Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma

BACKGROUND: A single-institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer. METHODS: Patients were eligible if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients could have received up to 3 prior chemotherapy regimens. Temozolomide and capecitabine were administered concomitantly to 4 sequential cohorts at different dosing levels on Days 1-5 and Days 8-12, with cycles repeated every 21 days until disease progression. RESULTS: Twenty-four patients with multiple brain lesions were treated, including 14 patients with newly diagnosed brain metastases and 10 patients with recurrent brain metastases. Only 1 patient was chemotherapy-naive. Fatigue and nausea were the most commonly observed toxicities observed at any dose levels. Significant antitumor activity was observed, with a total of 1 complete and 3 partial responses (18% objective response rate) in the brain. The median response duration was 8 weeks (range, 6-64 weeks) and the median time to progression in the brain was 12 weeks (range, 3-70 weeks). Neurocognitive function improved or remained stable in patients with a response or stable disease. CONCLUSIONS: The combination of temozolomide and capecitabine is an active, well-tolerated regimen. The observed antitumor activity warrants further evaluation of this combination as an alternative to or in combination with whole-brain radiation therapy for the treatment of multiple brain metastases.     

The effect of different doses of subconjunctival bevacizumab injection on corneal neovascularization

To evaluate the effects of various doses of subconjunctival bevacizumab injections in the treatment of patients with corneal neovascularization. During the 6-month-follow-up, no significant ocular or systemic adverse events were observed related to the subconjunctival bevacizumab injection. In Group 1, the total area of corneal neovascularization before injection was 14.8 ± 3.2 % of the corneal surface and 10.2 ± 2.8 % 6 months after injection (p < 0.01). The mean decrease in Group 1 was 32.0 ± 3.0 %. In Group 2, the total area of corneal neovascularization before and 6 months after the injection was 14.2 ± 2.5 and 9.8 ± 2.3 %, respectively (p < 0.01). The mean decrease in Group 2 was 31.0 ± 2.3 %. The difference between the two groups was not statistically significant (p > 0.05). Twenty-four eyes of 24 patients with corneal neovascularization who were treated with a subconjunctival injection of bevacizumab were included in this retrospective study. Fourteen eyes were treated with 2.5 mg/0.1 ml (Group 1), and 10 eyes were treated with 5.0 mg/0.2 ml (Group 2) of subconjunctival bevacizumab. Digital photographs of the cornea were used to determine the area of corneal neovascularization before injection and at 1 month, 3 months, and 6 months after treatment. Subconjunctival injection of bevacizumab is well tolerated and associated with a partial regression of corneal neovascularization. The efficacy of this treatment is not correlated to the injection dose.     

Efficacy of Hyperbaric Oxygen Therapy on Central Corneal Thickness,Intraocular Pressure,and Nerve Fiber Layer in Patients with Type 2 Diabetes: A Prospective Cohort Study

PurposeTo evaluate the effect of hyperbaric oxygen therapy (HBOT) on central corneal thickness (CCT), intraocular pressure (IOP), and the retinal nerve fiber layer (RNFL) thickness in patients with type 2 diabetes mellitus.MethodsThis prospective non-randomized cohort study consisted of type 2 diabetes mellitus patients who received 30 sessions of HBOT for diabetic foot ulcer. The CCT, IOP, and RNFL measured at baseline, after the 10th session of HBOT, after the 20th session of HBOT, after the 30th session of HBOT, and after the 3 months of the last session of HBOT. We gained the superior-nasal, superior-temporal, inferior-nasal, inferior-temporal, nasal and temporal quadrant RNFL values with a spectral-domain optical coharence tomography.ResultsForty-six eyes of 46 patients included in the study. During the study period, a statistically significant increase in mean IOP values compared to baseline was observed (p < 0.001). We found no significant changes at CCT and all quadrants of RNFL values during HBOT and after 3 months of the treatment (p > 0.05). During the study period, the IOP levels increased over 21 mmHg (between 22 and 28 mmHg) in seven eyes (15.2%). The mean hemoglobin A1c values of these patients with IOP >21 mmHg were 8.2 ± 0.9 mg/dL, and there was significant differences compared with those of patients with IOP values ≤21 mmHg (7.4 ± 2.8 mg/dL) (p = 0.001).ConclusionsHBOT increase IOP in type 2 diabetic patients especially in ones with impaired blood glucose regulation. However, it does not cause any changes in CCT and RNFL. As diabetic retinopathy and diabetic foot ulcer are in common pathologies, thus this brief report concludes a need for further studies with longer follow-up periods to explore the potential interaction of HBOT on CCT, IOP, and RNFL.     

Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results

Objective.

To compare the pathologic complete response (pCR) rate of patients treated with 5-fluorouracil (5-FU), doxorubicin, and cyclophosphamide (FAC) versus dose-intense FAC plus G-CSF in the neoadjuvant setting and to compare the delivered dose intensity, disease-free survival (DFS) and overall survival (OS) times, and toxicity between treatment arms in patients with breast cancer.

Methods.

Patients were randomized to receive preoperative FAC (5-FU, 500 mg/m²; doxorubicin, 50 mg/m²; cyclophosphamide, 500 mg/m²) every 21 days for four cycles or dose-intense FAC (5-FU, 600 mg/m²; doxorubicin, 60 mg/m²; cyclophosphamide, 1,000 mg/m²) plus G-CSF every 18 days for four cycles.

Results.

Two hundred two patients were randomly assigned. The median follow-up was 7.5 years. Patients randomized to FAC plus G-CSF had a higher pCR rate as well as clinical complete response rate; however, these differences were not statistically different from those with the FAC arm. Patients in the FAC + G-CSF arm had a higher delivered dose intensity of doxorubicin in the neoadjuvant and adjuvant settings than those in the standard FAC arm. DFS and OS times were not significantly different between the two groups. However, the OS and DFS rates were significantly higher for patients who achieved a pCR than for those who did not. Thrombocytopenia, febrile neutropenia, and infection rates were higher in the FAC + G-CSF arm.

Conclusions.

A higher delivered dose intensity of doxorubicin with the FAC + G-CSF regimen did not result in a statistically significant higher pCR rate. However, patients who achieved a pCR experienced longer DFS and OS times.     

Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations

More than 75% of breast cancers that develop in BRCA1 mutation carriers are triple-negative breast cancers (TNBC). The aim of this study was to compare the recurrence-free survival (RFS) and overall survival (OS) in high-risk patients with TNBC with and without deleterious BRCA1/2 mutations. A total of 227 women with TNBC who were referred for genetic counseling and underwent BRCA genetic testing between 1997 and 2010 were included in the study. The relationships between clinical variables and outcomes were evaluated using univariate and multivariate Cox proportional hazard regression models. Of 227 high-risk women with TNBC, 50% (n = 114) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA non-carriers and carriers. At a median follow-up of 3.4 years, the 5-year RFS rates were 74 and 81% (P = 0.21), and 5-year OS rates were 85 and 93% in BRCA non-carriers and BRCA carriers, respectively (P = 0.11). In a multivariate model, after adjusting for age and disease stage, BRCA carriers tended to have a decreased risk of recurrence (HR = 0.67; 95% CI: 0.38-1.19; P = 0.17) or death (HR = 0.51; 95% CI:0.23-1.17; P = 0.11) compared to non-carriers. Our data indicate a 50% prevalence of deleterious BRCA1/2 mutations in high-risk women diagnosed with TNBC. Overall prognosis of TNBC in BRCA carriers and non-carriers is not significantly different within the first 5 years following an initial diagnosis. Further studies need to evaluate whether different therapies will change the outcome in these subgroups of TNBC.     

Molecular mechanism of vasorelaxant and antiatherogenic effects of the statins in the human saphenous vein graft

In this study we aimed to investigate the vasorelaxant and antiatherogenic effects of the statins (fluvastatin and pravastatin) in the human saphenous vein grafts at the molecular level by using histopathologic, pharmacological and immunochemical techniques. The saphenous vein grafts evaluated histopathologically displayed a loss in their endothelium up to a ratio of 30% and set forth indications of functional deterioration. The pharmacological evaluations proved that the relaxation responses induced by fluvastatin and pravastatin were significantly inhibited by nitric oxide synthase inhibitor, N(G)-nitro-l-arginine, and cyclooxygenase inhibitor, indomethacin, while these responses were significantly increased by angiotensin converting enzyme inhibitors, captopril and enalapril, and rho kinase inhibitor, Y27632. The results of immunochemical studies are in accordance with the results of the pharmacological studies that the related statins increased the levels of nitric oxide, phospholipase A(2) and they decreased the levels of angiotensin II and active rho kinase. On the other hand mevalonolactone, a substrate of lipid metabolism, failed to change the effects of fluvastatin and pravastatin in the related tissue. The experimental results indicate that activation of nitric oxide synthase and phospholipase A(2)-cyclooxygenase pathway and inhibition of angiotensin converting enzyme and rho kinase may have a role on the effects of fluvastatin and pravastatin in the human saphenous vein grafts. It seems that the vasorelaxant and antiatherogenic effects of the related statins are independent of their lipid lowering mechanism.     

Early onset HER2-positive breast cancer is associated with germline TP53 mutations

BACKGROUND:

Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li‐Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.

METHODS:

We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls).

RESULTS:

Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor‐ and/or progesterone receptor‐positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2‐positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6‐18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91‐0.99).

CONCLUSIONS:

This study suggests an association between germline TP53 mutations and early onset HER2‐positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2‐targeted therapies, and elucidate some of the molecular pathways involved in breast cancer. Cancer 2012;. © 2011 American Cancer Society.     

A phase 1B dose escalation trial of Scutellaria barbata (BZL101) for patients with metastatic breast cancer

Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs). This study was conducted to determine the prevalence of suboptimal vitamin D levels in women initiating adjuvant letrozole for breast cancer and to determine whether supplementation with 50,000 IU of vitamin D3 weekly could reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels. Sixty women about to begin an adjuvant AI were enrolled. Baseline 25OHD levels were obtained, and women completed symptom questionnaires. They were then started on letrozole, along with standard dose calcium and vitamin D. Four weeks later, women with baseline 25OHD levels ≤40 ng/ml started additional vitamin D3 supplementation at 50,000 IU per week for 12 weeks. 25OHD levels were re-assessed at 4, 10, and 16 weeks; the questionnaires were repeated at weeks 4 and 16. At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20–31 ng/ml). 25OHD levels >40 ng/ml were achieved in all 42 subjects who received 12 weeks of supplementation with 50,000 IU vitamin D3 weekly, with no adverse effects. After 16 weeks of letrozole, more women with 25OHD levels >66 ng/ml (median level) reported no disability from joint pain than did women with levels <66 ng/ml (52 vs. 19%; P = 0.026). Vitamin D deficiency and insufficiency are prevalent in post-menopausal women initiating adjuvant AI. Vitamin D3 supplementation with 50,000 IU per week is safe, significantly increases 25OHD levels, and may reduce disability from AI-induced arthralgias.     

Effect of copper intrauterine device on the cyclooxygenase and inducible nitric oxide synthase expression in the luteal phase endometrium

Background

To evaluate the effect of copper intrauterine device (IUD) on the expression of cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) in the luteal phase endometrium.

Study Design

A prospective clinical study was conducted on 30 women who were willing to use a copper IUD contraception. Endometrial biopsies and blood samples were taken before and 3 months after the insertion of the IUD on Day 3 and Days 20–24 of the cycle. Main outcome measures were to evaluate the effect of copper IUD on uterine artery blood flow using pulsed color Doppler ultrasonography and the relationship of bleeding abnormalities and menstrual pain level with the uterine blood flow, COX-2 and iNOS expression.

Results

Only the left uterine artery pulsatility and resistance indices decreased statistically significantly (p=.005 and p=.039, respectively). Other Doppler parameters showed no change. Cyclooxygenase-2 expression of both endometrial luminal epithelium (p=.03) and gland epithelium (p=.03) increased significantly. Inducible NOS expression of the endometrial surface epithelium decreased significantly after IUD insertion (p=.01).

Conclusions

Although COX-2 expression increased 3 months after copper IUD insertion, iNOS expression of the luminal epithelium decreased. Local hypoxia caused by copper and vasoconstrictor prostanoids may play a role in IUD-related menstrual abnormalities.     

The relationship between dieting and body image, body ideal, self-perception, and body mass index in Turkish adolescents

OBJECTIVE: The current study examined the roles of body image, ideal body weight, self-perception, and body mass index (BMI) on the dieting behavior of Turkish adolescents. METHOD: The 531 subjects who participated in the study ranged from 15 to 17 years old and were recruited from five selected high schools in Ankara. They completed the Self-Perception Profile for Adolescents (SPPA), the Body Image Satisfaction Questionnaire (BISQ), and the Dieting Status Measure (DiSM). Height and weight were measured. RESULTS: Dieting adolescents received significantly lower scores than nondieters for most of the BISQ items and for the physical appearance and global self-worth subscales of the SPPA. A thinner body ideal, the physical appearance domain of self-concept, and low global self-worth were the predicting factors of frequent dieting. However, BMI and body image dissatisfaction were not predicting factors. DISCUSSION: The results indicate that a thinner body ideal, low self-worth, and low physical self-concept have more significant effects on body dissatisfaction and dieting than being actually overweight does. Furthermore, high physical self-concept scores and body satisfaction may not necessarily preclude having a thinner body ideal and, hence, dieting in girls.