[Possibility of Prolonging Treatment by Preventing Paclitaxel-Induced Peripheral Neuropathy Using Compression Therapy].

We evaluated the efficacy of surgical glove(SG)-compression therapy for paclitaxel (PTX)-induced peripheral neuropathy (PN)and the impact of PN prevention on treatment duration. Patients with advanced or metastatic breast cancer underwent a combined treatment of PTX and bevacizumab with(n=20; patients wore 2 SGs for 120 min)or without(n=15) compression therapy. SG-compression therapy significantly decreased the incidence of Common Terminology Criteria for Adverse Events(CTCAE)v4.0 Grade 2 or higher PN by 71.9% and prolonged time-to-treatment-failure(TTF)of PTX from 200 to 240 days. SG-compression therapy was effective for PTX-induced PN and may have prolonged the TTF of PTX.

Effectiveness of eribulin as first-line or second-line chemotherapy for HER2-negative hormone-resistant advanced or metastatic breast cancer: findings from the multi-institutional, prospective, observational KBCRN A001: E-SPEC study.

BACKGROUND: The optimal positioning of eribulin treatment remains unclear. This study aimed to investigate the effectiveness of eribulin administration as first- and second-line chemotherapy in patients with endocrine-resistant advanced or metastatic breast cancer (AMBC) in the real-world clinical setting. METHODS: This multi-institutional prospective cohort study enrolled patients with triple-negative AMBC or estrogen receptor-positive AMBC refractory to at least one previous endocrine therapy. The overall survival (OS) from the start of first-line (OS1) and second-line chemotherapy (OS2) was assessed. Data analysis included real-world chemotherapy sequences of first- to third-line chemotherapy regimens. The adjusted hazard ratio (HR) with 95% confidence interval (CI) for treatment regimen comparison was calculated using a stratified proportional hazards model. RESULTS: Among 201 patients enrolled, 180 were included in the final analysis. Eribulin was administered as first- and second-line chemotherapy to 46 (26.6%) and 70 (47.9%) patients, respectively. Median OS1 and OS2 were 2.25 (95% CI 1.07-2.68) and 1.75 (95% CI, 1.28-2.45) years for first- and second-line eribulin, respectively. Oral 5-FU followed by eribulin had a numerically longer OS1 (2.84 years) than the other sequences. Among patients who proceeded to second-line or later chemotherapy, the median OS1 for those treated with anthracycline or taxane as first- or second-line (n = 98) was 2.56 years (95% CI 2.27-2.74), while it was 2.87 years (95% CI 2.20-4.32) for those who avoided anthracycline and taxane as first- and second-line (n = 48) (adjusted HR, 1.20; 95% CI 0.70-2.06). In the exploratory analysis, OS1 was 2.55 (95% CI 2.14-2.75) and 2.91 years (95% CI 2.61-4.32) for those aged < 65 and ≥ 65 years, respectively (adjusted HR of ≥ 65, 0.91; 95% CI 0.56-1.46). CONCLUSIONS: Eribulin or oral 5-FU administration in first- and second-line chemotherapy without anthracycline/taxane was acceptable in the real-world setting. TRIAL REGISTRATION: This study is registered with Clinical Trials.gov (NCT 02,551,263).

Aortitis and aortic dissection after administration of pegfilgrastim during adjuvant chemotherapy for early breast cancer.

A 70 year-old woman on adjuvant chemotherapy for breast cancer developed acute aortitis after receiving pegfilgrastim. 12 days after pegfilgrastim administration, she presented to our hospital with fever and shoulder pain. White blood cell count and C-reactive protein were elevated. As the computed tomography scan revealed thickening of the walls of the aortic arch and surrounding arteries, we suspected granulocyte colony-stimulating factor-related aortitis. Although steroid treatment administered once improved the general condition, her symptoms and C-reactive protein worsened again. On increasing the steroid dose, her general condition recovered rapidly. On day 85, Stanford type A aortic dissection was incidentally detected by a follow-up computed tomography scan. Physicians should recognize these adverse events of filgrastim.

Evaluation of a novel medical device for pegfilgrastim administration.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.

Potential effectiveness of combining bevacizumab with paclitaxel for treating HER2-positive metastatic breast cancer.

Although various first- to third-line HER2-targeted therapies have been established, the optimal sequence after third-line therapy has not been determined yet. Here, we describe seven patients with HER2-positive metastatic breast cancer who underwent bevacizumab (BV) and paclitaxel (PTX) combination therapy after several HER2-targeted therapies. Re-biopsy of metastatic sites was performed on four patients during the treatment prior to BV + PTX; three patients presented the same HER2-positive status as that of the primary tumor and two of whom achieved partial response. Four of seven patients achieved partial response and a 10-month median progression-free survival. Therefore, bevacizumab combined with paclitaxel is potentially effective in the treatment of HER2-positive metastatic breast cancer, if standard HER2-targeted therapy fails.

Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.

Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants.

The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.

Two cases of breast angiosarcoma after breast conserving surgery.

BACKGROUND: Breast angiosarcoma (AS) is a rare malignant breast tumor arising from endothelial cells lining the blood vessels. The prognosis of AS is reportedly poor. However, the effectiveness of chemotherapy and radiation is still controversial. Surgery is the only curable treatment, and removal of AS with adequate surgical margin is important. CASE PRESENTATION: We report two cases of primary and radiation-induced breast angiosarcoma (AS) after performing breast conserving surgery (BCS) for breast cancer. In case 1, a 72-year-old woman underwent right BCS with adjuvant radiation therapy (RT) for breast cancer 5 years prior. She was diagnosed with AS of the right breast and underwent mastectomy with a wide skin resection of the breast. As the tumor cells were positive for c-myc, this tumor was diagnosed as a radiation-induced AS. In case 2, an 80-year-old woman underwent BCS without adjuvant RT. She was diagnosed with AS 3 years after BCS and underwent mastectomy with a wide skin resection of the breast. The tumor was diagnosed to be a primary AS because there were no episodes of RT or lymphedema. Both cases developed local recurrence within 1 year of surgery. CONCLUSION: Our cases suggest that surgical margin is associated with the risk of local recurrence, and the difficulty of deciding a safe surgical margin should be set during preoperative diagnosis.

[Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel as Neoadjuvant Chemotherapy in Breast Cancer Patients].

AIM: We investigated the efficacy and safety of preoperative neoadjuvant chemotherapy(NAC)with a nanoparticle albumin- bound paclitaxel(nab-PTX)-containing regimen. PATIENTS AND METHODS: Twenty-eight female patients with Stage Ⅰ-Ⅲ breast cancer received nab-PTX(260mg/m / 2,q3w)±trastuzumab followed by FEC(5-fluorouracil 500 mg/m2 plus epiru- bicin 75 or 100mg/m / 2 plus cyclophosphamide 500 mg/m2: q3w)between June 2013 and January 2015. Patients with HER2- positive breast cancer received trastuzumab concurrently with nab-PTX. Clinical response, pathological complete response (pCR), and adverse events were evaluated. RESULTS: The overall pCR rate was 32%. The pCR rates for each subtype were as follows: HER2-type 86%, Luminal B-HER2 20%, triple-negative 17%, and Luminal B 0%. HER2-type breast cancer demon- strated the best response to this regimen. The clinical response rate for nab-PTX was 64%(18/28), and the safety profile was tolerable. CONCLUSION: nab-PTX±trastuzumab followed by FEC as NAC is effective and safe for operative breast cancer, especially HER2-type breast cancer.

Effectiveness and safety of surgical glove compression therapy as a prophylactic method against nanoparticle albumin-bound-paclitaxel-induced peripheral neuropathy.

BACKGROUND: We have developed a surgical glove (SG)-compression therapy and reported that this method significantly reduced the overall occurrence of grade 2 or higher nanoparticle albumin-bound-paclitaxel (nab-PTX)-induced peripheral neuropathy (PN) from 76.1% to 21.4%. In this multicenter single-arm confirmatory study, we investigated the efficacy and safety of SG-compression therapy for the prevention of nab-PTX-induced PN, compared with the incidence of grade 2 or higher PN in published literature as controls. PATIENTS AND METHODS: Primary breast cancer patients who received 260 mg/m2 of nab-PTX were eligible for this study. Patients wore two SGs (one size smaller than the tight-fitting size) in each hand for 90 min. PN was evaluated at each treatment cycle using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire (PNQ). The temperature of each fingertip was measured using thermography. RESULTS: Between October 2016 and June 2017, 58 patients were evaluated. The incidence of CTCAE grade 2 or higher PN was as low as 13.8% following SG-compression therapy. A goodness-of-fit test proved that the overall incidence of 13.8% grade 2 or higher PN in this study was comparable to the hypothesis-predicted value (13%). No adverse events, including compression intolerance or skin disorders caused by use of SG, were observed. SG-compression therapy significantly reduced the temperature of each fingertip by 1.3°C-2.3 °C compared to pre-chemotherapy level. CONCLUSIONS: This study suggested the safety and efficacy of SG-compression therapy for the amelioration of CIPN. CLINICAL TRIAL NUMBER: UMIN 000024836.

Gemcitabine and Vinorelbine Combination Chemotherapy in Taxane-Pretreated Patients with Metastatic Breast Cancer: A Phase II Study of the Kinki Multidisciplinary Breast Oncology Group (KMBOG) 1015.

BACKGROUND: This phase II study was conducted to evaluate the efficacy and safety of the chemotherapy combination of gemcitabine and vinorelbine in taxane-pretreated Japanese metastatic breast cancer patients. METHODS: In this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2-negative breast cancer were administered gemcitabine (1,200 mg/m2) and vinorelbine (25 mg/m2) intravenously on days 1 and 8 every 3 weeks. The primary endpoint was the objective response rate, and other endpoints included progression-free survival, overall survival, and safety. RESULTS: A total of 42 patients were enrolled in this study. The objective response rate and clinical benefit rate were 24 and 43%, respectively. The median progression-free survival was 4.0 months. The median overall survival was 11.1 months. Grade 3/4 neutropenia was the most common hematologic toxicity, occurring in 22 patients (54%). Nonhematologic toxicity was moderate and transient, with fatigue (48%) being the most common condition and no severe adverse event reported. CONCLUSION: The combination of gemcitabine and vinorelbine is an effective and tolerable regimen for HER2-negative, taxane-pretreated, metastatic breast cancer patients in Japan.

Evaluation of the effect of compression therapy using surgical gloves on nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: a phase II multicenter study by the Kamigata Breast Cancer Study Group.

PURPOSE: To investigate the efficacy of using surgical glove (SG) compression therapy to prevent nanoparticle albumin-bound paclitaxel (nab-PTX)-induced peripheral neuropathy. PATIENTS AND METHODS: Patients with primary and recurrent breast cancer who received 260 mg/m2 of nab-PTX were eligible for this case-control study. Patients wore two SGs of the same size, i.e., one size smaller than the size that fit their dominant hand, for only 90 min. They did not wear two SGs on the non-dominant hand, which served as the control hand. Peripheral neuropathy was evaluated at each treatment cycle using common terminology criteria for adverse events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire. The temperature of each fingertip of the compression SG-protected hand and control hand was measured using thermography. RESULTS: Between August 2013 and January 2016, 43 patients were enrolled and 42 were evaluated. The occurrence rates of CTCAE grade 2 or higher sensory and motor peripheral neuropathies were significantly lower for SG-protected hands than for control hands (sensory neuropathy 21.4 vs. 76.1 %; motor neuropathy 26.2 vs. 57.1 %). No patients withdrew from this study because they could not tolerate the compression from the SGs. SG compression therapy significantly decreased the temperature of each fingertip by 1.6-2.2 °C as compared with the temperature before chemotherapy (p < 0.0001). CONCLUSIONS: SG compression therapy is effective for reducing nab-PTX-induced peripheral neuropathy. The nab-PTX exposure to the peripheral nerve may be decreased because the SG decreases microvascular flow to the fingertip.

Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report.

The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases.

Assessing the effects of neoadjuvant chemotherapy on lymphatic pathways to sentinel lymph nodes in cases of breast cancer: Usefulness of the indocyanine green-fluorescence method.

BACKGROUNDS: It is not clear how lymphatic pathways to the sentinel lymph node (SLN) change during neoadjuvant chemotherapy (NAC) for breast cancer. METHODS: Using the indocyanine green (ICG)-fluorescence method, we compared lymphatic pathways to the SLN (sentinel lymphatic pathways) and SLN location before and after NAC in 36 patients (38 breasts). RESULTS: Despite that 42.8% of the sentinel lymphatic pathways were changed by NAC, the locations of the SLNs were not affected by NAC. CONCLUSION: These results suggest that the true SLN can be detected even after NAC, and that SLNB can be performed after NAC for clinically node-negative patients.

Prevalence and risk factors of bone metastasis and skeletal related events in patients with primary breast cancer in Japan.

BACKGROUND: Bone metastasis (BM) is important for studying systemic spread of breast cancer. It often causes skeletal-related events (SREs) that worsen quality of life. We investigated the prevalence and risk factors for BM and SRE using a dataset from the Breast Oncology Research Network (BORN) in Japan. PATIENTS AND METHODS: We collected data on primary breast cancer patients with node-positive or node-negative disease at intermediate to high risk of recurrence. The risk factors affecting the BM-free rate, SRE-free rate and overall survival were analyzed by using the Cox proportional hazard model. RESULTS: Data of 1,779 patients who were diagnosed with breast cancer during 2003-2005 were collected from the BORN and 1,708 cases were used for analysis. The median follow-up duration was 5.71 years. BM developed in 193 cases (11.3 %) and the BM-free rate at 5 years was 89.2 %. The annual hazard ratio of BM development differs remarkably according to the tumor subtype. SREs occurred in 133 (68.9 %) out of 193 patients and the SRE-free rate at 5 years was 92.6 %. In the multivariate analysis, clinical stage (P < 0.0001), number of lymph node (LN) metastases (P = 0.0029), tumor subtype (P = 0.034) and progesterone receptor status (P = 0.038) were independently significant risk factors for BM-free rate, but only clinical stage (P < 0.0001) and number of LN metastases (P = 0.0004) significantly correlated with SRE-free rate. CONCLUSIONS: This retrospective study clarifies the prevalence and risk factors for BM and SRE in Japanese breast cancer patients. Our results show the importance of considering subtype in the care of BM and SRE.

Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with tamoxifen: results of the JMTO BC08-01 phase II trial.

The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER)-positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0-35.2%], the CBR was 62.2% (95% CI, 44.8-77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted.

[Usefulness of antimycotic agents (itraconazole) in chemotherapy-induced mucositis of breast cancer patients].

Chemotherapy-induced oral mucositis is a common adverse event in breast cancer patients. Breakdown of the mucosal barrier predisposes the patient to bacterial, fungal and viral superinfection, especially candidiasis. We demonstrated the frequency of chemotherapy-induced oral mucositis and oral candidiasis, and the efficacy of antimycotic agents in breast cancer patients. We investigated 32 patients with advanced and metastatic breast cancer who underwent chemotherapy in our department from March, 2009 to August, 2010. The chemotherapy regimens were as follows: FEC (epirubicin/5-FU/cyclophosphamide) followed by taxanes: 21, FEC: 1, TC (docetaxel/cyclophosphamide): 7, DOC (docetaxel): 3, and CPT-11/S-1: 1. Patients had blood and bacteria tests of the oral cavity at the time mucositis symptoms appeared. We administered an antimycotic agent (itraconazole) and evaluated its effect on mucositis at the time mucositis symptoms appeared. 56. 3% of patients had chemotherapy-induced oral mucositis, and 38. 9% of the mucositis patients had oral candidiasis. The incidence of mucositis increased when severe neutropenia occurred. 92. 9% of mucositis patients were cured or improved by itraconazole. In conclusion, chemotherapy caused oral candidiasis in 40% of cases with oral mucositis, and in about 56% of breast cancer patients. The antimycotic agent may be useful for chemotherapy-induced oral mucositis in breast cancer patients.

Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients.

Caveolin-1 (Cav-1) has been extensively characterized in cancer biological research. However, the role of Cav-1 in the interaction between tumor and stromal cells remains unclear. In the present study, we examined Cav-1 expression in tumor cells and stromal cells in breast cancer tissue by immunohistochemical analysis and evaluated its prognostic value in a training cohort. Immunohistochemical analysis of Cav-1 expression was scored as (++), (+) or (-) according to the proportion of positively stained tumor cells (T) and stromal cells (S). Correlation analysis between tumor/stromal Cav-1 expression and clinicopathological parameters revealed that only T(++) Cav-1 status was positively associated with tumor size and histological nodal status (P = 0.019 and 0.021, respectively). Univariate analysis revealed that combined T(++)/S(-) status was significantly correlated with unfavorable prognostic outcomes (P < 0.001). Multivariate analysis demonstrated that this combined status is an independent prognostic factor for primary breast cancer (P = 0.002). Clinical outcomes in different subgroups of breast cancer patients were also strictly dependent on this combined status (P < 0.05). The prognostic value of T(++)/S(-) Cav-1 status was also validated in the testing cohort. Collectively, our data indicate that high Cav-1 expression in tumor cells and lack of this expression in stromal cells could help identify a particular subgroup of breast cancer patients with potentially poor survival. Further studies are required to understand the regulatory mechanism of Cav-1 in the tumor microenvironment.

[More effective positioning of capecitabine for advanced and metastatic breast cancer].

We investigated 30 patients with advanced and metastatic breast cancer who underwent capecitabine therapy in our department from July, 2004 to April, 2009. Patients' backgrounds: 35-82 years of age (median, 62 years of age). Performance status (PS): 0 approximately 1 in 21 cases, PS:2 in 7 cases and PS:3 in 2 cases. 63% of patients were positive ER and/or PgR, and 33. 3% were positive HER2. Of these patients, 17 had bone, 15 lymph node, 13 lung, 7 liver, and 4 skin metastasis. The capecitabine response in these patients was evaluated as follows: partial response (PR) in 9, stable disease (SD)in 6, long SD in 4, and progressive disease(PD)in 11, indicating a response rate(RR)of 30% and a clinical benefit rate (CBR) of 43. 3%. In comparison with after third-line treatment, capecitabine proved more effective as first or second-line treatment. Interestingly, the capecitabine response in HER2 negative-expressing patients, especially in HR(+)/HER2(-)subgroup, was significantly better than that in HER2-over-expressing patients. The soft tissue lesions(primary tumor and metastasis of skin and lymph nodes)showed a significantly better response to capecitabine treatment than other metastases such as lung, liver and bone. There was a significant difference in the response rate between soft tissue metastasis (lymph nodes, skin and primary tumor)and other types of metastasis (lung, liver, and bone). Finally, it was suggested that use of capecitabine in upfront line for HER2-negative expressing cases or soft tissue metastatic cases contributed to the prolongation of time to treatment failure(TTF)and overall survival.

Inhibition of tumor necrosis factor-induced apoptosis in transgenic mouse liver expressing creatine kinase.

BACKGROUND: The mitochondrion acts as a pivotal decision center in many types of apoptotic responses. To clarify the effects of the enhanced mitochondrial function on tumor necrosis factoralpha (TNFalpha)-induced apoptosis, we studied hepatic injuries in transgenic mice whose livers express creatine kinase (CK). METHODS: Mice fed a diet containing 10% creatine, came to accumulate phosphocreatine and to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation activities. TNFalpha-mediated hepatic apoptosis in normally fed and Cr-feeding CK transgenic mice were assessed. RESULTS: TNFalpha and actinomycin D cause severe liver failure in normally fed transgenic mice, and in the wild-type mice. In contrast, no significant elevations in transaminase levels after injection were observed in Cr feeding transgenic mice. The disruption of the mitochondrial transmembrane potential at 2 h after TNFalpha injection, prior to ATP depletion, activation of caspase 3 like protease, and DNA fragmentation at 4-6 h after injection, were observed in normally fed transgenic mice. These were fully suppressed in Cr feeding transgenic mice. However, anti-Fas antibody-induced apoptosis was not inhibited in both groups. CONCLUSIONS: The results indicate that TNFalpha-induced apoptosis was inhibited in CK transgenic mice livers by maintaining mitochondrial function.