Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE: Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS: Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS: Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION: These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

Access Management Research and Awareness Program : Phase IV, 1999

Access management involves balancing the dual roles that roadways must play - through travel and access to property and economic activity. When these roles are not in proper balance, the result is a roadway system that functions sub-optimally. Arterial routes that have a too high driveway density and provide overly extensive access to property have high crash rates and begin to suffer in terms of traffic operations. Such routes become congested, delays increase, and mean travel speeds decline. The Iowa access management research and awareness project has had four distinct phases. Phase I involved a detailed review of the extensive national access management literature so lessons learned elsewhere could be applied in Iowa. In Phase II original case study research was conducted in Iowa. Phase III of the project concentrated on outreach and education about access management. Phase IV of the Iowa access management project extended the work conducted during Phases II and III. The main work products for Phase IV were as follows: 1) three additional before and after case studies, illustrating the impacts of various access management treatments on traffic safety, traffic operations, and business vitality; 2) an access management handbook aimed primarily at local governments in Iowa; 3) a modular access management toolkit with brief descriptions of various access management treatments and considerations; and 4) an extensive outreach plan aimed at getting the results of Phases I through IV of the project out to diverse audiences in Iowa and elsewhere.

Multimodal Investment Analysis Methodology, Phase One: The Conceptual Model, 1998

The purpose of this project is to develop an investment analysis model that integrates the capabilities of four types of analysis for use in evaluating interurban transportation system improvements. The project will also explore the use of new data warehousing and mining techniques to design the types of databases required for supporting such a comprehensive transportation model. The project consists of four phases. The first phase, which is documented in this report, involves development of the conceptual foundation for the model. Prior research is reviewed in Chapter 1, which is composed of three major sections providing demand modeling background information for passenger transportation, transportation of freight (manufactured products and supplies), and transportation of natural resources and agricultural commodities. Material from the literature on geographic information systems makes up Chapter 2. Database models for the national and regional economies and for the transportation and logistics network are conceptualized in Chapter 3. Demand forecasting of transportation service requirements is introduced in Chapter 4, with separate sections for passenger transportation, freight transportation, and transportation of natural resources and commodities. Characteristics and capacities of the different modes, modal choices, and route assignments are discussed in Chapter 5. Chapter 6 concludes with a general discussion of the economic impacts and feedback of multimodal transportation activities and facilities.

Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.

BACKGROUND: Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting. METHODS: This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (< or = 16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44-50 Gy. Letrozole was administered orally once daily at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273. FINDINGS: All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3-40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis). INTERPRETATION: Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes. FUNDING: Novartis Oncology France.

Surgical interventions with fatal outcome: Utility of multi-phase postmortem CT angiography

Cases of fatal outcome after surgical intervention are autopsied to determine the cause of death and to investigate whether medical error caused or contributed to the death. For medico-legal purposes, it is imperative that autopsy findings are documented clearly. Modern imaging techniques such as multi-detector computed tomography (MDCT) and postmortem CT angiography, which is used for vascular system imaging, are useful tools for determining cause of death. The aim of this study was to determine the utility of postmortem CT angiography for the medico-legal death investigation. This study investigated 10 medico-legal cases with a fatal outcome after surgical intervention using multi-phase postmortem whole body CT angiography. A native CT scan was performed as well as three angiographic phases (arterial, venous, and dynamic) using a Virtangio((R)) perfusion device and the oily contrast agent, Angiofil((R)). The results of conventional autopsy were compared to those from the radiological investigations. We also investigated whether the radiological findings affected the final interpretation of cause-of-death. Causes of death were hemorrhagic shock, intracerebral hemorrhage, septic shock, and a combination of hemorrhage and blood aspiration. The diagnoses were made by conventional autopsy as well as by postmortem CT angiography. Hemorrhage played an important role in eight of ten cases. The radiological exam revealed the exact source of bleeding in seven of the eight cases, whereas conventional autopsy localized the source of bleeding only generally in five of the seven cases. In one case, neither conventional autopsy nor CT angiography identified the source of hemorrhage. We conclude that postmortem CT angiography is extremely useful for investigating deaths following surgical interventions. This technique helps document autopsy findings and allows a second examination if it is needed; specifically, it detects and visualizes the sources of hemorrhages in detail, which is often of particular interest in such cases.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Unilateral ureteropelvic junction obstruction in children: long-term followup after unilateral pyeloplasty.

PURPOSE: The benefit of surgery on renal function in unilateral ureteropelvic junction stenosis (UPJS) is still debated. We evaluated renal function outcome after unilateral pyeloplasty in 53 children. MATERIALS AND METHODS: We retrospectively reviewed 123I-hippuran renography performed at diagnosis and 5 to 15 years (mean +/- SD 7 +/- 3 years) after successful pyeloplasty. UPJS was prenatally detected in 26 children because of urinary tract infection in 17 and miscellaneous reasons in 10. Relative function (RF) and absolute function were measured on background corrected renograms. Absolute function of the affected and contralateral kidneys was determined by an accumulation index (AI), representing the percent injected dose extracted by each kidney 30 to 90 seconds after the heart peak. RESULTS: Preoperatively 33 of the 53 UPJS kidneys had a decreased AI but only 8 had a RF of less than 40%, which was improved in 7 at followup. In addition, the AI improved in 29 kidneys, of which 19 (36%) normalized. Of the UPJS kidneys 14 had an initially decreased AI that remained abnormal at followup. In these kidneys preoperative RF was less than 40% in all. At followup RF was greater than 40% in 4 children, in whom the AI of the UPJS kidney did not improve but the AI of the contralateral one decreased from supranormal to normal. Seven contralateral kidneys had a supranormal AI, whereas the AI remained normal in 3, of which the RF in the UPJS kidney remained at less than 40%. The AI and RF were normal in 20 UPJS kidneys and remained normal. CONCLUSIONS: When normal, the AI and RF reflected renal function outcome similarly. The AI added relevant information in UPJS kidneys with impaired function, showing compensation of the contralateral kidney.

Epidote in hydrous mafic magmas : near solidus phase relations in the lower crust

Crystallisation of hydrous mafic magmas at high pressure is a subject of numerous petrologic and experimental studies since the last century and is mainly related to the process of continental crust formation and the possible link between mantle derived melts and low pressure granitoids. Albeit the sequence of crystallization is well constrained by experimental studies, the origin of exposed lower crustal rocks exposed on the earth surface is controversial. Ones line of argument is favouring high pressure crystallization of dry or wet mafic magmas, whereas others invoke partial melting of pre-existing crust. Therefore studies involving field, textural and chemical observations of exposed lower crust such as in Kohistan (Pakistan) or Talkeetna (Alaska) are crucial to understand the continental crust formation processes via arc magmatism. Epidote-bearing gabbros are very sparse and always associated with the deep part of continental crust (>30 km) as in the Kohistan Arc Complex (Pakistan) or in the Chelan Complex (western U.S.). Magmatic epidote is restricted to a small temperature interval above the water-saturated solidus of MORB and represent the last crystallizing liquids in lower crustal regions. However, epidote and melt stability at lower crustal pressures are not clearly established.¦The Chelan complex (western U.S.) at the base of the Cascadian Arc is composed mainly by peraluminous tonalité associated with gabbroic and ultramafic rocks and was traditionally interpreted as a migmatitic terrain. However field, chemical and mineralogical observations rather suggest a magmatic origin and point to a protracted crystallization at intermediate to high pressure ~ 1.0 GPa dominated by amphibole fractionation and followed by isobaric cooling down to 650°C. Crystal fractionation modelling using whole rock composition and field constraints is able to generate peraluminous tonalité. The modelled crystallisation sequence and the volume proportions are in agreement with experimental studies performed at these pressures. The Chelan complex was thus not formed during a partial melting event, but represent the sequence of crystallisation occurring at the base of the crust. Massive fractionation of hornblende is able to generate peraluminous tonalité without significant assimilation of crustal rock.¦Similarly to the Chelan complex, the base of the Kohistan arc is composed of cumulates derived by high pressure crystallization of hydrous magma. In garnet gabbros, epidote occurs as magmatic phase, crystallising from hydrous interstitial melt trapped between grain boundaries at lower crustal pressures (Ρ ~ 1.2 GPa) for temperature of (650-700 °C). Trace and REE signature in epidote indicate that epidote was formed through peritectic reaction involving garnet, clinopyroxene and plagioclase. At the beginning of the crystallisation epidote signature is dominated by REE content in the melt, whereas at the end the signature is dominated by reacting phases. Melt in equilibrium with epidote inferred from the partition coefficients available is similar to intrusive tonalité up the section indicating that hydrous melt was extracted from the garnet gabbros. In some gabbros epidote shows single homogeneous compositions, while in others coexisting epidote have different compositions indicating the presence of solvi along the Al-Fe3+ join. The overgowths are only observed in presence of paragonite in the assemblage, suggesting high water content. At high water content, the hydrous solidus is shift to lower temperature and probably intersects the solvi observed along the Al-Fe3+ join. Therefore, several compositions of epidote is stable at high water content.¦-¦La composition chimique de la croûte continentale est considérée comme similaire à celle du magmatisme calco-alcalin de marge continentale active (enrichissement en éléments mobiles dans les fluides, anomalies négatives en Nb, Ta et éléments à haut potentiel électronique, etc...). Cependant la nature andésitique de la croûte continentale (Si02 > 60 wt%), résultant des nombreuses intrusions de granitoïdes dans la croûte supérieure, est sujette à polémique et le lien entre les magmas dérivés du manteau et les roches évoluées de faible profondeur n'est pas clairement établi (fusion partielle de croûte basaltique, cristallisation fractionnée à haute pression, etc...).¦Les affleurements de croûte profonde sont rares mais précieux, car ils permettent d'observer les phénomènes se passant à grande profondeur. Le complexe de Chelan (Washington Cascades) en est un exemple. Formé à environ 30 km de profondeur, il est composé de roches gabbroïques et ultramafiques, ainsi que de tonalités, qui furent souvent interprétés comme le produit de la fusion partielle de la croûte. Cependant, les relations de terrain, la chimie des éléments majeurs et des éléments traces sont cohérentes avec l'évolution d'un complexe magmatique mafique dans la croûte profonde ou moyenne ( 1.0 GPa), dominée par le fractionnement de l'amphibole. Après son emplacement, le complexe a subi un refroidissement isobare jusqu'à des températures de l'ordre de 650 °C, déduit de la composition chimique des minéraux. Un bilan de masse contraint pax les observations de terrain permet de calculer la séquence et les volumes de fractionnement. Les faciès évolués légèrement hyperalumineux observés sur le terrain peuvent être générés par la cristallisation de 3 % de websterite à olivine, 12 % d'hornblendite à pyroxène 33 % d'hornblendite, 19 % de gabbros, 15 % de diorite et 2 % de tonalité. Nous montrons ainsi qu'une série de fractionnement contrôlée par l'amphibole permet de générer des tonalités sans assimilation de matériel crustal et l'exemple de Chelan illustre la viabilité de ce processus dans la formation de croûte continentale.¦Les réactions proches du solidus saturé en H20 dans les systèmes basaltiques à des pressions élevées restent énigmatiques. Diverses expériences tendent à montrer que l'épidote est stable dans ces conditions, mais rarement observée (décrite ?) comme phase primaire dans les systèmes naturels. Les épidotes trouvées dans les gabbros de Jijal (nord-Pakistan) montrent des textures de type .magmatique telles qu'observées dans les roches évoluées. Le contenu en terres rares de ces épidotes est très variable allant de signatures enrichies en terres rares légères impliquant la présence de liquide interstitiel à des signatures complètement déprimées en ces mêmes éléments, évoquant une cristallisation en coexistence avec du grenat. Ces diverses signatures reflètent un chemin de cristallisation en présence de liquide interstitiel et enregistrent des réactions péritectiques impliquant grenat, clinopyroxene et plagioclase à des pressions de ~ 1.2 GPa pour des températures de 650-700 °C. Cependant dans quelques échantillons deux ou trois compositions d'épidotes coexistent démontrant la présence de lacunes d'immiscibilité le long de la solution solide épidote-clinozoïsite. La forte teneur en H20 du liquide magmatique est certainement à l'origine de la coexistence de deux compositions distinctes.

Concurrent or Sequential Adjuvant Letrozole and Radiotherapy after Conservative Surgery for Early-stage Breast Cancer: Long-term Results of the Cohort Phase 2 Randomized Trial

Purpose/Objective(s): Letrozole radiosensitizes breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.Materials/Methods: The present study is registered with ClinicalTrials.gov, number NCT00208273. This Phase 2 randomized trial was undertaken in two centers in France and one in Switzerland between January 12, 2005, and February 21, 2007. One hundred fifty postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n = 75) or sequential radiotherapy and letrozole (n = 75). Randomization was open label with a minimization technique, stratified by investigational centers, chemotherapy (yes vs. no), radiation boost (yes vs. no), and value of radiation-induced lymphocyte apoptosis (#16% vs. .16%). The whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44 - 50 Gy. Letrozole was administered orally once daily at a dose of 2 - 5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks postradiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced Grade 2 or worse toxic effects of the skin and lung (functional pulmonary test and lung CT-scan). Analyses were by intention-to-treat. The long-term follow-up after 2 years was only performed in Montpellier (n = 121) and evaluated skin toxicity (clinical examination every 6 months), lung fibrosis (one CT-scan yearly), cosmetic outcome.Results: All patients were analyzed apart from 1 in the concurrent group who withdrew consent before any treatment.Within the first 2 years (n = 149), no lung toxicity was identified by CT scan and no modification from baseline was noted by the lung diffusion capacity test. Two patients in each group had Grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis [RISF]). After 2 years (n = 121), and with a median follow-up of 50 months (38-62), 2 patients (1 in each arm) presented a Grade 3 RISF. No lung toxicity was identified by CT scan. Cosmetic results (photographies) and quality of life was good to excellent. All patients who had Grade 3 subcutaneous fibrosis had an RILA value of 16% or less, irrespective of the sequence with letrozole.Conclusions:With long-term follow-up, letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy.

Treatment of brain metastases from non-small cell lung cancer with whole-brain radiotherapy (wbrt) in combination with gefitinib (gft) or temozolomide (tmz): a randomized multicenter phase ii trial of the swiss group of clinical cancer research (sakk #70/03)

BACKGROUND: Patients with BM rarely survive .6 months and are commonly excluded from clinical trials. We aimed at improving outcome by exploring 2 combined modality regimens with at the time novel agents for which single-agent activity had been shown. METHODS: NSCLC patients with multiple BM were randomized to WBRT (10 × 3 Gy) and either GFT 250 mg p.o. daily or TMZ 75 mg/m2 p.o. daily ×21/28 days, starting on Day 1 of RT and to be continued until PD. Primary endpoint was overall survival, a Simon's optimal 2-stage design was based on assumptions for the 3-month survival rate. Cognitive functioning and quality of life were also evaluated. RESULTS: Fifty-nine patients (36 M, 23 F; 9 after prior chemo) were included. Median age was 61 years (range 46-82), WHO PS was 0 in 18 patients, 1 in 31 patients, and 2 in 10 patients. All but 1 patients had extracranial disease; 33 of 43 (TMZ) and 15 of 16 (GFT) had adenocarcinoma histology. GFT arm was closed early after stage 1 analysis when the prespecified 3-mo survival rate threshold (66%) was not reached, causes of death were not GFT related. Main causes of death were PD in the CNS 24%, systemic 41%, both 8%, and toxicity 10% [intestinal perforation (2 patients), pneumonia (2), pulmonary emboli (1), pneumonitis NOS (1), seizure (1)]. We summarize here other patients' characteristics for the 2 trial arms: TMZ (n ¼ 43)/GFT (n ¼ 16); median treatment duration: 1.6 /1.8 mo; Grade 3-4 toxicity: lymphopenia 5 patients (12%)/0; fatigue 8 patients (19%)/2 patients (13%). Survival data for TMZ/GFT arms: 3-month survival rate: 58.1% (95% CI 42.1-73)/62.5% (95% CI 35- 85); median OS: 4.9 months (95% CI 2.5-5.6)/6.3 months (95% CI 2.2- 14.6); median PFS: 1.8 months (95% CI 1.5-1.8)/1.8 (95% CI 1.1-3.9); median time to neurol. progr.: 8.0 months (95% CI 2.2-X)/4.8 (95% CI 3.9-10.5). In a model to predict survival time including the variables' age, PS, number of BM, global QL, total MMSE score, and subjective cognitive function, none of the variables accounted for a significant improvement in survival time. CONCLUSIONS: The combinations of WBRT with GFT or TMZ were feasible. However, in this unselected patient population, survival remains poor and a high rate of complication was observed. Four patients died as a result of high-dose corticosteroids. Preliminary evaluation of cognitive function andQL failed to show significant improvement. Indications and patient selection for palliative treatment should be revisited and careful monitoring and supportive care is required. Research and progress for this frequent clinical situation is urgently needed. Trial partly supported by AstraZeneca (Switzerland), Essex Chemie (Switzerland) and Swiss Federal Government.

Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. METHODS: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). FINDINGS: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. INTERPRETATION: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Biases on the administered parenteral doses of an experimental drug during phase I clinical trials

Introduction: The pharmaceutical aspects of drug administration in clinical trials receive poor consideration compared with the important attention devoted to the analytical and mathematical aspects of biological sample exploitation. During PK calculations, many researchers merely use for dose the nominal amount declared, overlooking the noticeable biases that may result in the assessment of PK parameters. The aim of this work was to evaluate the biases related to doses injected of a biosimilar drug in 2 Phase I clinical trials. Patients (or Materials) and Methods: In trial A, 12 healthy volunteers received different doses of a biosimilar of interferon beta-1a by either subcutaneous (SC) or intravenous (IV) injection. The doses were prepared by partially emptying 0.5-mL syringes supplied by the manufacturer (drop count procedure). In trial B, 12 healthy volunteers received 3 different formulations of the drug by IV injection (biosimilar without albumin [HSA], biosimilar with HSA and original brand [Rebif®]) and 2 different formulations as multiple SC injections (biosimilar HSA-free and original brand). In both trials, the actual dose administered was calculated as: D = C·V - losses. The product titer C was assessed by ELISA. The volume administered IV was assessed by weighting. Losses were evaluated by in vitro experiments. Finally, the binding of 125I-interferon to HSA was evaluated by counting the free and HSA complexed molecule fractions separated by gel filtration. Results: Interferon was not significantly adsorbed onto the lines used for its IV administration. In trial A, the titer was very close to the one declared (96 ± 7%). In trial B, it differed significantly (156 ± 10% for biosimilar with/without HSA and 123 ± 5% for original formulation). In trial A, the dose actually administered showed a large variability. The real injected volume could be biased up to 75% compared with the theoretical volume (for the lower dose administered [ie, 0.03 mL]). This was mainly attributed to a partial re-aspiration of the drug solution before withdrawing the syringe needle. A strict procedure was therefore applied in trial B to avoid these inaccuracies. Finally, in trial B, 125I-Interferon beta-1a binding to HSA appeared time dependent and slow, reaching 50% after 16-hour incubation, which is close to steady state reported for the comparator Rebif®. Conclusion: These practical examples (especially biases on actual titer and volume injected) illustrate that actual dose assessment deserves attention to ensure accuracy for estimates of clearance and distribution volume in the scientific literature and for registration purposes, especially for bioequivalence studies.

Yeast vacuoles fragment in an asymmetrical two-phase process with distinct protein requirements.

Yeast vacuoles fragment and fuse in response to environmental conditions, such as changes in osmotic conditions or nutrient availability. Here we analyze osmotically induced vacuole fragmentation by time-lapse microscopy. Small fragmentation products originate directly from the large central vacuole. This happens by asymmetrical scission rather than by consecutive equal divisions. Fragmentation occurs in two distinct phases. Initially, vacuoles shrink and generate deep invaginations that leave behind tubular structures in their vicinity. Already this invagination requires the dynamin-like GTPase Vps1p and the vacuolar proton gradient. Invaginations are stabilized by phosphatidylinositol 3-phosphate (PI(3)P) produced by the phosphoinositide 3-kinase complex II. Subsequently, vesicles pinch off from the tips of the tubular structures in a polarized manner, directly generating fragmentation products of the final size. This phase depends on the production of phosphatidylinositol-3,5-bisphosphate and the Fab1 complex. It is accelerated by the PI(3)P- and phosphatidylinositol 3,5-bisphosphate-binding protein Atg18p. Thus vacuoles fragment in two steps with distinct protein and lipid requirements.

Les mesures de santé publique de la Confédération en matière de drogues illégales : monitoring 1999-2000 : étude menée dans le cadre de l'évaluation globale du ProMeDro, 4ème phase 1999-2003

[Table des matières] 1. Introduction. 2. Méthode. 3. Prévention. 4. Thérapies. 5. Réduction des risques. 6. Formation. 7. Coordination nationale. 8. Migration et santé. 9. Epidémiologie. 10. Recherche. 11. Evaluation. 12. Annexes.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.