[Five Cases of Pseudocirrhosis during Eribulin Treatment for Breast Cancer].

Pseudocirrhosis, which is radiologically and clinically similar to liver cirrhosis, may develop following chemotherapy for breast cancer with liver metastasis. There are few reports of eribulin treatment. We report 5 patients with metastatic or recurrent breast cancer who developed pseudocirrhosis during eribulin treatment. All patients had diffuse liver metastasis, and the liver metastases significantly reduced in size during the early phase of eribulin treatment, when they developed pseudocirrhosis. Subsequently, the patients had poor prognoses.

Relationship between serum lipid levels and the immune microenvironment in breast cancer patients: a retrospective study.

BACKGROUND: Therapeutic agents for dyslipidaemia, in particular statins, have been recently reported to suppress growth and metastasis of breast cancer. However, the predictive value of lipid control in breast cancer patients has not been discussed sufficiently. In addition, though immunometabolism is a relatively novel approach for tumour immunotherapy, the relationship between lipid metabolism and immune status has not been well documented. We therefore investigated the effects of lipid metabolism on antitumour immune response and cancer prognosis. METHODS: Except for patients with ductal carcinoma in situ, 938 patients treated with curative surgery were examined. The correlation between treatment for dyslipidaemia or serum lipid levels and clinicopathological features, including the prognosis, was evaluated retrospectively. Also, we stratified these results by intrinsic subtype of breast cancer, menopause, and type of therapeutic agents for dyslipidaemia. Moreover, neutrophil- to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs) were used as indicators of systemic and local immune status, respectively. RESULTS: Of 194 patients treated for dyslipidaemia, recurrence-free survival (RFS) and overall survival (OS) did not differ significantly between users of drugs for dyslipidaemia and non-users (p = 0.775 and p = 0.304, log-rank, respectively). Among postmenopausal, hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients treated for dyslipidaemia, the good serum lipid control group had significantly better RFS (p = 0.014, log-rank), lower postoperative NLR (p = 0.012), and higher TILs in resected tissues (p = 0.024) than the poor control group. Multivariate analysis showed that postoperative serum lipid levels were a risk factor for recurrence (hazard ratio = 4.722, 95% confidence interval 1.006-22.161, p = 0.049). CONCLUSIONS: Good control of serum lipid metabolism may improve the tumour immune microenvironment and prognosis in postmenopausal HR-positive/HER2-negative breast cancer patients.

Super-elderly patient-specific perioperative complications in breast cancer surgery.

PURPOSE: Geriatric surgery poses specific challenges due to patient vulnerability in relation to aging. We analyzed perioperative challenges concerning super-elderly patients with breast cancer. METHODS: Between 2013 and 2018, 908 patients with breast cancer were treated surgically. Of these, two patient groups were compared: Group A (≥ 85 years old, n = 34, 3.7%) and Group B (75-84 years old, n = 136, 15%). RESULTS: In Groups A and B, 26.4% and 36.8% of patients lived alone, respectively. Group A patients had higher rates of psychiatric and cardiovascular disease (32.4% and 41.2%) than Group B (8.8% and 16.2%) (p = 0.0009 and p = 0.0031, respectively). There was no marked difference in the type of surgery or length of hospital stay between groups, and most complications involved surgical site disorders. Postoperatively, Group A had a higher rate of delirium (29.4%) than Group B (3.7%) (p < 0.0001). The 30-day postoperative mortality rate was 0, and 76.5% of Group A and 45.6% of Group B patients received no adjuvant therapy (p = 0.0024). CONCLUSIONS: Age alone does not constitute a contraindication for appropriate surgery, although there are some challenges necessary to consider for super-elderly patients.

[A Case of Gallbladder Metastasis from Breast Cancer with Acute Calculous Cholecystitis].

In June 2018, a 75-year-old woman was admitted for right upper quadrant pain. She had a history of radical mastectomy for left breast cancer in April 2009. The axillary lymph node, bone, gastric, and pleural metastases had been treated with hormonal therapy for 2 years from April 2016. Based on the examination findings, we diagnosed her with acute calculous cholecystitis and performed emergency percutaneous transhepatic gallbladder drainage(PTGBD). Eleven days after PTGBD, we performed laparoscopic cholecystectomy. Pathological examination revealed a metastatic tumor from breast cancer in her gallbladder. Although her postoperative course was uneventful, the patient died of progression of the other organ metastasis 7 months after cholecystectomy. Gallbladder metastasis should be considered in patients with advanced breast cancer who present symptoms of cholecystitis.

[Undifferentiated Carcinoma of the Gallbladder with Rapid Postoperative Progression-A Case Report].

A 74-year-old woman presented with epigastric pain. Imaging revealed a tumor measuring 80 mm, with internal necrosis, originating from the gallbladder and invading the liver. We performed extended anterior segmentectomy of the liver and lymph node resection following a preoperative diagnosis of gallbladder cancer. Histologically, the tumor was diagnosed as an undifferentiated carcinoma of the gallbladder. Although curative resection was performed, the patient developed recurrence with liver metastasis and peritoneal dissemination after 6 postoperative weeks and died after 10 postoperative weeks.

Sentinel node biopsy for axillary management after neoadjuvant therapy for breast cancer: a single-center retrospective analysis with long follow-up.

PURPOSE: Sentinel node biopsy (SNB) after neoadjuvant therapy (NAT) for breast cancer remains controversial. We conducted a retrospective study of patients who underwent SNB after NAT to evaluate the effectiveness of this procedure. METHODS: A consecutive 105 women with locally advanced breast cancer (cT1-4, cN0-3, M0) were treated with NAT between 2006 and 2015. The subjects were 80 of these patients who became or remained clinically node-negative after NAT, 53 of whom had axillary management determined by SNB (group A) and the other 27 underwent axillary lymph node dissection (ALND) without SNB (group B). SNB was performed using a modified dye method. RESULTS: The sentinel node (SN) identification rate was 94.3% and the mean number of removed SNs was 2.4. ALND was avoided in 33 patients, who were confirmed as SN-negative. There was no difference in recurrence-free and overall survival rates between groups A and B (p = 0.71 and p = 0.46, respectively) during the median follow-up time of 63 months. Of the 33 patients who did not undergo ALND, 10 suffered recurrence (33%). One patient (3%) had recurrence in an axillary lymph node and four had recurrence in a supraclavicular lymph node. CONCLUSION: Axillary SNB after NAT did not affect the axillary failure rate or the prognosis. SNB may be a reliable procedure, even after NAT.

Outcome of sentinel lymph node biopsy in breast cancer using dye alone: a single center review with a median follow-up of 5 years.

PURPOSE: Various techniques are used for sentinel lymph node biopsy (SLNB) in breast cancer. While subareolar injection with dye alone is a relatively easy method, few studies have reported the outcome with a follow-up period. This study presents our results of SLNB using dye alone. METHODS: Between November 2002 and December 2010, 701 patients with breast cancer underwent SLNB using subareolar injection of indocyanine green or indigo carmine. Sentinel lymph node (SLN)-negative patients were followed without axillary lymph node dissection (ALND). RESULTS: SLNs were detected in 654 of 701 patients (93.3%), and the rate increased to 98.1% over the course of the study. The mean number of SLNs removed was 1.5. There was no significant difference in the detection rate between two dyes. No adverse events resulted from the injection of dyes. Of the 654 patients, 136 (20.8%) had SLN metastasis. Five hundred patients were followed without ALND. Thirty-six patients experienced disease relapse during a median follow-up of 60 months. Thirteen patients (2.6%) had regional lymph node relapse, and eight of them could undergo salvage lymph node dissection. The 5-year disease-free and overall survival rates were 92.4 and 96.1 %, respectively. CONCLUSION: SLNB using subareolar injection with dye alone was safe and feasible even after a long follow-up.

[Evaluation of recurrence rates on change in hormone receptor and human epidermal growth factor receptor 2 status after neo-adjuvant chemotherapy in breast cancer patients].

BACKGROUND: Neo-adjuvant chemotherapy(NAC)may affect hormone receptor(HR)and human epidermal growth factor receptor 2(HER2)status in breast cancer patients. However, the correlation between recurrence rates and this status change remains unclear. METHODS: We evaluated 70 consecutive breast cancer patients receiving NAC with anthracyclines and taxanes, with or without trastuzumab, between January 2005 and May 2012. Pre-treatment core needle biopsy samples and specimens obtained after surgery were tested to determine HR and HER2 status. The relationship between HR and HER2 status changes and recurrence rates was then assessed. RESULTS: Pathological complete response(pCR)was observed in 13 cases and non-pCR was observed in 57 cases. Of the non-pCR cases, HR-positive status changed to HR-negative status in 6.3% of patients, but a change from negativity to positivity was not observed. HER2-positive status changed to HER2-negative status in 48.0% of patients, and a change from negativity to positivity was observed in 12.5% of cases. The recurrence rate among patients with conversion to a HR-negative status was 0%and that among patients with conversion to a HER2-negative status was 25.0%. CONCLUSION: Recurrence rates were not significantly associated with HR and HER2 status conversion after NAC. Future research is warranted to confirm out results.

Dysregulated bile acid synthesis, metabolism and excretion in a high fat-cholesterol diet-induced fibrotic steatohepatitis in rats.

BACKGROUND AND AIMS: Cholesterol over-intake is involved in the onset of nonalcoholic steatohepatitis (NASH), and hepatocellular bile acid (BA) accumulation correlates with liver injuries. However, how dietary cholesterol influences cholesterol and BA kinetics in NASH liver remains ambiguous and needs to be clarified. METHODS: Molecular markers involved in cholesterol and BA kinetics were investigated at protein and mRNA levels in an already-established stroke-prone spontaneously hypertensive 5/Dmcr rat model with fibrotic steatohepatitis, by feeding a high fat-cholesterol (HFC) diet. RESULTS: Unlike the control diet, the HFC diet deposited cholesterol greatly in rat livers, where 3-hydroxy-3-methylglutaryl CoA reductase, low-density lipoprotein (LDL) receptor and LDL receptor-related protein-1 were expectedly downregulated, especially at 8 and 14 weeks, suggesting that cholesterol synthesis and uptake in response to cholesterol accumulation may not be disorganized. The HFC diet did not upregulate liver X receptor-α, conversely, it enhanced classic BA synthesis by upregulating cholesterol 7α-hydroxylase but downregulating sterol 12α-hydroxylase, and influenced alternative synthesis by downregulating sterol 27-hydroxylase but upregulating oxysterol 7α-hydroxylase, mainly at 8 and 14 weeks, indicating that there were different productions of primary BA species. Unexpectedly, no feedback inhibition of BA synthesis by farnesoid X receptor occurred. Additionally, the HFC diet impaired BA detoxification by UDP-glucuronosyltransferase and sulfotransferase 2A1, and decreased excretion by bile salt export pump at 8 and 14 weeks, although it induced compensatory export by multidrug resistance-associated protein-3. The disturbed BA detoxification may correlate with suppressed pregnane X receptor and constitutive androstane receptor. CONCLUSIONS: The HFC diet may accumulate BA in rat livers, which influences fibrotic steatohepatitis progression.

First indicators of relapse in breast cancer: evaluation of the follow-up program at our hospital.

BACKGROUND: Guidelines for breast cancer patient follow-up have not been widely adopted in Japan. To assess our intensive follow-up program, we evaluated first relapse and its indicators in patients with breast cancer. PATIENTS: Of 964 patients, 126 relapsed and 43 died in the median follow-up term of 45 months. Follow-ups were scheduled every 6-12 months for imaging and tumor marker (TM) evaluation. RESULTS: Of 126 relapsed patients, 30 (23.8%) had symptoms of relapse. First indicators of relapse in 96 asymptomatic patients were physical examination in 24 patients (19%); imaging, 57 patients (45.3%); and TMs, 15 patients (11.9%). The most sensitive indicators were physical examination for local relapse, ultrasonography for regional lymph nodes, scintigraphy for bone, computed tomography for lung, and TMs for liver metastasis. During intensive follow-up, 43% of relapsed patients were identified by symptoms or physical examination. These patients had poor prognosis compare to patients identified by imaging or TMs in overall survival and post-relapse survival (p = 0.009 and 0.019, respectively). In all 964 patients, the relapse rates for stage I, IIA, IIB, and III tumors were 7.4, 7.9, 19.9, and 43.5%, respectively. The percentage of first relapse detected by imaging or TMs for stage I, IIA, IIB, and III were 4.7, 5.1, 11.8, and 19.8%, respectively. The cost of our follow-up program for 10 years was approximately 290,000 yen per patient. CONCLUSION: A routine intensive follow-up program involving imaging and evaluation of TMs in all patients has low efficacy and high expenditure.

Caffeic acid phenethyl ester suppresses oxidative stress in 3T3-L1 adipocytes.

The generation of oxidative stress, characterized by enhanced reactive oxygen species (ROS) formation, has been found in obesity. ROS production was increased during the differentiation of 3T3-L1 cells into adipocytes. We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator-activated receptor γ. In this study, the preventive effect of CAPE on oxidative stress in 3T3-L1 cells was observed. The results were as follows: (1) ROS production during 3T3-L1 cell differentiation to adipocytes was significantly (p < 0.05) suppressed by CAPE treatment in a concentration-dependent manner, (2) with CAPE treatment, the extracellular superoxide dismutase mRNA expression level significantly increased, but the NOX4 mRNA expression level did not change, and (3) CAPE treatment significantly increased superoxide dismutase (SOD) activity in 3T3-L1 cells. From these results, we suggest that the increased oxidative stress in 3T3-L1 differentiation to adipocytes is attenuated by CAPE treatment. This attenuation may be partly caused by increased SOD production.

Caffeic acid phenethyl ester suppresses the production of pro-inflammatory cytokines in hypertrophic adipocytes through lipopolysaccharide-stimulated macrophages.

Obesity is a condition in which excess body fat accumulates due to lipids producing adipocytes and an increased number of differentiated mature cells. Recently, new findings have shown that macrophages infiltrate into adipose tissues and produce various pro-inflammatory cytokines in obese subjects. The inflammatory changes induced by the cross-talk between adipocytes and macrophages are critical for the pathophysiology of obesity and thus of metabolic syndrome. Caffeic acid phenethyl ester (CAPE) is known to have many functions, including antibacterial, anticancer and anti-inflammatory properties, but there is no evidence of its effect on the inflammatory responses in hypertrophic adipocytes through stimulation by macrophages. We investigated the effect of CAPE on macrophages and hypertrophic adipocytes in this study. CAPE significantly suppressed the levels of lipopolysaccharide (LPS)-induced interleukin (IL)-1-beta, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 from a macrophage cell line, RAW264.7. Supernatants of stimulated RAW264.7 macrophages drastically increased mRNA levels of pro-inflammatory cytokines such as IL-6, MCP-1 and TNF-alpha in 3T3-L1 hypertrophic adipocytes. CAPE also significantly and dose-dependently reduced the gene expression of these cytokines. Our findings indicate that CAPE has inhibitory effects on the production of pro-inflammatory cytokines from LPS-stimulated RAW264.7 macrophages. In addition, CAPE suppressed gene expressions of cytokines under inflammatory conditions of hypertrophic adipocytes, suggesting that it may have the potential to suppress inflammation by macrophage infiltration into adipose tissue in obese patients.

Evaluation of the metastatic status of lymph nodes identified using axillary reverse mapping in breast cancer patients.

BACKGROUND: Axillary reverse mapping (ARM) is a new technique to preserve upper extremity lymphatic pathways during axillary lymph node dissection (ALND), thereby preventing lymphedema patients with breast cancer. However, the oncologic safety of sparing the nodes identified by ARM (ARM nodes), some of which are positive, has not been verified. We evaluated the metastatic status of ARM nodes and the efficacy of fine needle aspiration cytology (FNAC) in assessing ARM node metastasis. METHODS: Sixty patients with breast cancer who underwent ARM during ALND between January 2010 and July 2012 were included in this study. Twenty-five patients were clinically node-positive and underwent ALND without sentinel lymph node biopsy (SLNB). Thirty-five patients were clinically node-negative but sentinel node-positive on the SLND. The lymphatic pathway was visualized using fluorescence imaging with indocyanine green. ARM nodes in ALND field, whose status was diagnosed using FNAC, were removed and processed for histology. We evaluated the correlation between the cytological findings of FNAC and the histological analysis of excised ARM nodes. RESULTS: The mean number of ARM nodes identified per patient was 1.6 ±0.9 in both groups. In most patients without (88%) and with (79%) SLNB, the ARM nodes were located between the axillary vein and the second intercostobrachial nerve. FNAC was performed for 45 ARM nodes, 10 of which could not be diagnosed. Six of the patients without SLNB (24%) and onewith SLNB (3%) had positive ARM nodes. Of these sevenpatients, four had >3 positive ARM nodes. There was no discordance between the cytological and histological diagnosis of ARM nodes status. CONCLUSIONS: Positive ARM nodes were observed in the patients not only with extensive nodal metastasis but also in those with a few positive nodes. FNAC for ARM nodes was helpful in assessing ARM nodes metastasis, which can be beneficial in sparing nodes essential for lymphatic drainage, thereby potentially reducing the incidence of lymphedema. However, the success of sampling rates needs to be improved.

Development of novel rat model for high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis progression in SHRSP5/Dmcr.

OBJECTIVES: Patients with nonalcoholic fatty liver disease are increasing worldwide, and preventive measures are an urgent need and primary concern today. AIM: This study aimed to develop and clarify the usefulness of the SHRSP5/Dmcr rat, derived from a stroke-prone spontaneously hypertensive rat, as a novel animal model for time-course analysis of steatohepatitis and the severe fibrosis progression often observed in the disease. METHODS: Ten-week-old male SHRSP5/Dmcr rats were divided into six groups: half were fed a high-fat and high-cholesterol-containing diet (HFC diet), and the others the control, stroke-prone (SP) diet for 2, 8, and 14 weeks. RESULTS: The HFC diet significantly increased serum transaminase and gamma glutamyl transpeptidase activities, tumor necrosis factor alpha levels, and serum and hepatic total cholesterol levels over time. In contrast, this diet decreased serum albumin, glucose, and adiponectin levels throughout or the later stage of the feeding period, but did not influence serum insulin levels. Histopathologically, the HFC diet increased microvesicular steatosis, and focal or spotty necrosis with lymphocyte infiltrations were observed in the liver at 2 weeks, macrovesicular steatosis, ballooned hepatocytes with Mallory-Denk body formation in some, and multilobular necrosis and fibrosis at 8 weeks. Interestingly, this fibrosis formed a honeycomb network at 14 weeks. These changes are very similar to those observed in patients with non-alcoholic steatohepatitis. CONCLUSIONS: SHRSP5/Dmcr rats appear to be a useful model for analyzing the time-dependent changes of HFC diet-induced steatohepatitis and fibrosis progression.

Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat.

OBJECTIVES: The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model. METHODS: SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed. RESULTS: Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu(2+)/Zn(2+)-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-ß1 (TGF-ß1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α(1) type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements. CONCLUSIONS: TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-ß1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.

Silibinin improves L-cell mass and function through an estrogen receptor-mediated antioxidative mechanism.

BACKGROUND: Silibinin, a major component of milk thistle extract silymarin, promotes hypoglycemia by activating estrogen receptor (ER) α and ß-mediated pathways in pancreatic ß-cells. Glucagon-like peptide-1 (GLP-1) is the enteroendocrine peptide produced in L-cells, and it controls glucose homeostasis through multiple pathways. The effect of silibinin on L-cell mass and function is still unknown. PURPOSE: The protective effect of silibinin on palmitate (PA)-treated intestinal L-cell line GLUTag cells and the SHRSP•Z-Leprfa/Izm-Dmcr (SP•ZF) diabetic rat model was investigated in current study. METHODS: After pre-incubation with 50 µM silibinin for 4 h, GLUTag cells were treated with 0.125 mM PA. MTT, Annexin V/PI apoptosis, Hoechst 33342 staining, western blot, DCFH-DA, GLP-1 ELISA, qRT-PCR and immunofluorescence analyses were undertaken to determine ER-dependent protection of silibinin against PA-induced cellular damage. The differential protein expression of GLUTag cells under different treatments was examined by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). The SP•ZF diabetic rat model was chosen for in vivo study. After 4 weeks of gastric gavage with 100 or 300 mg kg-1 of silibinin, the physiological indexes of the rats were measured. Cells expressing GLP-1, 8­hydroxy-2'-deoxyguanosine (8-OHdG), ERα, and/or ERß in duodenum tissues were detected by immunofluorescence. RESULTS: The current study showed that the GLUTag cells preincubated with silibinin activated the transcription factor nuclear erythroid-2 like factor-2 (Nrf2)-antioxidant pathway, reduced reactive oxygen species (ROS) generation, and improved cell survival and GLP-1 content, while the antioxidative effect of silibinin was blocked by the selective ERα antagonist MPP or ERß antagonist PHTPP in GLUTag cells. Our proteomics data further revealed that ERα or ß inactivation reduced glutathione peroxide and proteins associated with endocytosis and reproduction, thus at least partially reversing the protective effect of silibinin. SP•ZF rats received silibinin treatment showed increased serum GLP-1 content and improved glucose homeostasis. Furthermore, silibinin upregulated ERα and ß levels and reduced the level of 8-OHdG in GLP-1-positive cells. CONCLUSIONS: Our study showed that silibinin improved L-cell mass and function through an ER-mediated antioxidant pathway, and the proteomics analysis revealed for the first time the differential regulation of proteins by PA and silibinin in GLUTag cells.

Advantages of adjuvant chemotherapy for patients with triple-negative breast cancer at Stage II: usefulness of prognostic markers E-cadherin and Ki67.

INTRODUCTION: Triple-negative breast cancer (TNBC), which is characterized by negativity for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2), is a high risk breast cancer that lacks specific targets for treatment selection. Chemotherapy is, therefore, the primary systemic modality used in the treatment of this disease, but reliable parameters to predict the chemosensitivity of TNBC have not been clinically available. METHODS: A total of 190 TNBC patients who had undergone a curative resection of a primary breast cancer were enrolled. The adjuvant chemotherapy was performed for 138 (73%) of 190 TNBC cases; 60 cases had an anthracyclin-based regimen and 78 a 5-fluorouracil-based regimen. The prognostic value of E-cadherin, Ki67 and p53 expression in the outcome of TNBC patients with adjuvant chemotherapy was evaluated by immunohistochemistry. RESULTS: The adjuvant therapy group, especially those with Stage II TNBC, had a more favorable prognosis than the surgery only group (P = 0.0043), while there was no significant difference in prognosis between the anthracyclin-based regimen and 5-fluorouracil-based regimen. Patients with E-cadherin-negative and Ki67-positive expression showed significantly worse overall survival time than those with either E-cadherin-positive or Ki67-negative expression (P < 0.001). Multivariate analysis showed that the combination of E-cadherin-negative and Ki67-positive expression was strongly predictive of poor overall survival (P = 0.004) in TNBC patients receiving adjuvant chemotherapy. In contrast, p53 status was not a specific prognostic factor. CONCLUSIONS: Adjuvant therapy is beneficial for Stage II TNBC patients. The combination of E-cadherin and Ki67 status might be a useful prognostic marker indicating the need for adjuvant chemotherapy in Stage II TNBC patients.

Caffeic acid phenethyl ester suppresses the production of adipocytokines, leptin, tumor necrosis factor -alpha and resistin, during differentiation to adipocytes in 3T3-L1 cells.

We previously reported that caffeic acid phenethyl ester (CAPE) suppresses 3T3-L1 differentiation to adipocytes through the inhibition of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, fatty acid synthase (Fas) and adipocytes-specific fatty acid binding protein 2 (aP2) expressions (Juman et al., Biol. Pharm. Bull., 33, 1484-1488 (2010)). In the present study, we confirmed that CAPE had inhibitory effects on increased glycerol-3-phosphate dehydrogenase (GPDH) activity and an increased insulin receptor substrate 1 (IRS-1). Our data show that treatment with 50 µM CAPE significantly reduced the levels of leptin (p<0.05), resistin (p<0.05) and tumor necrosis factor (TNF)-alpha (p<0.05) which are known to aid adipocytokines production in adipocytes. In 3T3-L1 cells, treatment of CAPE decreased the triglyceride deposition similar to resveratrol, which is known to have an inhibitory effect on 3T3-L1 differentiation to adipocytes. In conclusion, we found that CAPE suppresses the production and secretion of adipocytokines from mature adipocytes in 3T3-L1 cells.

Inhibitory effect of rose hip (Rosa canina L.) on melanogenesis in mouse melanoma cells and on pigmentation in brown guinea pigs.

The compounds present in rose hips exerting an inhibitory action against melanogenesis in B16 mouse melanoma cells were investigated by dividing an aqueous extract of rose hips (RE) into four fractions. The 50% ethanol eluate from a DIAION HP-20 column significantly reduced the production of melanin and was mainly composed of procyanidin glycosides. We also found that this 50% ethanol eluate reduced the intracellular tyrosinase activity and also had a direct inhibitory effect on tyrosinase obtained as a protein mixture from the melanoma cell lysate. We also investigated the effect of orally administering RE on skin pigmentation in brown guinea pigs, and found that the pigmentation was inhibited together with the tyrosinase activity in the skin. These data collectively suggest that proanthocyanidins from RE inhibited melanogenesis in mouse melanoma cells and guinea pig skin, and could be useful as a skin-whitening agent when taken orally.