Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer

BackgroundThe therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data.SummaryTo develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas.Key MessagesThis article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.     

Asthma und asthmatypische Beschwerden bei Schulkindern: Vergleich von Gebieten in Deutschland und Osterreich

Conclusion

Geographical differences in morbidity of asthma and asthmalike complaints were ascertained and remained stable after adjustment for potential confounders. However, the choice of the way of presentation (relative risk versus deviation from the weighted mean of the prevalences) can provoke different suggestive effects.     

Mainstream medicine versus complementary medicine (homeopathic) intervention: a critical methodology study of care in pregnancy

This meticulously evaluated study investigated two fundamental questions. The first dealt with the usefulness and adequacy of the instruments (questionnaires and case report forms) presently available in mainstream clinical research when trying to evaluate two dissimilar therapeutic systems such as main stream medicine and homeopathy. The second question dealt with the comparability of the two populations of patients in terms of individual personality characteristics as well as regarding the progress of the pregnancies and the course of the deliveries under the two systems of care and control. It turned out that a study of that kind is feasible in principle but is very demanding and time consuming. In addition the study showed clearly that the instruments presently available in mainstream medicine do not cover essential aspects of homeopathy and, therefore, impede a comparison of the two therapeutic systems. In the homeopathic group the frequency of situations requiring a Cesarean was remarkably low. However, the number of cases is too small to draw qualifying conclusions.     

Imiquimod treatment induces expression of opioid growth factor receptor: a novel tumor antigen induced by interferon-alpha?

PURPOSE: Imiquimod represents a synthetic local immune response modifier that has demonstrated efficacy in clearing basal cell carcinoma. Via interaction with Toll-like receptor 7 on immune cells, imiquimod induces local production of cytokines, such as interferon (IFN)-alpha. EXPERIMENTAL DESIGN: To more closely define and elucidate mechanisms leading to basal cell carcinoma clearance in vivo, we examined gene expression profiles of skin basal cell carcinoma before and after treatment with 5% imiquimod cream (Aldara) by using high-density oligonucleotide arrays. RESULTS: We show that imiquimod predominantly induces genes involved in different aspects of immune response. In addition to effects on immunity, imiquimod treatment modulates the expression of genes involved in the control of apoptosis and oncogenesis. Array data indicated that imiquimod treatment induces expression of opioid growth factor receptor, a molecule recently reported to be a target for antitumor antibody responses. Immunohistochemistry revealed in vivo up-regulation of opioid growth factor receptor protein on tumor and on infiltrating cells after treatment. By using basal cell carcinoma cell lines treated with IFN-alpha or imiquimod, we show that opioid growth factor receptor up-regulation is IFN-alpha-mediated, rather then directly imiquimod-mediated. By using tissue microarray containing 52 basal cell carcinomas, we demonstrate opioid growth factor receptor expression in almost half of the cases. Expression of opioid growth factor receptor correlated with a longer recurrence-free period in basal cell carcinoma that recurred after radiotherapy (Kaplan-Meier analysis, P = 0.041). CONCLUSIONS: In addition to its immunomodulatory and antiproliferative activity, opioid growth factor receptor seems to have a prognostic significance in basal cell carcinoma patients. Our data add to the growing list of basal cell carcinoma-associated tumor antigens.     

Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor.

PURPOSE: To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. CONCLUSION: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.     

Health-related quality of life parameters as prognostic factors in a nonmetastatic breast cancer population: an international multicenter study.

PURPOSE: The purpose of this research was to evaluate whether baseline health-related quality of life (HRQOL) parameters are prognostic factors for survival in locally advanced breast cancer patients. Although the literature highlights the important role of HRQOL parameters in predicting survival in advanced metastatic disease, little evidence exists for earlier stages. PATIENTS AND METHODS: The overall sample consisted of 448 patients randomly assigned to receive cyclophosphamide, epirubicin, and fluorouracil versus epirubicin, cyclophosphamide, and granulocyte colony-stimulating factor. Patients were enrolled in 12 countries. HRQOL baseline scores were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. In addition, a bootstrap resampling technique was used to assess the stability of the outcomes. Bootstrap results were then applied for model averaging purposes as a means to account for the observed model selection uncertainty. RESULTS: The final multivariate model retained inflammatory breast cancer (T4d) as the only factor predicting overall survival (OS) with a hazard ratio of 1.375 (95% CI, 1.027 to 1.840; P =.03). The presence of inflammatory breast cancer lowers the median survival time from 6.6 to 4.2 years (36% reduction). None of the preselected HRQOL variables were prognostic for OS or disease-free survival, in either the univariate or multivariate analysis. CONCLUSION: Our findings suggest that baseline HRQOL parameters have no prognostic value in a nonmetastatic breast cancer population.     

Utricular dysfunction in patients with benign paroxysmal positional vertigo.

OBJECTIVE: The objective of this study was to test the hypothesis that utricular function is impaired in patients with idiopathic benign paroxysmal positional vertigo. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary dizziness clinic and vestibular research laboratory. PATIENTS: Twelve patients with unilateral idiopathic benign paroxysmal positional vertigo were examined 1 week and 1 month after successful treatment with positioning maneuvers and compared with 24 healthy subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Otolith function was assessed with estimation of the subjective visual vertical and analysis of the torsional otolith-ocular reflex. Unilateral stimulation of the utricle was performed on a rotator that allowed eccentric lateral displacement of the patient during earth-vertical rotation with constant velocity. The otolith-ocular reflex was recorded with three-dimensional video-oculography. RESULTS: There was no difference in the estimation of the subjective visual vertical between patients and controls. The peak-to-peak amplitude of the otolith-ocular reflex torsional eye position was smaller in patients than in the control group. The gain of the unilateral otolith-ocular reflex was reduced in patients on both sides on first testing. After several weeks, only the affected labyrinth showed a reduced otolith-ocular reflex gain. CONCLUSION: Our findings document otolith dysfunction in patients with idiopathic benign paroxysmal positional vertigo possibly secondary to degeneration of the utricular macula. This finding may account for the transient mild imbalance and dizziness that some patients with benign paroxysmal positional vertigo experience even after resolution of positional vertigo.     

Malignancy Rate and Malignancy Risk Assessment in Different Lesions of Uncertain Malignant Potential in the Breast (B3 Lesions): An Analysis of 192 Cases from a Single Institution

BackgroundThe question of how to deal with B3 lesions is of emerging interest.MethodsIn the breast diagnostics of 192 patients between 2009 and 2016, a minimally invasive biopsy revealed a B3 lesion with subsequent resection. This study investigates the malignancy rate of different B3 subgroups and the risk factors that play a role in obtaining a malignant finding.ResultsThe distribution of B3 lesions after minimally invasive biopsy was as follows: atypical ductal hyperplasia (ADH), 7.3%; flat epithelial atypia (FEA), 7.8%; lobular neoplasia (LN), 7.8%; papilloma (Pa), 49.5%; phylloidal tumour (PT), 8.9%; radial sclerosing scar (RS), 3.1%; mixed findings, 10.4%; and other B3 lesions, 5.2%. Most B3 lesions were detected by stereotactic vacuum-assisted biopsy (44.3%), 36.5% by ultrasound-assisted biopsy, and 19.3% by magnetic resonance imaging-assisted biopsy. Most B3 lesions (55.2%) were verified by surgical resection, whereas 30.7% were downgraded to a benign lesion. About 14.1% of the cases were upgraded to malignant lesions, 9.4% to ductal carcinoma in situ and 4.7% to invasive carcinoma. In relation to individual B3 lesions, the following malignancy rates were found: 28.6% (ADH), 13.3% (FEA), 33.3% (LN), 12.6% (Pa), 5.9% (PT), and 0% (RS). The most important risk factor was increasing age. Postmenopausal status was considered an increased risk for an upgrade (p = 0.015). A known malignancy in the ipsilateral breast was a significant risk factor for a malignant upgrade (p = 0.003).ConclusionIncreasing knowledge about B3 lesions allows us to develop a “lesion-specific” therapy approach in the heterogeneous group of B3 lesions, with follow-up imaging for some lesions with less malignant potential and concordance with imaging or further surgical resection in cases of disconcordance with imaging or higher malignant potential.     

IL-1α, IL-1β, IL-6, and IL-8 secretion of human keratocytes following photodynamic inactivation (PDI) in vitro

Purpose

With increasing resistance of microorganisms to antibiotics, photodynamic inactivation (PDI) may also be a potential therapeutic option in infectious keratitis. As part of the inflammatory response in infectious keratitis, keratocytes produce various interleukins. The purpose of this study was to evaluate the potential anti-inflammatory effect of PDI, analyzing interleukin-1 alpha (IL-1α), interleukine-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) secretion of human keratocytes following PDI, in vitro.

Methods

Primary human keratocytes were isolated by digestion in collagenase A (1.0 mg/ml) from human corneal buttons, and cultured in DMEM/Ham’s F12 medium supplemented with 10 % FCS. Keratocyte cell cultures underwent illumination using red (670 nm) light for 13 min following exposure to 100 nM concentration of the photosensitizer chlorin e6 (Ce6) in the culture medium. Five and 24 hours after PDI, secretion of IL-1α, IL-1β, IL-6, and IL-8 was measured by enzyme-linked immunoabsorbent assay (ELISA).

Results

The secretion of IL-1α was under the measurement limit in treated and untreated cell cultures 5 and 24 h after PDI. Compared to untreated controls, IL-6 and IL-8 secretion of keratocytes decreased (p?<?0.05 and 0.0001) significantly 5 hours after PDI, whereas IL-1β secretion remained unchanged. Twenty-four hours after PDI, secretion of IL-1β, IL-6, and IL-8 did not differ significantly from untreated controls.

Conclusions

In the short term, PDI does not have an impact on IL-1α and IL-1β secretion of keratocytes, in vitro. Photodynamic inactivation inhibits IL-6 and IL-8 secretion of keratocytes transiently (5 h), which normalizes 24 h following treatment. Through the short-term impact of chlorine e6-PDI on IL-6 and IL-8 secretion, PDI may inhibit the inflammatory cascade in at least keratocyte cultures.