant of her right breast. Ultrasonography indicated a 1.5×1.1 cm sized cyst with fluid-fluid level. Breast MRI showed a simple cyst with a benign contrast enhancement pattern. No malignant cells were observed by fine-needle aspiration. Considering the low sensitivity of mammography and breast MRI to DCIS, we performed an excisional biopsy. Histological examination revealed that the lesion was DCIS. The patient underwent right total mastectomy and was diagnosed with low grade DCIS(ER-positive, PgR-positive, HER2-negative). She continues endocrine therapy with an aromatase inhibitor.

A Phase II Study of Adjuvant Chemotherapy of Tegafur-Uracil for Patients with Breast Cancer with HER2-negative Pathologic Residual Invasive Disease After Neoadjuvant Chemotherapy.

BACKGROUND: There is no consensus on the need for adjuvant chemotherapy for patients with pathological residual invasive breast cancer (non-pCR) after neoadjuvant chemotherapy (NAC). We evaluated the tolerability and safety of tegafur-uracil (UFT) as adjuvant chemotherapy for patients with human epidermal growth factor receptor 2-negative breast cancer that resulted in non-pCR after NAC. PATIENTS AND METHODS: We treated patients with 270 mg/m2 UFT per day for 2 years after definitive surgery and radiotherapy, if necessary. In cases with hormone-sensitive cancer, patients received concurrent endocrine therapy. The primary end-point was the rate of completion of scheduled UFT therapy. Secondary end-points included safety and disease-free survival. RESULTS: Twenty-one out of 29 patients (72%) completed the scheduled therapy. Eight patients discontinued the study treatment because of disease recurrence, toxicities, and patients' wish. Excluding liver dysfunction, adverse events were quite mild. CONCLUSION: Adjuvant UFT therapy after NAC was feasible and safe.

Outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer.

The purpose of this study was to retrospectively analyze the feasibility of outpatient management without initial assessment for febrile patients undergoing adjuvant chemotherapy for breast cancer. A total of 131 consecutive patients with breast cancer treated with adjuvant or neoadjuvant chemotherapy from 2011 to 2013 at Osaka Medical College Hospital (Osaka, Japan) were retrospectively reviewed. In the case of developing a fever (body temperature, ≥38°C), the outpatients had been instructed to take previously prescribed oral antibiotics for 3 days without any initial assessment, and if no improvement had occurred by then, they were required to visit the hospital for examination and to undergo treatment based on the results of a risk assessment for complications. The primary aim of the present study was to assess the outcome of febrile episodes, while the secondary aim was to assess the incidence of febrile episodes, hospitalizations, and the type of chemotherapy. The 131 patients received 840 chemotherapy administrations. Fifty-five patients (42.0%) had a total of 75 febrile episodes after 840 chemotherapy administrations (8.9%). Treatment failure occurred in 12 of the 75 episodes (16.0%) in 11 of the 55 patients (20.0%). Only four episodes required hospitalization. Treatment success was achieved in 63 episodes (84.0%). In conclusion, the feasibility of outpatient management without initial assessment was evaluated in the present study for febrile patients undergoing adjuvant chemotherapy for breast cancer, and the outpatient strategy regimen may be safe and convenient for these patients.

[A Case of Squamous Cell Carcinoma of the Breast].

Squamous cell carcinoma(SCC)of the breast is a rare disease. We encountered a case of SCC of the breast that relapsed in the early postoperative period and rapidly progressed thereafter. A 38-year-old woman visited our hospital presenting with a tumor in the left breast consisting of a 5-cm mass with an irregularly sharped wall. Fine needle biopsy examination showed squamous cell carcinoma. A modified radical mastectomy by Auchincloss's method was performed on the left breast. SCC was confirmed by histological examination. Two months later, local recurrence on the chest wall was found during adjuvant chemotherapy. Thereafter, the disease rapidly progressed, and finally, the patient died of respiratory failure caused by lung metastasis. The prognosis of SCC of the breast is recognized as being more unfavorable than that of invasive ductal carcinoma. We should develop an effective chemotherapeutic strategy for this disease.