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Soldiers on military expeditions usually fail to compensate for the increase in energy expenditure, with potential deleterious consequences. We therefore analyzed the characteristics of energy compensation in 12 male soldiers, during a 15‐day expedition in the cold, while alleviating some of the contextual limitations of food intake (~20‐MJ daily bags of easy‐to‐use, highly palatable and familiar foods with multiple and long breaks allowed during the day). Body and fat mass losses were low and moderate, respectively (−1.13 ± 1.42% and −19.5 ± 15.6%, respectively, p, We analyzed the characteristics of energy compensation in 12 male soldiers, during a 15‐day expedition in the cold, while alleviating some of the contextual limitations of food intake (~20‐MJ daily bags of easy‐to‐use, highly palatable and familiar foods with multiple and long breaks allowed during the day). This study indicates that complete energy compensation can be reached in challenging field conditions when food intake is facilitated, offering some guidelines to limit energy deficit during operational missions.

The purpose of this work is to assess eight detectors performance for output factor (OF), percent depth dose (PDD), and beam profiles in a 6‐MV Clinac stereotactic radiosurgery mode for cone irradiation using Monte Carlo simulation as reference. Cones with diameters comprised between 30 and 4 mm have been studied. The evaluated detectors were ionization chambers: pinpoint and pinpoint 3D, diodes: SRS, P and E, Edge, MicroDiamond and EBT3 radiochromic films. The results showed that pinpoints underestimate OF up to −2.3% for cone diameters ≥10 mm and down to −12% for smaller cones. Both nonshielded (SRS and E) and shielded diodes (P and Edge) overestimate the OF respectively up to 3.3% and 5.2% for cone diameters ≥10 mm and in both cases more than 7% for smaller cones. MicroDiamond slightly overestimates the OF, 3.7% for all the cones and EBT3 film is the closest to Monte Carlo with maximum difference of ±1% whatever the cone size is. For the profiles and the PDD, particularly for the small cones, the size of the detector predominates. All diodes and EBT3 agree with the simulation within ±0.2 mm for beam profiles determination. For PDD curve all the active detectors response agree with simulation up to 1% for all the cones. EBT3 is the more accurate detector for beam profiles and OF determinations of stereotactic cones but it is restrictive to use. Due to respectively inappropriate size of the sensitive volume and composition, pinpoints and diodes do not seem appropriate without OF corrective factors below 10 mm diameter cone. MicroDiamond appears to be the best detector for OF determination regardless all cones. For off‐axis measurements, the size of the detector predominates and for PDD all detectors give promising results.

Background 1p/19q-codeleted anaplastic gliomas have variable clinical behavior. We have recently shown that the common 9p21.3 allelic loss is an independent prognostic factor in this tumor type. The aim of this study is to identify less frequent genomic copy number variations (CNVs) with clinical importance that may shed light on molecular oncogenesis of this tumor type. Materials and Methods A cohort of 197 patients with anaplastic oligodendroglioma was collected as part of the French POLA network. Clinical, pathological, and molecular information was recorded. CNV analysis was performed using single-nucleotide polymorphism arrays. Computational biology and feature selection based on the random forests method were used to identify CNV events associated with overall survival and other clinical-pathological variables. Results Recurrent chromosomal events were identified in chromosomes 4, 9, and 11. Forty-six focal amplification events and 22 focal deletion events were identified. Twenty-four focal CNV areas were associated with survival, and five of them were significantly associated with survival after multivariable analysis. Nine out of 24 CNV events were validated using an external cohort of The Cancer Genome Atlas. Five of the validated events contain a cancer-related gene or microRNA: CDKN2A deletion, SS18L1 amplification, RHOA/MIR191 copy-neutral loss of heterozygosity, FGFR3 amplification, and ARNT amplification. The CNV profile contributes to better survival prediction compared with clinical-based risk assessment. Conclusion Several recurrent CNV events, detected in anaplastic oligodendroglioma, enable better survival prediction. More importantly, they help in identifying potential genes for understanding oncogenesis and for personalized therapy. Implications for Practice Genomic analysis of 197 anaplastic oligodendroglioma tumors reveals recurrent somatic copy number variation areas that may help in understanding oncogenesis and target identification for precision medicine. A machine learning multivariable model built using this genomic information enables better survival prediction.

ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

The purpose of this work is to assess 8 detectors variation performance for output factor (OF) determination, in a clinical 6 MV Varian Clinac 2100C stereotactic radiosurgery mode for cone irradiation using Monte Carlo simulation as reference. We study 10 cones with diameters between 30 and 4 mm. The evaluated detectors were ionization chambers: pinpoint and pinpoint 3D (PTW), diodes: SRS, P and E (PTW), Edge (Sun Nuclear), microdiamond (PTW) and EBT3 radiochromic films (Ashland). The OF were normalized with the 30 mm cone and compared to Monte Carlo (MC). For the 8 detectors, the OF measurements reproducibility was very high: r = 0.99 and p 7% for smaller cones. Microdiamond slightly overestimates OF, 3.7% for all the cones and EBT3 film is the closest to MC with maximum difference ±1% whatever the cone size. Film is the more accurate detector for OF determination of stereotactic cones but it is restrictive to use. Pinpoints and diodes, respectively due to inappropriate size of sensitive volume and composition do not seem appropriate without corrective factors below 10 mm diameter cone. Microdiamond appears the best detector for all cones despite its sensitive volume size.

OBJECTIVEThe goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk.METHODSIn this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma.RESULTSFor gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal.CONCLUSIONSWhen a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management.■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

This text deals with the relationships between land transactions and the formalization of land rights in a Malagasy context, exploring the local procedures aiming at securing land transactions, while putting them in perspective with the legal formalization of land rights through land certification. Our research shows that (i) transactions are far from being limited to legally recorded plots of land, (ii) the local extra-legal procedures for formalizing transactions are highly standardized, (iii) the buyer’s choice regarding the way to secure the transaction varies according to his relation with the seller and to the type of document that previously secured the seller’s property rights on the plot, and (iv) rather than a substitute, the plot certificate comes as a complement, an ‘additional layer’, to local sales contracts formalization.

The paper deals with the professional dynamics of young farmers in Saharan neo-agriculture in Algeria, in the case of plasticulture (market gardening under plastic tunnels). Our analysis is based on a survey of 100 farmers in the municipality of El Ghrous (Biskra) and is illuminated by the literature on clusters (geographical concentrations of companies in the same sector) and on the agricultural ladder (a contractual trajectory allowing the accumulation of know-how and various types of capital). These dynamics result from the external benefits of the cluster that has emerged in the sector, and from the divisibility of the factors (water, land, greenhouses, agricultural inputs, and labor) in this type of production, which facilitates the installation of young farmers. Progress up the agricultural ladder should be read in conjunction with the existence of contractual arrangements regarding access to labor, land, and water.

The treatment of acromegaly is based on surgery, drugs, and radiotherapy as a third-line option. Fractionated stereotactic radiotherapy (FSRT) is a new technique with a need for long-term evaluation. The purpose of the study was to evaluate long-term results of FSRT in acromegaly. Overall, 34 patients [sex ratio 1.12, age 45 (5–65) years] with a pituitary adenoma of 24.5 (9–76) mm including 20 invasive tumors were treated by radiotherapy in fractionated stereotactic conditions delivering 50 gy in 27 sessions. Baseline growth hormone (GH) and IGF1 levels were 18 (±14.5) and 632.6 (±339) µg/L, respectively. Indications of FSRT were failure of surgery and drug treatments (n = 30) or contraindication/refusal of surgery (n = 4). Hormonal control was defined by normal age- and sex-adjusted IGF1. Remission was defined by hormonal control after withdrawal of drugs for a minimum of three consecutive months. Data were analyzed in SPSS software with a significance level at p

Stereotactic radiotherapy of brain metastases is increasingly proposed after polydisciplinary debates among experts. Its definition and modalities of prescription, indications and clinical interest regarding the balance between efficacy versus toxicity need to be discussed. Stereotactic radiotherapy is a 'high precision' irradiation technique (within 1mm), using different machines (with invasive contention or frameless, photons X or gamma) delivering high doses (4 to 25Gy) in a limited number of fractions (usually 1 to 5, ten maximum) with a high dose gradient. Dose prescription will depend on materials, dose constraints to organs at risk varying with fractionation. Stereotactic radiotherapy may be proposed: (1) in combination with whole brain radiotherapy with the goal of increasing (modestly) overall survival of patients with a good performance status, 1 to 3 brain metastases and a controlled extracranial disease; (2) for recurrence of 1-3 brain metastases after whole brain radiotherapy; (3) after complete resection of a large and/or symptomatic brain metastases; (4) after diagnosis of 3-5 asymptomatic new or progressing brain metastases during systemic therapy, with the aim of delaying whole brain radiotherapy (avoiding its potential neurotoxicity) and maintaining a high focal control rate. Only a strict follow-up with clinical and MRI every 3 months will permit to deliver iterative stereotactic radiotherapies without jeopardizing survival. Simultaneous delivering of stereotactic radiotherapy with targeted medicines should be carefully discussed.

Object The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed. Methods Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age ≥ 18 years at diagnosis, histological diagnosis of WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value ≤ 0.1) were included in the multivariate Cox proportional hazard regression model analysis. Results At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were an age ≥ 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a greater extent of resection. Conclusions This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.

International audience; Background - Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort.Methods - We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014.Results - Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs Conclusions - About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.

IntroductionAtypical and malignant meningiomas are a rare disease whose histological definition is still recent. Their management is not consensual. The aim of this study was to review the outcome, prognostic factors and the role of complementary therapies.Patients and methodsBetween 1999 and 2007, 36 patients with atypical or malignant meningiomas were managed in our hospital. All surgical specimens were reviewed according to the 2007 WHO classification system. The sex ratio was 1.25 male, the median age was 59 years. The median follow-up was 55 months. Thirty meningiomas were atypical and six were malignant.ResultsFive and 10 years overall survival rate are respectively 72 and 41%, whereas 5 and 10 years progression free survival rate are 61 and 23%. We only identify female sex, age over 70 years and Karnofsky status under 70% as negative prognostic factors.ConclusionAtypical and malignant meningiomas are difficult to manage and have high recurrence and poor survival rates. The prognostic of OMS II meningiomas is heterogeneous. Adjuvant radiation therapy is recommended in case of malignant menigioma or in case of atypical meningioma if incomplete surgical excision is performed.RésuméIntroductionLes méningiomes atypiques et malins sont une pathologie rare dont la définition histologique est encore récente. Leur prise en charge n’est pas consensuelle. Le but de notre étude est d’analyser le devenir, les facteurs pronostiques et le rôle des traitements complémentaires.Patients et méthodesL’étude a été menée de façon rétrospective au sujet de 36 patients présentant un méningiome atypique ou anaplasique pris en charge consécutivement entre 1999 et 2007 dans le service de neurochirurgie de Reims. Le diagnostic histologique a été établi selon les critères de la classification OMS de 2007. Le sex-ratio est 1,25 (H/F) et l’âge moyen 59ans. Sur les 36 méningiomes étudiés, 30 sont atypiques (OMS II) et six sont malins (OMS III). Le suivi médian est de 55 mois.RésultatsPour l’ensemble de la série, les taux de survie globale à cinq et dix ans sont respectivement de 72 et 41 %. Les taux de survie sans récidive à cinq et dix ans sont de 61 et 23 %. En analyse univariée, ces taux de survie sont influencés péjorativement par le sexe féminin, un âge supérieur à 70ans et un index de performance de Karnofsky inférieur à 70.ConclusionCette étude rétrospective monocentrique confirme le fort potentiel récidivant et le pronostic péjoratif des méningiomes atypiques et anaplasiques. Elle retrouve une hétérogénéité de pronostic au sein des méningiomes de grade OMS II.

Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity.This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm.Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted.This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France.

Background: This prospective multicentric phase II study aimed to confirm the results of the C5R protocol of high-dose methotrexate (MTX)-based chemotherapy (CT) for immunocompetent primary central nervous system lymphoma. Patients and methods: A total of 99 patients received age-adapted CT (C5R protocol) followed by radiotherapy. Patients younger than 61 years (group 1, n = 45) received the full C5R with MTX, doxorubicin, vincristine, cyclophosphamide, and cytarabine. Patients aged 61-70 years (group 2, n = 36) received reduced doses. Patients older than 70 years (group 3, n = 18) received four courses of MTX, cyclophosphamide, and etoposide. Results: Median age was 63 years and 51% of patients had performance status of more than one. Seventeen patients died of toxicity during CT. Complete response was achieved in 56%, 53%, and 28% of patients in groups 1, 2, and 3, respectively. With a median follow-up of 83 months, the 5-year progression-free survival was 31%, 28%, and 11% and the 5-year overall survival 42%, 31%, and 17% for groups 1, 2, and 3, respectively. Leukoencephalopathy occurred in 32% of assessable patients, in both group 1 and groups 2-3. Conclusion: The C5R protocol was feasible in the multicentric setting with favorable long-term survival in patients younger than 60 years. Despite dose adaptation, results in older patients were disappointing.

Resume Les meningiomes de la gaine du nerf optique representent un tiers des tumeurs du nerf optique, 1 a 2 % des meningiomes et enfin 2 a 3,5 % des tumeurs orbitaires. La baisse de l’acuite visuelle domine le tableau clinique. Le diagnostic est facilement evoque apres realisation du bilan neuroradiologique. Le traitement consacre est depuis peu la radiotherapie fractionnee en conditions stereotaxiques (RSF). Elle permet de facon optimale le respect de l’acuite visuelle et le controle du volume tumoral.

Purpose This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. Patients and Methods Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). Results Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. Conclusion The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.

[Departement_IRSTEA]GT [TR1_IRSTEA]RURAMEN / AMANDE; Following the implementation of the land reform in the 1990's, land rentals have developed in Romania, mainly in a reverse tenancy configuration. The paper provides an analysis of contractual practices in this configuration, based on empirical data collected through intensive field work in Transylvania. The paper depicts the reverse tenancy configuration and the conditions of its emergence in Romania, following the implementation of transition reforms in the agricultural sector. Characterizing the negotiation and enforcement of contracts in this configuration shows that in a situation where no effective enforcement mechanism is available, the market structure is such that tenants can choose very incomplete contracts or default on their contractual obligations. The analysis of the landowners' perspective, taking into account their perception of the contractual relationship contributes to explain why contractual practices persist in this context. The article concludes with a discussion, from a policy perspective, of the equity-enhancing role of the land lease market in such this reverse tenancy configuration.

Optic nerve sheath meningioma (ONSM) accounts for one-third of primary optic nerve tumors, and 2% of all meningiomas. ONSM must be distinguished from other meningiomas, in particular from cavernous meningiomas because of the different prognosis and treatment. The most frequent clinical sign is a progressive or sudden unilateral visual loss. Treatment of ONSM is still subject to discussion. This report covers a series of eight ONSM patients treated with fractionated stereotactic radiotherapy. Material and methods Between 2000 and 2006, we managed eight patients with ONSM. The average patient age was 47 years. There were five women and three men. The most frequent clinical signs were visual loss (100%), proptosis (35%), diplopia (25%). One patient was initially treated with surgery. All patient have been treated by fractionated stereotactic radiotherapy. 45 Gy in 25 fractions were delivered on the meningioma area at a rate of 5 fractions of 1.8 Gy per week. We used a Brainlab ® framework associated with a thermo-formed mask. A computed tomography then magnetic resonance imaging was obtained for each patient. The data was merged and planning took place on a Brainlab ® dosimetric console. The treatment was performed with a head-only Varion linear accelerator, with a Brainlab ® multi-blade collimator. Results The average follow-up was 27 months. Each patient had a complete radiological and ophthalmologic exam every 3 months during the first year, then every 6 months thereafter. Tumor control rate was 100%. Vision was re-established in five patients and three patients had improvement, including one patient during treatment. 100% of proptosis and diplopias regressed. No side effect was reported. Conclusion This is still a preliminary study, but the results suggest that fractionated stereotactic radiotherapy may emerge as a primary treatment for ONSM, delaying surgery, which has proven functionally disappointing.

To optimize and reduce the toxicity of pituitary adenoma irradiation by assessing the feasibility and effectiveness of fractionated stereotactic radiotherapy (FSR).Between 1990 and 1999, 110 consecutive patients, 47 with a functioning adenoma, were treated according to a strategy of either early surgery and FSR (n = 89) or FSR only (n = 21). Of the 110 patients, 75 had persistent macroscopic tumor and 47 persistent hormonal secretions; 15 were treated in the prophylactic setting. The linear accelerator-delivered dose was 50.4 Gy (5 x 1.8 Gy weekly), with a 2-mm safety margin.After a minimal follow-up of 48 months, only 1 patient had developed progression. Of the 110 patients, 27 (36%) had a complete tumor response, 67 (89.3%) had an objective tumor response, 20 (42%) had a hormonal complete response, and 47 (100%) had a hormonal objective tumor response. The proportion of patients without a complete tumor response, objective tumor response, complete hormonal response, and objective hormonal response was 85.1%, 62%, 83%, and 59.3% at 4 years and 49.3%, 9%, 59.3%, and 10.6% at 8 years, respectively. The sole unfavorable predictive factor was preoperative SSE20 mm for tumor response (p = 0.01) and growth hormone adenoma for the hormonal response (p0.001). No late complications, except for pituitary deficiency, were reported, with a probability of requiring hormonal replacement of 28.5% and 35% at 4 and 8 years, respectively. Nonfunctioning status was the sole unfavorable factor (p = 0.0016).Surgery plus FSR is safe and effective. FSR focused to the target volume seems more suitable than standard radiotherapy, and standard fractionation reduces the risk of optic neuropathy sometimes observed after single-dose radiosurgery. Therefore, FSR allows us to consider combined transrhinoseptal surgery and early radiotherapy, with a curative goal without patient selection.

Within the overall STTIS (Science Teacher Training in an Information Society) framework, this paper focuses on transformations of innovative teaching of optics, following a recommended change of approach to optics in the French curriculum. The empirical investigation of how teachers responded to this change, the main results of which are briefly presented here, identified a crucial aspect of the problem. This is the importance of “critical detail'': that is, the fact that the linkage between certain critical details of practice and the fundamental rationale of a teaching sequence is often not easily understood by teachers, even those who are strongly motivated. The paper then discusses the development of guidelines for the design of training materials based on these research findings, which show how teachers typically tend to transform innovations when putting them into practice. We describe the rationale behind and structure of some teacher training materials intended to facilitate awareness and mastery in this respect. © 2004 Wiley Periodicals, Inc. Sci Ed89:13–27, 2005

This paper focuses on difficulties students have in reading images, regarding the understanding of a particular domain, e.g. optics and colour. We concentrated upon what extent teachers were conscious of such difficulties and what they suggested doing to avoid possible pitfalls in this respect. A list of expected obstacles, set up to initiate the study, was shown to be appropriate. It shows that, when they predicted or observed a misunderstanding, the consulted teachers tended to add some elements to a misleading image rather than discussing the symbols that were used, their more or less realistic status and their possible ambiguity. Implications for teacher training and the design of innovative sequences are briefly discussed.

PURPOSE: To evaluate prospectively the feasibility and efficacy of early intensive therapy, including intensified cytoreductive chemotherapy (CT) and high-dose CT (HDCT) followed by autologous stem-cell transplantation (ASCT), in patients with advanced Hodgkin’s disease (HD) who failed to respond completely or relapsed after initial treatment. PATIENTS AND METHODS: Among 533 eligible patients with newly diagnosed stage IIIB-IV HD enrolled in the H89 trial, all 157 patients with induction failure (IF) (n = 67), partial response (PR) of less than 75% (n = 22), or relapse (n = 68) were included in this study. Planned salvage therapy included mitoguazone, ifosfamide, vinorelbine, and etoposide monthly for two to three cycles followed by high-dose carmustine, etoposide, cytarabine, and melphalan with ASCT. RESULTS: With a median follow-up of 50 months, the 5-year survival estimates were 30%, 72%, and 76% for the IF, PR, and relapse groups, respectively (P = .0001), 71% for the 101 patients given HDCT, and 32% for the 48 patients treated without HDCT (P = .0001). Multivariate analysis using time-dependent Cox model indicated that B symptoms at progression, salvage without HDCT, and chemoresistant disease before HDCT were significantly associated with shorter overall survival. CONCLUSION: Early intensive therapy improves the outcomes of patients with advanced HD who failed to respond completely to initial treatment and those who relapsed with adverse prognostic factors. However, for patients with IF and chemoresistant disease, this approach remains unsatisfactory.

This paper focuses on difficulties linked to situations in physics involving two models: geometrical optics and wave optics. The starting point is an investigation of university-level students’ difficulties. Excerpts from textbooks are given, to illustrate potential difficulties. A content analysis is then presented, underlining two important features required for dealing with such situations: awareness of the status of the drawings, and the “backward selection” of paths of light. These features could provide some guidelines for the designing of innovative teaching strategies.

The aim of this randomized open-label study was to compare a bimonthly with a monthly regimen of 5-fluorouracil (5-FU) and leucovorin for the adjuvant treatment of colon and high-rectum adenocarcinoma. The bimonthly regimen was administered for 2 consecutive days every 14 days as d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 as a 2-hour infusion followed by 5-FU bolus of 400 mg/m2 and a 600 mg/m2 5-FU 22-hour continuous infusion (LVSFU2). In the monthly regimen, d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 15-minute infusion followed by a 400 mg/m2 15 minute 5-FU bolus was administered for 5 consecutive days every 28 days (FUFOL). Nine hundred five patients with recently resected stage B2 or C colon or high-rectum adenocarcinoma (inferior pole of the tumor subperitoneal) were recruited into the study. Patients were randomized in a 2 x 2 factorial design to receive either LV5FU2 or FUFOL for 24 or 36 weeks. Characteristics of the patients in the two different treatment groups were similar at baseline. Compliance was good. Mean 5-FU dose intensities were 930 mg/ m2/wk and 463 mg/m2/wk for LVSFU2 and FUFOL, respectively. The incidence of maximal grade III-IV toxicities for LVSFU2 and FUFOL was neutropenia 6% and 16% (P < .001), diarrhea 4% and 10% (P < .001), and mucositis 2% and 7% (P < .001), respectively. Maximum grade III-IV toxicities in the LV5FU2 treatment group were significantly lower than in the FUFOL group (10% v 26%; P < .001). Although patients in the LV5FU2 group received twice the dose of 5-FU compared with those in the FUFOL group, LV5FU2 was shown to be less toxic. Efficacy data will be available in 2001.

BACKGROUND The prognostic impact of large mediastinal involvement (mediastinum/thorax [M/T] ratio > 0.33) in advanced Hodgkin disease (HD) and the optimal treatment with chemotherapy or combined treatment remains controversial. METHODS Among 533 assessable patients with Ann Arbor Stage IIIB/IV HD included in the H89 trial, 82 had large mediastinal mass defined on chest X-ray. All patients received induction with six cycles of chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone–doxorubicin, bleomycin, vinblastine or doxorubicin, vinblastine, bleomycin, procarbazine, prednisone); then complete and good partial responders were randomized between two consolidation treatments: 2 cycles of the same chemotherapy or (sub)total lymph node irradiation. RESULTS Among 82 patients with an M/T ratio greater than 0.33, 48 were very large (ratio > 0.45). A large mediastinal mass was associated with supradiaphragmatic disease, younger age, histologic nodular sclerosis, and different sex ratio compared with other H89 trial patients. Biologic parameters and prognostic factors were similar for both groups. Although the major response rate to induction chemotherapy (after 6 cycles) was lower for patients with large mediastinal mass (78% vs. 86%), the 5-year overall survival rate (80% vs. 79%) and event free survival rate (59% vs. 61%) were similar (P = 0.64 and 0.3, respectively). The outcome was the same for patients (74%) with a large mediastinal mass randomized to 1 of the 2 consolidation arms. Analysis of progression showed that 68% (21 of 31) of failures occurred early during treatment and involved the mediastinum in 86% of the cases. CONCLUSIONS For patients with large mediastinal mass and advanced HD who achieved a major response of at least 75% after 6 cycles of chemotherapy, a consolidation radiation therapy can be replaced by 2 additional cycles of chemotherapy. Cancer 2001;92:453–9. © 2001 American Cancer Society.

The paper highlights the great diversity of economic research on agricultural systems, through the presentation of selected approaches: modern farm management, farming systems research, agricultural household economics, French Africanist rural economics, and behavioral and multidisciplinary systems studies. Major differences among these studies are highlighted, in terms of research aims, organization and issues, type of “systemic” approach followed, theoretical framework, use of formal modeling, and the role of fieldwork. Trends in popularity of the different research types are discussed. The authors recommend integrating an institutional perspective in economic research on agricultural systems and broadening the research agenda.

Resume Objectif de l'etude. — Mise au point pour optimiser l'irradiation des tumeurs cerebrales benignes, la technique de radiotherapie stereotaxique fractionnee permet l'irradiation d'un volume reduit (2, 1 cm3 ; 16 mm de diametre) avec un fractionnement standard. Les resultats d'une analyse retrospective multicentrique sont presentes. Materiel et methodes. — La radiotherapie stereotaxique fractionnee utilise les principes balistiques et dosimetriques de la radiochirurgie : reperage stereotaxique, irradiation par multifaisceaux, collimation secondaire, dosimetrie tridimensionnelle. Le fractionnement est rendu possible par l'utilisation d'un dispositif stereotaxique non invasif et repositionnable. La technique a ete utilisee pour traiter des adenomes hypophysaires (86 patients), des neurinomes de l'acoustique (32 patients), et des meningiomes du sinus caverneux (26 patients). Resultats. — Adenomes hypophysaires: les taux cumules de reponse objective tumorale (42 patients) etaient respectivement de 42 %, 69 % et 88 % a 24, 48 et 60 mois. Les taux cumules de reponse objective hormonale (32 patients) etaient respectivement de 53 %, 75 % et 85 % a 24, 48 et 60 mois. Le risque cumule d'insuffisance hypophysaire radio-induite variait de 18 % pour la GH a 42 % pour la TSH a 48 mois. Aucune autre complication n'a ete energistree. Neurinomes de l'acoustique : 33 tumeurs de diametre inferieur a 25 mm ont ete traitees chez 32 patients. Le controle tumoral a ete assure pour 29 des 33 tumeurs : 14 stabilisations, 15 regressions et trois progressions. Une audition utile a pu etre maintenue chez neuf des dix patients. Seuls trois patients (9 %) avaient une complication persistante. Meningiome du sinus caverneux: il a ete note 17 reponses cliniques sur 19, 20 stabilisations tumorales, une reponse partielle et une progression (22 patients evaluables par IRM). Une cecite unilaterale radio-induite a ete observee. Conclusion. — Pour ces tumeurs benignes, la reduction du volume irradie obtenue par radiotherapie stereotaxique fractionnee semble plus adaptee au traitement des tumeurs benignes de petit volume que la radiotherapie standard. Le fractionnement de la dose reduit le risque de lesion severe des tissus sains en comparaison avec la radiochirurgie qui delivre une dose unique elevee.

Objective: To study the prognostic impact of O 6 -methylguanine-DNA methyltransferase (MGMT) on newly diagnosed glioblastoma patients being treated with carmustine-releasing wafers (Gliadel®) along with temozolomide (TMZ). Background MGMT promoter methylation status was proposed as a prognostic biomarker for glioblastoma patients. However, the prognostic impact of MGMT on newly diagnosed glioblastoma patients treated using surgical resection and Gliadel® implants followed by Stupp9s protocol is still unknown. Design/Methods: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received Gliadel® followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy, while being enrolled in a French multicenter prospective study. Results: For the whole cohort, median overall survival (OS) and progression-free survival (PFS) were 17.5 and 10.3 months, respectively. Patients with tumors harboring MGMT methylation displayed a significantly longer OS compared to those with wild-type MGMT (21.7 vs . 15.1 months, p=0.025). Similarly, patients with low MGMT protein expression (≤15%) exhibited significantly improved OS compared to those with high MGMT expression (27.0 vs. 15.1 months, p=0.021). The extent of resection was the strongest clinical outcome predictor. In multivariate Cox models adjusted for gender, performance status, and extent of surgery, both MGMT methylation and protein expression were found to be independent prognosticators, which was internally validated using bootstrap resampling techniques. However, no significant correlation was found between protein expression and MGMT methylation status, thus suggesting that the two assays probably assess different biological features. Conclusions: MGMT promoter methylation status and low MGMT expression were both found to be positive prognosticators in newly diagnosed glioblastoma patients treated using surgical resection and Gliadel® implants followed by Stupp9s protocol. Disclosure: Dr. Guillamo has nothing to disclose. Dr. Levallet has nothing to disclose. Dr. Dugue has nothing to disclose. Dr. Vital has nothing to disclose. Dr. Diebold has nothing to disclose. Dr. Menei has nothing to disclose. Dr. Colin has nothing to disclose. Dr. Peruzzy has nothing to disclose. Dr. Emery has nothing to disclose. Dr. Bernaudin has nothing to disclose. Dr. Chapon has nothing to disclose. Dr. Lechapt-Zalcman has nothing to disclose.

Purpose To evaluate long-term outcomes and efficacy of fractionated stereotactic radiotherapy in the treatment of acoustic neuromas. Material and methods Between January 1996 and December 2009, 158 acoustic neuromas were treated by FSR in 155 patients. They received a dose of 50.4Gy, with a safety margin of 1–2mm with a median tumor volume at 2.45mL (range: 0.17–12.5mL) and a median follow-up duration at 60months (range: 24–192). Results FSR was well tolerated in all patients with mild sequelae consisting in radiation-induced trigeminal nerve impairments (3.2%), Grade 2 facial neuropathies (2.5%), new or aggravated tinnitus (2.1%) and VP shunting (2.5%). The treatment failed in four patients (2.5%) who had subsequent surgery respectively at 20, 38, 45 and 84months post-FSR. The local tumor control rates were respectively 99.3%, 97.5% and 95.2% at 3, 5 and >7-year of follow-up. For initial Gardner–Robertson Grade 1 and 2 ANs, the preservation of useful hearing was possible in 54% of the cases; only Grade 1 ANs had stabilized during the course of the follow-up with 71% >7years. However, hearing preservation was not correlated to the initial Koos Stage and to the radiation dose delivered to the cochlea. Tinnitus (70%), vertigo (59%), imbalance (46%) and ear mastoid pain (43%) had greatly improved post-FRS in most patients. Tumor control, hearing preservation and FRS toxicity were quite similar in patients with NF2, cystic acoustic neuroma, prior surgical resection and Koos Stage 4 AN. No secondary tumors were observed. Conclusion FSR is a safe and effective therapeutic for acoustic neuromas and could be an alternative to microsurgery. Compared to radiosurgery, there are no contraindications for fractioned doses of stereotactic radiotherapy especially for Stage-4 tumors and patients at high risk of hearing loss.

Purpose We discuss our experiences with fractionated stereotactic radiotherapy (FSR) in the treatment of cavernous sinus meningiomas. Methods and Materials From 1995 to 2006, we monitored 100 patients diagnosed with cavernous sinus meningiomas; 84 female and 16 male patients were included. The mean patient age was 56 years. The most common symptoms were a reduction in visual acuity (57%), diplopia (50%), exophthalmy (30%), and trigeminal neuralgia (34%). Surgery was initially performed on 26 patients. All patients were treated with FSR. A total of 45 Gy was administered to the lesion, with 5 fractions of 1.8 Gy completed each week. Patient treatment was performed using a Varian Clinac linear accelerator used for cranial treatments and a micro-multileaf collimator. Results No side effects were reported. Mean follow-up period was 33 months, with 20% of patients undergoing follow-up evaluation of more than 4 years later. The tumor control rate at 3 years was 94%. Three patients required microsurgical intervention because FSR proved ineffective. In terms of functional symptoms, an 81% improvement was observed in patients suffering from exophthalmy, with 46% of these patients being restored to full health. A 52% improvement was observed in diplopia, together with a 67% improvement in visual acuity and a 50% improvement in type V neuropathy. Conclusions FSR facilitates tumor control, either as an initial treatment option or in combination with microsurgery. In addition to being a safe procedure with few side effects, FSR offers the significant benefit of superior functional outcomes.

BACKGROUND. Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study. METHODS. In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS. A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients ≤75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population. CONCLUSIONS. The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population. Cancer 2007. © 2007 American Cancer Society.

Purpose This randomized, 2 × 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer. Patients and Methods LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m2) as a 2-hour infusion, followed by 400 mg/m2 FU bolus and a 600-mg/m2 FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m2 FU 15-minute infusion. The primary end point was disease-free survival (DFS). Results Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, ≥ 2 years; log-rank test for trend P, .0497). Conclusion DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

Background There is no community standard for the treatment of glioblastoma in patients 70 years of age or older. We conducted a randomized trial that compared radiotherapy and supportive care with supportive care alone in such patients. Methods Patients 70 years of age or older with a newly diagnosed anaplastic astrocytoma or glioblastoma and a Karnofsky performance score of 70 or higher were randomly assigned to receive supportive care only or supportive care plus radiotherapy (focal radiation in daily fractions of 1.8 Gy given 5 days per week, for a total dose of 50 Gy). The primary end point was overall survival; secondary end points were progressionfree survival, tolerance of radiotherapy, health-related quality of life, and cognition. Results We randomly assigned 85 patients from 10 centers to receive either radiotherapy and supportive care or supportive care alone. The trial was discontinued at the first interim analysis, which showed that with a preset boundary of efficacy, radiotherapy and supportive care were superior to supportive care alone. A final analysis was carried out for the 81 patients with glioblastoma (median age, 73 years; range, 70 to 85). At a median follow-up of 21 weeks, the median survival for the 39 patients who received radiotherapy plus supportive care was 29.1 weeks, as compared with 16.9 weeks for the 42 patients who received supportive care alone. The hazard ratio for death in the radiotherapy group was 0.47 (95% confidence interval, 0.29 to 0.76; P = 0.002). There were no severe adverse events related to radiotherapy. The results of quality-of-life and cognitive evaluations over time did not differ significantly between the treatment groups. Conclusions Radiotherapy results in a modest improvement in survival, without reducing the quality of life or cognition, in elderly patients with glioblastoma. (ClinicalTrials.gov number, NCT00430911.)

Cet article traite des rapports entre la dynamique d'exploitation du milieu et l'émergence et l'évolution des droits sur la terre en pays yambassa, au Cameroun. Le pays yambassa, au contact entre la forêt tropicale humide et la savane, se caractérise par une situation d'abondance foncière et par la présence de bosquets forestiers de création anthropique. Notre étude se base sur une enquête agrofoncière et agro-économique approfondie de la zone. Trois axes de recherche sont privilégiés : (i) les implications d’une mise en place originale de la végétation forestière, développée autour des premières habitations en savane, déterminant une émergence et une évolution particulière des droits de propriété sur ces terrains; (ii) l’évolution des dynamiques foncières caractérisées par le nouvel enjeu que représente l'appropriation des terres libres en savane, en réponse aux évolutions techniques et économiques du système de production agricole; et (iii) l’émergence timide d’une marchandisation des terres de savane, terrains pourtant soumis à une pression foncière modérée comparativement aux terres de forêt., This article deals with the relationship between the dynamics of resource use and the emergence and evolution of rights to land in Yambassa country, Cameroon. The Yambassa country, at the contact between tropical forest and savannah, is characterized by a situation of land abundance and the presence of man-made forest thickets. Our study is based on a thorough study of the land and agroeconomic situations in the zone. Three research orientations are privileged: (i) implications of the particular origin of the forest vegetation, developed around the first dwellings in the savannah and determining original emergence and evolution schemes of ownership rights on these grounds; (ii) evolution of the agricultural dynamics characterized by the new stake associated with appropriation of the unoccupied savannah land, in response to the technical and economic evolutions of the agricultural production system; and (iii) the timid emergence of a land market for savannah grounds, although it is subject to a moderate land pressure compared to forest land.

This paper focuses on difficulties linked to physical situations implying two models: geometrical optics and wave optics. The starting point is an investigation of students’ difficulties, at university level, in this respect. A content analysis is presented, that underlines two main features required in order to deal with such situations: ≪backward selection≫ of paths of light and awareness of the status of the drawings. Teachers’ viewpoints, collected through ten interviews, concerning students’ difficulties as well as various possible presentations of the contents, make it possible to infer some likely obstacles and possible facilitating factors in the communication of an innovative teaching process in line with our content analysis. The paper ends in a discussion of such a ≪bridging≫ approach for the design of research-based teaching programmes.

Purpose In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B). Patients and Methods Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m2 or dl-LV 400 mg/m2 followed by a FU bolus 400 mg/m2 and 46-hour infusion 2,400 to 3,000 mg/m2 every 46 hours every 2 weeks, either with irinotecan 180 mg/m2 or with oxaliplatin 100 mg/m2 as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B). Results Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P = .99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P = .64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P = .26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6. Conclusion Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.

Purpose: This randomized, 2 × 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes’ B2) and III (Dukes’ C) colon cancer. Patients and Methods: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. Results: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P = .74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P = .63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P = .18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P < .001). Conclusion: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.

A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy.From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis.Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively.In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Summary Background Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin–5-FU and gemcitabine combination. Patients and methods This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m2 in a two-hour infusion, followed by 5-fluorouracil 400 mg/m2 bolus and 2 or 3 g/m2 continuous infusion over 46 hours; gemcitabine 1 g/m2 was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m2 every two cycles up to 1500 mg/m2) in the absence of NCI-CTC toxicity > 2. Results Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%–37.8%) and 22.6% (95% CI: 12%–33.2%) in the intent-to-treat population; the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression- free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3–4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. Conclusions Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.

PURPOSE To conduct a multicenter phase II study of a concomitant combination of chemotherapy and radiotherapy followed by surgery, where feasible, in patients with nonmetastatic esophageal tumor, stratified on operability at diagnosis. METHODS Each cycle consisted of fluorouracil (5FU) 800 mg/m2/d by continuous intravenous (IV) infusion on days 1 to 5, cisplatin (CDDP) 50 mg/m2/d IV bolus on days 1 and 8, hydroxyurea (HU) 1.5 or 2 g/d orally on days 8 to 12 and concomitant radiotherapy 20 Gy in 10 fractions over 12 days. All patients were to receive two cycles on days 1 and 22. If feasible, surgery was performed 3 to 6 weeks after cycle two completion. Otherwise, a third cycle was administered. RESULTS Eighty-eight patients were included between September 1990 and September 1993. Of the 47 operable patients, 41 (87%) underwent surgery and 38 (81%) had a complete resection. No residual primary tumor was found in the surgical specimen in 17 cases (36%), and only microscopic foci in 13 (28%). Two-year overall and disease-free survival probabilities were 51% (95% confidence interval [CI]; 37 to 65) and 43% (95% CI, 28 to 57), respectively. Among the 41 inoperable patients, 12 (29%) became operable. Seven (17%) had complete resection, two incomplete resection, and three exploratory surgery. Two-year overall and disease-free survival probabilities were 29% (95% CI, 15 to 43) and 27% (95% CI, 13 to 40), respectively. Five deaths occurred during chemoradiotherapy, six postoperatively and four in patients with evidence of cancer. Five late complications (one myelopathy) were observed. CONCLUSION Despite a high histologic response rate in initially operable patients, overall survival was similar to that observed in other preoperative chemoradiation series because of substantial toxicity.

7112 Background: Local control rate of LA-NSCLC seems better after concurrent CCR than after sequential schedule; the role of additional chemotherapy is not clearly defined. A multi-institutional phase-III trial was conducted to evaluate the role of chemotherapy consolidation after CCR Methods: Eligibility criteria included mediastinoscopy-controlled unresectable NSCLC stage IIIA (27%) - IIIB (59%) and inoperable mediastinal recurrence after surgery (14%), PS < 3, clinical target volume compatible with a minimal 60 Gy dose radiation. After registration, patients (pts) were treated with combination of weekly P (45 mg/m2), C (AUC 2), and radiotherapy 60–66 Gy (5 × 2 Gy per week). The pts with response or stable disease were randomized either to receive 3 cycles of P (175 mg/m2) and C (AUC 5) consolidation on days 1–22–43 or observation. Primary endpoint was OS (log-rank test), planned sample was 122 pts. Results: Actually, 71 pts were enrolled. Thirty pts (42%) were not randomized because of progression (22%) and disease-related death (22%), toxicity (26%), refusal (9%), protocol violation (21%). Toxicity grade 3–4 per patient: for the PC-TRT sequence; neutropenia 5%, febrile neutropenia 5%, thrombopenia 5%, pneumonitis 5%, oesophagitis 19%. For the PC consolidation sequence; neutropenia 24%, febrile neutropenia 6%, thrombopenia 0% (no treatment-related death). After a minimal follow-up of 3 years, despite poor inclusion rate, OS and PFS were greater in the PC consolidation group with 3-year OS: 29.9% vs 10% (HR = 0.45; CI 0.95: 0.22–0.91) (p = 0.002) and 3-year PFS: 27.8% vs 10% (HR = 0.6; CI 0.95: 0.3–1.3) (p = 0.17). Nine pts developed metastasis in each treatment arm. Conclusions: The addition of PC consolidation to PC-CCR is not easily feasible for all LA-NSCLC. For selected pts (only 58% of pts in this trial), despite premature ending of the trial because of slow accrual, PC consolidation significantly improved the 3-year OS and probably PFS. Because no difference in the metastatic incidence was observed, the effect of chemotherapy dosage in the consolidation arm could be explained by delaying metastasis. No significant financial relationships to disclose.