Joint modeling of longitudinal drug using pattern and time to first relapse in cocaine dependence treatment data

An important endpoint variable in a cocaine rehabilitation study is the time to first relapse of a patient after the treatment. We propose a joint modeling approach based on functional data analysis to study the relationship between the baseline longitudinal cocaine-use pattern and the interval censored time to first relapse. For the baseline cocaine-use pattern, we consider both self-reported cocaine-use amount trajectories and dichotomized use trajectories. Variations within the generalized longitudinal trajectories are modeled through a latent Gaussian process, which is characterized by a few leading functional principal components. The association between the baseline longitudinal trajectories and the time to first relapse is built upon the latent principal component scores. The mean and the eigenfunctions of the latent Gaussian process as well as the hazard function of time to first relapse are modeled nonparametrically using penalized splines, and the parameters in the joint model are estimated by a Monte Carlo EM algorithm based on Metropolis-Hastings steps. An Akaike information criterion (AIC) based on effective degrees of freedom is proposed to choose the tuning parameters, and a modified empirical information is proposed to estimate the variance-covariance matrix of the estimators.Comment: Published at http://dx.doi.org/10.1214/15-AOAS852 in the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Overexpression of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in Long-term Survivors of Advanced High-Grade Serous Ovarian Cancer

Objective: The prognosis for high-grade serous ovarian cancer (HGSOC) patients is poor. There are no defined biomarkers to identify between good and poor prognosis at the present. This study is to analyze if there are differences in angiogenesis biomarkers between long-term survivors and poor survivors, using tumor samples from a large cohort of long-term survivors and matched controls. Methods: Tumor samples of 62 “long-term survivors” and 62 matched controls were identified from the Tumor Bank Ovarian Cancer. All patients were diagnosed as HGSOC in advanced stages [Federation International of Gynecology and Obstetrics (FIGO) stage III-IV]. Patients with no relapse for at least 5 years (5+ years) after primary platinum-based chemotherapy were defined as “long-term survivor”, and patients who had the first relapse occurred between 6 months and 3 years were selected for controls. Long-term and control cohorts were matched by age and post-surgical tumor residuals. A pathological review has been performed in order to prove the high-grade serous histology. Immunohistochemistry was performed on tumor samples to determine the expressions of vascular endothelial growth factor (VEGF) A and VEGF receptor 2 (VEGFR2). Chi-square test or Fisher’s test were used to access the difference in biomarkers between long-term and control groups. Results: VEGFA expression was found to be significantly correlated with VEGFR2 expression (p<0.0001, Spearman coefficient 0.347). Although VEGFA expression was not related to 5+ years progression-free survival (PFS) (p=0.075), VEGFR2 overexpression was seen more frequently in long-term survivors (77.4%, 48/62) than in controls (51.6%, 30/62, p=0.001). The difference in VEGFR2 remained significant after adjusting FIGO stage and VEGFA expression (p=0.005). Within the whole cohort of analyzed patients, the highest expression level of VEGFR2 was seen in subgroup of patients with PFS longer than 10 years (10+ years) (p=0.001). Conclusion: Our study showed a significant correlation between VEGFR2 overexpression and 5+ year PFS in HGSOC patients, independent of age, FIGO stage, residual tumor mass and VEGFA expression.Ziel: Die Prognose für Patienten mit hochgradigem serösem Ovarialkarzinom (HGSOC) ist schlecht. Derzeit gibt es keine definierten Biomarker, die zwischen einer guten und einer schlechten Prognose unterscheiden könnten. In dieser Studie soll untersucht werden, ob es Unterschiede bei den Angiogenese-Biomarkern zwischen Langzeitüberlebenden und denen mit schlechter Prognose gibt, wobei Tumorproben aus einer großen Kohorte von Langzeitüberlebenden und passenden Kontrollen verwendet werden. Methoden: Aus der Tumor Bank Ovarian Cancer wurden Tumorproben von 62 "Langzeitüberlebenden" und 62 passenden Kontrollen identifiziert. Alle Patienten wurden als HGSOC in fortgeschrittenen Stadien diagnostiziert [Federation International of Gynecology and Obstetrics (FIGO) Stadium III-IV]. Patienten, bei denen nach einer primären platinbasierten Chemotherapie für mindestens 5 Jahre (5+ Jahre) kein Rezidiv auftrat, wurden als „Langzeitüberlebende“ definiert, und Patienten, bei denen das erste Rezidiv zwischen 6 Monaten und 3 Jahren auftrat, wurden für die Kontrollen ausgewählt. Langzeit- und Kontrollkohorten wurden nach Alter und postoperativen Tumorresten verglichen. Eine pathologische Untersuchung wurde durchgeführt, um die hochgradige seröse Histologie nachzuweisen. Immunhistochemie wurde an Tumorproben durchgeführt, um die Expression des vaskulären endothelialen Wachstumsfaktors (VEGF) A und des VEGF-Rezeptors 2 (VEGFR2) zu bestimmen. Der Chi-Quadrat-Test oder der Fisher-Test wurde verwendet, um den Unterschied zwischen Langzeit- und Kontrollgruppen bei den Biomarkern festzustellen. Ergebnisse: Die VEGFA-Expression korrelierte signifikant mit der VEGFR2-Expression (p <0,0001, Spearman-Koeffizient 0,347). Obwohl die VEGFA-Expression nicht mit dem progressionsfreien 5-Jahres-Überleben (PFS) (p = 0,075) zusammenhängt, wurde eine Überexpression von VEGFR2 bei Langzeitüberlebenden häufiger beobachtet (77,4%, 48/62) als bei Kontrollpersonen (51,6%, 30) / 62, p = 0,001). Der Unterschied in VEGFR2 blieb nach Anpassung des FIGO-Stadiums und der VEGFA-Expression signifikant (p = 0,005). In der gesamten Kohorte der analysierten Patienten wurde das höchste Expressionsniveau von VEGFR2 in einer Untergruppe von Patienten mit PFS über 10 Jahre (10+ Jahre) beobachtet (p = 0,001). Schlussfolgerungen: Unsere Studie zeigte eine signifikante Korrelation zwischen VEGFR2-Überexpression und 5+ Jahre PFS bei HGSOC-Patienten, unabhängig von Alter, FIGO-Stadium, restlicher Tumormasse und VEGFA-Expression

Myelodysplastic Syndrome Combined with Systemic Lupus Erythematosus: A Case Report

The literature on myelodysplastic syndrome combined with systemic lupus erythematosus is rarely reported. We reviewed and analysed the clinical data of a patient with myelodysplastic syndrome combined with systemic lupus erythematosus who had skin petechiae and fever as the main symptoms, and reviewed the relevant theories. There may be a close relationship between myelodysplastic syndrome and systemic lupus erythematosus, and further research is needed on the pathogenesis. When patients with autoimmune diseases (including systemic lupus erythematosus) presented with blood cell reduction，it is important to pay attention to them, and early bone marrow examination should be carried out to screen for the presence of hematological malignancies