Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up.

BACKGROUND: Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. METHODS: EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. CONCLUSION: GSK's post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E's benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa.

Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies.

BACKGROUND: Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti-HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm. METHODS: Serum anti-HPV-16/18 antibodies were determined at baseline and every 12 months in baseline DNA-negative women (N = 2687 for HPV-16 and 2705 for HPV-18) by enzyme-linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6-months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7-year period. The association between the risk of type-specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models. RESULTS: Risk of newly detected HPV-16-associated 6-month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC-US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV-16-associated incident infections (HR = 0.81 [0.56; 1.16]) and 12-month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV-18-seropositive vs -seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6-month PIs, HR = 0.31 [0.07; 1.36] for 12-month PIs, and HR = 0.61 [0.23; 1.61] for ASC-US+). CONCLUSIONS: Naturally acquired anti-HPV-16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15- to 25-year-old women.

Risk of HPV-16/18 Infections and Associated Cervical Abnormalities in Women Seropositive for Naturally Acquired Antibodies: Pooled Analysis Based on Control Arms of Two Large Clinical Trials.

Background: Studies on the role of antibodies produced after infection with human papillomavirus 18 (HPV-18) and subsequent protection from HPV-18 infection have been conflicting, mainly due to inadequate sample size. Methods: We pooled data from the control arms of the Costa Rica Vaccine Trial and the PATRICIA trial. Using Poisson regression we compared the risk of newly detected 1-time HPV-18 infection, HPV-18 1-year persistent infection (12MPI), and HPV-18-associated atypical squamous cells of undetermined significance or greater (ASC-US+) lesions between HPV-18 seropositive and seronegative women. Results: High HPV-18 antibodies at enrollment was associated with reduced subsequent HPV-18 detection (P trend = 0.001; relative rate [RR] = 0.69; 95% confidence interval [CI], 0.47-1.01 for the third quartile; RR = 0.63; 95% CI, 0.43-0.94 for the fourth quartile, compared to seronegative). The risk of 12MPI showed a decreasing trend with increasing antibodies (P trend = 0.06; RR = 0.72; 95% CI, 0.29-1.77; RR = 0.42; 95% CI, 0.13-1.32 for the third and fourth quartiles, respectively). Lastly, we observed a significant decreased risk of HPV-18 ASC-US+ with increasing antibody (P trend = 0.01; RR = 0.46; 95% CI, 0.21-0.97 for the fourth quartile). We also observed a significant decreased risk of HPV-16 infection, 12MPI, and ASC-US+ with increasing HPV-16 antibody level. Conclusions: High HPV-18 naturally acquired antibodies were associated with partial protection from future HPV-18 infections and associated lesions. Clinical Trials Registration: NCT00128661 and NCT001226810.

Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study.

The control arm of the phase III VIVIANE (Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; NCT00294047) study in women >25 years was studied to assess risk of progression from cervical HPV infection to detectable cervical intraepithelial neoplasia (CIN). The risk of detecting CIN associated with the same HPV type as the reference infection was analysed using Kaplan-Meier and multivariable Cox models. Infections were categorised depending upon persistence as 6-month persistent infection (6MPI) or infection of any duration. The 4-year interim analysis included 2,838 women, of whom 1,073 (37.8%) experienced 2,615 infections of any duration and 708 (24.9%) experienced 1,130 6MPIs. Infection with oncogenic HPV types significantly increased the risk of detecting CIN grade 2 or greater (CIN2+) versus non-oncogenic types. For 6MPI, the highest risk was associated with HPV-33 (hazard ratio [HR]: 31.9 [8.3-122.2, p < 0.0001]). The next highest risk was with HPV-16 (21.1 [6.3-70.0], p < 0.0001). Similar findings were seen for infections of any duration. Significant risk was also observed for HPV-18, HPV-31, and HPV-45. Concomitant HPV infection or CIN grade 1 or greater associated with a different oncogenic HPV type increased risk. Most women (79.3%) with an HPV infection at baseline cleared detectable infections of any duration, and 69.9% cleared a 6MPI. The risk of progression of HPV infection to CIN2+ in women >25 years in this study was similar to that in women 15-25 years in PATRICIA.

Induction or consolidation chemotherapy for unresectable stage III non-small-cell lung cancer patients treated with concurrent chemoradiation: a randomised phase II trial GFPC - IFCT 02-01.

PURPOSE: The objective of this randomised phase II study was to evaluate the impact in terms of response and toxicities of induction or consolidation chemotherapy respectively before or after concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer. PATIENTS AND METHODS: In the induction arm, patients received induction chemotherapy with cisplatin (80 mg/m(2)) and paclitaxel (200 mg/m(2)) on days 1 and 29 followed by a concurrent chemoradiotherapy (66 Gy in 33 fractions, cisplatin 80 mg/m(2) days 1, 29 and 57, vinorelbine 15 mg/m(2) days 1, 8, 29, 36, 57 and 64). In consolidation arm, the same concurrent chemoradiotherapy began on day 1 followed by two cycles of cisplatin and paclitaxel. RESULTS: One hundred twenty seven patients were randomised. The intent to treat response rates in induction and consolidation arms were 58% and 56% respectively. Median survival was 19.6 months in induction arm and 16.3 months in consolidation arm and 4-year survival rates were 21% and 30% respectively. Haematologic and non-haematologic toxicities were similar in both arms, except grade 3/4 oesophagitis, more frequent in consolidation arm than in induction arm (17% versus 10%). CONCLUSION: Cisplatin-based chemotherapy as induction or consolidation with concurrent chemoradiotherapy can be administrated safely. Response rates were similar in both arms with a trend in favour for consolidation arm for long-term survival.

Risk of first cervical HPV infection and pre-cancerous lesions after onset of sexual activity: analysis of women in the control arm of the randomized, controlled PATRICIA trial.

BACKGROUND: More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer. METHODS: The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15-25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6 months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models. RESULTS: A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48 months, respectively. The overall incidence rate was 27.08 per 100 person-years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development. CONCLUSIONS: More than 25% of women were infected with HPV within 1 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation. TRIAL REGISTRATION: clinicaltrials.gov: NCT00122681 .

Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study.

BACKGROUND: The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. METHODS AND FINDINGS: Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. CONCLUSIONS: Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Epirubicin and ifosfamide in relapsed or refractory small cell lung cancer patients.

INTRODUCTION: In small cell lung cancer (SCLC), despite the high response rates induced by platinum-based first line chemotherapies, relapse happens in 85% of the first-line responding tumors. Since 1992 we used a combination of epirubicin and ifosfamide (EI) as a non-cross-resistant regimen in relapsed or refractory SCLC. With the topotecan approval in second line treatment, this combination has been moved from the second line to the third line setting. METHODS: Patients presenting with a relapsed or refractory, histologically proven, SCLC were considered for this combination associating ifosfamide 3 g/m(2) day 1-2 with uroprotection using mesna, and epirubicin 90 mg/m(2) day 1 given every four weeks until progression or unacceptable toxicity. RESULTS: Seventy patients were accrued between September 1992 and August 2010 (seven women). Median age was 56 years. Performance Status was 0, 1, 2 and 3 for 16 (23%), 25 (35%), 20 (29%) and 9 (13%) patients respectively. Proportion of refractory, resistant and sensitive tumors was 20, 21 and 59% respectively. Median time from first line chemotherapy until progression was 90 days (range 5-1720 days). Forty-four patients were treated in second line setting whereas the 26 others have had received two lines at time of accrual. A total of 203 cycles were delivered (median 2 cycles, range: 1-6). Fifteen patients (21.4%) achieved an objective response (including one complete), and 10% had a stable disease. Median overall survival was 3.9 months (95% confidence interval: 3.3-5.1). Overall NCI-CTC grade 3 and 4 toxicity was mainly hematological: neutropenia (71% of the patients, febrile neutropenia 9.4% of the cycles), thrombocytopenia (23%), and anemia (22%). In univariate analysis, previous anthracyclines treatment was associated with a trend towards shorter survival (median overall survival 3.9 versus 4.6 months, p=0.12). In multivariate analysis, only a high serum NSE level and presence of brain metastases were independent prognostic variables. CONCLUSION: The EI combination is an active regimen in relapsed or refractory SCLC. The trend towards a greater activity of this regimen in patients not pretreated using anthracyclines suggests that class of agents should be tested in SCLC relapsing after the etoposide-platinum standard regimen.

[Is the use of plastic capillary tubes justified for blood gases analysis?]. / L'utilisation d'un tube capillaire en plastique est-elle justifiée pour l'analyse des gaz du sang ?

Some clinical units, such as neonatal or maternity units, preferentially use capillary tubes when analysing blood gases. Using glass tubes is delicate and nurses must recollect blood when breaking. In order to eliminate this problem, we tested flexible, plastic capillary tubes in both the above mentionned units and in our biochemistry laboratory. Each unit, where glass tubes were habitually used, tested 200 flexible, plastic capillary tubes. In addition, the nursing staffed filled out a questionnaire concerned tube usage. Both units clearly preferred using the flexible tubes. In the laboratory, results for blood gas analyses were compared between rigid glass and flexible plastic capillary tubes for 112 patients. Concordance tests did not showed significant differences between the two tube types, except for hematocrit and total haemoglobin. A questionnaire was also presented to the lab technician, who confirmed the easier usability of plastic capillary tubes.

Is chronic hepatitis C virus infection a risk factor for breast cancer?

AIM: To evaluate the prevalence of breast tumors in adult females with chronic hepatitis C virus (HCV) infection. METHODS: Prospective, single-center study, based on female outpatients consulting in a liver unit, for 1 year. The study group included females with present and/or past history of chronic infection by HCV. Patients with spontaneous recovery were excluded. Chronic hepatitis had been proved by liver biopsy in the majority of cases and/or biological markers of inflammation and fibrosis. The control group included female patients with other well documented chronic liver diseases: chronic hepatitis B, alcoholic liver disease, autoimmune hepatitis, hemochromatosis, non alcoholic liver disease, chronic cholangitis. Participating patients were prospectively questioned during consultation about past breast history and follow-up by mammography. RESULTS: Breast carcinoma was recorded in 17/294 patients with HCV infection (5.8%, 95% CI: 3.1-8.4) vs 5/107 control patients (4.7%, 95% CI: 0.67-8.67). Benign tumors of the breast (mastosis, nodules, cysts) were recorded in 75/294 patients with HCV infection (25.5%, 95% CI: 20.5-30.5) vs 21/107 (19.6%, 95% CI: 12.1-27.1) in the control group. No lesion was noted in 202 patients with HCV (68.7%, 95% CI: 63.4-74) vs 81 control patients (75.7%, 95% CI: 67.6-83.8). Despite a trend to an increased prevalence in the group with HCV infection, the difference was not significant compared to the control group (P = NS). In patients over 40 years, the results were, respectively, as follows: breast cancer associated with HCV: 17/266 patients (6.3%, 95% CI: 3.4-9.3) vs 5/95 patients (5.2%, 95% CI: 0.7-9.7) in the control group; benign breast tumors: 72/266 patients with HCV infection (27%, 95% CI: 21.7-32.4) vs 18/95 patients (18.9%, 95% CI: 11-26.8) in the control group; no breast lesion 177/266 (66.5%, 95% CI: 60.9-72.2) in patients with HCV infection vs 72/95 (75.7%, 95% CI: 67.1-84.4) in the control group. The differences were not significant (P = NS). CONCLUSION: These results suggest that chronic HCV infection is not a strong promoter of breast carcinoma in adult females of any age.

Recursive Partitioning Analysis Groups II-III brain metastases of non-small cell lung cancer: a phase II randomized study comparing two concurrent chemoradiotherapy regimens.

PURPOSE: To compare the response rates and safety profiles of two investigational chemotherapies that were delivered concurrently with whole-brain radiotherapy in a population of patients with chemonaive non-small cell lung cancer. METHODS: Eligible patients included those presenting with brain metastases belonging to the Recursive Partitioning Analysis of prognostic factors from the Radiation Therapy Oncology groups II or III, who were not able to undergo surgery or stereotactic radiotherapy. Other main eligibility criteria were age <75 years and Eastern Cooperative Oncology Group performance status = 0 to 2. The study design was as follows: all patients received whole-brain radiotherapy in three split courses of 18 gy/10 fractions. They were randomly (1:1) assigned to regimen A, consisting of a triplet cisplatin-vinorelbine-ifosfomide, or to regimen B, consisting of high-dose single-drug ifosfamide. In both groups, chemotherapy was delivered on a 4-week cycle, for three courses. Each course was delivered concurrently with radiotherapy. Brain and other tumor lesion assessments were performed in both groups at the end of the three courses (RECIST). Neurologic symptoms were evaluated quantitatively at each step of the treatment program. All analyses were carried out in an intention to treat basis, and statistical tests were two sided. RESULTS: Seventy patients were randomly allocated into groups A (n = 37) and B (n = 33). With regards to the whole lesions, overall response rates did not significantly differ between the groups (group A: 45.9%; group B: 33.3%; chi(2); p = 0.28). When brain-target lesions were separately analyzed, respective response rates were 59.5% and 48.5%; (chi(2); p = 0.0.53). Febrile neutropenia was more frequently observed in the former group (n = 19, 54.29%) than in the latter (n = 12, 36.36%; p = 0.13), and a similar difference was also observed regarding documented infections. Red blood cell transfusions and readmission for antibiotic infusions significantly affected more patients in group A than in group B. The longitudinal evaluation of neurologic symptoms (by means of Generalized Estimating Equation) slightly improved during the treatment program, and there was no difference between the groups. Median overall survival did not significantly differ between the two groups (months [95% confidence interval], 8.5 [6.4-10.8] and 5.7 [4.6-11.9] in groups A B, respectively; p= 0.82). In the Cox model, a high neuron-specific enolase serum level was the only significant prognostic determinant. CONCLUSION: Both regimens were active and induced a high rate of response, particularly for brain-target lesions. Myelotoxicity jeopardizes the acceptability of both regimens. Despite such an aggressive approach, none of the regimens suggested a putative overall improvement of outcome in this poor prognosis presentation of metastatic non-small cell lung cancer. The search for alternative therapies to chemotherapy, such as targeted therapy, is urgently warranted in this setting.

Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer.

PURPOSE: The previous individual patient data meta-analyses of chemotherapy in locally advanced non-small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy. METHODS: Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity. RESULTS: Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity. CONCLUSION: Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

Medico-economic evaluation of infliximab in rheumatoid arthritis--prospective French study of a cohort of 635 patients monitored for two years.

OBJECTIVES: To perform, in real conditions of prescription, the medico-economic evaluation of infliximab in severe RA. METHODS: A cost-effectiveness analysis of the annual costs was done with a comparison between the previous and the following year under infliximab. The effectiveness, determined from the HAQ, was expressed in clinically significant units and in quality-adjusted life years (QALYs). The incremental net benefit (INB), defined as willingness to pay (lambda), was used to express the results. RESULTS: A cohort of 635 patients was formed. Before the use of infliximab, after 1 and 2 years, the mean annual cost per patient for the care of RA was 9832, 27,723 and 46,704 euro, respectively. Among the direct costs, infliximab accounts for 21,182 euro for the first year. The distribution of the different costs was similar after 2 years. By using the INB, the difference before and after 1 year under infliximab is significant, on average by 1.86 (S.E.M. = 0.76) when the effectiveness is expressed in clinically significant units. For severe HAQ, lambda is 9841 euro (18,593 for all HAQ). When it is expressed in QALYs, also for severe HAQ, lambda > 100,000 euro. This can be explained by a short follow-up although severe complication of RA appears later. CONCLUSION: An evaluation of the more long-term costs is required in order to determine whether there are any full economic benefits with this treatment.

Circulating serum vascular endothelial growth factor is not a prognostic factor of non-small cell lung cancer.

INTRODUCTION: High circulating serum vascular endothelial growth factor (VEGF) levels might reflect enhanced angiogenesis in patients suffering from non-small cell lung cancer (NSCLC). This study aimed at determining the prognostic significance of circulating VEGF as a prognostic factor in NSCLC. METHODS: Four hundred fifty-one histologically or cytologically proven and previously untreated NSCLC patients have been studied. Median follow-up was 13 years and 9 months. Eleven clinical and biologic variables were recorded. The levels of circulating VEGF were measured in the serum by quantitative immunoassay. Patients have had received conventional treatment (without anti-VEGF therapy) according to the international guidelines. All statistical tests were two-sided. RESULTS: Receiver operating characteristic curves (area under the ROC curve: 0.66 +/- 0.05) showed that circulating VEGF serum level did not demonstrate a high sensitivity-specificity relationship, and therefore, demonstrated a low ability to differentiate NSCLC from benign lung diseases. A 600 pg/mL level of circulating VEGF serum was considered as threshold with 40.8% of NSCLC patients presenting with a high level. The circulating VEGF distribution differed significantly according to disease stage, nodal status, and performance status (PS), with the highest levels observed in metastatic stage, positive mediastinal nodal status, and poor PS. In univariate survival analysis, patients with a high pretreatment circulating VEGF serum level proved to have a shorter overall survival when compared with patients presenting with a circulating VEGF serum level /=2, nodal status N2-3, metastatic disease, neuron-specific enolase >12.5 ng/mL, CYFRA 21-1 >3.6 ng/mL. CONCLUSION: The prognostic information given by a high circulating VEGF serum level is not an independent determinant of survival owing to a high relationship with main prognostic variables such as PS, stage of the disease, and nodal status. This finding does not preclude a putative prognostic impact of in situ detection of VEGF and VEGF receptors in tumor specimen.

Influence of idiopathic scoliosis on three-dimensional thoracic growth.

STUDY DESIGN: Prospective clinical study of three-dimensional thoracic growth in children with idiopathic scoliosis and a reference group. OBJECTIVE: To measure thoracic dimensions and volume in relation to growth and to verify the influence of scoliosis. SUMMARY OF BACKGROUND DATA: Scoliosis represents a three-dimensional spinal deformity leading to thoracic deformity. Vertical expandable prosthetic titanium rib distraction primarily treats this deformity, but little is known about thoracic growth in scoliosis. METHODS: One hundred and thirty children with scoliosis (20 boys, 110 girls; 4-16 years; curves 15 degrees -45 degrees ; rib hump 5-25 mm) were compared with 126 children without spinal deformity (61 boys, 65 girls). The ORTEN system was used for optical trunk surface data acquisition. Thoracic volume, perimeter, anterior-posterior and transversal diameters, T1-T12 and sternal lengths were calculated and related to age, weight, standing and sitting height. RESULTS: There was no significant difference in thoracic volume between the 2 groups (P > 0.05). The correlation between thoracic volume (3-16 dm) and growth parameters was greater (R > 0.70) than with age. At 4 years, thoracic volume represents 33%, and at 10 years, it represents 55% of its volume at 16 years. It triples between 4 and 16 years and doubles during puberty. These relationships were constant in all groups. During growth, the transversal diameter corresponds to 30%, the anterior-posterior diameter represents 20% and the thoracic perimeter 100% of sitting height. CONCLUSION: The thoracic deformity in scoliosis is measurable with ORTEN, but scoliosis 45 degrees , leading to major thoracic asymmetry.

Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study.

PURPOSE: We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy (RT) and chemotherapy (CT) in unresectable stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to one of the two treatment arms. In the sequential arm, patients received induction CT with cisplatin (120 mg/m2) on days 1, 29, and 57, and vinorelbine (30 mg/m2/wk) from day 1 to day 78, followed by thoracic RT at a dose of 66 Gy in 33 fractions (2 Gy per fraction and 5 fractions per week). In the concurrent arm, the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d (days 1 to 5 and days 29 to 33); patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127. RESULTS: Two hundred five patients were randomly assigned. Pretreatment characteristics were well balanced between the two arms. There were six toxic deaths in the sequential arm and 10 in the concurrent arm. Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm (log-rank test P = .24). Two-, 3-, and 4-year survival rates were better in the concurrent arm (39%, 25%, and 21%, respectively) than in the sequential arm (26%, 19%, and 14%, respectively). Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm (32% v 3%). CONCLUSION: Although not statistically significant, clinically important differences in the median, 2-, 3-, and 4-year survival rates were observed, with a trend in favor of concurrent chemoradiation therapy, suggesting that is the optimal strategy for patients with locally advanced NSCLC.

Influence of sex on disease severity in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether patient's sex influences the severity of rheumatoid arthritis (RA) in terms of clinical severity or need for treatments. METHODS: This was a retrospective, single-center study. We compared 133 male patients with 133 female patients presenting with RA and matched for disease duration. Data collection included demographic characteristics, pattern of joint involvement, extraarticular manifestations, medical treatment, and joint surgery. Biological measures, HLA genotypes, Larsen radiological scores on radiographs of hands and feet, and Health Assessment Questionnaire (HAQ) results were obtained. RESULTS: Mean disease duration was 7.4 +/- 6.9 years. Concerning clinical pattern of involvement, sicca syndrome was more frequent in women than in men (p = 0.0003). There were no significant differences concerning absence or presence of at least one disease associated gene (HLA-DRB1*01 or *04) in our patients; however, women more often carried 2 disease associated genes (21% vs 11%). No other difference in clinical, biological, or radiological indicators was noted between the 2 populations. Concerning treatment, there was no difference for large joint arthroplasties; female patients underwent significantly more distal joint arthrodesis, 6.7% vs 1.5% (p = 0.03); they were prescribed slightly more disease modifying drugs, 3.33 vs 2.83 (p = 0.04); and showed a trend toward more large joint arthrodesis, 15% vs 7.5% (p = 0.05), and metacarpophalangeal joint arthroplasties, 5.2% vs 0.7% (p = 0.08). CONCLUSION: When patients are matched for RA duration, sex has little effect on the disease pattern and severity, yet women undergo more distal joint surgery.

Predictive factors of 5-year health assessment questionnaire disability in early rheumatoid arthritis.

OBJECTIVE: To determine prognostic factors of disability in early rheumatoid arthritis (RA) and to investigate the radiological and functional course of the disease. METHODS: A total of 191 patients with early RA (diagnosed for less than one year) according to American College of Rheumatology criteria were followed prospectively for 5 years. At baseline and at endpoint, Stanford Health Assessment Questionnaire (HAQ) scores and radiological scores (Sharp's score modified by van der Heijde) were performed. Correlations between numerous baseline data and HAQ score at endpoint were analyzed, using nonparametric tests. A multilinear regression model was performed to select independent prognostic factors of HAQ disability. RESULTS: During the 5-year followup, mean HAQ decreased from 1.3 (+/- 0.7) to 0.6 (+/- 0.6). There were 98 (65.3%) patients with a score > 1 point at baseline, but only 46 (27.4%) after 3 years and 34 (21.8%) after 5 years. Moreover, 90% of the patients had an improvement of the disability score. Final HAQ disability was associated with baseline values of HAQ score, Pain, Ritchie index, tender joint count, Disease Activity Score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and erosion. Multivariate analysis selected baseline HAQ score, Ritchie index, ESR, CRP, and presence of erosion as independent prognostic factors of HAQ disability. The probability cutoff in the logistic model was selected to minimize the sum of false positive and false negative values: negative predictive value = 92.71%, positive predictive value = 46.15%, p = 0.408. Sex, age, IgM and IgA rheumatoid factors, other tested autoantibodies, and HLA class II genes did not contribute significantly to prediction of the disability after 5 years. At baseline, mean scores were 3.6 units (+/- 7.7) for total radiological score, 1.7 (+/- 4.5) for erosion score, and 1.9 (+/- 3.7) for joint space narrowing score. After 5 years, they were 17.9 +/- 22.3, 6.9 +/- 9.5, and 11.0 +/- 15.4, respectively. No erosion was present at the start in 58.0% of patients, compared to 24.2% and 22.4% at 3 and 5 years. Global radiographic progression concerned 87 patients (55.8%) during the 5 years. CONCLUSION: During the first 5 years of RA, radiological damage increased progressively in half of the patients, whereas HAQ disability improved in most of them during the same period of time and could be predicted by baseline values of HAQ score, Ritchie index, ESR, CRP, and presence (or absence) of erosion.