[Show abstract][Hide abstract] ABSTRACT: Brain metastases from breast cancer occur in 20%-40% of patients, and the frequency has increased over time. New radiosensitizers and cytotoxic or cytostatic agents, and innovative techniques of drug delivery are still under investigation.
Five patients with brain metastases who did not respond to whole-brain radiotherapy and then received bevacizumab combined with paclitaxel were identified using our database of records between 2011 and 2012. The clinicopathological data and outcomes for these patients were then reviewed.
The median time to disease progression was 86 days. Of five patients, two (40%) achieved a partial response, two had stable disease, and one had progressive disease. In addition, one patient with brain metastases had ptosis and diplopia due to metastases of the right extraocular muscles. However, not only the brain metastases, but also the ptosis and diplopia began to disappear after 1 month of treatment. The most common treatment-related adverse events (all grades) were hypertension (60%), neuropathy (40%), and proteinuria (20%). No grade 3 toxicity was seen. No intracranial hemorrhage was observed.
We present five patients with breast cancer and brain metastases, with benefits from systemic chemotherapy when combined with bevacizumab.
OncoTargets and Therapy 01/2012; 5:185-9. · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We reported that doxorubicin and cyclophosphamide (DC) followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. However, as one of the side effects of paclitaxel, neuropathy was noted in up to 30% of patients. Cyclooxygenase-2 (COX-2) and its derived prostaglandins play a role in stimulating angiogenesis, inhibiting apoptosis, and suppressing the immune response. Some recent studies showed that COX-2 inhibitors, such as meloxicam, have the potential to enhance tumor suppression and reduce the severity of paclitaxel-induced neuropathy.
Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 600 mg/m(2)) administered intravenously (i.v.) on day 1 every 21 days were followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. During paclitaxel therapy, breast cancer patients were administered meloxicam (10 mg per day) daily, when experiencing symptoms of grade 2 neuropathy (motor or sensory). The primary endpoint was the pCR rate achieved with the treatment.
Forty-three patients received preoperative chemotherapy between April 2004 and March 2007 at six centers. The patient population was identified from a database of the Japan Breast Cancer Research Network. Clinical responses were rated as clinically complete response (cCR) in 9 patients (22%), clinically partial response (cPR) in 25 patients (59%), and clinically stable disease (cSD) in 9 patients (19%). pCR was seen in 25.6%. In addition, we identified 15 patients, who developed grade 2 neuropathy during paclitaxel therapy and subsequently received meloxicam. Meloxicam application had a marked effect within 28 days of initiation. The sensory neuropathy of the patients was reduced gradually, but their motor neuropathy did not improve. Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration). Furthermore, among the 15 patients, who received meloxicam, clinical responses were rated as cCR in 2 patients, cPR in 4 patients, and cSD in 9 patients. The pCR was seen in 4 patients (26.7%).
Although meloxicam in combination with DC and weekly paclitaxel chemotherapy did not show promising therapeutic activity, it may provide some relief for neuropathy.
Anticancer research 10/2011; 31(10):3567-71. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neoadjuvant chemotherapy (NAC) is one of the main strategies for patients with locally advanced breast cancer. In our previous study, biological markers such as estrogen receptor (ER), progesterone receptor (PgR), and HER2 were essential predictors of the effectiveness of NAC to help individualize treatment. This study examined the effect of NAC on the disease-free survival (DFS) of breast cancer patients. Furthermore, the study was expanded by adding Ki-67 as a biological marker, and examined the correlation between Ki-67 and the prognosis.
Between September 2005 and September 2007, 43 patients with breast cancer received NAC and surgery. Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 500 mg/m(2)) were administered intravenously (i.v.) on day 1 every 21 days, followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. The primary endpoint was the pathological complete response (pCR) rate and the secondary endpoint was DFS; the pCR rate was estimated for each groups stratified by the presence or absence of different factors (PcR, ER/PgR, and Ki-67).
The clinical response (cCR+cPR) rate was 81.0%, and the pCR rate was 25.6%. The pCR rate was 75, 50, 9 and 0% in HER2(+)/ER(-), HER2(+)/ER(+), HER2(-)/ER(-), and HER2(-)/ER(+) patients, respectively. The 4-year DFS rate was estimated at 78% for all patients. The HER2 status was an independent predictor of pathological complete response (pCR). The DFS rate of patients with lower Ki-67 values (<15%) was higher than that of patients with higher Ki-67 values (≥15%). The treatment-related adverse events were manageable: the majority were mild, but five patients experienced grade 3 (neutropenia and sensory neuropathy) adverse events.
DC followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. HER2 overexpression may be a good predictive marker of pCR, and the Ki-67 value after NAC may be a prognostic factor for DFS.
Anticancer research 04/2011; 31(4):1483-7. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT: BACKGROUND: Claudin-1 is a membrane protein of tight junctions, and is associated with the development of various cancers. However, the significance of claudin-1 expression in cancer cells is not well understood. Here, we showed for the first time the anti-apoptotic effect of claudin-1 in human breast cancer MCF-7 cells. METHODS: Human breast cancer MCF-7 and T47D cells were treated with or without tamoxifen, siRNA against claudin-1, or tamoxifen and claudin-1 siRNA. The samples were analyzed by RT-PCR, Western blotting or immunofluorescent staining. RESULTS: The expression of claudin-1 was upregulated in tamoxifen-treated MCF-7 cells, whereas the expression of claudin-1 was not altered in tamoxifen-treated T47D cells. Knockdown of claudin-1 by siRNA increased the amount of poly (ADP-ribose) polymerase (PARP) regardless of tamoxifen treatment in MCF-7 cells, but not T47D cells. In the cell membranes of the MCF-7 cells, tamoxifen treatment increased the amount of claudin-1, but decreased the amount of beta-catenin. Claudin-1 siRNA increased the amount of E-cadherin in the cytoplasm of the MCF-7 cells as well as the amount of beta-catenin in their cell membranes. CONCLUSION: These results indicate that claudin-1 has anti-apoptotic effects, and is involved in the regulation of the expression and subcellular localization of beta-catenin and E-cadherin in MCF-7, but not T47D cells.
BMC Cancer 10/2010; 10(1):548. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S-1 is an orally administered fluorinated pyrimidine with high activity in metastatic breast carcinoma (MBC) and in chemotherapy-pretreated metastatic breast carcinoma.
Forty patients with MBC who did not respond to capecitabine-based chemo-therapy and then received S-1 were identified from our data base of records between 2006 and 2008. The clinico-pathological data and outcomes of these patients were then reviewed.
The overall response rate was 27.8%. The median survival was 19.2 months, and the median time to disease progression was 6.2 months. The most common treatment-related adverse events (all grades) were hand-foot syndrome (15%), nausea (15%), vomiting (7.5%), disorder of taste (7.5%), and diarrhea (5%). However, the majority were mild to moderate in intensity, and only one patient experienced grade 3 (according to the National Cancer Institute of Canada Common Toxicity criteria) adverse events. Myelosuppression and alopecia were rare, and there were no reported treatment-related deaths.
The results of the current study demonstrate that S-1 is an effective and well-tolerated treatment in patients with capecitabine-resistant MBC. In addition, it is a convenient, orally administered drug, which makes it an attractive agent for use in outpatient treatment.
Anticancer research 09/2010; 30(9):3827-31. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a woman in her 30s who developed a right breast tumor 10 years after undergoing mastectomy for invasive ductal carcinoma of the left breast. She underwent modified radical mastectomy for the right breast cancer, which was diagnosed histologically as invasive ductal carcinoma with metastasis to the axillary lymph nodes. Because of the risk of recurrence, she received postoperative systemic adjunctive chemotherapy using CMF, but this had to be withdrawn because of liver toxicity. The patient therefore received hormonal therapy with goserelin and tamoxifen for 24 months. During this period, however, she became menopausal, necessitating withdrawal of the goserelin. After a disease-free interval of 34 months, liver metastasis appeared, and so tamoxifen was changed to exemestane. After 3 months, the metastasis showed a marked response, and this has been subsequently maintained for 48 months. Because the patient's menstrual cycle then returned, goserelin was restarted after consultation with a gynecologist. This case illustrates that exemestane and goserelin combination therapy is effective for recurrent breast cancer.
Gan to kagaku ryoho. Cancer & chemotherapy 06/2009; 36(5):811-4.
[Show abstract][Hide abstract] ABSTRACT: To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer.
A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy.
Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand-foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1-2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death.
Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.
Cancer Chemotherapy and Pharmacology 04/2008; 61(3):509-14. · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Claudins (CLDNs) constitute the major transmembrane proteins of tight junctions. It may be hypothesized that changes in or loss of expression of tight junctional proteins such as CLDNs can lead to cellular disorientation and detachment, which is commonly seen in neoplasia. Recent studies have suggested that claudin-1 (CLDN1) plays an important role in invasion and metastasis and claudin-4 (CLDN4) has a particular role in mammary glandular cell differentiation and carcinogenesis. In this study, we examined 83 breast cancer cases and demonstrated immunohistochemical expression patterns of CLDN1/CLDN4 in recurrent and non-recurrent groups. We found significant results between the recurrent and non-recurrent group for expression of CLDN1/CLDN4. The recurrent group (26 cases) showed decreased expression patterns of CLDN1 (p<0.001), compared to the non-recurrent group (57 cases). Decreased expression of CLDN1 (p<0.0001) correlated with short disease-free interval. The lymph node metastasis-positive group showed decreased expression patterns of CLDN1 (p=0.001). However, there was no significance between the recurrent group and non-recurrent group in CLDN4 expression. There was no significance between histological factors and CLDN4 expression. The results indicated that CLDN1 expression correlated with the recurrence status and malignant potential of breast cancer.
International Journal of Molecular Medicine 08/2007; 20(2):139-43. · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 32-year-old woman underwent modified radical mastectomy for right breast cancer (invasive ductal carcinoma, f, INF beta, v0, ly1, pT2, pN1, M0, Stage II B ER (+/-), PR (-), Her2 (3+)) in June 2003, and received postoperative systemic adjunctive chemotherapy using epirubicin combined with cyclophosphamide, followed by paclitaxel. In August 2004, after a disease-free interval of 14 months, liver metastasis appeared, and therefore from September 2004, combination chemotherapy with oral capecitabine (2,400 mg/day) and injected trastuzumab (120 mg/week) was started. After 3 cycles, all the metastases responded and this marked response has been maintained for 16 months. This therapy is currently being continued (19 cycles), and no serious side effects have been encountered. Capesitabine and trastuzumab combination therapy is effective for recurrent breast cancer showing overexpression of HER2 and resistance to taxane, and can be considered as a first-line therapy for this purpose. It is anticipated that many cases treated with this regimen will be reported and discussed in the near future.
Breast Cancer 02/2007; 14(3):297-301. · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer-associated retinopathy (CAR) is an ocular manifestation of a paraneoplastic syndrome whereby immunological reactions toward recoverin, a retina-specific calcium binding protein, and other retinal antigens aberrantly expressed in tumor cells lead to the degeneration of retinal photoreceptor cells. Recently we reported that aberrant expression of recoverin was identified in more than 50% of tumor cells and their cell lines from several kinds of cancers, including gastric cancer, lung carcinoma, and other cancers. To elucidate the clinicopathological significance of aberrantly expressed recoverin in cancer cells, we performed immunocytochemical analysis using a monoclonal antibody against human recoverin. Within 18 patients with different clinical stages (I-IV) of gastric cancer, the aberrant expression of recoverin in tumor cells was recognized in 6 out of 18 patients (2 out of 2 stage IA, 1 out of 1 stage IB, 2 out of 3 stage II, 0 out of 7 stage IIIA, 0 out of 1 stage IIIB, and 1 out 4 stage IV). The present data are consistent in part with the previous observations that recoverin-expressing cancer cells induced tumor immunity and provide a favorable prognosis for primary cancer in CAR patients.
The Tohoku Journal of Experimental Medicine 04/2004; 202(3):213-9. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer has an unfavorable prognosis; surgery and chemotherapy at present have only limited value. To improve the prognosis of pancreatic cancer, effective non-surgical therapy is necessary. NF-kappaB is reported to be related to resistance to apoptosis, but its role in chemosensitivity remains controversial. We examined the effects on chemosensitivity of inhibition by induction of the super-repressor IkappaBalpha in pancreatic cancer cell lines, BxPC-3, Capan-1 and Panc-1. IkappaBalpha protein was transduced by infection of adenovirus vector AxCAhIkBDeltaN. Sensitivity to VP-16 and doxorubicin was increased significantly by IkappaBalpha induction in all three pancreatic cell lines. To investigate molecular events during IkappaBalpha induction, we examined the changes in expression of drug-resistance-related genes by real-time RT-PCR and those in apoptosis-related genes by cDNA microarray. There was no common change of gene expression before and after IkappaBalpha induction among the three pancreatic cancer cell lines, except for mdm2. Further examination of other genes is necessary for a better understanding of the molecular mechanisms of enhancement of chemosensitivity through IkappaBalpha induction. However, we have confirmed that IkappaBalpha induction leads to an increase of chemosensitivity of pancreatic cancer. Many problems remain before clinical application of this adenoviral system will be feasible, but our results may ultimately lead to an improved therapy of pancreatic cancer.
Cancer Science 06/2003; 94(5):467-72. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer-associated retinopathy (CAR) is an ocular manifestation of a paraneoplastic syndrome whereby immunological reactions toward recoverin (Rec), a retina-specific Ca(2+) binding protein, and its aberrant expression in tumor cells lead to the retinal degeneration. To elucidate functional roles of the aberrantly expression in cancer cells, we performed immunoprecipitation using anti-human Rec mAb. We observed co-precipitation of G-protein-coupled receptor kinases (GRKs) and caveolin-1 with Rec from cell lysates of 293 or SSTW cells. Immunocytochemistry revealed that immunoreactivities toward Rec within the cancer cells were almost identical to those toward GRKs and caveolin-1. The present data strongly suggest that aberrantly expressed Rec should be involved in the GRK-dependent cellular regulation in cancer cells.
Biochemical and Biophysical Research Communications 02/2003; 300(3):669-73. · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer has an unfavorable prognosis; surgery and chemotherapy at present have only limited value. To improve the prognosis of pancreatic cancer, effective non-surgical therapy is necessary. NF-kB is reported to be related to resistance to apopto-sis, but its role in Chemosensitivity remains controversial. We examined the effects on Chemosensitivity of inhibition by induction of the super-repressor IkBα in pancreatic cancer cell lines, BxPC-3, Capan-1 and Panc-1. IkBα protein was transduced by infection of adenovirus vector AxCAhlkBδN. Sensitivity to VP-16 and doxorubicin was increased significantly by IkBα induction in all three pancreatic cell lines. To investigate molecular events during IkBα induction, we examined the changes in expression of drug-resistance-related genes by real-time RT-PCR and those in apoptosis-related genes by cDNA microarray. There was no common change of gene expression before and after IkBα induction among the three pancreatic cancer cell lines, except for mdm2. Further examination of other genes is necessary for a better understanding of the molecular mechanisms of enhancement of Chemosensitivity through IkBα induction. However, we have confirmed that IkBα induction leads to an increase of Chemosensitivity of pancreatic cancer. Many problems remain before clinical application of this adenoviral system will be feasible, but our results may ultimately lead to an improved therapy of pancreatic cancer. (Cancer Sci 2003; 94: 467–472)
Cancer Science 01/2003; 94(5):467-472. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alpha-synuclein was originally identified as the presynaptic nerve terminal protein. Recently, we reported that alpha-synuclein is also expressed in cultured human astrocytes and that its levels are increased by stimulation with interleukin-1beta, suggesting that it may be involved in inflammatory processes. We therefore investigated the effect of inflammatory stimuli on alpha-synuclein expression in human macrophages. Alpha-synuclein mRNA and protein were detected in cultured human macrophages and levels of alpha-synuclein protein were increased by stimulation with lipopolysaccharide and interleukin-1beta in a time- and concentration-dependent manner. Immunofluorescent staining showed that alpha-synuclein protein was expressed within the cytoplasm and nucleus. Furthermore, alpha-synuclein immunoreactivity was present in alveolar macrophages from human lung tissues. These findings suggest that the function of alpha-synuclein is not exclusive to the nervous system and that alpha-synuclein may play a role in inflammatory processes and immune responses.
Pathology International 10/2002; 52(9):572-7. · 1.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tissue-specifi c promoter has been used for cancer-specifi c suicide gene therapy, but its transcriptional activity is relatively low. For more effi cient gene therapy of HER2-expressing tumor, a double adenovirus infection system was established, in which a ‘regulator’ vector carried Cre gene under the control of HER2 promoter and ‘target’ vectors carried target genes activated by Cre. We constructed a Cre recombinase expression vector, AxHER2Cre, for the ‘regulator’ vector. By the combination of this vector and AxCALNLZ, β-D-galactosidase was induced in 90% and 70% of MKN7 and MDA-MB-453, HER2‒overexpressing cell lines, but only about 20% and 10% of MKN28 and MCF7, low HER2-expressing cell lines. By the quantifi cation analysis, the β-galactosidase activities induced by this system were comparable to those by the combination of AxCANCre and AxCALNLZ. These results indicated that Cre/ loxP system under the regulation of HER2 promoter could induce effi cient gene expression, maintaining the HER2- expression specifi city. Breast cancer with HER2 overexpression is treated with trastuzumab. However, refractory or resitance of HER2 positive breast cancer against trastuzumab becomes a severe clinical problem, recently. This system seemed to be another therapeutic option.