Davide Radice

Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial

Summary Background Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot–Marie–Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. Methods Adult patients (aged 18–70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL). Findings We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI −0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, −0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI −0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group. Interpretation Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A. Funding Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.

Best choice of central venous insertion site for the prevention of catheter-related complications in adult patients who need cancer therapy: a randomized trial

BACKGROUND Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable. METHODS Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patients death or ending of the study. RESULTS Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272). CONCLUSIONS Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

The multiple sclerosis functional composite: different practice effects in the three test components

BACKGROUND The multiple sclerosis functional composite (MSFC) is a multidimensional, MS-specific outcome measure for use in clinical trials, comprising three tests: timed 25-foot walk (T25FW), paced auditory serial addition (PASAT), and 9-hole peg (9HP). OBJECTIVE To assess interrater and intrarater reliability and practice/fatigue effects in the MSFC. METHODS The MSFC was administered by two neurologists after a formal training session to 32 MS outpatients. Patients were assessed four times by one examiner and twice by the other. The six tests were administered in a single day, with at least 20 min of rest between them. The examiners were blinded to the results of previous assessments. Testing order was random. RESULTS Interrater reliability was excellent, with intraclass correlation coefficients (ICC) ranging from 0.93 for 9HP (95% confidence interval [CI] 0.84-0.96) to 0.99 for T25FW (95% CI 0.97-0.99). For intrarater reliability, ICC ranged from 0.93 for PASAT (95% CI 0.82-0.97) to 0.98 for T25FW (95% CI 0.93-1.00). We found no practice effect for T25FW after the first administration. However, performance improved with testing over the first three sessions for PASAT and over the first four sessions for 9HP. CONCLUSIONS The MSFC is characterised by excellent reliability. Practice effects for the three MSFC components differed, being negligible for T25FW and evident for PASAT and 9HP. To improve efficiency, we suggest one prebaseline administration of T25FW, three of PASAT and four of 9HP.

Role of maximal primary cytoreductive surgery in patients with advanced epithelial ovarian and tubal cancer: Surgical and oncological outcomes. Single institution experience.

OBJECTIVE To determinate the impact of maximal cytoreductive surgery on progression free survival (PFS), overall survival (OS) rates and morbidity, in patients with advanced epithelial ovarian or fallopian tube cancer. METHODS We reviewed all medical records of patients with stages IIIC-IV epithelial ovarian and fallopian tube cancer that were managed at our institution between January 2001 and December 2008. The following information was collected: demographics, tumor characteristics, operative information, surgical outcomes and peri-operative complication. RESULTS A total of 288 patients with advanced epithelial ovarian and fallopian tube cancer were referred to our institution between January 2001 and December 2008, 259 consecutive patients were enrolled in the study. After a median follow-up of 29.8 months, the PFS and OS were 19.9 and 57.6 months, respectively. At univariate analysis, factors significantly associated with decreased PFS included: age greater than median (>60 years), stage IV, presence of ascites >1000 cc, presence of diffuse peritoneal carcinomatosis and diameter of residual disease. This was confirmed also at multivariate analysis with age greater than 60 years (P=0.025), stage IV vs IIIC (P=0.037) and any residual disease (P=0.032) having an independent association with worse PFS. CONCLUSIONS Our study seems to demonstrate that a more extensive surgical approach is associated with prolonged disease-free interval and improved survival in patients with stages IIIC-IV epithelial ovarian and fallopian tube cancer. Moreover all patients with no residual tumor seem to have the best prognosis and in view of these results we believe that the goal of primary surgery should be considered as leaving no macroscopic disease.

Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome.

OBJECTIVE The quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease. METHODS Three hundred and forty-nine pre- and post-menopausal women, aged 18 years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample. RESULTS Median serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p<0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients. CONCLUSIONS Data presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

Reliability of clinical outcome measures in Charcot-Marie-Tooth disease

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Anxiety and depression in multiple sclerosis patients around diagnosis

OBJECTIVES To prospectively identify anxiety and depressive symptoms, and their predictors, during the multiple sclerosis (MS) peridiagnostic period. METHODS The Hospital Anxiety and Depression Scale (HADS) was administered during diagnostic workup (baseline), and one and six months after diagnosis disclosure, to SIMS-Trial participants (ISRCTN81072971). RESULTS Of 197 screened patients, 120 (61%) were diagnosed with MS. At baseline, median HADS anxiety (HADS-A) score was 7.0 (interquartile range [IQR] 5.0-9.5), ≥8 (anxiety cut-off) in 43% (95% confidence interval [CI] 34%-52%). Median HADS depression (HADS-D) was 3.0 (IQR 1.0-5.0), ≥8 (depression cut-off) in 11% (95% CI 5%-16%). Independent predictors of anxiety were female sex (odds ratio [OR] 2.8, 95% CI 1.1-7.2) and HADS-D score (OR 20.8, 95% CI 2.5-175.5). The only predictor of depressive symptoms was HADS-A score (OR 20.0, 95% CI 2.8-260.9). Anxiety symptoms had decreased slightly but significantly (p<0.001) at six months. Depressive symptoms remained low. CONCLUSIONS Anxiety was prominent in the period surrounding MS diagnosis disclosure, particularly in women. A slight but significant reduction occurred six months after diagnosis disclosure. Depressive symptoms were less common and stable over time. In addition to sex, depressive symptoms were the only variable independently associated with anxiety.

Typing of human papillomavirus in women with cervical lesions: Prevalence and distribution of different genotypes

Human papillomavirus (HPV) are distributed widely and persistent infection with high‐risk (HR) HPV is recognized as a necessary cause of cervical cancer. The aim of this study was to evaluate the distribution of different HR‐HPV genotypes in 199 women with cervical pre‐invasive lesions undergoing conservative treatment. A Linear Array HPV Genotyping Test was used to identify individual HPV genotypes in cervical samples. It was observed that the most prevalent HPV genotypes were HPV 16 (52.6%), HPV 51 (13.5%), and HPV 31 (10.9%); HPV 18 was found in 7.3% of the patients. Stratifying the different HPV genotypes according to the severity of the cervical lesion, a strong association between the increasing severity of the histological diagnosis and the detection of more carcinogenic HR‐HPV type was found, and in all but one cervical intraepithelial neoplasia of grade 3 the presence of at least one HR‐HPV could be detected, with more than 70% of cervical intraepithelial neoplasia of grade 3 patients bearing HPV 16. Multiple infections, comprising between 2 and 6 HPV types, were found in 43% of patients; however, the presence of more than 1 HR‐HPV type was not associated with an increased risk of high grade lesions. In conclusion, this data show that HPV 16, 51, 31, 52, and 18 were the prevalent types found in patients with cervical lesion undergoing conservative treatment, with a high prevalence of HPV 16 in cervical intraepithelial neoplasia of grade 3 patients. No association between multiple infection and severity of the lesion could be found. J. Med. Virol. 81:271–277, 2009.

Self-collected human papillomavirus testing acceptability: comparison of two self-sampling modalities.

BACKGROUND Human papillomavirus (HPV) testing can be used as a primary test for cervical cancer screening. HPV self-sampling has the potential to replace physician/nurse sampling. Our objective was to compare the acceptability of two self-sampling methods among 205 women undergoing an excisional procedure for cervical intraepithelial neoplasia (CIN) at the European Institute of Oncology (IEO). METHODS One hundred eleven patients were given a Hybrid Capture (HC) Cervical Sampler™ (Qiagen, Hilden, Germany), and 94 received a self-lavaging device, the Delphi® Screener (Delphi Bioscience, Scherpenzeel, The Netherlands), both with written instructions. Self-sampling was performed just before the clinician-collected cervical sample. Women responded to questions using 5-point ordinal scales on the general acceptability of self-sampling and the physical comfort, embarrassment, pain, and difficulty experienced. Participants were also asked whether they prefer self-sampling or clinician sampling. RESULTS Both self-sampling methods were generally accepted with a significantly high score (p = 0.005) and significantly lower embarrassment (p = 0.042) in favor of the Delphi Screener. Both self-sampling methods were physically well accepted, not painful, and easy to perform. Most women (n = 117, 68%) preferred the self-sampled compared to the clinician-sampled test, with a significantly higher proportion in the Delphi Screener group (n = 59, 77.6%) compared to those using the HC Sampler (n = 58, 60.4%) (p = 0.021). CONCLUSIONS The present study shows that self-sampling for HPV testing is favorably received by women. A sampling device specifically developed for self-sampling, such as the Delphi Screener, shows the highest degree of satisfaction. A well-accepted HPV sampling method could be especially useful for women who do not take part in cervical screening or in settings where organized screening is not fully implemented.

Randomized phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules.

Screening CT identifies small peripheral lung nodules, some of which may be pre- or early invasive neoplasia. Secondary end point analysis of a previous chemoprevention trial in individuals with bronchial dysplasia showed reduction in size of peripheral nodules by inhaled budesonide. We performed a randomized, double-blind, placebo-controlled phase IIb trial of inhaled budesonide in current and former smokers with CT-detected lung nodules that were persistent for at least 1 year. A total of 202 individuals received inhaled budesonide, 800 μg twice daily or placebo for 1 year. The primary endpoint was the effect of treatment on target nodule size in a per person analysis after 1 year. The per person analysis showed no significant difference between the budesonide and placebo arms (response rate 2% and 1%, respectively). Although the per lesion analysis revealed a significant effect of budesonide on regression of existing target nodules (P = 0.02), the appearance of new lesions was similar in both groups and thus the significance was lost in the analysis of all lesions. The evaluation by nodule type revealed a nonsignificant trend toward regression of nonsolid and partially solid lesions after budesonide treatment. Budesonide was well tolerated, with no unexpected side effects identified. Treatment with inhaled budesonide for 1 year did not significantly affect peripheral lung nodule size. There was a trend toward regression of nonsolid and partially solid nodules after budesonide treatment. Because a subset of these nodules is more likely to represent precursors of adenocarcinoma, additional follow-up is needed. Cancer Prev Res; 4(1); 34–42. ©2010 AACR.