Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial

<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p

Η επίδραση της άσκησης στην κύηση με ΣΔ

Στις μέρες μας ένα σημαντικό ποσοστό των κυήσεων επιπλέκεται από σακχαρώδη διαβήτη. Το μεγαλύτερο μέρος αφορά γυναίκες με ΣΔΚ ενώ παράλληλα ένα άλλο μέρος αφορά γυναίκες με προυπάρχοντα ΣΔτ1 και ΣΔτ2. Σε κάθε περίπτωση είναι πιθανό να υπάρξουν σοβαρές επιπλοκές τόσο για τη μητέρα όσο και για το έμβρυο με σημαντικό αντίκτυπο στη μετέπειτα υγεία και των δυο. Απαραίτητη κρίνεται συνεπώς η προσεκτική παρακολούθηση της εγκύου και οι κατάλληλες παρεμβάσεις που θα συμβάλλουν στην όσο το δυνατόν πιο ομαλή και χωρίς επιπλοκές πορεία της εγκυμοσύνης. Ο τακτικός γλυκαιμικός έλεγχος, η φαρμακευτική αγωγή όταν αυτή χρειάζεται και η σωστή διατροφή της εγκύου, αποτελούν ισχυρά όπλα στη φαρέτρα του επιβλέποντος θεράποντος ιατρού. Παράλληλα, πολλές είναι και οι έρευνες σχετικά με το ρόλο που διαδραματίζει η άσκηση πριν αλλά και κατά τη διάρκεια μιας εγκυμοσύνης με σακχαρώδη διαβήτη. Η άσκηση τόσο η αερόβια όσο και η αναερόβια καθώς και οι διατατικές ασκήσεις και οι ασκήσεις χαλάρωσης προσφέρουν σημαντικά οφέλη στο γενικότερο πληθυσμό. Σημαντικός φαίνεται να είναι και ο ρόλος που διαδραματίζει τόσο ως μέσο πρόληψης όσο και ως μέσο διαχείρησης σοβαρών επιπλοκών κατά την κύηση με σακχαρώδη διαβήτη, συμβάλλοντας έτσι στην ομαλή πορεία της εγκυμοσύνης και τη μετέπειτα υγεία μητέρας και νεογνού.Nowadays, a significant proportion of pregnancies are complicated by diabetes mellitus. Most of them concern women with GDM, while another part concerns women with pre-existing DM 1 and DM 2. In any case, there are likely to be serious complications for both the mother and the fetus with a significant impact on their later health. Precise follow-up of the pregnant women and appropriate interventions that will contribute to the smoothest and most uncomplicated course of pregnancy are therefore essential. Regular glycemic control, medication when needed and proper pregnancy nutrition are powerful weapons in the queer of the supervising physician. At the same time, there are many researches regarding the role of exercise before and during a pregnancy with diabetes. The exercise, both aerobic and anaerobic as well as stretching and relaxation exercises offer significant benefits to the general population. As it appears, the exercise plays an important role as a mean of preventing and management of serious complications in pregnancy with diabetes, thus contributing to the smooth course of pregnancy and the subsequent maternal and neonatal health

Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma

Purpose A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was unique for the incorporation of an induction phase of maximally tolerated dosages of intravenous (IV) therapy for the initial 4 weeks. This is the only trial that has shown prolongation of overall survival and relapse-free survival (RFS) in comparison with observation. Analysis of the hazard curves for RFS and overall survival (OS) in E1684 revealed separation of the high-dose and observation arms, suggesting that the induction phase may represent a critical component of this regimen, although this has not been tested prospectively. Patients and Methods We conducted a prospective randomized study of IV induction therapy versus a full year of high-dose IFN, with primary end points of RFS and OS for patients with stage IIB, IIC, and III melanoma, within 56 days of curative surgery. Patients were randomly assigned to receive IFN-alpha-2b 15 x 10(6) U/m(2) IV x 5/7 days weekly x 4 weeks (arm A) versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat dose) administered subcutaneously three times a week for 48 weeks (arm B). Results Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A, n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI, 58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P = .9) and the median OS was 64.4 months versus 65.3 months (P = .49). Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity. Conclusion There were no significant differences in OS and RFS between the regimens of 1 month and 1 year of treatment

Decomposition of study graphs <i>g</i> (picture represents both cases and control subcohorts) into <i>rrp</i>'s 1–8.

<p>Case <b><i>rrp</i></b>'s are shown by solid, control by dashed edges. Coefficients show the multiplicities of respective <b><i>rrp</i></b>'s in the <b><i>g</i></b>-decompositions (top  =  case graph, bottom  =  control graph). Symbols as in Fig. 1.</p

Study graphs <i>g</i>(a) and <i>G</i> (b) constructed as union of all <i>prp</i>'s (<i>g</i>) or <i>PRP</i>'s (<i>G</i>).

<p>Symbols as in Fig. 1, thickness of edges in <b><i>g</i></b> and <b><i>G</i></b> are proportional to co-occurrence frequencies of respective SNP pairs, connected by the edge.</p

Three examples showing how elements of distance vectors are computed for the same patient #55.

<p>In all figures, <b><i>prp</i></b><b>(</b><b><i>RRP</i></b> in <b>c)</b>) for this patient  =  dashed lines, <b><i>rrp</i></b>'s (or <b><i>RRP</i></b> in <b>c)</b>)  =  solid lines. Double arrows indicate mismatch in SNP co-occurrences. Elements of are sums of these mismatches (in computations, we add negative sign to make identity (zero mismatches) mathematically largest). <b>a,b)</b> Comparison of patient's genotype to the second and third reference SNP relationship patterns <b><i>rrp₃</i></b> and <b><i>rrp₂</i></b>_<b>.</b><b>c)</b> Comparison of patient's genotype to the 4^th reference SNP relationship pattern <b><i>RRP₄</i></b><b>.</b></p

Comparison of CTLA-4 genotype relationship profiles of five most case-control discriminating <i>RRP</i>'s.

<p><b><i>RRP₂</i></b> (dashed edges) is shown in both panels for reference. Symbols as in Fig. 1.</p