Lack of prognostic significance of conventional peritoneal cytology in colorectal and gastric cancers: results of EVOCAPE 2 multicentre prospective study.

AIM: In digestive cancers, the prognostic significance of intraperitoneal free cancer cells remains unclear (IPCC). The main objective of this study was to assess the prognostic significance of IPCC in colorectal and gastric adenocarcinoma. The secondary objectives were to evaluate the predictive significance of IPCC for the development of peritoneal carcinomatosis (PC) and to evaluate the prevalence of synchronous PC and IPCC. METHODS: This was a prospective multicentre study. All patients undergoing surgery for a digestive tract cancer had peritoneal cytology taken. Patients with gastric and colorectal cancer with no residual tumour after surgery and no evidence of PC were followed-up for 2 years. The primary end point was overall survival. RESULTS: Between 2002 and 2007, 1364 patients were enrolled and 956 were followed-up over 2 years. Prevalence of IPCC was 5.7% in colon cancer, 0.6% in rectal cancer and 19.5% in gastric cancer. The overall 2-year survival rate for patients with IPCC was 34.7% versus 86.8% for patients with negative cytology (p<0.0001). By multivariate analysis, IPCC was not an independent prognostic factor. No relationship between cytology and recurrence was found. CONCLUSION: The presence of IPCC was not an independent prognostic and didn't add any additional prognostic information to the usual prognostic factors related to the tumour (pTNM and differentiation). Moreover the presence of IPCC detected with this method didn't appear to predict development of PC. Peritoneal cytology using conventional staining doesn't seem to be a useful tool for the staging of colorectal and gastric cancers.

Great saphenous vein ablation with steam injection: results of a multicentre study.

OBJECTIVE: To assess the safety and efficiency of steam vein sclerosis (SVS) of the great saphenous vein (GSV) in a multicentre open prospective cohort study. DESIGN: 75 consecutive adult patients with GSV reflux, CEAP C2-C5 and vein diameter 4-13 mm. METHODS: Patients treated using an SVS™ generator delivering homogenous pulses of superheated steam were followed up at 8 days and 1, 3, 6 and 12 months (clinical, duplex ultrasound, quality of life [QoL] with SF12). RESULTS: 88 veins were treated in 75 patients. At 6 months, 72/75 (96%) veins were obliterated (95% CI: 89-99) and Kaplan-Meier analysis found an obliteration rate of 96.1% at 12 months. QoL increased at 6 months for both the physical and mental components (p = 0.049 and p < 0.001 respectively). SVS was well tolerated: no major complications were reported. Adverse events occurred mainly at day 8 and incidents amounted to ecchymosis (n = 60) and pain (n = 7). CONCLUSIONS: SVS achieved an obliteration rate similar to that of other thermal ablation techniques. It was well tolerated with minimal post-operative pain.

[A programme to support clinical evaluation of medical devices: pilot experiment in the Rhône-Alpes region]. / Structure de soutien à l'évaluation clinique des dispositifs médicaux : expérience pilote en région Rhône-Alpes.

INTRODUCTION: The drug and medical devices Committee of the University Hospital of Lyon faces the weakness of clinical data available to justify medical devices purchase. The Hospital of Lyon has worked with several organisms of the Rhône-Alpes region to set up a pilot programme aimed at encouraging small and medium enterprises (SMEs) to realise clinical studies for the evaluation of their medical device. We report the results of this experiment which took place from 2007 to 2010. METHODS: Eligible projects were selected on the basis of their scientific interest. A specific structure for regulatory and methodological support was set up. RESULTS: Twenty companies applied, seventeen were selected. Eight research protocols were written; four clinical studies were implemented. These studies were performed by micro-companies for medical devices that could be considered as innovative device or substantial novelty. Two draft protocols were started but deferred by choice of the company. For projects that did not lead to a research protocol or study, the main causes were: a longer than expected development phase (n = 3); a problem linked to methodological feasibility (n = 1); the unsuccessful search for a principal investigator (n = 2); or the company's choice (n = 5). DISCUSSION AND CONCLUSION: This pilot experience in France has supported and trained regional SMEs in clinical research. Its continuation could encourage manufacturers to conduct clinical trials of good quality.

Return home at the end of life: Patients' vulnerability and risk factors.

Although most of the people in good health questioned about the subject said they would like to die at home, in the western world between 60 and 80% of deaths occur in hospital. Most authors consider that the indispensable conditions for a return home are the patient's desire and presence of the family and caregivers with the appropriate skills. The assessment of other factors predictive of a return home is inadequate. The aim of this study is to clarify how the return home is influenced by the vulnerability of the patient at the end of life, and by that of the family and caregivers. We carried out a multicentric, observational, prospective, exhaustive and longitudinal epidemiological study (three months follow-up), including 146 patients hospitalized at the end of their life and desiring to return home. For these patients the caregivers respected their freedom to choose to die at home in over half the cases (56%). Their overall vulnerability (personal, family context and caregivers) had a significant influence on the return home. This overall vulnerability was in fact identified as applying in 40% of the clinical situations, and made the possibility of a return home 50% less likely.

Total on-line analysis of a target protein from plasma by immunoextraction, digestion and liquid chromatography-mass spectrometry.

A total on-line analysis of a target protein from a plasma sample was made using a selective immunoextraction step coupled on-line to an immobilized enzymatic reactor (IMER) for the protein digestion followed by LC-MS/MS analysis. For the development of this device, cytochrome c was chosen as model protein due to its well-known sequence. An immunosorbent (IS) based on the covalent immobilization of anti-cytochrome c antibodies on a solid support was made and an immunoextraction procedure was carefully developed to assess a selective extraction of the target protein from plasma. For the first time, IS was easily coupled on-line with a laboratory-made IMER based on pepsin. The whole on-line device (IS-IMER-LC-MS/MS) allowed the quantification of cytochrome c from 8.5pmol to 1.7nmol in buffer medium. Finally, this device was applied to the analysis of only 85pmol of cytochrome c from plasma with a RSD value lower than 10% (n=3).

Molecularly imprinted polymer for analysis of zidovudine and stavudine in human serum by liquid chromatography-mass spectrometry.

A molecularly imprinted polymer (MIP) using zidovudine (AZT) as template and methacrylic acid as monomer was prepared. The synthesis of the MIP was performed in acetonitrile. The synthesized material was then tested for the solid-phase extraction of AZT from different media (pure organic solvents and hydro-organic mixtures). An optimised procedure was developed for the selective extraction of AZT with a recovery of 96% using the MIP and only 3% on a non-imprinted polymer used as control polymer. A specific capacity of 0.2 micromol g(-1) was determined. The specificity of the MIP was evaluated by studying the retention behaviour of two others nucleoside analogues. The feasibility of the MIP to selectively extract AZT and stavudine (d4T) from human serum was also demonstrated with recoveries of 80 and 85% respectively. The lower limit of quantification (LLOQ) and the lower limits of detection (LLOD) for AZT were 5.10(-7) and 10(-7) M respectively.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Evaluation of various immobilized enzymatic microreactors coupled on-line with liquid chromatography and mass spectrometry detection for quantitative analysis of cytochrome c.

An in-line procedure for protein analysis using a trypsin-based immobilized enzymatic reactor (IMER) coupled to LC-MS/MS has been developed. Various IMERs were synthesized and characterized by estimating the digestion yield of a pattern peptide in UV detection. Laboratory-made IMERs were optimized by studying the effect of different parameters as the nature of the functionalized immobilization support (silica, agarose), the amount of immobilized trypsin and the binding density. The potential of the laboratory-made IMERs were compared with a batch digestion and with a commercial trypsin-based IMER. The laboratory-made IMER based on CNBr-activated Sepharose showed the best performances in terms of digestion yields, digestion time, price and repeatability (RSD<4%). Cytochrome c was then digested on this IMER and used in-line with LC-MS. The target protein was easily recognized by the Mascot database until 17pmol injected.

Selective and automated sample pretreatment by molecularly imprinted polymer for the analysis of the basic drug alfuzosin from plasma.

A molecularly imprinted polymer synthesized in dichloromethane, was evaluated for the selective extraction of a pharmaceutical compound from human plasma and integrated on-line with liquid chromatography. The target drug is an alpha-blocker called alfuzosin widely used for the treatment of benign prostatic hyperplasia. By a comprehensive approach of the retention mechanism, a selective extraction procedure was established by exploiting the development of electrostatic interactions between the target analyte and the selective support in LC compatible solvents. By applying this method to plasma, extraction recoveries close to 100% were obtained for alfuzosin while various pharmaceutical compounds currently found in biological fluids were not retained on the support. The high selectivity of the support coupled to the chromatographic system permitted an easy and fast analysis of the drug with a limit of quantification of 15 microg L(-1) by UV detection.

[Long-term outcome in patients with symptomatic low-grade oligodendrogliomatous tumors treated by cytotoxic agents]. / Effets à long terme de la chimiothérapie chez 7 patients présentant un gliome de bas grade symptomatique.

INTRODUCTION: Whether aggressive treatment or no treatment is the optimal management for low-grade gliomas is controversial. However, symptomatic low-grade gliomas require prompt therapeutic intervention because of neurological impairment, uncontrolled seizures, and deterioration of life quality. METHODS: We report the long-term follow-up, 71 months, of seven patients treated by procarbazine, lomustine and vincristine (PCV) therapy for a symptomatic low-grade oligodendrogliomatous tumor. The mean age at diagnosis was 47 years, the mean time from first symptoms to initiation of PCV therapy was 62 months (range 15-147). RESULTS: All patients initially responded favorably, with improvement of the neurological symptoms and radiological response. Chemotherapy was clinically well tolerated, the main side effect being low hematological toxicity. During the follow-up, no progression was observed in two patients. For the five remaining patients, the time to progression after the PCV induction was 56+/-12 months (range 38 to 73). Four of these patients showed favorable response to a second line of treatment. CONCLUSION: PCV therapy is an interesting therapeutic option for progressively symptomatic low-grade gliomas, even in cases with large tumoral volume. This treatment, of moderate toxicity, improves the quality of life and can result in long-term tumor stabilization.

Micro-vascular decompression for primary Trigeminal Neuralgia (typical or atypical). Long-term effectiveness on pain; prospective study with survival analysis in a consecutive series of 362 patients.

BACKGROUND: Few publications on primary Trigeminal Neuralgia treated by Micro-Vascular Decompression (MVD) report large series, with long-term follow-up, using Kaplan-Meier (K-M) analysis. None was specifically directed to the comparative study of MVD effectiveness on Trigeminal Neuralgia with typical (i.e., with paroxysmal pain only) and atypical features (i.e., with association of a permanent background of pain). METHOD: The authors report a series of 362 patients having clearcut vascular compression and treated with pure MVD - i.e., without any additional cut or coagulation of the adjacent root fibers. Follow-up was 1 to 18 y (8 y on average, with a median of 7.2 y). Results were considered overall, then separately for patients with typical (237 (65.5%)) and atypical (125 (34.5%)) clinical presentation. FINDINGS: One year after operation, (294 (81.2%) of patients were totally-free - of paroxysmal pain, and also of permanent background pain - and not needing any medication) 13 (3.6%) still had a background of pain but without the need for medication which 55 patients (15.2%), treatment had failed. At latest review (8 y on average) the corresponding rates were 80, 4.9 and 15.1%, respectively. Kaplan-Meier analysis estimated the probability of total cure at 15 y to be 73.4%. There was no difference in the cure rate between patients with typical and atypical features at one year: 81 and 81.16%, respectively. The probability of cure at 15 y was identical for the two clinical presentations. CONCLUSIONS: Pure MVD offers patients affected by Trigeminal Neuralgia due to vascular compression a long-lasting cure in three-fourths of the cases. Both typical and atypical presentations respond well to MVD, view in contrast to the classical view that an atypical presentation has an adverse effect on outcome after surgery.

Reinforced follow-up for children and adolescents with type 1 diabetes and inadequate glycaemic control: a randomized controlled trial intervention via the local pharmacist and telecare.

AIM: To evaluate the effectiveness and feasibility of reinforced follow-up via telecare mediated by the local pharmacist in contact with the hospital team to improve glycaemic control in children and adolescents with type 1 diabetes (DT1). METHODS: One hundred patients, aged 8 to 17 years, with a history of DT1 of more than 1 year, with HbA(1c) >=8%, were randomly assigned to either the "reinforced follow-up" group (RFG) or the "usual follow-up" group (UFG). The intervention consisted in downloading and then printing data stored in a glucometer every two weeks, by the local pharmacist. Printouts were faxed to the hospital team which then communicated adapted instructions for better glycemic control directly to the family. RESULTS: Fifty patients were assigned to each group. The two groups were comparable at the beginning. 71 children had a doctor's visit at 6 +/- 1 months (36 in RFG and 35 in UFG). At this date, there was no significant difference between the average HbA(1c) levels of the two groups (9.12 +/- 1.46 in RFG versus 9.27 +/- 1.20 in UFG). We had various difficulties setting up and gaining compliance with the intervention procedure, which explains why only 33 children in the RFG transmitted at least one fax. CONCLUSION: At this stage, the reinforced follow-up has not proved to be superior to the usual follow-up. However, it would be possible to make numerous improvements in order to make the former more feasible and probably more efficient.

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis.

Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.

Unresectable hepatocellular carcinoma: survival and prognostic factors after lipiodol chemoembolisation in 89 patients.

BACKGROUND: The majority of patients with hepatocellular carcinoma are not eligible for surgical radical treatment (resection or liver transplantation) and lipiodol chemoembolisation is an efficient alternative procedure in this indication. AIMS: To identify prognostic factors in patients treated with lipiodol chemoembolisation. PATIENTS AND METHODS: During 10 years, 89 consecutive patients with unresectable hepatocellular carcinoma underwent lipiodol chemoembolisation as a single treatment. There were 80 males and 9 females, with a median age of 65 years. Treatment consisted of one to six courses of hepatic intra-arterial lipiodol with doxorubicine and gelatin sponge. RESULTS: The median survival was 13 months with a 13.6% survival rate at 4 years. Univariate analysis showed that serum levels of albumin, bilirubin, alkaline phosphatase and alpha-fetoprotein, Child's class, tumour type, tumour size and intensity of lipiodol capture after the first course of lipiodol chemoembolisation were significant prognostic factors of survival. In the multivariate analysis, four parameters remained associated with a significantly better outcome: Child's class A, largest lesion<5 cm, uninodular tumour and intense lipiodol capture. CONCLUSIONS: While lipiodol chemoembolisation is associated with good results only in some patients, in the absence of lipiodol capture, it should be ruled out.

Results of vascular resections during pancreatectomy from two European centres: an analysis of survival and disease-free survival explicative factors.

OBJECTIVES: The object of our study was to report on the experience with vascular resections at pancreatectomy in two European specialist hepatopancreatobiliary centres and evaluate outcome and prognostic factors. PATIENTS AND METHODS: From 1989 to 2002, 45 patients (21 men, 24 women) underwent pancreatectomy for a pancreatic mass: Whipple's procedure (n=33), total pancreatectomy (n=10) or left splenopancreatectomy (n=2), along with a vascular resection, i.e. venous (n=39), arterial (n=1) or venous + arterial (n=5). RESULTS: Operative mortality was nil, postoperative mortality was 2.2% (n=1); 34 patients had an uneventful postoperative course. Reoperations were performed for portal vein thrombosis (n=1), pancreatic leak (n=1), gastric outlet syndrome (n=1) and gastrointestinal bleeding (n=1). In all, 43 patients had cancer on pathology examination, with retropancreatic invasion in 72% and lymph node extension in 62.8%. Resection was R0 in 21 cases. Vessel wall invasion was present in 13 cases and 19 had perivascular invasion. Disease-free survival (DFS) at 1, 2 and 3 years was 36.0%, 15.0% and 12.0%, respectively. Median DFS length was 8.7 months (95% CI: 7.2; 10.2). Overall survival rates were 56.6%, 28.9% and 19.2%, respectively. Median survival length was 14.2 months (95% CI: 9.8; 18.6). A multivariate analysis of prognostic variables identified tumour location (other than head of pancreas), neoadjuvant chemotherapy and advanced disease stage as adverse factors for DFS. CONCLUSION: Survival and DFS rates of these patients are comparable to those without vascular resection. Tumour localization, tumour stage, neoadjuvant treatment and tumour recurrence are explanatory variables of survival. Tumour localization, tumour stage and neoadjuvant treatment were explanatory variables for DFS. However, the type and extent of vascular resections as well as vessel wall invasion does not affect survival and DFS.

[Legal framework relating to human tissues used for research ends]. / Droit concernant les tissus humains à finalité de recherche.

Development in cell and tissue engineering needs human tissue samples. If French jurisdiction concerning the human tissue sample collected in a therapeutic goal is well established, the French and European legal context concerning the scientific research is not clear and controversial. In our lab, we aim to conjugate the professional and the moral duty and to impose on our researchers the respect of strictly defined procedures. In order to organize the management of these biological resources, we chose not only to take into account the present legal context concerning the collection of tissues for research purposes, but also to precede the French legal framework by inspiring from good practice, concerning on one hand the conservation, the transformation and the transport of human tissues used to therapeutic ends (decree of December 29, 1998) and on the other hand, from the ethical recommendations of the european directives. It is why, we put some procedures in place to guarantee the donor's information, the staff's security, the confidentiality as well as the tracability.

Authorship ignorance: views of researchers in French clinical settings.

OBJECTIVES: To assess the knowledge and behaviour of researchers regarding criteria for authorship, and the practices of ghost and gift authorship. DESIGN: Semidirective interviews of senior clinical researchers. SETTING: University hospital. PARTICIPANTS: Thirty-nine main investigators of clinical research programmes. MAIN MEASUREMENTS: Awareness and use of International Committee of Medical Journal Editors (ICMJE) criteria for authorship, and perceptions about ghost and gift authorship. RESULTS: A total of 48 protocols submitted by 42 principal investigators between 1994 and 1996 were identified. Thirty-nine investigators were contacted; 37 (one of whom delegated a co-author) were interviewed between May 2002 and March 2003. Two co-authors of two principal investigators were also interviewed. In all, 42 studies were represented. The interviews lasted for 40-90 minutes and were conducted with openness and respect for confidentiality. The choice of names of co-authors did not follow the ICMJE recommendations. Half of the respondents stated they were aware of criteria for authorship and knew of ICMJE, but most of them did not cite any of the ICMJE criteria among those they applied in deciding authorship. Most of them disagreed with the obligation to meet the three criteria justifying co-authorship because they found these too rigid and inapplicable. Gift authorship was a common practice; 59% of the respondents had been a recipient of gift authorship. Twenty-five (64%) were aware of ghost authorship and the majority considered it questionable and blameworthy. CONCLUSIONS: The ICMJE criteria were ignored by clinicians at a university hospital. Ghost and gift authorship were frequent among them. There is a need for French guidelines for authorship to be prepared and implemented.

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis.

Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B (L-AmB) is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B (AmB) is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.

Any clinical benefit from the use of oncofoetal markers in the management of chemotherapy for patients with metastatic colorectal carcinomas?

AIMS: Computed tomography (CT) is the reference technique for evaluating response to chemotherapy. The potential helpfulness of tumour markers is debated. MATERIALS AND METHODS: From March 1997 to January 1999, 91 consecutive patients receiving chemotherapy for metastatic colorectal carcinoma underwent whole-body spiral CT, estimates of anti-carcinoembryonic antigen (CEA) and CA19-9 every 8 weeks. RESULTS: CEA and CA19-9 levels were above normal in 78 (85.7%) and 61 (67.5%) patients, respectively. Tumour response evaluation according to the RECIST criteria was obtained at 8-week evaluation in 83 (91%) patients. The positive predictive values (PPV) for response of a decrease of the marker levels were 53.8 for CEA and 41.7 for CA19-9 using a 30% decrease threshold, and 60/52.2, respectively, using a 50% decrease threshold. Meaningful PPV values (> 90%) for progression of an increase of the marker levels were only obtained using the 200% increase threshold for CEA alone or a combination of CEA and CA 19-9. A 100% CEA increase between baseline and the 8-week evaluation was correlated to overall survival (P = 0.0023). The need for a radiological confirmation of tumour progression could be avoided by the systematic dosage of tumour markers at baseline and after 8 weeks of treatment only in a sub-population of 13% of the patients with a 200% increase of CEA or CA 19-9 at 8 weeks. CONCLUSIONS: CEA, CA 19-9, or both should be used with caution for tumour response evaluation to chemotherapy in addition to CT in metastatic colorectal carcinoma.