Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

Introduction

The PACS01 trial has demonstrated that a docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel's benefit.

Methods

Tumor samples from 1,099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested.

Results

Progesterone receptor-negativity (HR = 0.66; 95% CI 0.47 to 0.92, P = 0.013), and Ki67-positivity (HR = 1.53; 95% CI 1.12 to 2.08, P = 0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR = 0.51, 95% CI 0.33 to 0.79 for Ki67-positive versus HR = 1.10, 95% CI 0.75 to 1.61 for Ki67-negative tumors, P for interaction = 0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR = 1.16, 95% CI 0.73 to 1.84); the reduction in the relapse risk was 53% (HR = 0.47, 95% CI 0.22 to 1.01), 34% (HR = 0.66, 95% CI 0.37 to 1.19), and 12% (HR = 0.88, 95% CI 0.49 to 1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively.

Conclusions

In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity.     

Efficient Resource Use in Simplified Complete Denture Fabrication

Purpose: Conventional dentures will remain the only treatment available to most edentulous people for the foreseeable future. In this study, we compared the efficiency of two methods of making complete conventional dentures—the traditional academic standard (T) and a simplified technique (S) used in private practice. We have previously shown that they produce similar levels of patient satisfaction and denture quality. Materials and Methods: Data were gathered during a randomized controlled clinical trial of 122 subjects from initial examination until 6‐month follow‐up. For this report, the direct costs of providing one set of conventional complete dentures by T or S techniques were estimated. All materials used were recorded and their cost was calculated in Canadian dollars (CAN$). The costs of fabrication in an outside laboratory were added. Clinician's labor time was recorded for every procedure. Between‐group comparisons for each clinical procedure were carried out with independent t‐tests. The number of patients in each group who needed postdelivery treatment was compared with Chi‐square tests. The effect of group assignment and of treatment difficulty on outcomes was analyzed with multiple regression analysis. Results: The mean total cost of the T method was significantly greater than S (CAN$166.3; p < 0.001), and clinicians spent 90 minutes longer (p < 0.001) on clinical care. The difficulty of the case had no significant influence on outcomes. Conclusions: The results indicate that the S method is the more cost‐efficient method and that there are no negative consequences that detract from the cost savings.     

A randomized, double-blind, placebo-controlled safety and acceptability study of two Invisible Condom® formulations in women from Cameroon

Background

The objectives of this clinical trial were to evaluate the safety, tolerance and acceptability of two gel formulations of the Invisible Condom®: (i) the polymer alone and (ii) the polymer-containing sodium lauryl sulfate (SLS) compared to placebo when applied intravaginally with our unique applicator in sexually abstinent and active woman volunteers.

Study Design

A randomized, doubled-blind, placebo-controlled study in healthy women from Yaoundé, Cameroon. Two hundred sixty women were randomized into three gel arms: (a) gel alone, (b) gel plus SLS and (c) placebo gel. Thirty-seven sexually abstinent women applied gel intravaginally once a day for 14 days, while 75, 74 and 74 sexually active women applied gel intravaginally once, twice or three times daily for 14 days, respectively.

Results

Retention rate was high at 85% and 221 women applied the two products and the placebo for a total of 6005 times. Nugent score, H₂O₂-producing lactobacilli and vaginal pH were stable throughout the study and were not affected by the study products. Colposcopy showed neither genital ulceration nor mucosal lesions. No study product-related serious adverse events were reported. The majority of reported adverse events were mild or moderate and largely similar in all 3 arms. Satisfaction questionnaire showed that the gel formulations and applicator were generally comfortable and acceptable.

Conclusion

The Invisible Condom® formulations and applicator were found to be comfortable, well tolerated and acceptable when applied intravaginally once, twice or thrice daily for 14 days. Thus, expanded safety evaluation is warranted.     

Serological studies of piperacillin antibodies

BACKGROUND: Penicillin‐induced immune hemolytic anemia (IHA) is associated with immunoglobulin G antipenicillin detected by testing penicillin‐coated red blood cells (RBCs). Antibodies to piperacillin, a semisynthetic penicillin, would be expected to react similarly; however, antipiperacillin can be detected by testing in the presence of the drug. Piperacillin is commonly used in combination with tazobactam, which causes nonimmunologic protein adsorption onto RBCs. In six cases of piperacillin‐induced IHA, reactivity with piperacillin‐coated RBCs was not similar to reactivity of antipenicillin with penicillin‐coated RBCs. STUDY DESIGN AND METHODS: Antipiperacillin was tested against piperacillin‐coated RBCs prepared using different pH buffers. Plasma from blood donors and sera/plasma from patients were tested with piperacillin‐coated, penicillin‐coated, and uncoated RBCs. Hapten inhibition studies were performed using different concentrations of piperacillin. Donors' plasma were tested in the presence of piperacillin; sera from patients with IHA were tested in the presence of tazobactam. RESULTS: Piperacillin required high pH for binding to RBCs. Agglutination of piperacillin‐coated RBCs was observed in 91 percent of donors' and 49 percent of patients' plasma and was inhibited by piperacillin. In contrast to patients with IHA due to piperacillin, donors' plasma tested in the presence of piperacillin did not react. Tazobactam antibodies were not detected. CONCLUSION: A high percentage of donors' and patients' plasma contain an antibody to piperacillin or a chemically related structure detected by testing with piperacillin‐coated RBCs. A diagnosis of piperacillin‐induced IHA should not be made solely on the reactivity of a patient's plasma/serum with piperacillin‐ or piperacillin/tazobactam‐coated RBCs; testing in the presence of piperacillin is more reliable.     

Schools for health, education and development: a call for action

In 2007, the World Health Organization, together with UnitedNations and international organization as well as experts, metto draw upon existing evidence and practical experience fromregions, countries and individual schools in promoting healththrough schools. The goal of the meeting was to identify currentand emerging global factors affecting schools, and to help themrespond more effectively to health, education and developmentopportunities. At the meeting, a Statement was developed describingeffective approaches and strategies that can be adopted by schoolsto promote health, education and development. Five key challengeswere identified. These described the need to continue buildingevidence and capturing practical experience in school health;the importance of improving implementation processes to ensureoptimal transfer of evidence into practice; the need to alleviatingsocial and economic disadvantage in access to and successfulcompletion of school education; the opportunity to harness mediainfluences for positive benefit, and the continuing challengeto improve partnerships among different sectors and organizations.The participants also identified a range of actions needed torespond to these challenges, highlighting the need for actionby local school communities, governments and international organizationsto invest in quality education, and to increase participationof children and young people in school education. This paperdescribes the rationale for and process of the meeting and thedevelopment of the Statement and outlines some of the most immediateefforts made to implement the actions identified in the Statement.It also suggests further joint actions required for the implementationof the Statement.     

Nectin-4 is a new histological and serological tumor associated marker for breast cancer

Introduction

Breast cancer is a complex and heterogeneous disease at the molecular level. Evolution is difficult to predict according to classical histoclinical prognostic factors. Different studies highlight the importance of large-scale molecular expression analyses to improve taxonomy of breast cancer and prognostic classification. Identification of new molecular markers that refine this taxonomy and improve patient management is a priority in the field of breast cancer research. Nectins are cell adhesion molecules involved in the regulation of epithelial physiology. We present here Nectin-4/PVRL4 as a new histological and serological tumor associated marker for breast carcinoma.

Methods

Expression of Nectin-4 protein was measured on a panel of 78 primary cells and cell lines from different origins and 57 breast tumors by FACS analysis and immunohistochemistry (IHC), respectively. mRNA expression was measured by quantitative PCR. Serum Nectin-4 was detected by ELISA and compared with CEA and CA15.3 markers, on panels of 45 sera from healthy donors, 53 sera from patients with non-metastatic breast carcinoma (MBC) at diagnosis, and 182 sera from patients with MBC. Distribution of histological/serological molecular markers and histoclinical parameters were compared using the standard Chi-2 test.

Results

Nectin-4 was not detected in normal breast epithelium. By contrast, Nectin-4 was expressed in 61% of ductal breast carcinoma vs 6% in lobular type. Expression of Nectin-4 strongly correlated with the basal-like markers EGFR, P53, and P-cadherin, and negatively correlated with the luminal-like markers ER, PR and GATA3. All but one ER/PR-negative tumors expressed Nectin-4. The detection of Nectin-4 in serum improves the follow-up of patients with MBC: the association CEA/CA15.3/Nectin-4 allowed to monitor 74% of these patients compared to 67% with the association CEA/CA15.3. Serum Nectin-4 is a marker of disease progression, and levels correlate with the number of metastases (P = 0.038). Serum Nectin-4 is also a marker of therapeutic efficiency and correlates, in 90% of cases, with clinical evolution.

Conclusion

Nectin-4 is a new tumor-associated antigen for breast carcinoma. Nectin-4 is a new bio-marker whose use could help refine breast cancer taxonomy and improve patients' follow-up. Nectin-4 emerges as a potential target for breast cancer immunotherapy.     

Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection

PURPOSE: To investigate whether pravastatin mitigates delayed radiation-induced enteropathy in rats, by focusing on the effects of pravastatin on acute cell death and fibrosis according to connective tissue growth factor (CTGF) expression and collagen inhibition. METHODS AND MATERIALS: Mitigation of delayed radiation-induced enteropathy was investigated in rats using pravastatin administered in drinking water (30 mg/kg/day) 3 days before and 14 days after irradiation. The ileum was irradiated locally after surgical exteriorization (X-rays, 19 Gy). Acute apoptosis, acute and late histologic alterations, and late CTGF and collagen deposition were monitored by semiquantitative immunohistochemistry and colorimetric staining (6 h, 3 days, 14 days, 15 weeks, and 26 weeks after irradiation). Pravastatin antitumor action was studied in HT-29, HeLa, and PC-3 cells by clonogenic cell survival assays and tumor growth delay experiments. RESULTS: Pravastatin improved delayed radiation enteropathy in rats, whereas its benefit in acute and subacute injury remained limited (6 h, 3 days, and 14 days after irradiation). Delayed structural improvement was associated with decreased CTGF and collagen deposition but seemed unrelated to acute damage. Indeed, the early apoptotic index increased, and severe subacute structural damage occurred. Pravastatin elicited a differential effect, protecting normal intestine but not tumors from radiation injury. CONCLUSION: Pravastatin provides effective protection against delayed radiation enteropathy without interfering with the primary antitumor action of radiotherapy, suggesting that clinical transfer is feasible.     

Quality index for the quantification of the information recorded along standard microelectrode tracks to the subthalamic nucleus in parkinsonian patients.

OBJECTIVE: To quantify the usefulness of the neuronal activity recorded on a standard microelectrode track to the subthalamic nucleus (STN) for the determination of the transition between the thalamus and the STN. METHODS: The study is based on analysis of 689 extracelullar single units recorded on 70 tracks passing through the thalamus and the STN. Using four neuron parameters that were correlated with electrode depth, a quality index (QI) for each track was computed and compared with the subjective assessment by the electrophysiologist of the track quality. RESULTS: Subjectively, the transition between the thalamus and the STN was detected in 49 tracks (usual track) and not detected on 21 tracks (unusual tracks). Objectively, spike frequency, cell burst index (BI), signal relative root mean square (RMS) and spike relative amplitude were correlated with electrode depth and used to compute track QI. The average QI index of usual and unusual tracks was 0.25 +/- 0.9 and 0.85 +/- 0.15 (mean +/- confidence interval at P < 0.001), respectively. In 20 patients, QI correlates with post-operative measurement of electrode length in the STN. CONCLUSION: These results demonstrate that simple statistical analysis taking into account the variation of single-unit characteristics with electrode depth can discriminate between useful and useless tracks for the determination of the STN localisation.     

Sleep/wake cycles in the dark: sleep recorded by polysomnography in 26 totally blind subjects compared to controls.

OBJECTIVES: To evaluate subjective sleep difficulties and nocturnal sleep with polysomnography in 26 completely blind subjects, living in normal social environments and to compare the findings with those of matched controls.METHODS: Twenty-six blind individuals with no light perception and free-running melatonin rhythms, as assessed by measurements of urinary and salivary 6-sulfatoxymelatonin, were polygraphically monitored. Actigraphy and Braille sleep logs were obtained from the individuals for 14 days. Their sleep was compared to that of matched controls.RESULTS: Blind individuals were 'free-running' despite normal and regular social interaction. Each had ordinary working conditions and/or a family life with seeing spouse and children. Actigraphy obtained on 14 successive days showed the presence of small amount of daytime 'sleep' - 24.7+/-25.1 min per day. Total sleep time, sleep latency, sleep efficiency, and total REM sleep were significantly lower than in matched controls. Working blind subjects had a slightly higher total sleep time than those retired and unemployed. Congenital blindness, acquired blindness, presence of bilateral prosthetic eyes or presence of normal human eyes did not produce different nocturnal sleep and 'free-running' pattern results.CONCLUSIONS: Reduced total sleep time and other sleep abnormalities were associated with the complaint of daytime sleepiness and poor sleep in blind subjects. The abnormalities of sleep, which may be related to the free-running condition, present an additional challenge for these subjects, who are already severely impaired by their complete lack of vision.