Multicentre Basis Research Articles

Role of orthodontist in cleft lip and palate

Cleft lip and palate is one of the most common congenital anomalies occurring round the world varying with the race, ethnicity and geography. Cleft lip and/or palate problems tends to worsen as the individual grows older. Although it occurs as a different entity in itself but its presence can hamper aesthetics as well as functions by effecting growth, dentition, speech, hearing and overall appearance resulting in social and psychological problems for the child as well as the parents. Cleft lip and palate is of a multifactorial origin such as inheritance, teratogenic drugs, and nutritional deficiencies and can also occur as syndromic or non-syndromic cleft. Treatment of Cleft Lip and Palate comprises of different specialists having an individual insight in a particular case ultimately reaching to a consensus for a successful culmination of the treatment. Although appropriate timing and method of each intervention is still arguable. An orthodontist plays a role in pre surgical maxillary orthopaedics, in aligning the maxillary segments and dentition, in preparation for secondary alveolar bone grafting and finally in obtaining ideal dental relation and preparing the dentition for prosthetic rehabilitation or orthognathic surgery if required. Therefore, for efficient treatment outcome and refinement of individual techniques or variations of the treatment protocol a highly able team of specialists from different specialities is a must, preferably on a multicentre basis.

Classification of paediatric brain tumours by diffusion weighted imaging and machine learning

To determine if apparent diffusion coefficients (ADC) can discriminate between posterior fossa brain tumours on a multicentre basis. A total of 124 paediatric patients with posterior fossa tumours (including 55 Medulloblastomas, 36 Pilocytic Astrocytomas and 26 Ependymomas) were scanned using diffusion weighted imaging across 12 different hospitals using a total of 18 different scanners. Apparent diffusion coefficient maps were produced and histogram data was extracted from tumour regions of interest. Total histograms and histogram metrics (mean, variance, skew, kurtosis and 10th, 20th and 50th quantiles) were used as data input for classifiers with accuracy determined by tenfold cross validation. Mean ADC values from the tumour regions of interest differed between tumour types, (ANOVA P < 0.001). A cut off value for mean ADC between Ependymomas and Medulloblastomas was found to be of 0.984 × 10−3 mm2 s−1 with sensitivity 80.8% and specificity 80.0%. Overall classification for the ADC histogram metrics were 85% using Naïve Bayes and 84% for Random Forest classifiers. The most commonly occurring posterior fossa paediatric brain tumours can be classified using Apparent Diffusion Coefficient histogram values to a high accuracy on a multicentre basis.

Feasibility and efficacy of salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer.

For highly selected patients with Stage III non-small-cell lung cancer (NSCLC) who relapse or have residual disease after definitive chemoradiotherapy, salvage lung resection is likely to be one of the options for local control and possible better prognosis. However, the long-term benefit has not been verified. We conducted a retrospective study on salvage surgery on a multicentre basis. Patients included in this study met the following criteria: (i) prior treatment of lung cancer with curative-intent radiotherapy (≥60 Gy); (ii) no a priori plans for induction multimodality therapy; (iii) confirmation of loco-regional recurrence or persistent tumour in the irradiated area; (iv) pretherapeutic pathological results of NSCLC and (v) Stage III disease prior to chemoradiotherapy. A total of 18 patients were eligible for evaluation (Stage IIIA/IIIB, 14/4). The prior median radiation therapy dose was 60 Gy (60-74 Gy), and the median time between the last day of radiotherapy and resection was 38 weeks. The indications for surgery were primary tumour regrowth (10 patients) or tumour persistence (8 patients). Surgical procedures included lobectomy in 13 patients and pneumonectomy in 5 patients. Postoperative complications occurred in 5 patients (28%) without perioperative death. Complete resection was shown in 16 patients (89%) and a complete pathological response in 5 patients (28%). The median follow-up time was 1405 days, and the 3-year overall survival and recurrence-free survival rates were 78 and 72%, respectively. In the highly selected Stage III NSCLC after curative-intent chemoradiation therapy, salvage surgery was safely performed and contributed to satisfactory long-term survival.

Wie sicher ist die Sedierung in der gastrointestinalen Endoskopie? Eine multizentrische Auswertung von 388 404 Endoskopien und Auswertung der Daten aus prospektiv geführten Komplikationsregistern von Mitgliedern der Arbeitsgemeinschaft leitender Gastroenterologen im Krankenhaus (ALGK)

Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty-one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class ≥ 3. Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class ≥ 3.

Conformational Sensitivity in Photoelectron Circular Dichroism of 3‐Methylcyclopentanone

A study of (R)-3-methylcyclopentanone [(R)-3-MCP] by photoelectron spectroscopy and photoelectron circular dichroism (PECD) is presented. The synchrotron radiation gas-phase photoelectron spectra of (R)-3-MCP were measured and are discussed on the basis of different theoretical methodologies. The experimental dichroism of (R)-3-MCP for selected deconvoluted valence states and for the carbonyl carbon 1s core state are reported and reproduced well by calculated dispersions generated by considering the contributions of two different conformers. The theoretical dichroic parameters are calculated by employing a multicentre basis set of B-spline functions and a Kohn-Sham Hamiltonian. Temperature-dependent PECD studies of the HOMO state and the carbonyl carbon 1s core level allowed the separation of the contributions of each conformer by photoelectron dichroism. This new approach clearly shows how the PECD methodology is sensitive to conformational and structural changes of unoriented (R)-3-MCP in the gas phase, opening up new perspectives in the characterisation of chiral molecular systems.

New proposal for the treatment of poor prognosis young patients with advanced stage diffuse large B-cell lymphoma

Patients with DLBCL now have a better outcome with a longer survival because of two major developments: 1) increasing the dose of active drugs with shortening the time between cycles, resulting in dose-dense or dose-intense regimens; and 2) combining rituximab with chemotherapy. Both strategies were associated with a better clinical outcome, particularly in patients without adverse prognostic factors. Poor risk patients in the age range of 60 to 65 years may benefit from a combination of dose-dense or dose-intense regimens plus rituximab. Young patients with poor risk DLBCL defined by an aaIPI of 2 or 3 and age younger than 60 years, are characterized by truly refractory disease, evidenced by progression during or early after treatment, or later relapse. Attempts to modify treatment including immunotherapy to improve the response rate and reduce the proportion of patients with progressive disease have been only partially successful: to date: the best progression-free survival was 51%. In contrast, some attempts to decrease the high resistant and relapse rate with sequential high-dose chemotherapy with rituximab (R-HDS) and autologous stem cell transplantation (ASCT) have succeeded. On the basis of these promising results, GITIL launched a prospective phase III randomized trial comparing the efficacy and safety of dose-dense CHOP plus rituximab with R-HDS and ASCT. Preliminary data show that intensive programs such as dose-dense chemo-immunotherapy and R-HDS with ASCT are feasible until 65 years with a manageable toxic profile, also on multi-centre basis.

A GITIL Prospective Randomized Multicenter Phase III Study of High Dose Sequential Chemotherapy with Rituximab (R-HDS) and Autologous Transplantation (ASCT) of Peripheral Blood Stem Cells Versus CHOP and Rituximab Delivered Every 14 Days (R-CHOP-14) in High-Risk Patients with Diffuse Large B-Cell Lymphomas (DLBCL): Interim Analysis on Feasibility and Toxicity (Protocol R-HDS 0305).

R-HDS 0305 (Clinical Trials. gov. number NCT00355199) is a multi-centre, unblinded, randomized controlled phase III trial involving 240 patients in 3 years from 16 Italian Cancer Centres, with DLBCL without CNS involvement, advanced stage (stage ≥IIB, bulk), age from 18 to 60 years with ECOG-PS=0–3 and aaIPI=2–3 or age from 61 to 65 years with ECOG-PS=0–2 and IPI 3–5. The control group received R-CHOP-14, which comprised 8 courses of chemotherapy every 14 days, supported by GCSF (day 7–11)±IFRT, if they achieved at least a PR after 4 cycles. Cases refractory to R-CHOP-14 were given R-HDS as salvage therapy. Experimental arm consisted in a R-HDS program, including a debulking phase of 3 courses of doxorubicin-containing chemotherapy (APO), followed by high-dose (HD)-cyclophosphamide (CTX) 7g/sqm, HD-Ara-C (2 g/sqm every 12 hours for 6 days), HD-etoposide 2g/sqm+Cisplatin 100 mg/sqm. After HDS chemotherapy, HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) or a BEAM (BCNU 300 mg/sqm, etoposide 200 mg/sqm, Ara-C 4000 mg/sqm, L-PAM 140 mg/sqm) conditioning regimen with ASCT±IFRT was planned. Rituximab (375 mg/sqm) is given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest, and twice after ASCT. The primary outcomes of the study are complete remission and disease-free survival, overall survival, event-free survival and toxicity. From July 2005 to July 2007, 89 patients were enrolled in the study (R-CHOP-14=43; R-HDS=46). The median age was 51 (range 19–65 years), 11 (12%) had ≥60 years and the M/F was 1.3. Patients presented with adverse features such as advanced stage (88%), BM infiltration (28%), bulky disease (71%), elevated LDH (84%), poor ECOG-PS (55%) and >1 extranodal sites (59%). Until now only 3 patients (3.4%) were refractory to planned treatment: 1/43 (2%) patients belonging to R-CHOP-14 arm shifted to R-HDS salvage treatment and other 2 patients died from lymphoma progression. The main G 3–4 WHO toxicity was haematological: anemia, granulocytopenia and thrombocytopenia occurred in 8%, 18% and 13% of patients, respectively. Grade 2–3 gastrointestinal toxicity and infectious episodes were recorded in 6% and 9% of patients, respectively. Two patients recovered from acute respiratory distress and 2 died of treatment-related toxicity (2.2%). In conclusion, if the R-HDS trial confirms earlier results, preliminary data show that intensive programs such as dose-dense chemo-immunotherapy and R-HDS with ASCT are feasible until 65 years with an acceptable toxic profile, also on the multi-centre basis. At completion of the trial we will assess the role of R-HDS and ASCT on the outcome of high-risk patients with DLBCL.

Magnetic-field-induced phase transitions in Wigner molecules

A theoretical analysis of formation and symmetry transformationsis presented for Wigner molecules with N = 2,..., 20 electronsconfined in quantum dots at high magnetic fields. Using the unrestricted Hartree–Fockmethod with the multicentre Gaussian basis, we have found that Wigner molecules withN ≥ 6abruptly change their shape and symmetry with an associated jump in the firstderivative of the ground-state energy, i.e. they undergo phase transitions. Inparticular, the phases of the Wigner molecules obtained just after emerging fromthe maximum-density droplet (MDD) phase possess a different symmetry fromthat formed at a high magnetic field. We show that the properties of theelectron–electron interaction energy demonstrate very well both the breakdown ofthe MDD and the quasi-classical character of the Wigner molecule in the highmagnetic field. Possible mechanisms of the MDD decay are discussed.

Acute liver failure: Targeted artificial and hepatocyte-based support of liver regeneration and reversal of multiorgan failure

Acute liver failure (ALF) still represents a major therapeutic challenge for hepatologists due to its high mortality rate as a result of multiorgan failure. Although emergency orthotopic liver transplantation represents a major advance in the management of selected patients, it is not applicable to all candidates due to limited organ availability. Therefore, new therapeutic options should be developed to bridge selected patients to transplantation or to treat patients not candidates for liver transplantation. Although new techniques for cell culture and perfusion have resulted in a number of promising devices for the provision of temporary liver support in acute liver failure, their clinical efficacy is as yet uncertain. Controlled trials on a multi-centre basis in well-defined patient groups and with standardised outcome measures, including the extent to which treatment influences cell damage and regeneration and prevents or reverses multiorgan failure, will be essential to properly evaluate the clinical value of current and evolving artificial and bioartificial devices. The same considerations must also apply to the assessment of therapeutic efficacy of hepatocyte transplantation. A better understanding of mechanisms responsible for the development of liver cell death, along with cellular and molecular mechanisms allowing surviving cells to proliferate in a hostile environment, will be required if a more targeted therapeutic approach to decreasing hepatocellular injury and enhancing liver regeneration is to be achieved. Whether extracorporeal devices or the transplantation of primary hepatocytes, stem cells or cells genetically engineered to over-express key metabolic functions, a proliferative phenotype and/or cytoprotective pathways will be best suited to meeting these demanding challenges remains to be determined.

Effect of high-dose ifosfamide in advanced soft tissue sarcomas. A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group

In this phase II study the effect of high-dose ifosfamide (HDI) given as a 3-day continuous infusion at a dose of 12 g/m 2 repeated every 4 weeks with adequate mesna protection and hydration was evaluated in patients with advanced soft tissue sarcomas. A total of 124 patients entered the trial of which 10 were ineligible. HDI was given both as first-line and second-line chemotherapy. Median age was 46 years (19–66 years). Median World Health Organization (WHO) performance status was 1 (0–1). Fifty two per cent of the patients were males. The predominant histology was leiomyosarcoma (33%). A maximum of six cycles was given. At the time of analysis 55 patients have died. The partial response (PR) rate was 16%. The median time to progression was 15 weeks. 8 of the 18 responding patients (44%) had synovial sarcomas, whereas only 5% of the patients having leiomyosarcomas responded. The grade 3+4 haematological toxicity encountered was neutrophils in 78% and platelets in 12%. The major grade 3+4 non-haematological toxicities encountered were febrile neutropenia in 39%, infection in 20%, and acute renal failure in 4%. In conclusion, it is possible to administer HDI on a multicentre basis, but the toxicity is substantial. HDI given as a continuous infusion at this dose cannot be recommended as the standard treatment of advanced soft tissue sarcomas, even in selected patients.

Extracorporeal support and hepatocyte transplantation in acute liver failure and cirrhosis.

The relative shortage of donor organs and lack of immediate availability mean that many patients with acute liver failure die before orthotopic liver transplantation can be performed. An effective temporary liver support system could improve the chance of survival with or without a transplant being ultimately carried out. Recent technological advances resulting in improved maintenance of hepatocyte viability and function in culture and bioreactor designs which facilitate adequate perfusion of the cellular component and removal of products of cellular metabolism have led to the development of a number of bioartificial devices for liver support. Three such devices have undergone preliminary clinical evaluation in the setting of acute liver failure, with a statistically significant reduction in raised intracerebral pressure along with improvements in consciousness level and some biochemical parameters associated with treatment with one of these. Several other devices with different characteristics have shown promise in vitro and/or in animal models but await clinical evaluation. Several new totally artificial systems have also been described, along with the emergence of isolated hepatocyte transplantation, with reports of successful 'bridging' to liver transplantation. Controlled trials on a multicentre basis in well-defined patient groups and with standardized outcome measures will be required to properly evaluate the clinical value of each of these approaches to providing liver support in acute liver failure and cirrhosis. A better understanding of mechanisms underlying multiorgan failure and of factors inhibiting liver regeneration, thereby allowing a more targeted approach, will be essential to the further development of effective liver support strategies in these settings.

Prognosis in IgA nephropathy

Summary: IgA nephropathy it is now widely recognized as the most common glomerulonephritis causing end‐stage renal failure (ESRF) in many parts of the world. Large series of patients have been analysed in an attempt to identify prognostic clinical and histological features. Increasingly the importance of stage specific analysis of such factors has been reflected in the literature. Such analysis suggests that if therapeutic trials are to be conducted in an attempt to improve prognosis in IgA nephropathy these will need to be organized on a multicentre basis under the auspices of an international organization.

Para-umbilical block: a new concept for regional anaesthesia in children.

This preliminary study describes a new technique to provide analgesia in children undergoing umbilical hernia repair. The para-umbilical block consists of infiltrating the anterior cutaneous branches of the two tenth spinal roots over and under the rectus sheath far from the operative field. Intra and postoperative analgesia as well as operative conditions were assessed in 11 children 16.7 +/- 31 months old, weighing 8421 +/- 6941 g, the block being performed before surgery under light general anaesthesia. Intraoperative analgesia, operative conditions and recovery were good in all patients. Analgesia was adequate one h after surgery in ten patients, six h after surgery in eight. The block proved to be safe and on the whole effective in this short series. The study should proceed on a multi-centre basis if possible. Indications can be extended.

Bioartificial liver support: developments in hepatocyte culture and bioreactor design.

Bioartificial liver devices aim to support patients with acute liver failure (ALF) until orthotopic liver transplantation (OLT) or spontaneous recovery due to hepatic regeneration can occur. However, initial clinical experiences with two devices have indicated that functional efficacy in this setting may be less than in the experimental situation. Several fundamental issues remain unresolved, including the cell mass required to provide meaningful support and which of those hepatocyte components and bioreactor designs so far proposed is best able to do this. In particular, further studies of the efficacy of devices incorporating human hepatocyte lines transformed by either cultural conditions or genetic engineering and those based on multi-channel or flat bed bioreactor designs in which hepatocytes are co-cultured with non-parenchymal cells are awaited. Controlled trials on a multicentre basis in well-defined patient groups and with standardised outcome measures will be required to properly evaluate the clinical value of these devices. A better understanding of factors promoting recovery and regeneration of the native liver and to what extent these can be provided by extracorporeal devices will be essential to the further development of effective bioartificial liver support systems.

Hepatitis C infection after blood product transfusion.

HCV infection has been demonstrated in multiply transfused children who received blood products or transplanted organs before universal screening in 1990. The risk of active infection is related to the number of transfusions or pooled blood products. Accurate diagnosis of infection is dependent on utilisation of third generation RIBA and identification of HCV RNA by RT-PCR. The natural history of HCV in childhood is undetermined and prospective long term studies should be undertaken. It is likely that about develop chronic hepatitis with progression at some time to cirrhosis and have an increased risk of developing liver cancer. Treatment with interferon alfa may be effective in up to 50% of children and only those children with documented infection with HCV RNA should be selected for treatment. In order to answer important questions about natural history, outcome, and the necessity and efficacy of treatment response, treatment for these children should only be as part of scientifically conducted studies on a multicentre basis.

Reports of Action Groups

Two Action Groups, each consisting of a chair person and four or five delegates, were established in the first plenary session of the Congress to promote the development of research projects on specific topics on a multidisciplinary, multicentre basis. The areas of research selected for the Action Groups were: Rehabilitation research in the elderly and Social and vocational integration of young disabled adult. In the closing session of the Congress the chairpersons of the Action Groups made reports on their progress. In addition, an initiative to form a database of research in rehabilitation was reported. Abstracts of these reports are given below.

Retrospective analysis of 318 cases of uterine sarcoma

A study of data from 318 cases of uterine sarcoma presenting during a 10-year period (1967–1976) is reported. All but 6 of the patients had at least a 5-year follow-up (98% 5-year follow-up). Overall 5-year survival was 31%, with the major prognostic indicator being tumour stage. Despite the tendency for mixed mesodermal tumours to present in older women with more advanced disease, survival was not statistically different to those patients with leiomyosarcomas. Thus, the propensity for tumour dissemination in leiomyosarcomas should not be underestimated. Leiomyosarcomas are less likely to present with abnormal symptoms than are other sarcomas, and their occurrence as an incidental finding on histological examination underlines the need for an adequate inspection of the intra-abdominal contents at hysterectomy. The tendency to treat all sarcomas as if they were endometrial tumours may be fallacious, and an alternative classification (such as the TNM system) may be required. Recurrence of tumour tended to be at distant sites (distant:pelvic recurrence rate 3:1). Adjuvant radiotherapy is unlikely to alter distant disease foci, and thus the development of combination chemotherapeutic regimens using agents which have shown to result in tumour response seem warranted. Such trials will need to be organised on a multicentre basis to attain statistically evaluable numbers of patients.

An epidemiologic approach to computerized medical diagnosis—AEDMI program

A program called “An Epidemiological Approach to Computerized Medical Diagnosis” (AEDMI) is presented. Using an interactive questionnaire, physician-patient interviews are conducted and a summary of the relevant clinical data is provided. Standard items, obained on a multi-centre basis, form a large-scale data base. Simultaneously, the reasoning of clinical experts in each real case is analyzed to obtain a knowledge-rules data base. The methodology of the program combines Bayesian systems, expert systems, and other new lines of researcg such as neural networks or case-based reasoning. The general concepts of clinical decision making aid systems are reviewed. This publication is aimed at obtaining international cooperation.

A Comprehensive Database Management System for a Variety of Clinical Trials

SummaryA multicentre database management system has been developed which permits individual centres to enter, update, and retrieve their data while allowing detailed analysis to take place on a multicentre basis. Individual centres can access only their own data; summaries, reports and graphics output can be used as a teaching device for seminars and rounds. In one instance, the system provides interactive services to 12 kidney transplant centres spanning a distance of 5000 kilometres; the database contains 20,000,000 items.The database management system is discussed and comparisons are made with other available systems.

Variational solution of the dirac equation within a multicentre basis set of gaussian functions

The Dirac equation for one-electron polynuclear systems is solved variationally within an analytical multicentre basis set. Each of the four components of the molecular spinor is expanded separately into a scalar basis set. The expansion coefficients are obtained from the variational principle. Calculations using gaussian functions are performed for hydrogen-like atoms and for hydrogen-ion-like molecules with constituents of nuclear charge Z = 1, 50 and 90.