An Exploratory Phase II Study of Eribulin Re-challenge After Short Term Therapy of 5-Fluorouracil for HER2 Negative, Advanced or Recurrent Breast Cancer.

BACKGROUND/AIM: In our previous study, first-line eribulin (ERI) showed 25 weeks of progression-free survival (PFS). This study investigated the efficacy and safety of ERI re-administration in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: HER2-negative MBC patients who had never received chemotherapy for MBC received first-line ERI for 18 weeks if they did not have disease progression, and then one cycle of S-1 before ERI re-administration. RESULTS: Twelve patients received ERI re-administration. The PFS of re-administered ERI was 13 weeks. Total duration of ERI use was 30 weeks. The incidence and severity of adverse events were consistent with previous reports. CONCLUSION: In the first-line setting, the total PFS of eribulin was extended by S-1 administration before disease progression, compared with that of our previous report.

[Two Cases of Breast Cancer with Extensive Invasion to Skin].

Case 1: A 48-year-old female was admitted to our hospital because of left HER2 type breast cancer with a skin invasion of 10×11 cm in the chest wall. Since she had previously received anti-HER2 therapy, we performed anti-HER2 therapy in our department as well, but the tumor gradually became larger and presented with a cancerous ulcer. The use of metronidazole gel in the tumor area reduced the odor. The tumor progressed and she died 1 year and 1 month after the first visit to our hospital. Case 2: A 51-year-old female visited our hospital because of a cauliflower-like right breast tumor measuring 20×17 cm with bleeding and infection. After diagnosis of right breast cancer with multiple bone metastasis, CMF therapy was performed, and then 40 cycles of docetaxel and bevacizumab therapy were performed. As a result, her breast tumor is no longer visible macroscopically, and she runs her daily life without problems. Breast cancer with an extensive skin invasion has a poor prognosis. However, in some cases such as case 2, the proper chemotherapy might be beneficial for long survival.

Neoadjuvant Chemotherapy With Nab-paclitaxel Plus Trastuzumab Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide for HER2-positive Operable Breast Cancer: A Multicenter Phase II Trial.

AIM: This study was conducted in order to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus trastuzumab followed by 5-fluorouracil/ epirubicin/cyclophosphamide (FEC) in a neoadjuvant chemotherapy (NAC) setting for patients with human epidermal growth factor receptor 2 (HER2)-positive operable breast cancer. PATIENTS AND METHODS: Each patient received four cycles of 260 mg/m2 nab-paclitaxel with 6 mg/kg trastuzumab (8 mg/kg as the loading dose) every 3 weeks (q3w) followed by four cycles of FEC (500/100/500 mg/m2) q3w. The primary endpoint was pathological complete response (pCR) rate. RESULTS: Twenty-nine patients were analyzed for the efficacy and safety of this treatment. All patients completed four cycles of nab-paclitaxel and trastuzumab, and 28 patients completed four cycles of FEC. Twenty-seven patients subsequently underwent surgery. The pCR rate was 74.0%. The most frequent toxicity was sensory neuropathy (96.6%), but grade 3 neuropathy rate was 3.4%. CONCLUSION: Nab-paclitaxel plus trastuzumab followed by FEC in patients with HER2-positive operable breast cancer is considerably effective and well tolerated.

Safety and Efficacy of Low-dose Nanoparticle Albumin-bound Paclitaxel for HER2-negative Metastatic Breast Cancer.

BACKGROUND/AIM: Nab-paclitaxel (nab-PTX) is an albumin-bound paclitaxel formulation. Although nab-PTX has shown superior efficacy compared to conventional paclitaxel (PTX) in metastatic breast cancer (MBC), chemotherapy-induced peripheral neuropathy (CIPN) was more frequently observed in nab-PTX. In this study, we aimed to estimate the feasibility of the nab-PTX 175 mg/m2/3weeks regimen. PATIENTS AND METHODS: Patients having metastatic or inoperable HER2-negative breast cancer received 175 mg/m2 of nab-PTX every three weeks. The primary endpoint was safety and the secondary endpoints were response and survival. RESULTS: Seventeen patients were enrolled with a median age of 64 years. Ten patients had estrogen receptor positive disease and seven had triple-negative disease. CIPN was observed in seven patients (41%) however, grade 3 CIPN was only seen in one patient (6%). Objective response rate was 41% and progression-free survival was 23 weeks. CONCLUSION: Nab-PTX 175 mg/m2/3wks regimen has a good safety profile and less frequent CIPN. This regimen can contribute to the strategy of MBC treatment.

Phase I study of nanoparticle albumin-bound paclitaxel, carboplatin and trastuzumab in women with human epidermal growth factor receptor 2-overexpressing breast cancer.

Although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of human epidermal growth factor receptor 2 (HER2)-overexpressing early breast cancer, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study. In addition, tri-weekly treatment with nanoparticle albumin-bound paclitaxel (nab-paclitaxel) resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic breast cancer patients in another phase III study. Based on these results, a phase I study of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its efficacy and safety for HER2-overexpressing locally advanced breast cancer. The present study was designed to determine the dose-limiting toxicity (DLT), maximum tolerated dose and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced breast cancer. The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2). Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly. A total of 6 patients were enrolled. Although no DLT was observed during the first cycle, 4 patients developed grade 4 thrombocytopenia, 2 had grade 4 neutropenia and 3 exhibited a grade 4 decrease in hemoglobin levels. In the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well tolerated. However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted.

A phase II, multicenter, single-arm trial of eribulin as first-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer.

The treatment goals for metastatic breast cancer (MBC) are prolonging survival and improving the quality of life. Eribulin, a non-taxane tubulin inhibitor, demonstrated improved survival in previous studies and also showed mild toxicity when used in late-line therapy for MBC. We conducted a phase II study to investigate the efficacy of eribulin mesylate as the first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative MBC. This was a phase II, open-label, single-arm, multicenter trial conducted in Japan. Patients with HER2-negative MBC received intravenous eribulin (1.4 mg/m(2) on days 1 and 8 of each 21-day cycle). The primary efficacy outcome was overall response rate (ORR). Secondary outcomes included time to treatment failure, progression-free survival (PFS), overall survival (OS), and safety. A total of 35 patients were enrolled and received a median of 8 (range 1-21) cycles of eribulin therapy. ORR and clinical benefit rate were 54.3 and 62.9 %, respectively. Median PFS was 5.8 months and median OS was 35.9 months. Grade 3 or 4 neutropenia was observed in 63 % of patients. The majority of non-hematological adverse events were mild in severity. The present trial demonstrated that eribulin has antitumor activity comparable with other key established cytotoxic agents with acceptable safety and tolerability. Thus, eribulin as first-line chemotherapy might be beneficial for patients with HER2-negative MBC.

Bullous pemphigoid as a dermadrome associated with spindle cell carcinoma of the gallbladder.

Skin disorders that appear in association with internal malignancies are called dermadromes. Bullous pemphigoid (BP), which is a major autoimmune disease of the skin, is considered to be a dermadrome, although there have been conflicting reports. We report a case of BP that preceded the diagnosis of an internal malignancy. Although we could not detect any malignancies on chest, abdominal or pelvic computer tomography on the first hospital admission, intensive screening on the third admission revealed a gallbladder malignancy. Laparoscopic cholecystectomy was performed. Histopathology showed a spindle cell carcinoma of the gallbladder. To the best of our knowledge, this is the first report of a spindle cell carcinoma of the gallbladder in a patient with BP.

Involvement of the 3'-untranslated region of cyclooxygenase-2 gene in its post-transcriptional regulation through the glucocorticoid receptor.

Functional roles of the 3'-untranslated region (3'-UTR) of the human Cyclooxygenase-2 (COX-2) gene were evaluated by transient transfection using luciferase (Luc) reporter vectors into bovine arterial endothelial cells (BAEC). Insertion of the 3'-UTR into the downstream of a Luc coding region resulted in decreased reporter activity (23%), although insertion into the upstream was no effect. The reporter activity of the downstream insertion but not the upstream insertion was induced by bacterial lipopolysaccharide (LPS). Moreover, LPS selectively stabilized COX-2 mRNA. Next, to evaluate the role of the 3'-UTR together with glucocorticoid receptor (GR), a GR-expression vector was cotransfected with the reporter vector of the downstream insertion of the 3'-UTR. As a result, the LPS-induced reporter activity was suppressed by dexamethasone in a dose-dependent manner. These data suggest that the 3'-UTR of the COX-2 gene is involved in not only the induction by LPS but also the suppression by DEX of COX-2 expression at the post-transcriptional level.

Electrical connections between pulmonary veins: implication for ostial ablation of pulmonary veins in patients with paroxysmal atrial fibrillation.

BACKGROUND: Electrical disconnection of the myocardial extensions into arrhythmogenic pulmonary veins (PVs) is recognized as a curative technique for paroxysmal atrial fibrillation (AF). However, the presence of electrical connections between the PVs, which may make achievement of PV disconnection difficult, has not been systematically evaluated. METHODS AND RESULTS: Forty-nine consecutive patients with drug-resistant AF underwent ostial radiofrequency (RF) catheter ablation of arrhythmogenic PVs with foci triggering AF. Pacing from inside the targeted PV was performed after each RF delivery to identify the left atrial exit site of the residual venoatrial conduction. Successful PV disconnection was defined as achieving elimination of the PV potentials during sinus rhythm or left atrial pacing, and the loss of left atrial conduction during intra-PV pacing. A total of 112 arrhythmogenic PVs were identified. PV disconnection was achieved with 10+/-6.1 minutes of RF delivery to the ostia of 101 targeted PVs. In 7 left superior (LS) PVs from 7 patients (14%), the earliest atrial activity was recorded from the left inferior (LI) PV ostium during intra-LSPV pacing after 11+/-4.7 minutes of RF delivery to the LSPV ostium. Disconnection of these LSPVs was achieved by LIPV disconnection. In the remaining 4 PVs from 4 patients, PV disconnection could not be achieved. CONCLUSIONS: Fourteen percent of the patients had electrical connections between contiguous PVs. In these patients, ostial ablation of an untargeted PV was required for successful targeted PV disconnection.