Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Methods/Design Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. Discussion This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. Trial registration ClinicalTrials.gov Identifier NCT0158936

Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

This study is being supported by grant no 04-2012-0290 from the SNUH Research fund and by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIP)(No. 2013005540). Letrozole and metformin are being supplied by the pharmaceutical company, Shin Poong Pharm. Co., Ltd.Background : Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Methods/Design : Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. Discussion : This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. Trial registration : ClinicalTrials.gov Identifier NCT01589367Peer Reviewe

Vitamin C Nutriture in Newly Diagnosed Diabetes

This study was performed to investigate the relationship between serum L-ascorbic acid, vitamin C intake, and diabetes in a nested case-control study. A cross-sectional survey of diet and health was conducted in 2,048 adults with an age of 30 y or older in Yonchon County, Korea. An oral glucose tolerance test was administered to all participants. One hundred cases of newly diagnosed diabetes were identified. Two healthy controls for each case matched with age, gender, drinking status, and smoking status were selected among the survey participants. L-Ascorbic acid levels were analyzed in fasting serum samples and one 24-h dietary recall was performed. Dietary vitamin C intake of persons with diabetes was 50.1 +/- 47.6 mg/d and that of controls was 55.1 +/- 41.1 mg/d. People with diabetes (22.3 +/- 16.8 mu mol/L) have lower serum ascorbic acid levels than their controls (26.3 +/- 17.0 mu mol/L) and the difference was significant by paired t-test (p<0.01.). The association between diabetes and serum ascorbic acid level was still significant in non-smokers (24.2 +/- 17.8 mu mol/L for the diabetes group and 29.5 +/- 16.7 mu mol/L for the control group, p<0.01) but not in smokers (19.4 +/- 15.7 mu mol/L for the diabetes group and 21.2 +/- 16.0 mu mol/L for the control group). Our results suggest that diabetes and smoking interactively affect serum ascorbic acid levels. Since this population had poor nutritional status of vitamin C, further investigation of association between serum ascorbic acid level and diabetes and smoking by the level of vitamin C consumption is warranted.Song YQ, 2009, AM J CLIN NUTR, V90, P429, DOI 10.3945/ajcn.2009.27491Meydani M, 2009, AM J CLIN NUTR, V90, P253, DOI 10.3945/ajcn.2009.28177Block G, 2008, NUTR J, V7, DOI 10.1186/1475-2891-7-35Kim SG, 2008, J KOREAN MED ASSOC, V51, P791de Jesus CCL, 2008, COCHRANE DB SYST REV, DOI 10.1002/14651858.CD006695.pub2Leclerc PC, 2008, AM J HYPERTENS, V21, P67, DOI 10.1038/ajh.2007.1HARDING AH, 2008, ARCH INTERN MED, V168, P1492*MIN HLTH WELF FAM, 2008, 2007 KOR NAT HLTH NUAfkhami-Ardekani M, 2007, INDIAN J MED RES, V126, P471Anderson RA, 2006, DIABETIC MED, V23, P258, DOI 10.1111/j.1464-5191.2005.01767.xChen H, 2006, AM J PHYSIOL-HEART C, V290, pH137, DOI 10.1152/ajpheart.00768.2005GIBSON R, 2005, PRINCIPLES NUTR ASSE, P529Montonen J, 2004, DIABETES CARE, V27, P362, DOI 10.2337/diacare.27.2.362*AM DIAB ASS, 2004, DIABETES CARE S1, V27, pS36*WHO, 2003, WHO TECHN REP SER, V916Darko D, 2002, CLIN SCI, V103, P339Sargeant LA, 2000, DIABETES CARE, V23, P726Will JC, 1999, AM J CLIN NUTR, V70, P49Cross CE, 1998, AM J CLIN NUTR, V67, P184Park Y, 1996, DIABETES RES CLIN PR, V34, pS65Will JC, 1996, NUTR REV, V54, P193LYKKESFELDT J, 1995, ANAL BIOCHEM, V229, P329PARK YS, 1995, DIABETES CARE, V18, P545JOHNSTON CS, 1994, AM J CLIN NUTR, V60, P735LECOMTE E, 1994, AM J CLIN NUTR, V60, P255PAMUK ER, 1994, AM J CLIN NUTR, V59, P891ROSE RC, 1993, FASEB J, V7, P1135BODE AM, 1993, BIOCHEM BIOPH RES CO, V191, P1347CUNNINGHAM JJ, 1993, MED HYPOTHESES, V26, P263DAVIE SJ, 1992, DIABETES, V41, P167JACQUES PF, 1992, ANN NY ACAD SCI, V669, P205NIKI E, 1991, AM J CLIN NUTR, V54, pS1119CUNNINGHAM JJ, 1991, METABOLISM, V40, P146YUE DK, 1990, DIABETES RES CLIN PR, V9, P239FREI B, 1989, P NATL ACAD SCI USA, V86, P6377SCHECTMAN G, 1989, AM J PUBLIC HEALTH, V79, P158YUE DK, 1989, DIABETES, V38, P257SALONEN JT, 1988, AM J CLIN NUTR, V48, P1226MCLENNAN S, 1988, DIABETES, V37, P359VANDERJAGT DJ, 1987, AM J CLIN NUTR, V46, P290LEVINE M, 1986, NEW ENGL J MED, V314, P892YOSHIOKA M, 1984, INT J VITAM NUTR RES, V54, P343GARRY PJ, 1982, AM J CLIN NUTR, V36, P332BROOK M, 1968, AM J CLIN NUTR, V21, P1254PATTERSON JW, 1950, J BIOL CHEM, V183, P81Friedman GJ, 1940, J CLIN INVEST, V19, P685

Correction: The effects of losartan on cytomegalovirus infection in human trabecular meshwork cells.

[This corrects the article DOI: 10.1371/journal.pone.0218471.]

The effects of losartan on cytomegalovirus infection in human trabecular meshwork cells.

BackgroundHuman cytomegalovirus (CMV) has been emerged as one of the causes of acute recurrent or chronic hypertensive anterior uveitis in immunocompetent. In hypertensive anterior uveitis, human trabecular meshwork (TM) cells are considered a focus of inflammation. We investigated the effects of losartan, a selective angiotensin II receptor antagonist, on CMV infection in human TM cells.MethodsHuman TM cells were infected with CMV AD169. Virus infected and mock-infected cells were treated with losartan or dexamethasone or ganciclovir with or without transforming growth factor (TGF)-β1. Viral DNA accumulation and host cell response were analyzed using real-time PCR. Levels of secreted TGF-β1 were measured by determining its concentration in conditioned medium using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits.ResultsCMV infection significantly increased the concentrations of the secreted TGF-β1 at 3, 5, and 7 day post infection in TM cells. Treatment with dexamethasone or losartan significantly decreased the levels of TGF-β1, whereas treatment with ganciclovir did not affect TGF-β1 levels. TM cells treated with TGF-β1 along with the presence of losartan for 48 hours showed marked decrease in the expression of α-smooth muscle actin (SMA), lysyl oxidase (LOX), connective tissue growth factor (CTGF), fibronectin and collagen-1A, compared with cells treated with TGF-β1 alone. CMV-infected TM cells stimulated by TGF-β1 significantly increased the expression of α-SMA and CTGF, which were attenuated by additional treatment with losartan.ConclusionLosartan inhibited the expression of TGF-β1 and fibrogenic molecules in human TM cells. Thus, losartan has the potential to decrease TM fibrosis in patients with CMV-induced hypertensive anterior uveitis

Transcriptional changes after herpes simplex virus type 1 infection in human trabecular meshwork cells.

BackgroundHerpes simplex virus type 1 (HSV-1) is causative for hypertensive anterior uveitis. Trabecular meshwork (TM) cells, which are the key cells regulating intraocular pressure (IOP), is considered to be the site of inflammation. We explored the profiles of genes expressed in human TM primary cells upon HSV-1 infection.MethodsHuman TM cells were infected with HSV-1 and total RNA was isolated. The global transcriptional gene network analyses were performed in mock-infected and HSV-1 infected TM cells. Using ingenuity pathway analysis, we determined the key biological networks upon HSV-1 infection. The results of microarray analyses were validated using quantitative PCR.ResultsTM cells had a high susceptibility to HSV-1 infection. HSV-1 induced transcriptional suppression of many components related to fibrosis in TM cells. The top biological network related to the genes which were significantly altered upon HSV-1 infection was organismal injury and abnormalities involving TGF-β1 and PDGF-BB. The results of PCR analyses for selected molecules were found to be in good agreement with the microarray data. HSV-1-infected TM cells showed an 80-fold increase in the expression of PDGF-BB, which was further increased by treatment with TGF-β1. HSV-1 also induced a 4-fold increase in the expression of the monocyte chemoattractant protein (MCP)-1, the downstream molecules of PDGF-BB.ConclusionsIn human TM cells, HSV-1 induced transcriptional suppression of many components related to fibrosis and enhanced expression of both PDGF-BB and MCP-1. Our study may provide a novel mechanism for the pathogenesis of HSV-1 infection in TM cells

Successful in vitro fertilization and embryo transfer after transplantation of cryopreserved ovarian tissue: Report of the first Korean case

For patients at risk of premature ovarian failure with cancer treatment, it is an important option to re-implant the ovarian tissue (OT) after cryopreservation to preserve endocrine function and fertility. With this technique, about 30% of pregnancy success rate and about 90 live births have been reported to date. However, there has been no case report of successful in vitro fertilization (IVF) and embryo transfer (ET) with oocytes collected from transplanted cryopreserved OT in Korea. We report a 30-year old woman with rectal cancer who underwent IVF and ET after cryopreserved OT thawing and re-implantation. She has been diagnosed with stage IIIC rectal cancer after surgery, and right ovary was removed and cryopreserved between cycles of chemotherapy. After completion of chemotherapy and radiotherapy, the patient underwent orthotopic transplantation of cryopreserved OTs. Three months after transplantation, the serum follicle-stimulating hormone level decreased from 91.11 mIU/mL to 43.69 mIU/mL. Thereafter, the patient underwent 11 ovarian stimulation cycles, and in 7 cycles, follicle growth was observed at the OT graft site. In one of these cycles, the oocyte was successfully retrieved and one embryo was transplanted after IVF. The patient was not pregnant, but the cryopreservation of OT can save the fertility after anticancer chemotherapy.Y