We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5 ؉ group differed significantly from that of the CD5 ؊ group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL. (Blood. 2010;

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Rationale: Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs.Objectives: To develop a predictive score for LC risk for patients with COPD.Methods: The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP.Measurements and Main Results: By regression analysis, age greater than 60, body mass index less than 25 kg/m 2 , pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category.Conclusions: The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings.

To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating corespecific T-helper (Th) cell precursors by the limitingdilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (

increase in protein expression level. This suggested that UV irradiation promotes both activation and expression levels of the Rfp-Ret kinase. Rfp-Ret kinase is constitutively active due to its oncogenic mutation (Takahashi et al, 1985). Thus, UV-mediated superactivation of the mutant Ret kinase, which was originally demonstrated in vitro (Kato et al, 2000), probably occurred also in vivo. The signal triggered through superactivation of Rfp-Ret kinase by UV might have promoted the production of Rfp-Ret together with ERK and c-Jun, although alternative mechanisms remain to be excluded. Whatever the underlying mechanism is, our data suggest that UV-induced full activation of a single oncogene and its product is included in the mechanism of malignant melanocytic tumor promotion, in addition to previously reported stepwise recruitment of multiple oncogene activations (Ziegler et al, 1994) and defects in the host defense mechanism (Kripke, 1979). This may stimulate new experiments for fully understanding the general mechanism of malignant tumor promotion following initiation.We thank K. Ban, Y. Umeda, Y. Kato, H. Saeki, and K. Uchiyama for their technical assistance.

Citation: Larrosa JM, Moreno-Montañés J, Martinez-de-la-Casa JM, et al. A diagnostic calculator for detecting glaucoma on the basis of retinal nerve fiber layer, optic disc, and retinal ganglion cell analysis by optical coherence tomography. Invest Ophthalmol Vis Sci. 2015;56:6788-6795. DOI:10.1167/iovs.15-17176 PURPOSE. The purpose of this study was to develop and validate a multivariate predictive model to detect glaucoma by using a combination of retinal nerve fiber layer (RNFL), retinal ganglion cell-inner plexiform (GCIPL), and optic disc parameters measured using spectraldomain optical coherence tomography (OCT). METHODS.Five hundred eyes from 500 participants and 187 eyes of another 187 participants were included in the study and validation groups, respectively. Patients with glaucoma were classified in five groups based on visual field damage. Sensitivity and specificity of all glaucoma OCT parameters were analyzed. Receiver operating characteristic curves (ROC) and areas under the ROC (AUC) were compared. Three predictive multivariate models (quantitative, qualitative, and combined) that used a combination of the best OCT parameters were constructed. A diagnostic calculator was created using the combined multivariate model. RESULTS.The best AUC parameters were: inferior RNFL, average RNFL, vertical cup/disc ratio, minimal GCIPL, and inferior-temporal GCIPL. Comparisons among the parameters did not show that the GCIPL parameters were better than those of the RNFL in early and advanced glaucoma. The highest AUC was in the combined predictive model (0.937; 95% confidence interval, 0.911-0.957) and was significantly (P ¼ 0.0001) higher than the other isolated parameters considered in early and advanced glaucoma. The validation group displayed similar results to those of the study group.CONCLUSIONS. Best GCIPL, RNFL, and optic disc parameters showed a similar ability to detect glaucoma. The combined predictive formula improved the glaucoma detection compared to the best isolated parameters evaluated. The diagnostic calculator obtained good classification from participants in both the study and validation groups.

Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i؉2 to i؉7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules.

Pretreatment variables that could predict the response of chronic hepatitis C to interferon alfa treatment have not been fully assessed. Eighteen baseline variables were evaluated in a series of 100 consecutive patients treated with a 12 month course of interferon alfa. For the purposes of this study, response was defined as the return to normal of aminotransferase activities before the third month of treatment.Seventy per cent of the patients responded to treatment. Six variables were associated with an increased likelihood of response assessed by univariate analysis. With stepwise multiple regression analysis assessment, however, only three variables remained independently predictive of response: low y glutamyltransferase (yGT) activities (p<0.001), absence of obesity (p=0.005), and absence of cirrhosis (p=0-01). The response rate in patients with yGT activities <066 iikat/l (n=55) was 78% and 60% in patients with values >066 ikat/l (n=45) (p=.0048). Response was attained in 75% of non-obese patients (n=80), compared with only 50% of obese patients (n=20) (p=003). Finally, 80% of patients without cirrhosis (n=76) responded, while among those with cirrhosis (n=24) the response rate was only 37% (p<0001). All 23 patients without cirrhosis, <40 years old, and with yGT activities <0-66 tkat/l responded to treatment, while only 28-5% of 14 patients with cirrhosis, >40 years old, and with yGT activities >0 66 pkat/l responded to interferon affa (p<0-001).Those findings may be useful when evaluating interferon alfa trials and it is suggested that this treatment should be applied early in the course of chronic hepatitis C.