Ping Xu

Randomized Trial Using Gonadotropin-Releasing Hormone Agonist Triptorelin for the Preservation of Ovarian Function During (Neo)Adjuvant Chemotherapy for Breast Cancer

PURPOSEnChemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer.nnnPATIENTS AND METHODSnPremenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels.nnnRESULTSnTargeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status.nnnCONCLUSIONnWhen stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.

Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial.

BACKGROUNDnConcerns regarding the risk of estrogen replacement have resulted in a significant increase in the use of soy products by menopausal women who, despite the lack of evidence of the efficacy of such products, seek alternatives to menopausal hormone therapy. Our goal was to determine the efficacy of soy isoflavone tablets in preventing bone loss and menopausal symptoms.nnnMETHODSnThe study design was a single-center, randomized, placebo-controlled, double-blind clinical trial conducted from July 1, 2004, through March 31, 2009. Women aged 45 to 60 years within 5 years of menopause and with a bone mineral density T score of -2.0 or higher in the lumbar spine or total hip were randomly assigned, in equal proportions, to receive daily soy isoflavone tablets, 200 mg, or placebo. The primary outcome was changes in bone mineral density in the lumbar spine, total hip, and femoral neck at the 2-year follow-up. Secondary outcomes included changes in menopausal symptoms, vaginal cytologic characteristics, N -telopeptide of type I bone collagen, lipids, and thyroid function.nnnRESULTSnAfter 2 years, no significant differences were found between the participants receiving soy tablets (n = 122) and those receiving placebo (n = 126) regarding changes in bone mineral density in the spine (-2.0% and -2.3%, respectively), the total hip (-1.2% and -1.4%, respectively), or the femoral neck (-2.2% and -2.1%, respectively). A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group. No significant differences were found between groups in other outcomes.nnnCONCLUSIONSnIn this population, the daily administration of tablets containing 200 mg of soy isoflavones for 2 years did not prevent bone loss or menopausal symptoms.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00076050.

The effect of cyproheptadine hydrochloride (Periactin®) and megestrol acetate (Megace®) on weight in children with cancer/treatment-related cachexia

Background Children with cancer frequently have associated cachexia and malnutrition. Failure to thrive affects nearly 40% of oncology patients with advanced or progressive disease. Malnutrition can erode quality of life and adversely impact disease prognosis. Appetite stimulation and increased food intake is 1 approach to combat cancer-related cachexia. Materials and Methods Cyproheptadine hydrochloride (CH), an appetite stimulant, was administered to children with cancer-associated cachexia to prevent further weight loss. All participants started CH and were evaluated for response after 4 weeks. Efficacy of megestrol acetate (MA) was evaluated in patients who did not respond to CH. Medical evaluation, weight measurements, prealbumin, and serum leptin levels were preformed at follow-up visits. Results Seventy patients were enrolled. Of the 66 evaluable patients, 50 demonstrated a response to CH (average weight gain 2.6u2009kg and mean weight-for-age z-score change of 0.35, P=0.001). Seven of the 16 nonresponders received MA. Six patients completed 4 weeks of MA, 5 responded (average weight gain of 2.5u2009kg). The most commonly reported side effect of CH was drowsiness. One patient on MA developed low cortisol levels and hyperlipidemia. Conclusions This study demonstrates that CH is a safe and effective way to promote weight gain in children with cancer/treatment-related cachexia.

Prognostic Performance of Metabolic Indexes in Predicting Onset of Type 1 Diabetes

OBJECTIVE In this investigation we evaluated nine metabolic indexes from intravenous glucose tolerance tests (IVGTTs) and oral glucose tolerance tests (OGTTs) in an effort to determine their prognostic performance in predicting the development of type 1 diabetes in those with moderate risk, as defined by familial relation to a type 1 diabetic individual, a positive test for islet cell antibodies and insulin autoantibody, but normal glucose tolerance. RESEARCH DESIGN AND METHODS Subjects (n = 186) who had a projected risk of 25–50% for developing type 1 diabetes within 5 years were followed until clinical diabetes onset or the end of the study as part of the Diabetes Prevention Trial–Type 1. Prognostic performance of the metabolic indexes was determined using receiver operating characteristic (ROC) curve and survival analyses. RESULTS Two-hour glucose from an OGTT most accurately predicted progression to disease compared with all other metabolic indicators with an area under the ROC curve of 0.67 (95% CI 0.59–0.76), closely followed by the ratio of first-phase insulin response (FPIR) to homeostasis model assessment of insulin resistance (HOMA-IR) with an area under the curve value of 0.66. The optimal cutoff value for 2-h glucose (114 mg/dl) maintained sensitivity and specificity values >0.60. The hazard ratio for those with 2-h glucose ≥114 mg/dl compared with those with 2-h glucose <114 mg/dl was 2.96 (1.67–5.22). CONCLUSIONS The ratio of FPIR to HOMA-IR from an IVGTT provided accuracy in predicting the development of type 1 diabetes similar to that of 2-h glucose from an OGTT, which, because of its lower cost, is preferred. The optimal cutoff value determined for 2-h glucose provides additional guidance for clinicians to identify subjects for potential prevention treatments before the onset of impaired glucose tolerance.

A Phase II Randomized, Placebo-Controlled Clinical Trial of Purified Isoflavones in Modulating Steroid Hormones in Men Diagnosed With Localized Prostate Cancer

Abstract Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.

Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy

Purpose The purpose of this Phase II randomized-controlled trial was to evaluate the safety and effect of administering several doses of lycopene to men with clinically localized prostate cancer, on intermediate endpoint biomarkers implicated in prostate carcinogenesis. Methods Forty-five eligible men with clinically localized prostate cancer were supplemented with 15, 30 or 45 mg of lycopene or no supplement from biopsy to prostatectomy. Compliance to study agent, toxicity, changes in plasma lycopene, serum steroid hormones, PSA and tissue Ki-67 were analyzed from baseline to completion of intervention. Results Forty-two of forty-five five subjects completed the intervention for approximately 30 days from the time of biopsy until prostatectomy. Plasma lycopene increased from baseline to post treatment in all treatment groups with greatest increase observed in the 45 mg lycopene-supplemented arm compared to the control arm without producing any toxicity. Overall, subjects with prostate cancer had lower baseline levels of plasma lycopene similar to those observed in previous studies in men with prostate cancer. Serum free testosterone decreased with 30 mg lycopene supplementation and total estradiol increased significantly with 30 mg and 45 mg supplementation from baseline to end of treatment, with no significant increases in serum PSA or tissue Ki-67. These changes were not significant compared to the control arm for this sample size and duration of intervention. Conclusions Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, our study suggests that other mechanisms mediated by steroid hormones may also be involved.

Reduction in CD4 Central Memory T-Cell Subset in Costimulation Modulator Abatacept-Treated Patients With Recent-Onset Type 1 Diabetes Is Associated With Slower C-Peptide Decline

We previously reported that continuous 24-month costimulation blockade by abatacept significantly slows the decline of β-cell function after diagnosis of type 1 diabetes. In a mechanistic extension of that study, we evaluated peripheral blood immune cell subsets (CD4, CD8-naive, memory and activated subsets, myeloid and plasmacytoid dendritic cells, monocytes, B lymphocytes, CD4+CD25high regulatory T cells, and invariant NK T cells) by flow cytometry at baseline and 3, 6, 12, 24, and 30 months after treatment initiation to discover biomarkers of therapeutic effect. Using multivariable analysis and lagging of longitudinally measured variables, we made the novel observation in the placebo group that an increase in central memory (CM) CD4 T cells (CD4+CD45R0+CD62L+) during a preceding visit was significantly associated with C-peptide decline at the subsequent visit. These changes were significantly affected by abatacept treatment, which drove the peripheral contraction of CM CD4 T cells and the expansion of naive (CD45R0−CD62L+) CD4 T cells in association with a significantly slower rate of C-peptide decline. The findings show that the quantification of CM CD4 T cells can provide a surrogate immune marker for C-peptide decline after the diagnosis of type 1 diabetes and that costimulation blockade may exert its beneficial therapeutic effect via modulation of this subset.

Prognostic Accuracy of Immunologic and Metabolic Markers for Type 1 Diabetes in a High-Risk Population Receiver operating characteristic analysis

OBJECTIVE To establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study. RESEARCH DESIGN AND METHODS A total of 339 subjects from the Diabetes Prevention Trial–Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers. RESULTS Individually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70–0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively). CONCLUSIONS The combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.

Treatment of Idiopathic Pulmonary Fibrosis with Losartan: A Pilot Project

BackgroundIdiopathic pulmonary fibrosis is a progressive interstitial lung disease with no current effective therapies. Treatment has focused on antifibrotic agents to stop proliferation of fibroblasts and collagen deposition in the lung. We present the first clinical trial data on the use of losartan, an antifibrotic agent, to treat idiopathic pulmonary fibrosis. The primary objective was to evaluate the effect of losartan on progression of idiopathic pulmonary fibrosis measured by the change in percentage of predicted forced vital capacity (%FVC) after 12xa0months. Secondary outcomes included the change in forced expiratory volume at 1 second, diffusing capacity of carbon monoxide, 6-minute walk test distance, and baseline/transition dyspnea index.MethodsPatients with idiopathic pulmonary fibrosis and a baseline %FVC of ≥50xa0% were treated with losartan 50xa0mg by mouth daily for 12xa0months. Pulmonary function testing, 6-minute walk, and breathlessness indices were measured every 3xa0months.ResultsTwenty participants with idiopathic pulmonary fibrosis were enrolled and 17 patients were evaluable for response. Twelve patients had a stable or improved %FVC at study month 12. Similar findings were observed in secondary end-point measures, including 58, 71, and 65xa0% of patients with stable or improved forced expiratory volume at 1 second, diffusing capacity for carbon monoxide, and 6-minute walk test distance, respectively. No treatment-related adverse events that resulted in early study discontinuation were reported.ConclusionLosartan stabilized lung function in patients with idiopathic pulmonary fibrosis over 12xa0months. Losartan is a promising agent for the treatment of idiopathic pulmonary fibrosis and has a low toxicity profile.

Chemical Characterization and Biological Properties of NVC-422, a Novel, Stable N-Chlorotaurine Analog

ABSTRACT During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent, N-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce N,N-dichlorotaurine (NNDCT). In the present study, 2,2-dimethyltaurine was used to prepare a more stable N-chlorotaurine, namely, N,N-dichloro-2,2-dimethyltaurine (NVC-422). In addition, we report on the chemical characterization, in vitro antimicrobial properties, and cytotoxicity of this compound. NVC-422 was shown effectively to kill all 17 microbial strains tested, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium. The minimum bactericidal concentration of NVC-422 against Gram-negative and Gram-positive bacteria ranged from 0.12 to 4 μg/ml. The minimum fungicidal concentrations against Candida albicans and Candida glabrata were 32 and 16 μg/ml, respectively. NVC-422 has an in vitro cytotoxicity (50% cytotoxicity = 1,440 μg/ml) similar to that of NNDCT. Moreover, our data showed that this agent possesses rapid, pH-dependent antimicrobial activity. At pH 4, NVC-422 completely killed both Escherichia coli and S. aureus within 5 min at a concentration of 32 μg/ml. Finally, the effect of NVC-422 in the treatment of an E. coli-infected granulating wound rat model was evaluated. Treatment of the infected granulating wound with NVC-422 resulted in significant reduction of the bacterial tissue burden and faster wound healing compared to a saline-treated control. These findings suggest that NVC-422 could have potential application as a topical antimicrobial.