Separate and combined analysis of successive dependent outcomes after breast-conservation surgery: recurrence, metastases, second cancer and death

<p>Abstract</p> <p>Background</p> <p>In the setting of recurrent events, research studies commonly count only the first occurrence of an outcome in a subject. However this approach does not correctly reflect the natural history of the disease. The objective is to jointly identify prognostic factors associated with locoregional recurrences (LRR), contralateral breast cancer, distant metastases (DM), other primary cancer than breast and breast cancer death and to evaluate the correlation between these events.</p> <p>Methods</p> <p>Patients (n = 919) with a primary invasive breast cancer and treated in a cancer center in South-Western France with breast-conserving surgery from 1990 to 1994 and followed up to January 2006 were included. Several types of non-independent events could be observed for the same patient: a LRR, a contralateral breast cancer, DM, other primary cancer than breast and breast cancer death. Data were analyzed separately and together using a random-effects survival model.</p> <p>Results</p> <p>LRR represent the most frequent type of first failure (14.6%). The risk of any event is higher for young women (less than 40 years old) and in the first 10 years of follow-up after the surgery. In the combined analysis histological tumor size, grade, number of positive nodes, progesterone receptor status and treatment combination are prognostic factors of any event. The results show a significant dependence between these events with a successively increasing risk of a new event after the first and second event. The risk of developing a new failure is greatly increased (RR = 4.25; 95%CI: 2.51-7.21) after developing a LRR, but also after developing DM (RR = 3.94; 95%CI: 2.23-6.96) as compared to patients who did not develop a first event.</p> <p>Conclusion</p> <p>We illustrated that the random effects survival model is a more satisfactory method to evaluate the natural history of a disease with multiple type of events.</p

Differential Recruitment of T- and IgA B-lymphocytes in the Developing Mammary Gland in Relation to Homing Receptors and Vascular Addressins

The mammary gland (MG) develops new vasculature and is colonized by lymphocytes, primarily T-cells, during pregnancy. In contrast, during lactation it is colonized primarily by IgA-containing B-cells (c-IgA cells). To explain this difference, we analyzed the spatiotemporal relationships between lymphocytes that expressed peripheral or mucosal homing receptors (HR) and the location of their vascular counterreceptors using quantitative immunohistochemical techniques. We observed that the density of β7+/CD3+ T-cells varied with the amount of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1)-stained area. Both increased during pregnancy to peak at delivery, decreased rapidly in early lactation to a steady level in mid- and late lactation, and returned to resting values after weaning. Although 60% of these β7+/CD3+ T-cells scattered in the epithelium co-expressed αEβ7, whereas the remaining 40% in association with blood vessels were α4β7, these results are consistent with a role of MAdCAM-1 in the localization of α4β7+ T-cells. In contrast to T-cells, β7+/c-IgA+ B plasmablasts (∼ 30% of total c-IgA cells) were located at the alveolar confluence, and their numbers increased in mid- and late lactation when MAdCAM-1 density plateaued. However, both T-and B-cells decreased after weaning. These results show an association between MAdCAM-1 expression level and recruitment of T-cells that does not hold for c-IgA B cells. Furthermore, the recruitment and accumulation of α4β7+ c-IgA cells are reminiscent of locally produced chemoattractants

Understanding the drug exposure-response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug-resistant tuberculosis

Aims: To externally validate an earlier characterized relationship between bedaquiline exposure and decline in bacterial load in a more difficult-to-treat patient population, and to explore the performances of alternative dosing regimens through simulations. Methods: The bedaquiline exposure-response relationship was validated using time-to-positivity data from 233 newly diagnosed or treatment-experienced patients with drug-resistant tuberculosis from the C209 open-label study. The significance of the exposure-response relationship on the bacterial clearance was compared to a constant drug effect model. Tuberculosis resistance type and the presence and duration of antituberculosis pre-treatment were evaluated as additional covariates. Alternative dosing regimens were simulated for tuberculosis patients with different types of drug resistance. Results: High bedaquiline concentrations were confirmed to be associated with faster bacterial load decline in patients, given that the exposure-effect relationship provided a significantly better fit than the constant drug effect (relative likelihood = 0.0003). The half-life of bacterial clearance was identified to be 22% longer in patients with pre-extensively drug-resistant (pre-XDR) tuberculosis (TB) and 86% longer in patients with extensively drug-resistant (XDR) TB, compared to patients with multidrug-resistant (MDR) TB. Achievement of the same treatment response for (pre-)XDR TB patients as for MDR TB patients would be possible by adjusting the dose and dosing frequency. Furthermore, daily bedaquiline administration as in the ZeNix regimen, was predicted to be as effective as the approved regimen. Conclusion: The confirmed bedaquiline exposure-response relationship offers the possibility to predict efficacy under alternative dosing regimens, and provides a useful tool for potential treatment optimization

Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens

Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens

Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy

Abstract As cancer strikes, individuals vary not only in terms of factors that contribute to its occurrence and development, but as importantly, in their capacity to respond to treatment. While exciting new therapeutic options that mobilize the immune system against cancer have led to breakthroughs for a variety of malignancies, success is limited to a subset of patients. Pre-existing immunological features of both the host and the tumor may contribute to how patients will eventually fare with immunotherapy. A broad understanding of baseline immunity, both in the periphery and in the tumor microenvironment, is needed in order to fully realize the potential of cancer immunotherapy. Such interrogation of the tumor, blood, and host immune parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. To approach these opportunities for progress, the Society for Immunotherapy of Cancer (SITC) reconvened the Immune Biomarkers Task Force. Comprised of an international multidisciplinary panel of experts, Working Group 4 sought to make recommendations that focus on the complexity of the tumor microenvironment, with its diversity of immune genes, proteins, cells, and pathways naturally present at baseline and in circulation, and novel tools to aid in such broad analyses