The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen

Introduction

The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.

Methods

The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.

Results

PHD1, PHD2 and PHD3 were detected in 47/179 (26.7%), 85/163 (52.2%) and 69/177 (39%) of tumours at baseline. PHD2 and PHD3 expression was moderate/strong whereas PHD1 expression was generally weak. There was a significant positive correlation between HIF-1α and PHD1 (P = 0.002) and PHD3 (P < 0.05) but not PHD2 (P = 0.41). There was a significant positive relationship between VEGF and PHD1 (P < 0.008) and PHD3 (P = 0.001) but not PHD2 (P = 0.09). PHD1, PHD2 and PHD3 expression was significantly increased after epirubicin therapy (all P < 0.000) with no significant difference in PHD changes between the treatment arms. There was no significant difference in response in tumours that expressed PHDs and PHD expression was not associated with survival.

Conclusions

Although expression of the PHDs was not related to response or survival in patients receiving neoadjuvant epirubicin, our data provide the first evidence that these enzymes are upregulated on therapy in breast cancer and that the biological effects independent of HIF make them therapeutic targets.     

Relation of folates, vitamin B12 and homocysteine to vertebral bone mineral density change in postmenopausal women. A five-year longitudinal evaluation

Elevation of homocysteine is associated with an increased risk for bone fractures. Whether the risk is due to homocysteine or to the reduced levels of cofactors necessary for its metabolisation, such as folates or vitamin B12, is not completely clear. In this study we wanted to determine whether in postmenopausal women, levels of folates, homocysteine or vitamin B12 are predictive of the rate of vertebral bone mineral density (BMD) change. The study was conducted at the centre for the menopause of our university hospital. Between September 2001 and March 2002, 161 healthy postmenopausal women volunteered for a cross-sectional evaluation of BMD and levels of serum folates, homocysteine and vitamin B12. Women were recalled for a second evaluation of vertebral BMD after about 5 years. Women having used anti-resorptive therapies for more than 1 year were excluded. The analysis was possible in 117 postmenopausal women. The annual rate of vertebral BMD change was independently related to levels of folates (coefficient of regression (CR): 2.040; 95%CI: 0.483, 3.596; p=0.011), and initial BMD values (CR: -0.060; 95%CI: -0.117, -0.003; p=0.040). No significant relation was found between the change of vertebral BMD and homocysteine or vitamin B12. BMD values at the first (r=0.225; p=0.016) and the second (r=0.206; p=0.027) evaluation were related to levels of folates, but not of homocysteine or of vitamin B12. These data suggest an important role for folates deficiency in the vertebral BMD decline of postmenopausal women.     

Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer

Metastatic castrate-resistant prostate cancer remains a disease hard to cure, and for this reason predictive tools to monitor disease progression and therapy response are an urgent need. In this respect, liquid biopsy on circulating cell-free nucleic acids represents an interesting strategy based on robust data. The low invasiveness and the possibility to target circulating cell-free tumor deoxyribonucleic acid underline the high specificity, sensitivity and clinical usability of the technique. Moreover, it has been observed that the cell-free tumor deoxyribonucleic acid of metastatic castrate-resistant prostate cancer patients can be representative of the tumor heterogeneity. Cell-free tumor deoxyribonucleic acids express the same behaviors as mutations: Variation in gene copy number or the methylation rate of the tumor tissue. Recently, circulating cell-free ribonucleic acid molecules have emerged as interesting markers to stratify the disease. Due to high-throughput technologies, liquid biopsy on circulating cell-free nucleic acids will soon be utilized in the clinical management of metastatic castrate-resistant prostate cancer patients.     

Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw?

Osteonecrosis of the jaw (ONJ) is a serious event that uncommonlycomplicates the natural history of bone metastatic patientstreated with bisphosphonates [1]. The pathogenesis of this adverseevent is unknown and probably multifactorial [2, 3]. The mechanismsby which bisphosphonates may cause ONJ are unclear. It is commonlybelieved     

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

Background: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. Methods: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. Results: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio = 0.59, 95% CI:0.42-0.84; P = 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio = 0.79, 95%CI: 0.63-0.98; P = 0.03), and response rate (hazard ratio = 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. Conclusion: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumors.     

Right mesothelial pericardial cyst determining intractable atrial arrhythmias

Pericardial cysts are intrathoracic lesions usually considered to be congenital and less frequently to be acquired. They are normally found incidentally upon chest radiography, computed tomography (CT)-scan or echocardiography. They are usually asymptomatic and have a benign behavior although sometimes they can cause clinical symptoms and diagnosis can be uncertain. We present, herein, the case of a 51-year-old male with a history of atrial arrhythmia resistant to transcatheter ablation therapies with an accidental finding of a pericardial cyst adherent to the lateral wall of the right atrium at the emerging superior vena cava. The patient was studied with transesophageal echocardiography, CT-scan and cardiovascular magnetic resonance with the evidence of dimensional increasing of the cyst at seriate controls. Considering this, in the absence of a definitive diagnosis and suspecting a link between the mass and the arrhythmia, the cyst was surgically removed through median sternotomy, off-pump on a beating heart. Postoperative course was unremarkable. Histopathologic examination confirmed it was a mesothelial pericardial cyst. At 12 months of follow-up the patient is doing well and he is in sinus rhythm. In conclusion, we believe that, although the majority of pericardial cysts need only radiological and clinical follow-up, surgical resection should be performed when the patient is symptomatic and when diagnosis is uncertain.     

Variazione degli indici parodontali durante la giornata. Studio pilota in fase di mantenimento

ObjectivesThe aim of this study was to determine whether periodontal indexes, which are the main basis for choices regarding periodontal therapy, can be influenced by the time of day they are measured.Materials and methodsUsing specific inclusion and exclusion criteria, we enrolled 11 patients. The Full-Mouth Plaque Score (FMPS), Full-Mouth Bleeding Score (FMBS), and the Periodontal Screening and Recording (PSR) index were recorded for each patient at baseline (T0). The same periodontal indexes were re-evaluated during the maintenance phase, and each was measured three times during the same day, i.e., 8:30 AM (T1), at 11:30 AM (T2), and at 2:00 PM (T3).ResultsComparison of findings recorded before (T0) and after therapy (T1, T2, T3) revealed significant improvement in all indexes. Comparing of maintenance therapy indices revealed that the FMBS (mean ± standard deviation 4.82 ± 2.95) measured at T1 was significantly higher than that measured at T2 (2.69 ± 1.49) and T3 (2.03 ± 1.51). Analysis of the non-smokers showed significant improvement of the indexes from T0 to the final re-evaluations (which were not significantly different from one another). In contrast, among smokers, the FMBS did not improve significantly from T0 to T1, and the T1 index was higher than those recorded at T2 and T3.ConclusionsDespite the limitations of our study, our findings indicate that the FMBS is not significantly stable within the same day. They suggest that this finding is particularly relevant in smokers and raise the possibility of an additional inflammatory pathogenic pathway to periodontal damage in these patients.     

Immune Globulin Intravenous: Myasthenia Gravis (Acute Exacerbation)

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to ude.uk@larenegj.