Meta-analysis of studies analyzing the role of human papillomavirus in the development of bladder carcinoma

PURPOSE We aimed to ascertain the degree of association between bladder cancer and human papillomavirus (HPV) infection. MATERIALS AND METHODS We performed a meta-analysis of observational studies with cases and controls with publication dates up to January 2011. The PubMed electronic database was searched by using the key words "bladder cancer and virus." Twenty-one articles were selected that met the required methodological criteria. We implemented an internal quality control system to verify the selected search method. We analyzed the pooled effect of all the studies and also analyzed the techniques used as follows: 1) studies with DNA-based techniques, among which we found studies with polymerase chain reaction (PCR)-based techniques and 2) studies with non-PCR-based techniques, and studies with non-DNA-based techniques. RESULTS Taking into account the 21 studies that were included in the meta-analysis, we obtained a heterogeneity chi-squared value of Q(exp)=26.45 (p=0.383). The pooled odds ratio (OR) was 2.13 (95% confidence interval [CI], 1.54 to 2.95), which points to a significant effect between HPV and bladder cancer. Twenty studies assessed the presence of DNA. The overall effect showed a significant relationship between virus presence and bladder cancer, with a pooled OR of 2.19 (95% CI, 1.40 to 3.43). Of the other six studies, four examined the virus's capsid antigen and two detected antibodies in serum by Western blot. The estimated pooled OR in this group was 2.11 (95% CI, 1.27 to 3.51), which confirmed the relationship between the presence of virus and cancer. CONCLUSIONS The pooled OR value showed a moderate relationship between viral infection and bladder tumors.

Parasite load and risk factors for poor outcome among children with visceral leishmaniasis. A cohort study in Belo Horizonte, Brazil, 2010-2011

Clinical and laboratory risk factors for death from visceral leishmaniasis (VL) are relatively known, but quantitative real-time polymerase chain reaction (qPCR) might assess the role of parasite load in determining clinical outcome. The aim of this study was to identify risk factors, including parasite load in peripheral blood, for VL poor outcome among children. This prospective cohort study evaluated children aged ≤ 12 years old with VL diagnosis at three times: pre-treatment (T0), during treatment (T1) and post-treatment (T2). Forty-eight patients were included and 16 (33.3%) met the criteria for poor outcome. Age ≤ 12 months [relative risk (RR) 3.51; 95% confidence interval (CI) 1.89-6.52], tachydyspnoea (RR 3.46; 95% CI 2.19-5.47), bacterial infection (RR 3.08; 95% CI 1.27-7.48), liver enlargement (RR 3.00; 95% CI 1.44-6.23) and low serum albumin (RR 7.00; 95% CI 1.80-27.24) were identified as risk factors. qPCR was positive in all patients at T0 and the parasite DNA was undetectable in 76.1% of them at T1 and in 90.7% at T2. There was no statistical association between parasite load at T0 and poor outcome.

Gregorius IX, papa, Decretales, libri I-II.

Cet exemplaire de la Lectura d’Henri de Suso sur les Décrétales, dont il ne reste que le premier volume, présente la particularité de contenir aussi le texte des Décrétales, chacune d’elles étant suivie par le commentaire correspondant. Certaines anomalies de la copie permettent de préciser que les copistes avaient comme modèle deux manuscrits différents, un pour la Lectura et l’autre pour les Décrétales dans une édition augmentée des Novelles d'Innocent IV, qui devaient être insérées à la suite des titres correspondants, selon la prescription pontificale de 1245. Le texte même des Novelles qui n’était pas commenté dans la Lectura n’a pas été repris dans la copie, sauf l’Extravagante Quia frequenter, au f. 37v, et Sext. I, 13, 1, au f. 133. F. 1-360v. F. 1-177v. "Apparatus [HENRICI de SEGUSIO cardinalis] Ostiensis super textum Decretalium". [Prooemium:] "[A]d Dei omnipotentis gloriam et universalis ecclesie decus et decorem necnon rei publice et maxime scolasticorum utilitatem... - ...emendate"; — [In epistola dedicatoria Gregorii IX:] "Vicarius regis pacifici ad communem utilitatem et maxime studencium quinque compilationes... - ...et punit" (éd.Venise, I, 3-3v). — "Incipit liber primus Decretalium". [GREGORIUS IX papa, Epistola dedicatoria, salutatio] ; suivi de [HENRICUS DE SEGUSIO, Lectura :] "Gregorius episcopus. Omnes sunt episcopi licet vocentur archiepiscopi, primates vel patriarche... de manu apud eum"; — [GREGORIUS IX papa, Epistola dedicatoria] terminée par l'inscription rubriquée de la première Décrétale; suivi de: [HENRICUS DE SEGUSIO, Lectura in epistola dedicatoria :] "Rex. Regum et omnium potestatum. VIII di. que contra mores... - ...super verbo hac tantum"; et de [ID., Lectura in prima rubrica : ]"Quoniam omne quod non est in fine... - ...de fide catholica" (éd.Venise, I, 3v-5) (1-2v). — Extra 1, 1, 1 ; suivi de [ID., Lectura : ] "Firmiter credimus. Bene dicit nam dubius in fine... - ...Extra 1, 37, 1 ; suivi de [ID., Lectura : ] "Clerici... Et si beneficio etc. careant... de foro compe.", incomplet de la fin par lacune matérielle (éd.Venise, I, 5-182, § 10) (2v-177v). A noter: var. de plusieurs lignes à l'explicit des commentaires sur Extra 1, 1, 2 et 1, 3, 11. A noter les anomalies suivantes :L’inscription de chaque Décrétale, à quelques exceptions près, a été inscrite à la fin du texte de la Décrétale précédente. Le libellé: "Innocentius IIIIus" ou bien "Innocentius IIIIus in concil. Lugdun", qui a été inscrit à la fin des titres I, 3 (25v), 6, (85), 10 (103), 28 (132v), 29 (153), 30 (155v), 31 (164) correspond, en fait, à l'inscription des Novelles d'Innocent IV éditées dans le Sexte, livre I, en tête des titres 3, 6, 8, 13, 14, 15, 16.Au f. 37v, à la suite d'Extra 1, 6, 6, le texte de la constitution d'Innocent IV Quia frequenter a été copié, puis exponctué en marge par un correcteur avec la mention "vacat": "Quia frequenter in electione summorum pontificum colupna Dei... - ...minime computato" avec l'inscription: "Idem" écrite à la fin de la Décrétale précédente qui renvoie à Alexandre III. Sur ce texte qui n’a pas été repris dans le Sexte ; cf. H. Singer, Zeitschrift der Savigny-Stiftung für Rechtesgeschichte, Kan. Abt., VI (1916), 1-140 (éd. Friedberg, 946, Sext. 1, 6, 3, note c). Autres manuscrits recensés : Londres, B.L. ms. Add. 18368, f. 8v ; Paris, BNF ms. latin 14324, f. 234 ; Paris, Bibl. Sainte-Geneviève ms. 339, f. 90 ; Prague, I-B4, f. ? (renseignement aimablement communiqué par Michèle Bégou-Davia).Au f. 133, le titre I, 28 est suivi du texte de Sext. I, 13, 1.Au f.114v, le texte d’Extra 1, 15, 1 §1-6 a été copié une première fois dans le module de la glose à la fin d'un cahier, puis exponctué en marge avec la mention "vacat" et recopié dans le gros module habituel sur un feuillet additionnel (115).Aux ff. 133v-134, les Décrétales 1, 29, 3 et 4, suivies de leurs commentaires, ont été interverties ; de même que les Décrétales 1, 29, 42 et 43, aux ff. 152v-153v. F. 178-360v. "Incipit liber secundus". Extra 2, 1, 1 ; suivi de [HENRICUS DE SEGUSIO, Lectura:] "[D]e Quovultdeo etc. Supple ita statutum est d. n. sed propter hoc plene non subvenitur constronccioni [sic].." - ... Extra 2, 30, 6 "... archid. c. fi. § fi". "Explicit liber secundus. Benedictus sit Deus." (éd.Venise, II, 2-209v). Comme dans le livre I, le libellé inscrit à la fin des titres II, 1 (187), 2 (196v), 5 (202), 13 (240), 14 (247), 15 (249), 18 (252v), 25 (312v), 27 (329v), 28 (357v) correspond à l'inscription des Novelles d'Innocent IV éditées dans le Sexte, livre II, en tête des titres 1-3, 5-7, 9, 12, 14, 15.Au f. 196v, le copiste a copié à la suite les commentaire sur Extra 2, 2, 19 et 20, omettant le texte de Extra 2, 20 qu'il a dû ajouter ensuite dans la marge. Au f. 205, le copiste a mal apprécié l’espace réservé pour Extra 6, 2, le texte commencé normalement en gros module d'écriture, se poursuit en petit module et se termine dans la marge inférieure. De même, au f. 227, les dernières lignes d’ Extra 12, 7 ont dû être écrites dans la marge, avec un signe de renvoi. F. 360v-362. Commentaire anonyme sur Extra 2, 28, 59 De appellationibus: "Ut debitus honor etc. More solito dominus Innocencius premittit causam constitutionis exprimens duas causas motivas: qualiter hec constitutio promulgatur antipophornando... - ... se scit et c. arguta". A noter, f. 1-72v, en marge. PETRUS DE SAMPSONA, Distinctiones super Decretalibus 1, 1, 1-1, 6, 44, excerpta; cf. M. Bertram, "Pierre de Sampson et Bernard de Montmirat...", dans L'Eglise et le droit dans le Midi (XIIIe-XIVe s.) (Cahiers de Fanjeaux, 29), Toulouse, 1994, 37-74 et part. 66, parmi les mss recensés. En marge de l'inscription de l'épitre de Grégoire IX: "Greg. ep. etc. Dominus papa Christi universitatis vicarius set episcopus dicitur singularis quare dominus papa dicatur servus... - ...a papa"; en marge de l'épitre dédicatoire: "Rex pacificus quarum alique propter nimiam similitudinem quedam propter contrarietatem sed numquid in hac compilacione... - ...per totum", incipit A de M. Bertram, art. cit., 64 (1) ; — en marge de la Lectura sur l'épitre dédicatoire: Rex pacificus dicitur esse pacificus et Christus pacem diligit temporalem... - ...approbatur" (1v). — Dernière glose en marge d'Extra 1, 6, 44: "Itaque interim etc. Hii etiam qui pape... - ... et similibus" (72v). A noter, au f. 55v, à la fin de la glose, la signature "P. Sampsone" et au f. 67, "P. Samp.". F. 1-69v, passim et 124v-125. Gloses marginales ajoutées par une main cursive anglaise, contemporaine de la copie. « Doctoribus. Qui faciunt universitatem... - ...dilectus. [signé] Abb(at)is" (Bernardus de Montmirat, Lectura in Decretales, ed. Venise, 1588, I, 2) (1). —En marge de la Lecture sur Extra 1, 6, 42: "B. in apostillis suis dicit quod si aliquis potestatem... - ...commento Hostiensis" (69v).

RTOG 0525: A randomized phase iii trial comparing standard adjuvant temozolomide (tmz) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (gbm)

Radiotherapy with concomitant and adjuvant TMZ is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. This trial, conducted by the RTOG, EORTC, and NCCTG, determined if intensified TMZ improves survival (OS) or progression free survival (PFS) in all patients or specific to MGMT status. Eligibility criteria included age . 18 yrs, KPS ≥ 60, and existence of a tissue block with . 1cm2 tumor for prospective MGMT and retrospective molecular analysis. Patients were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom burden, quality of life (QOL), and neurocognition were prospectively and longitudinally assessed in a patient subset. 833 patients were randomized (1173 registered). Inadequate tissue (n ¼ 144) was the most frequent reason for nonrandomization.No statistical difference was observed between Arms 1 and 2 for median OS (16.6, 14.9 mo, p ¼ 0.63), median PFS (5.5, 6.7 mo, p ¼ 0.06), or methylation status. MGMT methylation was associated with improved OS (21.2, 14 mo, p , 0.0001), PFS (8.7, 5.7 mo, p , 0.0001), and treatment response (p ¼ 0.012). Cox modeling identifiedMGMT status and RPA class as significant predictors of OS; treatment arm and radiation technique (EORTC vs. RTOG) were not. There was increased grade ≥ 3 toxicity in Arm 2 (19%, 27%, p ¼ 0.008), which was mostly lymphopenia and fatigue. This study did not demonstrate improved efficacy for dd TMZ for newly diagnosed GBM regardless of methylation status. However, it confirmed the prognostic significance of MGMT methylation in GBM, demonstrated the feasibility of tumor tissue collection, molecular stratification, and collection of patient outcomes in a large transatlantic intergroup trial, thereby establishing a viable clinical trial paradigm. Support: NCI U10 CA 21661 and U10 CA37422.

The course of inflammatory bowel disease during pregnancy and postpartum: a prospective European ECCO-EpiCom Study of 209 pregnant women.

BACKGROUND: The impact of pregnancy on the course of IBD is still controversial. AIM: To investigate the impact of pregnancy on IBD and to search for factors with potential impact on remission. METHODS: Pregnant IBD women from 12 European countries were enrolled between January 2003 and December 2006 and compared at conception (1:1) with nonpregnant IBD women. Data on disease course were prospectively collected at each trimester during pregnancy and in the postpartum (6 months) using a standardised questionnaire. RESULTS: A total of 209 pregnant IBD women were included: 92 with Crohn's disease (CD; median age 31 years, range 17-40) and 117 with ulcerative colitis (UC; median age 32 years, range 19-42). No statistically significant difference in disease course during pregnancy and postpartum was observed between pregnant and nonpregnant CD women. Longer disease duration in CD and immunosuppressive therapy were found to be risk factors for activity during pregnancy. Pregnant UC women were more likely than nonpregnant UC women to relapse both during pregnancy (RR 2.19; 95% CI: 1.25-3.97, 0.004) and postpartum (RR 6.22; 95% CI: 2.05-79.3, P = 0.0004). During pregnancy, relapse was mainly observed in the first (RR 8.80; 95% CI 2.05-79.3, P < 0.0004) and the second trimester (RR 2.84, 95% CI 1.2-7.45, P = 0.0098). CONCLUSIONS: Pregnant women with Crohn's disease had a similar disease course both during pregnancy and after delivery as the nonpregnant women. In contrast, pregnant women with ulcerative colitis were at higher risk of relapse during pregnancy and in the postpartum than nonpregnant ulcerative colitis women.

Health risk behavior pattern among students from Cartagena, Colombia: prevalence and associated variables

The aim of the study was to determine the prevalence and variables associated with the pattern of risky health behavior (PRHB) among adolescent students in Cartagena, Colombia. A cross-sectional study was designed to investigate PRHB in a random cluster sample of students from middle and high schools. The associations were adjusted by logistic regression. A total of 2,625 students participated in this research, with ages from 10 to 20 years, mean=13.8 years (SD=2.0), and 54.3% were women. A total of 332 students reported PRHB (12.7%, 95%CI 11.4–14.0). Age over 15 years (OR=2.19, 95%CI 1.72–2.79), not being heterosexual (OR=1.98, 95%CI 1.36-2.87), poor/mediocre academic performance (OR=1.87, 95%CI 1.47–2.38), family dysfunction (OR=1.78, 95%CI 1.40–2.28) and male gender (OR=1.58, 95%CI 1.24–2.01) were associated with PRHB. One in every eight students presented a PRHB. It is important to pay greater attention to students who are over 15 years of age, male, not heterosexual, with a poor/mediocre academic performance and a dysfunctional family.

Arterial hypertension and associated factors in patients submitted to myocardial revascularization

OBJECTIVE To identify the prevalence of arterial hypertension and associated factors in patients submitted to myocardial revascularization. METHOD Cross-sectional study using the database of a hospital in São Paulo (SP, Brazil) containing 3010 patients with coronary artery disease submitted to myocardial revascularization. A multiple logistic regression was performed to identify variables independently associated with hypertension (statistical significance: p<0.05). RESULTS Prevalence of hypertension was 82.8%. After the variables were adjusted, the associated factors were as follows: age, odds ratio (OR): OR=1.01; 95% confidence interval (CI): CI:1.00-1.02; female gender: (OR=1.77;CI:1.39-2.25); brown-skin race: (OR=1.53;CI:1.07-2.19); obesity: (OR=1.53;CI:1.13-2.06); diabetes: (OR=1.90;CI:1.52-2.39); dyslipidemia: (OR=1.51;CI:1.23-1.85); and creatinine>1.3: (OR=1.37;CI:1.09-1.72). CONCLUSION A high prevalence of arterial hypertension and association with both non-modifiable and modifiable factors was observed.

Surgical site infections in colon surgery: the patient, the procedure, the hospital, and the surgeon.

Objective: To determine the role of the surgeon in the occurrence of surgical site infection (SSI) following colon surgery, with respect to his or her adherence to guidelines and his or her experience.Design, Setting, and Patients: Prospective cohort study of 2393 patients who underwent colon surgery performed by 31 surgeons in 9 secondary and tertiary care public Swiss hospitals, recruited from a surveillance program for SSI between March 1, 1998, and December 31, 2008, and followed up for 1 month after their operation.Main Outcome Measures: Risk factors for SSI were identified in univariate and multivariate analyses that included the patients' and procedures' characteristics, the hospitals, and the surgeons as candidate covariates. Correlations were sought between surgeons' individual adjusted risks, their self-reported adherence to guidelines, and the delay since their board certification.Results: A total of 428 SSIs (17.9%) were identified, with hospital rates varying from 4.0% to 25.2% and individual surgeon rates varying from 3.7% to 36.1%. Features of the patients and procedures associated with SSI in univariate analyses were male sex, age, American Society of Anesthesiologists score, contamination class, operation duration, and emergency procedure. Correctly timed antibiotic prophylaxis and laparoscopic approach were protective. Multivariate analyses adjusting for these features and for the hospitals found 4 surgeons with higher risk of SSI (odds ratio [OR] = 2.37, 95% confidence interval [CI], 1.51-3.70; OR = 2.19, 95% CI, 1.41-3.39; OR = 2.15, 95% CI, 1.02-4.53; and OR = 1.97, 95% CI, 1.18-3.30) and 2 surgeons with lower risk of SSI (OR = 0.43, 95% CI, 0.19-0.94; and OR = 0.19, 95% CI, 0.04-0.81). No correlation was found between surgeons' individual adjusted risks and their adherence to guidelines or their experience.Conclusion: For reasons beyond adherence to guidelines or experience, the surgeon may constitute an independent risk factor for SSI after colon surgery.

Clinical characteristics and outcome of patients admitted to a medico-surgical ICU requiring non invasive ventilation (NIV) for hypercapnic respiratory failure

Introduction: Because it decreases intubation rate and mortality, NIV has become first-line treatment in case of hypercapnic respiratory failure (HRF). Whether this approach is equally successful for all categories of HRF patients is however debated. We assessed if any clinical characteristics of HRF patients were associated with NIV intensity, success, and outcome, in order to identify prognostic factors. Methods: Retrospective analysis of the clinical database (clinical information system and MDSi) of patients consecutively admitted to our medico-surgical ICU, presenting with HRF (defined as PaCO2 >50 mm Hg), and receiving NIV between January 2009 and December 2010. Demographic data, medical diagnoses (including documented chronic lung disease), reason for ICU hospitalization, recent surgical interventions, SAPS II and McCabe scores were extracted from the database. Total duration of NIV and the need for tracheal intubation during the 5 days following the first hypercapnia documentation, as well as ICU and hospital mortality were recorded. Results are reported as median [IQR]. Comparisons with Chi2 or Kruskal-Wallis tests, p <0.05 (*). Results: 164 patients were included, 45 (27.4%) of whom were intubated after 10 [2-34] hours, after having received 7 [2-19] hours of NIV. NIV successful patients received 15 [5-22] hours of NIV for up to 5 days. Intubation was correlated with increased ICU (20% vs. 3%, p <0.001) and hospital (46.7% vs. 30.2, p >0.05) mortality. Conclusions: A majority of patients requiring NIV for hypercapnic respiratory failure in our ICU have no diagnosed chronic pulmonary disease. These patients tend to have increased ICUand hospital mortality. The majority of patients were non-surgical, a feature correlated with increased hospital mortality. Beside usual predictors of severity such as age and SAPS II, absence of diagnosed chronic pulmonary disease and non-operative state appear to be associated with increased mortality. Further studies should explore whether these patients are indeed more prone to an adverse outcome and which therapeutic strategies might contribute to alter this course.

Terrestrial arthropods from tree canopies in the Pantanal of Mato Grosso, Brazil

Terrestrial arthropods from tree canopies in the Pantanal of Mato Grosso, Brazil. This study represents a contribution to the knowledge of the diversity of arthropods associated to the canopy of Vochysia divergens Pohl (Vochysiaceae). Three trees individuals were sampled during two seasonal periods in this region: a) by spraying one tree canopy during high water (February); b) by fogging two tree canopies during low water (September/October). The 15,744 arthropods (183.2±38.9 individuals/m²) obtained from all three trees (86 m²) represented 20 taxonomic orders, 87.1% were Insecta, and 12.9% Arachnida. The dominant groups were Hymenoptera (48.5%; 88.9 individuals/m²), mostly Formicidae (44.5%; 81.4 individuals/m²), followed by Coleoptera (14.0%; 25.5 individuals/m²) and Araneae (10.2%; 19.5 individuals/m²), together representing 62.5% of the total catch. Fourteen (70%) of all orders occurred on three trees. Dermaptera, Isoptera, Neuroptera, Odonata, Plecoptera and Trichoptera were collected from only one tree. Of the total, 2,197 adult Coleoptera collected (25.5±11.3 individuals/m²), 99% were assigned to 32 families and 256 morphospecies. Nitidulidae (17.9% of the total catch; 4.6 individuals/m²), Anobiidae (16.7%; 4.3 individuals/m²), Curculionidae (13.2%; 3.4 individuals/m²) and Meloidae (11.4%; 2.9 individuals/m²) dominated. The communitiy of adult Coleoptera on V. divergens indicated a dominance of herbivores (37.8% of the total catch, 127 spp.) and predators (35.2%, 82 spp.), followed by saprophages (16.2%, 32 spp.) and fungivores (10.8%, 15 spp.). The influence of the flood pulse on the community of arboreal arthropods in V. divergens is indicated by the seasonal variation in evaluated groups, causing changes in their structure and composition.

Fat oxidation in nonobese and obese adolescents: effect of body composition and pubertal development.

OBJECTIVES: To measure postabsorptive fat oxidation (F(ox)) and to assess its association with body composition (lean body mass [LBM] and body fat mass [BFM]) and pubertal development. DESIGN: We studied 235 control (male/female ratio = 116/119; age [mean +/- SD]: 13.1 +/- 1.7 years; weight: 45.3 +/- 10.5 kg; LBM: 34.3 +/- 7.1 kg; BFM: 11.0 +/- 4.5 kg) and 159 obese (male/female ratio = 93/66; age: 12.9 +/- 2.1 years; weight: 76.2 +/- 19.1 kg; LBM: 47.4 +/- 10.9 kg; BFM: 28.8 +/- 9.2 kg) adolescents. Postabsorptive F(ox) was calculated from oxygen consumption, carbon dioxide production, and urinary nitrogen as measured by indirect calorimetry and Kjeldahl's method, respectively. Body composition was determined by anthropometry. RESULTS: Postabsorptive F(ox) (absolute value and percentage of resting metabolic rate) was significantly (p < 0.001) higher in the obese adolescents (76.7 +/- 26.3 gm/24 hours, 42.3% +/- 18.7%) than in the control subjects (40.0 +/- 26.3 gm/24 hours, 28.7% +/- 17.0%), even if adjusted for LBM. F(ox) corrected for BFM was similar in control and in obese children, but was significantly lower in girls compared with boys (control male subjects: 62.1 +/- 29.1 gm/24 hours, control female subjects: 51.6 +/- 28.4 gm/24 hours, obese male subjects: 57.3 +/- 29 gm/24 hour, obese female subjects: 45.0 +/- 28.4 gm/24 hours). BFM and LBM showed a significant positive correlation with F(ox). By stepwise regression analysis the most important determinant of F(ox) was BFM in obese and LBM in control children. There was a significant rise in F(ox) during puberty; however, it was mainly explained by changes in body composition. CONCLUSIONS: Obese adolescents have higher F(ox) rates than their normal-weight counterparts. Both LBM and fat mass are important determinants of F(ox).

Comparative short-term response and remission rates for tacrolimus, cyclosporine, and infliximab for steroid-refractory ulcerative colitis

BACKGROUND: Calcineurin inhibitors (cyclosporine (CsA) and tacrolimus (Tcl)) and the anti-TNF-antibody infliximab (IFX) are established therapeutic options in steroid-refractory ulcerative colitis (UC). In acute severe UC failing steroids, a randomized trial showed an 85% short term response to CsA or IFX, with avoidance of colectomy. Comparative responses to the three drugs in outpatients with steroid-refractory UC are unknown. METHOD: Response to treatment in patients with steroid-refractory moderate to severe UC was retrospectively studied in three cohorts of patients: Cohort A (n=24) treated with oral Tcl (initially 0.05mg/kg twice daily, aiming for serum trough levels of 5-10 ng/mL); Cohort B (n=19) treated with intravenous CsA 2mg/kg/daily and then oral CsA 5mg/kg/daily; Cohort C. (n= 41) treated with IFX (5mg/kg intravenously at week 0, 2, 6 and then every 8 weeks). After successful rescue therapy with Tcl or CsA, thiopurine maintenance therapy was introduced. The endpoint was evaluation of clinical remission or response at week 6, on the basis of modified Truelove-Witts severity index (MTWSI). RESULTS: After 6 weeks, 42% (10/24) of patients treated with Tcl achieved remission (MTWSI score ≤4) compared to 47% (9/ 19) on CsA and 66% (27/41) of patients treated with IFX (Tcl & CsA vs IFX p=0.127). Clinical response (decrease of MTWSI score of more than 4 points) at week 6 was reached in 25% (6/24) patients on Tcl, compared to 11% (2/19) on CsA and 20% (8/41) given IFX (p=0.484). Subgroup analysis showed the highest rates of remission in those with moderate steroid-refractory UC treated with IFX: 29% (2/7) in Tcl group compared to 50% (2/4) in CsA group and 76 % (19/25) in IFX group (Tcl &CsA vs IFX p= 0.058) Patients with severe colitis showed similar rates of remission in all three groups: 47% (8/17) on Tcl, 47% (7/ 15) on CsA and 50% (8/16) on IFX (p= 0.700). Colectomy within 6 weeks occurred in 4% (1/24) after Tcl, 5% (1/19) after CsA and 0% (0/41) after IFX. Adverse effects in the first 6 weeks were observed in 13% (3/24) on Tcl, 26% (5/19) on CsA, and 10% (4/41) on IFX (p=0.224) CONCLUSION: No significant differences in response, remission, colectomy rate or adverse events between the three agents were found, although the study is too small for definitive conclusions. There are intriguing differences, with potentially greater response to IFX in moderate, steroid-refractory UC.

Integrated Analysis of High-Resolution Gene Expression and Copy Number Profiling Identified Biallelic Deletion of CDKN2A/2B Tumor Suppressor Locus As the Most Frequent and Unique Genomic Abnormality in Diffuse Large B-Cell Lymphoma (DLBCL) with Strong Prognostic Value in Both GCB and ABC Subtypes and Not Overcome by a Dose-Intensive Immunochemotherapy Regimen Plus Rituximab. Results of a Prospective GELA Clinical Trial Program

Background and aim of the study: Genomic gains and losses play a crucial role in the development and progression of DLBCL and are closely related to gene expression profiles (GEP), including the germinal center B-cell like (GCB) and activated B-cell like (ABC) cell of origin (COO) molecular signatures. To identify new oncogenes or tumor suppressor genes (TSG) involved in DLBCL pathogenesis and to determine their prognostic values, an integrated analysis of high-resolution gene expression and copy number profiling was performed. Patients and methods: Two hundred and eight adult patients with de novo CD20+ DLBCL enrolled in the prospective multicentric randomized LNH-03 GELA trials (LNH03-1B, -2B, -3B, 39B, -5B, -6B, -7B) with available frozen tumour samples, centralized reviewing and adequate DNA/RNA quality were selected. 116 patients were treated by Rituximab(R)-CHOP/R-miniCHOP and 92 patients were treated by the high dose (R)-ACVBP regimen dedicated to patients younger than 60 years (y) in frontline. Tumour samples were simultaneously analysed by high resolution comparative genomic hybridization (CGH, Agilent, 144K) and gene expression arrays (Affymetrix, U133+2). Minimal common regions (MCR), as defined by segments that affect the same chromosomal region in different cases, were delineated. Gene expression and MCR data sets were merged using Gene expression and dosage integrator algorithm (GEDI, Lenz et al. PNAS 2008) to identify new potential driver genes. Results: A total of 1363 recurrent (defined by a penetrance > 5%) MCRs within the DLBCL data set, ranging in size from 386 bp, affecting a single gene, to more than 24 Mb were identified by CGH. Of these MCRs, 756 (55%) showed a significant association with gene expression: 396 (59%) gains, 354 (52%) single-copy deletions, and 6 (67%) homozygous deletions. By this integrated approach, in addition to previously reported genes (CDKN2A/2B, PTEN, DLEU2, TNFAIP3, B2M, CD58, TNFRSF14, FOXP1, REL...), several genes targeted by gene copy abnormalities with a dosage effect and potential physiopathological impact were identified, including genes with TSG activity involved in cell cycle (HACE1, CDKN2C) immune response (CD68, CD177, CD70, TNFSF9, IRAK2), DNA integrity (XRCC2, BRCA1, NCOR1, NF1, FHIT) or oncogenic functions (CD79b, PTPRT, MALT1, AUTS2, MCL1, PTTG1...) with distinct distribution according to COO signature. The CDKN2A/2B tumor suppressor locus (9p21) was deleted homozygously in 27% of cases and hemizygously in 9% of cases. Biallelic loss was observed in 49% of ABC DLBCL and in 10% of GCB DLBCL. This deletion was strongly correlated to age and associated to a limited number of additional genetic abnormalities including trisomy 3, 18 and short gains/losses of Chr. 1, 2, 19 regions (FDR < 0.01), allowing to identify genes that may have synergistic effects with CDKN2A/2B inactivation. With a median follow-up of 42.9 months, only CDKN2A/2B biallelic deletion strongly correlates (FDR p.value < 0.01) to a poor outcome in the entire cohort (4y PFS = 44% [32-61] respectively vs. 74% [66-82] for patients in germline configuration; 4y OS = 53% [39-72] vs 83% [76-90]). In a Cox proportional hazard prediction of the PFS, CDKN2A/2B deletion remains predictive (HR = 1.9 [1.1-3.2], p = 0.02) when combined with IPI (HR = 2.4 [1.4-4.1], p = 0.001) and GCB status (HR = 1.3 [0.8-2.3], p = 0.31). This difference remains predictive in the subgroup of patients treated by R-CHOP (4y PFS = 43% [29-63] vs. 66% [55-78], p=0.02), in patients treated by R-ACVBP (4y PFS = 49% [28-84] vs. 83% [74-92], p=0.003), and in GCB (4y PFS = 50% [27-93] vs. 81% [73-90], p=0.02), or ABC/unclassified (5y PFS = 42% [28-61] vs. 67% [55-82] p = 0.009) molecular subtypes (Figure 1). Conclusion: We report for the first time an integrated genetic analysis of a large cohort of DLBCL patients included in a prospective multicentric clinical trial program allowing identifying new potential driver genes with pathogenic impact. However CDKN2A/2B deletion constitutes the strongest and unique prognostic factor of chemoresistance to R-CHOP, regardless the COO signature, which is not overcome by a more intensified immunochemotherapy. Patients displaying this frequent genomic abnormality warrant new and dedicated therapeutic approaches.