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Resume Objectif: Le nombre de femmes victimes d’agression sexuelle reste eleve, malgre les campagnes de prevention et d’information. Ces victimes peuvent etre des adolescentes, des femmes en âge de procreer ou des femmes menopausees. Dans le cadre des examens de victimes d’agression sexuelle, la diversite morpho-anatomique de l’appareil genital feminin impose une connaissance des variations physiologiques existantes par les praticiens prenant en charge ces victimes. Notre travail avait pour objectif de decrire et de caracteriser l’examen genital des femmes ayant une activite sexuelle consentie. Methode: Notre cohorte etait constituee de 196 femmes âgees de 14 a 81 ans, examinees dans le cadre de consultations de gynecologie medicale de deux maternites francaises. Resultats: Les lesions traumatiques genitales d’allure recente etaient retrouvees chez 12,8% des femmes dont le dernier rapport sexuel datait de moins de 5 jours. Les hymens intacts, indemnes de dechirure traumatique malgre une activite sexuelle reguliere, etaient presents chez 10,7% de ces femmes. Conclusion: Ainsi, dans de nombreux cas, l’examen genital seul ne permet ni d’affirmer, ni d’infirmer l’existence d’un rapport sexuel anterieur, qu’il soit ou non consenti. Le developpement de travaux sur les donnees de l’anatomie genitale feminine, permettrait d’optimiser la prise en charge medico-legale des victimes d’agression sexuelle.

Introduction Des facteurs cliniques et biologiques associés à des formes graves de l’infection à SARS-CoV-2 ont été publiés dans le monde entier. Dans notre département, un cluster urbain composé principalement d’une population gitane a rapidement émergé. L’objectif de l’étude est de décrire ce cluster et de mettre en évidence les facteurs associés aux formes graves de COVID-19. Matériels et méthodes Du 11/03 au 17/04/2020, une étude rétrospective observationnelle a été menée dans notre centre hospitalier. Étaient inclus les patients avec un diagnostic de COVID-19 confirmé par PCR ou présumé sur un faisceau d’argument cliniques, biologiques et radiologiques. Ils appartenaient à un cluster défini par la localisation géographique de leur lieu de résidence. Les données anamnestiques, cliniques et biologiques ont été recueillies et analysées à partir des dossiers médicaux. Résultats Quatre-vingt-dix-sept patients ont été inclus, dont 61 (62,9 %) avaient une PCR positive. L’âge médian était de 52 ans (IQR : 43–70), 31 (32 %) étaient des hommes. Soixante-quatorze patients (79,6 %) étaient obèses (IMC > 30), 46 (47,4 %) étaient diabétiques et 56 (57,7 %) avaient une HTA. La fièvre, la toux et la dyspnée étaient les symptômes les plus fréquemment rapportés par respectivement 80 (82,5 %), 79 (81,4 %) et 71 (73,2 %) patients. Quatre-vingt-un (83,5 %) étaient lymphopéniques avec un taux médian de 1150c/mm3 (IQR : 800–1410). La CRP médiane était de 80 mg/L (IQR : 36–149). Trois quarts des patients ont eu une TDM thoracique, 100 % étaient évocateurs de COVID-19 dont 24 (34,7 %) avec une atteinte supérieure à 50 % du parenchyme. Une antibiothérapie a été administrée chez 45 patients (46,4 %). L’hydroxychloroquine et les corticoïdes ont été principalement prescrits en réanimation pour respectivement 16 (16,5 %) et 18 (18,6 %) patients. La durée médiane des symptômes avant hospitalisation était de 7 jours (IQR : 4–10), 67 (69,1 %) patients ont été hospitalisés plus de 5 jours, 33 (34 %) sont passés en réanimation dont 21 (21,6 %) intubés et 7 (7,2 %) sont décédés. En analyse univariée, les facteurs associés au passage en réanimation étaient l’âge (OR = 1,03, IC95 % [1,003 ; 1,058] p = 0,05), le sexe masculin (OR = 3,79, IC95 % [1,55 ; 9,56] p = 0,004), un antécédent d’HTA (OR = 2,67, IC95 % [1,10 ; 6,89], p = 0,03), ainsi que la lymphopénie 100 mg/L (OR = 4,74, IC95 % [1,96 ; 12,03] p 100 mg/L (OR = 4,2 IC95 % [1,7 ; 10,8] p = 0,002), et la lymphopénie

Summary Background: The DNA repair protein O 6 -alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m 2 , divided over two days. Fotemustine 100 mg/m 2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m 2 (200 mg/m 2 /d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.

Unrelated cord blood transplantation (UCBT) after a reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly patients and those with co-morbidities without an HLA-identical donor, although post-transplant relapse remains a concern in high-risk acute myeloid leukemia (AML) patients. HLA incompatibilities between donor and recipient might enhance the alloreactivity of natural killer (NK) cells after allogeneic hematopoietic stem-cell transplantation (HSCT). We studied the reconstitution of NK cells and KIR-L mismatch in 54 patients who underwent a RIC-UCBT for AML in CR in a prospective phase II clinical trial. After RIC-UCBT, NK cells displayed phenotypic features of both activation and immaturity. Restoration of their polyfunctional capacities depended on the timing of their acquisition of phenotypic markers of maturity. The incidence of treatment-related mortality (TRM) was correlated with low CD16 expression (P=0.043) and high HLA-DR expression (P=0.0008), whereas overall survival was associated with increased frequency of NK-cell degranulation (P=0.001). These features reflect a general impairment of the NK licensing process in HLA-mismatched HSCT and may aid the development of future strategies for selecting optimal UCB units and enhancing immune recovery.

Background It has been shown that androgens are immunosuppressive. Androgen deprivation with GnRH agonists regenerates the thymus and its functions in adults, leading to increase in blood and lymphoid organ lymphocytes, in naive lymphocytes with expansion of TCR Vbeta repertoire, and in Tumour Infiltrating Lymphocytes (TILs) in prostate tumours. This phase I study evaluated the safety of triptorelin in combination with nivolumab, as well as its potential to reverse resistance to PD-1 inhibitors in male melanoma patients. Methods Treatment consisted of triptorelin 3.75 mg i.m. every 4 weeks and nivolumab 3 mg/kg i.v. every 2 weeks. Bicalutamide 50 mg p.o. QD was added for the first 28 days. Evaluation of response was performed after 3 months. Triptorelin PK was assessed and various PDy markers were measured in blood and tumour samples. Planned treatment duration was 48 weeks. Results Fourteen male patients were included, of whom 11 were white and 3 were black, with mean age 65 years (range 45-82). At screening 4 were locally advanced while 10 had distant metastases (2 with M1a, 1 with M1b, 6 with M1c and 1 with M1d). Ten patients had cutaneous melanoma, 2 patients had mucosal melanoma, and 2 had an unknown primary. Safety: No grade 4 AEs were reported. Five grade 3 AEs were reported in 4 patients, of which one (abdominal pain) was attributed to triptorelin and resolved after 39 days (causing no treatment interruption as it started on the day treatment was discontinued due to progression), and one (neutropenia) was considered related to nivolumab and resolved following treatment interruption for 14 days. Efficacy: BOR (RECIST 1.1) was assessed as 2 PR, 5 SD, and 7 PD. The two patients with PR showed reductions from baseline in Target Lesions of 76% (one pancreas metastasis) and32% (two inguinal lymph nodes), following an initial pseudoprogression. Conclusion The association of triptorelin to nivolumab was well tolerated and yielded partial response in two patients. Legal entity responsible for the study Debiopharm International S.A. Funding Debiopharm International S.A. Disclosure C. Robert: Advisory / Consultancy: Novartis, Bristol-Myers Squibb, MSD, Roche, Sanofi, Amgen, Pierre Fabre. F.J. Lejeune: Honoraria (self): Debiopharm International SA. C. Lebbe: Honoraria (self): Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, Pierre Fabre, Pfizer, Incyte; Advisory / Consultancy: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen; Travel / Accommodation / Expenses: Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Roche, Bristol-Myers Squibb, Novartis ,Amgen; Advisory / Consultancy: Aventis. T. Lesimple: Research grant / Funding (self): Roche; Advisory / Consultancy: MSD, Novartis, Pierre Fabre. E. Lundstrom: Full / Part-time employment: Debiopharm International SA. V. Nicolas: Full / Part-time employment: Debiopharm International SA. B. Gavillet: Full / Part-time employment: Debiopharm International SA. V. Gregoire: Full / Part-time employment: Debiopharm International SA. P. Crompton: Full / Part-time employment: Debiopharm International SA.

A survey of state mental health agencies found that a majority have no specific policy or procedure regarding how to provide mental health services to persons who are deaf or who are deaf-blind. Agency representatives report that staff lack knowledge of how to provide mental health services to persons who are deaf-blind and the agencies lack qualified interpreters. They recommend training for social workers and counselors to address best practices in working with people who are deaf-blind concerning communication methods and strategies, physical interaction, cultural issues, everyday life, sensory deprivation, ethics, use of an interpreter, and other general issues.

Gynandroblastoma is a rare ovarian tumor, derived sex cord-stromal, malignant, with low scalable potential. Clinical investigations include endocrinology or gynecological troubles, or pelvic mass syndrome. After pelvic MRI of reference, optimum surgery is the treatment of gynandroblastoma. Fragile X syndrome is the most common inherited cause of mental retardation, and females are more affected. Association of both is totally new.

Background and Objectives Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a limb salvage therapy for non-resectable soft tissue sarcomas (STS) of the extremities. It is indicated for patients for whom amputation or debilitating surgery is the only alternative. It can be used either as an exclusive therapy (in palliation) or as a neo-adjuvant treatment, followed by marginal resection of tumor remnants with minimal functional impairment. Methods Between February 1992 and March 2006, 57 TM-ILPs were performed on 51 patients with 88% high grade and 84% advanced stage tumors. Results Mean follow-up is 38.9 months (4–159, median 22 months). Twenty-one percent patients had significant early complications, with 3 major re-operations, and 23% suffered long-lasting complications. Complete response was observed in 25%, partial response in 42%, stable disease in 14% and progressive disease in 14%. Resection of the tumor remnants was possible in 65%. A complementary treatment was necessary in 31%, mostly radiation therapy. A local recurrence was observed in 35%, after a mean of 20.3 months (2–78), and distant relapse was seen in 45%, after a mean of 13.4 months (5–196). Mean Disease-free survival was 14.9 months, and overall 5-year-survival 43.5%. Amputation rate at 5 years was 24%. Conclusions TM-ILP is a conservative treatment with a high complications rate, but it can be successful even for the most severe STS of extremities. As a consequence the limb can be spared from amputation or debilitating surgery on the long term in about 75% of patients. J. Surg. Oncol. 2008;98:148–155. © 2008 Wiley-Liss, Inc.

Three enzymes intervening in de novo purine synthesis, as well as cystathionine B-synthetase, have been mapped to chromosome 21. In order to gain a better understanding of purine synthesis anomalies in Down's syndrome, the present authors studied the variations in mitotic index of lymphocyte cultures to which various inhibitors or metabolites of purine synthesis had been added. In spite of common gene dosage effects, unexpected and highly significant differences were noted between Down's syndrome patients without complications and those presenting with additional psychotic features. In Down's syndrome patients without complications, a highly significant decrease in mitotic index was noted in the presence of exogenous inosine. A significant decrease in the presence of adenosine and guanosine was also noted. These findings are in keeping with the expected metabolic repercussions of genes mapped to chromosome 21. In Down's syndrome patients with psychotic complications, the in vitro reactions were quite different. A paradoxal increase in mitotic index was noted in the presence of inosine and of adenosine, but the response to guanosine did not differ from that observed in normal controls. These findings were unexpected and seem to indicate that, in spite of the gene dosage effect, psychotic Down's syndrome patients are unable to compensate abnormal purine synthesis and resulting imbalances. Furthermore, a marked difference in purine metabolic reactions was noted between Down's syndrome patients receiving supplemental folic/folinic acid and those on no therapy. This suggests that some modulation of the gene dosage effect may be possible.

Classical metastatic melanoma therapy is disappointing but important progress has been made in the understanding of melanoma biology. Genetic lesions and several intracellular signaling pathways that could serve as targets for novel therapy have been identified and a number of new agents are under evaluation. Promising tumor cell targets were identified in the cell membrane, cytoplasm and nucleus. New therapeutic approaches, besides monoclonal antibodies and vaccination, include an increasing number of small molecules that have been shown to interfere restrictively with intracellular signaling pathways in melanoma and decrease proliferation, survival, migration or invasion. Other agents can interfere with stromal components of melanoma, such as angiogenesis and components of the immune system.

International audience; Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-kappaB activation. Concomitant activation of PKB/Akt and NF-kappaB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon gamma synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-kappaB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.Oncogene (2007) 26, 5722-5732; doi:10.1038/sj.onc.1210354; published online 19 March 2007.

Clinical oncologists have not been paying enough attention to the fact that poor tumor penetration represents a major impediment to the efficiency of cancer chemotherapeutics. The cytokine tumor necrosis factor (TNF) was the first treatment shown to affect tumor vessel destruction and improve vascular permeability of drugs in a clinical setting. TNF produces an early increase of vessel permeability followed by a dual targeting: TNF induces apoptosis of intratumoral angiogenic endothelial cells and melphalan during the apoptosis of tumor cells. Given the systemic toxicity, TNF has to be administered by regional therapy. However, experimental data indicate that a systemic approach will be possible, thanks to TNF targeting. Three fusion proteins with TNF were shown to target tumors: anti-EDB fibronectin/TNF, Asn-Gly-Arg-TNF, and anti-gp240/TNF. Current approaches to blocking angiogenesis include strategies that target vascular endothelium growth factor (VEGF)-A. However, little attention has been paid to possible drawbacks, which may include vessel destruction and reduced penetration by chemotherapeutic agents administered simultaneously or subsequently. An antiangiogenic treatment is optimal when it is given at a critical dose and at a critical time. Current protocols seem not to take these prerequisites into consideration. Other new approaches to increased tumor vessel permeability include histamine and combretastatin analog. The current paradigm of antitumor strategy based on the synergism of empirical drug combinations is obsolete. Instead, the design of protocols based on new pharmacodynamic concepts should provide better efficiency of cancer treatment as exemplified in the use of TNF and anti-VEGF antibody.

This paper reports on the scientific session on sentinel node biopsy, surgery and locoregional treatments that took place during the Third Research Meeting on Melanoma, Milan, Italy, held in May 2003. It provides an overview of contributions presented at the meeting grouped according to subject - ultrasound scanning, sentinel node biopsy, mini-invasive surgery and stop-flow limb perfusion. The main comments made by the respective rapporteurs are also summarized.

To elucidate the functional heterogeneity of Ag-specific T lymphocyte populations, we combined labeling of lymphocytes with MHC/peptide tetramers and a cell surface affinity matrix for IFN-γ. Magnetic cell sorting of IFN-γ-positive lymphocytes allowed the selective enrichment and identification of live Ag-specific cytokine-secreting cells by flow cytometry. Naive, memory, and effector Ag-specific populations were evaluated in healthy HLA-A2 individuals. Significant fractions of influenza- and CMV-specific cells secreted IFN-γ upon challenge with cognate peptide, consistent with an effector/memory status. The sensitivity of the approach allowed the detection of significant numbers of CMV-specific IFN-γ-secreting cells ex vivo (i.e., without Ag stimulation). This was not apparent when using previously described assays, namely, ELISPOT or intracellular IFN-γ staining (cytospot). CD8+ T cells specific for the melamoma-associated Ag Melan-A/MART-1 did not produce IFN-γ upon challenge with cognate peptide, reminiscent with their naive functional state in healthy individuals. In contrast, CD45RAlow Melan-A/MART-1 tumor-specific cells from three of three melanoma patients presented levels of activity similar to those found for influenza- or CMV virus-specific lymphocytes, compatible with a functional differentiation into competent effector/memory T lymphocytes in vivo. Notably, a sizable fraction of Melan-A/MART-1-specific cells from a patient secreted IFN-γ ex vivo following peptide-based vaccination. Thus, the high sensitivity of the assay provides a valuable tool to monitor effector T cell responses in different clinical situations.

A flameless atomic absorption spectrometric (AAS) method has been developed and validated for the determination of platinum (Pt) in human plasma, plasma ultrafitrate and urines from cancer patients receiving the orally available platinum derivative, JM216. Sample pretreatment is minimal for urine, which is diluted with 10% HCl prior to AAS analysis. Pt analysis in plasma requires the application of the matrix modifier 5% Triton X-100 directly onto the integrated L'vov platform of the graphite furnace prior to the addition of plasma samples. For Pt in ultrafiltrates, enhanced sensitivity is achieved by pre-concentrating ultrafiltrate samples onto the platform prior to the ashing/atomisation step. The AAS program was set specifically for each considered matrix enabling to achieve limit of quantitations as low as 50, 10 and 5 ng Pt ml(-1) for urine, plasma and plasma ultrafiltrate, respectively. The calibration was linear (r(2)>0.993) over the working range 5-150 ng Pt ml(-1). The method has been validated according to the Recommendations on Bioanalytical Methods Validation. The stability of Pt in samples has been explored, as well as the specificity of the method. In the urine intra-assay precision of control samples at 60, 90 and 140 ng Pt ml(-1) is always lower than 3.0, 1.3 and 4.7%, respectively, with concentrations not deviating more than -5.5 to -1.0% from their nominal values, while inter-assay precision is within 5.7-7.7% and inter-assay deviation within the -1.9 to +4.3% range. Intra-assay precision of plasma control samples at 20, 70 and 140 ng Pt ml(-1) is always lower than 8% and concentrations never deviating more than 7.1% from their nominal values. Inter-assay precision of plasma control samples is always lower than 9% with inter-assay deviation from their nominal concentrations within the -3.9 to +1.8% range. In plasma ultrafiltrate, intra-assay CVs of control samples at 12, 25 and 45 ng Pt ml(-1) are always lower than 2.6, 1.7 and 6.8%, respectively, with concentrations not deviating more than -2.6 to -0.2% from their nominal values, while inter-assay CVs are within 5.1-9.5% and inter-assay deviation within the -1.6 to +5.3% range. The proposed method has, therefore, the required performance to measure Pt in biological samples and has been successfully applied to the determination of Pt in samples from cancer patients receiving JM216 in a phase I (daily administration for 14 days, dose escalation 10-50 mg m(-2)) and a phase II (fixed dose 120 mg m(-2) over 5 days) clinical study. In phase I study, both total and ultrafiltrable Pt accumulated upon repetitive dosings, showed long elimination half-lives (t(1/2)) and were measurable 2 weeks after the end of JM216 administration.

According to the Centers for Disease Control (Langlois, Rutland-Brown, & Thomas, 2006), traumatic brain injury (TBI) affects more than 1.4 million persons annually in the United States. Those who are most affected are children and adolescents, aged 0-4 and 15-19, young adults aged 19-25 (among military personnel in war zones), and persons aged 60 and older (Brain Injury Association of America, 2010). These incidences include shaken baby and child abuse cases, automobile accidents, sports injuries, war injuries, and falls. We do know that older persons with vision loss are more likely to fall and that falls among this age group are one of the major causes of TBI. We also know that older persons often have strokes and other neurological conditions, known as acquired brain injury (ABI), that have an impact on cognition and independence in much the same way as does TBI. Unfortunately, the wars in Iraq and Afghanistan have added to the number of young adults with TBI and vision loss, but the related work of the Department of Veterans Affairs has also given us more empirical information on how to work with this population. One of the roles of universities is to conduct research and integrate the results of research into the preparation of professionals in a given program of study. As a result, I believe that vision-related personnel preparation programs need to address this issue. Mississippi State University (MSU) has a Vision Specialist in Vocational Rehabilitation Graduate Certificate Program that is designed for vocational rehabilitation counselors with caseloads of persons who are blind or have low vision. Usually about 80% of the students in this program are working vocational rehabilitation counselors, some with many years of experience, and a few are teachers of students with visual impairments, vision rehabilitation teachers, and orientation and mobility (O&M) specialists or graduate students, who are from all over the United States. Over the past 5 years, we have noticed that more and more vocational rehabilitation counselors who serve persons who are blind have persons with brain injuries in their caseloads. In our program, under the general topic of special populations, we have covered vision loss related to ABI and TBI and HIV in a superficial way, but have paid more attention to the visual conditions associated with aging, diabetes, and deaf-blindness. But because of the increase in cases of brain injury in caseloads and my own experience when my husband, who has been legally blind all his life, acquired a TBI three years ago, MSU has increased the attention that is given this area of service. The motivation for the increased attention to brain injury is that specialization brain in jury-related vision loss is not well addressed in our field, and resources for treating this condition vary considerably around the United States. The program at Mississippi State University consists of four hybrid distance education courses with three weeks of intensive residency. In a nutshell, our courses cover the medical aspects of blindness and low vision with implications for employment, low vision, special populations, history and legislation, assistive technology, O&M, vocational rehabilitation therapy, transition, various resources (including organizations and professionals), special education perspectives, career development, job placement, and a field experience practicum. …

Administration of high doses of TNF and IFNγ by isolated limb perfusion to patients affected by in transit melanoma metastases or inoperable soft tissue sarcoma of the limb, results in a high rate of complete response compared to chemotherapy alone. TNF/IFNγ induce apoptosis of angiogenic endothelial cells and selectively disrupt the tumor vasculature. The study of the cellular and molecular events mediating this effect has revealed that TNF and IFNγ inhibit the function of integrin αVβ3, an adhesion receptor expressed on angiogenic endothelial cells and essential for their survival, resulting in impaired endothelial cell adhesion, spreading, focal adhesion formation and cell survival. These and other recent findings may open new perspectives in the clinical use of TNF as anti-tumor agent as well as in the design of new anti-vascular strategies aimed to disrupt the tumor vasculature.

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.

Hyperthermic isolated limb perfusion (HILP) with various chemotherapeutic agents has been used for the local treatment of high-grade soft tissue sarcomas (STS) of the extremities, but in most cases with a disappointing result. Most regimens should certainly not be considered superior to surgery plus radiotherapy. Although the majority of extremity STS can be resected locally, some have a very large size and are in close proximity to bones, nerves or blood vessels. In these cases, amputation is the only means of resecting the tumour. A new combination of drugs used in the set-up of HILP with tumour necrosis factor- α and melphalan has emerged as a very promising option for the limb-saving management of locally advanced STS. In recent studies, complete response rates of approximately 30% and partial remission rates of 50% have been achieved, while the overall limb-salvage rate is more than 80%.

Recombinant tumour necrosis factor-alpha (rTNFalpha) possesses the unique property of activating and selectively destroying the tumour-associated microvasculature. Systemic application of rTNFalpha has shown that the maximum tolerated dose (MTD) is 10 times lower than the efficient dose in animals. The main toxicity corresponds to the systemic inflammatory response syndrome (SIRS), with a decrease of vascular resistance and hypotension. We found that it is possible to administer rTNFalpha at 10 times the MTD in an isolated limb perfusion system, using a heart-lung machine, for advanced melanoma and sarcoma of the limbs. Our results, using the combination of high dose rTNFalpha, interferon-gamma and melphalan (TIM), produced an overall objective response rate of 100% in 2 successive studies on melanoma, with 90% and 78% complete response, respectively. In sarcoma, there was an overall response rate of 64%, with 36% complete response. Angiographic and immunohistological studies demonstrated selective and early damage of the tumour-associated microvasculature, preceded by upregulation of adhesion molecules and intratumoural leak of von Willebrand factor. Tumour invasion by platelets and, in some cases, by polymorphonuclear cells, appeared within hours after the application of rTNFalpha, long before the lysis of the tumour. Systemic changes after rTNFalpha treatment included the production of soluble TNFalpha receptors and of interleukin-6. A typical acute phase reaction was observed within 3 days, with increase of C-reactive protein parallelled by an increase of tenascin-C. A selective effect on intratumoural endothelial cells seems to be involved in the mechanism of the impressive antitumour effect of rTNFalpha, but the role of acute phase protein production is not fully understood. In selected cases of melanoma, specific cytotoxic T lymphocytes were increased after perfusion.

Melanoma risk among subjects from Germany, France and Belgium who had lived for 1 year or more in sunny climates was examined in a one-to-one unmatched case-control study conducted among white subjects 20 years old or more. A total of 412 consecutive patients with melanoma diagnosed from 1 January 1991 onwards, were derived from hospital registers; 445 controls were randomly chosen in the same municipality as the cases. After adjustment for host characteristics, melanoma risk associated with residence in a sunny area was 2.7 (95% CI: 1.4-5.2), increasing to 4.7 (95% CI: 1.4-13.5) if subjects sought a suntan when residing in sunny climates, and to 4.3 (95% CI: 1.7-11.1) if subjects arrived before the age of 10 years in the sunny area. Residence in sunny areas and recreational sun exposure seemed to combine their effects on melanoma risk. Increase in melanoma risk conveyed by deliberate sun exposure during adulthood was highest among subjects who had lived in sunny areas as a child or adolescent and lowest among subjects who had never resided in sunny areas. Our results support conclusions from migrant studies that indicated that childhood is a critical period of either vulnerability to solar radiation or more frequent exposures to melanoma risk factors. They also suggest that moderate sun exposure of an adult who was heavily sun exposed in childhood is associated with a higher melanoma risk than that of high sun exposure of an adult who was sun protected in childhood.

Resume Une etude preliminaire des concentrations plasmatiques et urinaires des acides amines chez des sujets trisomiques 21 compares a des temoins avait mis en evidence des anomalies. Patients et methodes. — Une etude comparative de l'evolution de ces acides amines en fonction de l'âge dans un groupe de sujets trisomiques 21 de 0 a 60 ans et dans un groupe temoin de 0 a 94 ans a ete realisee afin de determiner si ces anomalies pouvaient etre rapportees a un vieillissement precoce generalise ou a un effet specifique de surdosage genique. Resultats. — Deux anomalies majeures (p Conclusions. — D'autres etudes sont necessaires afin d'evaluer les consequences possibles des anomalies observees.

PURPOSE Ocular melanoma is characterized by a high rate of liver metastases and is associated with a median survival time less than 5 months. There is no standard treatment available. Treatment strategies have, without success, relied on the experience with metastatic cutaneous melanoma. The only effective treatment is chemoembolization using cisplatin and polyvinyl sponge, which has never become accepted on a large scale. The objective of the study was to establish prospectively the efficacy and toxicity of hepatic intraarterial fotemustine, a third-generation nitrosourea, in patients with liver metastases from ocular melanoma. PATIENTS AND METHODS Thirty-one patients were subjected to laparotomy to place a totally implantable catheter into the hepatic artery and received fotemustine 100 mg/m2 as a 4-hour infusion, first once a week for four times and then, after a 5-week rest period, every 3 weeks until progression or toxicity. Cox regression models were used to assess the prognostic role of patient survival characteristics. RESULTS Objective responses were observed in 12 of 30 assessable patients (40%; 95% confidence interval, 22% to 59%). The median duration of response was 11 months and the median overall survival time, 14 months. Lactate dehydrogenase (LDH) appeared to be the strongest prognostic factor for survival. Toxicity was minimal and treatment could be administered on an outpatient basis. CONCLUSION The results of hepatic arterial chemotherapy with fotemustine produced a high response rate and survival similar to chemoembolization therapy. It involves no major toxicity and preserves the quality of life. To assess further its effectiveness, a randomized study to compare hepatic intraarterial versus intravenous chemotherapy is being planned.

PURPOSE To determine the efficacy of isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) in combination with interferon-gamma (IFN) and melphalan as induction therapy to render tumors resectable and avoid amputation in patients with nonresectable extremity soft tissue sarcomas (STS). PATIENTS AND METHODS Among 55 patients with 30 primary and 25 recurrent sarcomas, there were 48 high-grade and seven grade 1 sarcomas (very large, recurrent, or multiple). The composition of this series of patients is unusual: 13 patients (24%) had multifocal primary sarcomas or multiple recurrent tumors; tumors were very large (median, 18 cm); and nine patients (16%) had known systemic metastases. IFN was administered subcutaneously on the 2 days before ILP with TNF, IFN, and melphalan. A delayed marginal resection of the tumor remnant was usually performed 2 to 3 months after ILP. RESULTS A major tumor response was seen in 87% of patients and rendered the sarcomas resectable in most cases. Clinical response rates were as follows: 10 (18%) completes responses (CRs), 35 (64%) partial responses (PRs), and 10 (18%) no change (NC). Final outcome was defined as follows by clinical and pathologic response: 20 (36%) CRs, 28 (51%) PRs, and seven (13%) NC. Limb salvage was achieved in 84% (follow-up duration, 20+ to 50+ months). In 39 patients, resection of the tumor remnant (n = 31) or of two to eight tumors (n = 8) after ILP was performed; local recurrence developed in five (13%). When no resection was performed (multiple tumors or systemic metastases), local recurrences were frequent (five of 16), but limb salvage was often achieved as patients died of systemic disease. Regional toxicity was limited and systemic toxicity minimal to moderate with no toxic deaths. Histology showed hemorrhagic necrosis; angiographies showed selective destruction of tumor-associated vessels. CONCLUSION ILP with TNF, IFN, and melphalan is a safe and highly effective induction biochemotherapy procedure that can achieve limb salvage in patients with nonresectable extremity STS. TNF is an active anticancer drug in humans in the setting of ILP.

It has been reported from supply data that at a population level, every 628kJ/d (150kcal/d) increase in sugar availability, (equivalent to approximately one can of sugar-sweetened beverage daily), is independently associated with a 1.1% increase in diabetes mellitus prevalence (1) . The WHO has recommended restricting non-milk extrinsic sugars (NMES) to £ 10% of E (2) . Reformulation of sugarcontaining processed foods is considered by some as a key option for achieving this target and for improving population health (3) . The impact of a sugar reformulated product exchange on cardiovascular risk factors was assessed using a randomised controlled, double-blind, crossover dietary intervention study. Fifty healthy volunteers (16 male, 34 female; age 31.3 (SD 9.6) years; BMI 24.0 (SD 3.3) kg/m 2 ) were randomly assigned to consume either unmodified or sugar reformulated foods and drinks, including juice, soft drinks, pasta sauces, baked beans, muesli, chocolate, ketchup and jam, for an 8-week period. This was followed by a 4-week washout period before volunteers crossed to the alternate intervention. The minimum target difference in dietary NMES intake between the unmodified and reformulated product exchange was 38g/d. Fasting serum was collected pre-and post-intervention and used to determine glucose, lipid and inflammatory markers. Logarithmically transformed data were statistically analysed using ANCOVA. There was no significant effect of the intervention on BMI. When adjusted for BMI, dietary restraint, age and gender there were no differences in fasting serum glucose, total cholesterol, TAG, NEFA or C-reactive protein (CRP) concentrations between interventions.

Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy.

Use of sunscreens is widely advocated as a preventive measure against sun-induced skin cancers. However, to date, no epidemiologic study has reported a decreased melanoma risk associated with sunscreen use. We have conducted a case-control study aimed at evaluating the influence of sunscreen use on the occurrence of cutaneous malignant melanoma. In 1991 and 1992, 418 melanoma cases and 438 healthy controls were interviewed in Germany, France and Belgium. The questionnaire used differentiated between regular sunscreens, psoralen sunscreen (prepared with 5-methoxypsoralen, a tanning activator and photocarcinogen), and self-tanning cosmetics (which produce a tan without ultraviolet radiation). After adjusting for age, sex, hair colour and holiday weeks spent each year in sunny resorts, the melanoma risk was of 1.50 (95% Cl:1.09-2.06) for regular sunscreens, and of 2.28 (95% Cl: 1.28-4.04) for psoralen sunscreens. No melanoma risk was associated with use of self-tanning cosmetics. Among subjects with a poor ability to tan, psoralen sunscreen users displayed a melanoma risk of 4.45 (95% Cl: 1.25-15.8) when compared with regular sunscreen users. There was a significant negative interaction between regular sunscreen use and sunburns experienced in adulthood. Use of sunscreens, especially psoralen sunscreen, was associated with higher density of pigmented lesions of the skin. Although we cannot exclude the presence of an unknown confounding factor, our results support the hypothesis that sunscreens do not protect against melanoma, probably because of their ability to delay or avoid sunburn episodes, which may allow prolonged exposure to unfiltered ultraviolet radiation. Serious doubts are raised regarding the safety of sunscreens containing psoralens.

The study objective was to assess whether exposure to sunlamps and sunbeds represents a risk factor for cutaneous malignant melanoma (CMM). A 1-to-1 unmatched case-control study was conducted among subjects 20 years old or more with naturally non-pigmented skin in Germany, France and Belgium. A total of 420 consecutive patients with CMM diagnosed from 1 January 1991 onward were derived from hospital registers; 447 controls with no history of skin cancer were chosen at random in the same municipality as the cases. Exposure to sunlamps or sunbeds starting before 1980 is associated with a crude estimated risk of CMM of 2.71 (95% CI: 1.06-7.78) for at least 10 hr of accumulated exposure. This risk is of 2.12 (95% CI: 0.84-5.37) after adjustment for age, sex, hair colour and average number of holiday weeks each year in sunny resorts. Subjects who experienced skin-burn due to sunlamps or sunbeds, and who had accumulated at least 10 hr of exposure, displayed a crude estimated CMM risk of 4.47 (95% CI: 1.45-13.7), which rose to 8.97 (95% CI: 2.10-38.6) for those who exposed their skin for tanning purposes. The risk associated with skin-burn is only marginally modified after multiple adjustments for host characteristics and recreational exposure to sunlight. Apparently, sunlamps and sunbeds share the increased risk of CMM, which seems to concentrate in subjects exhibiting hazardous behaviour towards ultraviolet radiation sources. However, although it is reasonable to believe that high doses of pure ultraviolet A radiation can be dangerous, this is not firmly established by this study. Most exposures to ultraviolet A tanning devices began after 1980; therefore, epidemiologic studies have difficulty in revealing any increase in risk of CMM starting after 1980 because of the latent period between exposure and occurrence of melanoma. Public health authorities should have a cautious approach towards the rapidly developing fashion of tanning under sunlamps or sunbeds.

To obtain insight in the effect of TNF on the synthesis of acute phase proteins like CRP, alpha 1-antitrypsine, alpha 1-acidglycoprotein, C3 and C4 and the immunoglobulins (IgG-M-A), nine cancer patients who were treated with an isolated limb perfusion (ILP) with high dose recombinant TNF-alpha (rTNF-alpha) were investigated during a 7-day period after the end of the perfusion. Resorption of rTNF-alpha from out of these limbs into the circulation after the ILP induced within 30 min to 6 h in all patients elevated serum levels of IL6. At the same time C-reactive protein became detectable in serum. The highest serum levels were obtained at 48 h after ILP. The serum levels of the other acute phase proteins (alpha 1-acidglycoprotein, alpha 1-antitrypsine, C3, C4), rose more slowly and the highest serum levels were found at the third day. All investigated proteins declined after they had reached their peak levels. Levels of alpha(1)-acidglycoprotein and alpha(1)-anti-trypsin alpha(1)-acid declined slower than both complement component. In regard to the immunoglobulin levels a nearly continuous increase in the serum level of specifically IgM was observed. This study clearly shows the interrelationship between TNF-alpha and IL-6 in regard to the synthesis of the different acute phase proteins; and moreover also a striking effect on IgM synthesis.

Marked differences in the tumor uptake of a 125I-labeled monoclonal antibody (MAb) directed against carcinoembryonic antigen (CEA) were observed in 4 serially transplanted human colorectal carcinomas in nude mice. A comparative study showed that elevated values of measurable tumor vascular parameters, such as permeability, blood flow and blood volume, correlated better with high MAb tumor uptake than the concentration of target antigen in the tumor. In an attempt to modify the vascular parameters and to determine if this could increase antibody uptake by the tumor, rhTNF alpha (TNF) was injected i.t. or i.v. and antibody localization experiments were performed immediately thereafter. Results showed that the permeability of the tumor vessels increased 8 to 10 fold 1 hr after i.t. injection of TNF as compared to control tumors injected with saline. Tumor uptake of 125I-labeled anti-CEA MAb, was 3 times higher 2 hr after i.v. injection and still 27% higher 22 hr later, as compared to results from controls. Intravenous injection of TNF simultaneously with the 125I-labeled anti-CEA MAb also resulted in a 2-fold increase in tumor uptake 4 hr after injection, but the increase was no longer significant 24 hr after injection. Interestingly after i.v. injection of TNF, the MAb concentration in the blood and other normal tissues, such as liver, kidneys, lungs and heart was decreased, resulting in significantly higher ratios of tumor to normal tissue. Taken together the results demonstrate that injection of TNF can increase tumor vascular permeability and improve radio-antibody uptake. This raises the possibility of increasing the radiation dose delivered by antibody to the tumor in the course of radioimmunotherapy.

Farming employs one of the most diverse work forces, while at the same time it is one of the most dangerous occupations in the U.S. Individuals associated with the livestock industry face an additional risk: zoonotic diseases. In an effort to improve the overall well-being of the farming community, this review addresses zoonoses as a health concern for the farming community. The discussion of agriculturally acquired zoonoses includes infections naturally transmitted from vertebrate animals to man (e.g., rabies) and those common to animals and man (e.g., Salmonella). Special consideration is given to identifying individuals potentially at higher risk for developing disease. Case reports and epidemiological studies are reviewed from published veterinary and human-health literature to illustrate exposure scenarios and associated health outcomes. Additionally, key livestock zoonoses in the U.S. are summarized, and an overview of prevention and control strategies is provided. Findings show that livestock can transmit many zoonoses directly and indirectly, and human health can be significantly impacted, but the number of people adversely impacted is largely unknown. This review concludes that more education about zoonosis transmission and prevention is needed, and healthcare providers serving rural communities are a critical link in providing this information. In order for healthcare providers to address the educational gap, we recommend greater collaboration with veterinary specialists schooled in population medicine, zoonosis prevention and control, and animal production.

Preliminary Phase I trials have shown iodine 131 (131I)-Lipiodol (ethiodized oil; Laboratoires Guerbet, Aulnaysous-Bois, France) to be well tolerated and most likely effective in the treatment of hepatocellular carcinoma (HCC). In this multicenter Phase II trial, the authors tested the feasibility and reproducibility of this treatment in other medical institutions and evaluated its efficacy in 50 patients with unresectable Stage I or II HCC, by the classification of Okuda et al. The authors studied 47 men and 3 women (63.9 +/- 7.1 years old) with Stage I (n = 18) or II (n = 32) HCC, by the classification of Okuda et al., which was verified by histologic findings (n = 25), cytologic findings (n = 11), or association of a tumor with alpha-fetoprotein serum values greater than 500 micrograms/l (n = 14). This multicenter trial (1) confirmed that the 131I-Lipiodol treatment is well tolerated; (2) showed that there is a high reproducibility of results with respect to other institutions and an objective tumor response in 40% of the cases; and (3) indicated the necessity of performing a randomized controlled study.

PURPOSE: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). EXPERIMENTAL DESIGN: Gemcitabine at 500, 750 and 1,125 mg/m(2) was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-flow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH /=1.35. The tolerability of this procedure was also assessed. RESULTS: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-flow perfusion, with C (max) levels in the abdominal circuit of 246 (+/-37%), 2,039 (+/-77%) and 4,780 (+/-7.3%) mug/ml for the three dose levels 500, 750 and 1,125 mg/m(2), respectively. These C (max) were between 13 (+/-51%) and 290 (+/-12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUC(t0-20), was between 5.5 (+/-43%) and 200 (+/-66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C (max) and AUC(t0-20), both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P < 0.05) was found between systemic C (max) of gemcitabine and the nadir of both leucocytes and neutrophils. CONCLUSIONS: Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m(2). However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherapy.

Introduction Patients with substance use disorders (SUD) represent a significant part of psychiatric emergency. However the clinical characteristics of this population have been poorly documented. The Crisis-unit of the CHR Citadelle (Liege, Belgium) has been admitting patients with SUD for short emergency stays since 2003. Objectives We investigated personality and electrophysiological patterns in Crisis-unit inpatients, as a function of socio-demographic and clinical characteristics (comorbidities, substance of choice). Aims We aim to describe psychiatric emergency patients with SUD and highlight common and distinct patterns, in order to improve the understanding and treatments provided to this population. Methods 2062 inpatients with a diagnostic of substance abuse or substance dependence (978 males, mean age=35.9) were admitted between 2005-2013; 1262 fulfilled the TCI-R personality questionnaire and 1115 completed an event-related potential examination. Results The prevalence of axis-1 disorders other than SUD was 39%, and 46% for axis-2 disorders; 31% of the patients presented either slowed reaction time and/or electrophysiological abnormalities. Low selfdirectedness was found in patients with SUD regardless the presence of comorbidities and the substance of choice. However, other personality dimensions (novelty seeking, harm avoidance, reward dependence and self-transcendence) as well as electrophysiological examination show specific patterns as a function of these characteristics. Conclusions Low selfdirectedness is confirmed as a major predictor of poor psychosocial functioning including SUD, stressing the major importance in mental health of self-responsibility, purposefulness and one's ability to regulate and adapt his/her behavior to the situation in accord with his/her goals and values.

Introduction Robust relationships between personality and depression have been repeatedly reported, including a high negative-affectivity score and a low constraint score, as measured by harm avoidance (HA) and selfdirectedness (SD), respectively, as regards to Cloninger's biosocial model. However, the relationships between personality and fine-grained characteristics of depression (such as emotional and neurocognitive patterns, and the nature and intensity of depressive symptoms) have been poorly documented. Objectives Therefore, the present study investigates the relationships between personality and specific symptoms and characteristics of depression. Aims We aim to help understanding the mediating processes involved in personality-depression relationships. Methods 43 inpatients with a diagnosis of major depressive disorder (17 males, 20-60 year-old) fulfilled the TCI-R personality questionnaire, the Beck depression inventory-II and the PANAS-X emotion scale. Patients also completed a behavioral and electrophysiological testing including several alert tasks and an EEG at rest. Results HA and SD are related to cognitive but not somatic symptoms of depression, and more particularly symptoms accounting for the negative attitude toward self. Interestingly, characters but not temperaments were related to the emotional pattern in depressed participants: high SD to less negative emotions and high self-transcendence to more positive emotions. Right frontal alpha asymmetry was related to HA, SD and positive emotions. Conclusions Despite several limitations, the present results shed some light on the mediating role of emotions and neurocognitive pattern in personality-depression relationships.

Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+-fibronectin, sVEGFR-2, sVEGFR-1, sαVβ3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. sαVβ3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and sαVβ3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value. © 2005 Wiley-Liss, Inc.

BACKGROUND: The optimal dose of TNF-alpha delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown. PATIENTS AND METHODS: Randomised phase II trial comparing hyperthermic ILP (38-40 degrees ) with melphalan and one of the four assigned doses of TNF-alpha: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2-3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group. RESULTS: One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-alpha. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively. CONCLUSION: At the range of TNF-alpha doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-alpha doses. Efficacy and safety of low-dose TNF-alpha could greatly facilitate ILP procedures in the near future.

Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of malignant brain tumors. The purpose was to assess TMZ pharmacokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covariates and to explore relationships between systemic or cerebral drug exposure and clinical outcomes.Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacokinetic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area under the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival.Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 h−1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma→CSF), 7.2 × 10−4h−1 and the backwards rate, 0.76 h−1. Body surface area significantly influenced both clearance and VD, and clearance was sex dependent. The AUCCSF corresponded to 20% of the AUCplasma. A trend toward an increased Kplasma→CSF of 15% was observed in case of concomitant radiochemotherapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect.Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUCCSF/AUCplasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Isolation limb perfusion (ILP) is the treatment of choice for locally advanced limb melanoma. With melphalan, the referral drug, complete response (CR) is achieved in about 50% of patients, but significant local toxicity occurs in up to 30%. The aim of the present phase I-II study was to challenge fotemustine (F) in ILP after systemic chemosensitization with dacarbazine (DTIC), given its lower toxicity and greater efficacy, as reported in a previous pilot study. Eleven patients with locally advanced limb melanoma were subdivided into triplets, and given F ILP at escalating doses (starting from 25 mg/l) after intravenous administration of 500 mg/m2 DTIC. Acute and chronic locoregional and systemic toxicity, tumour response and clinical outcome were evaluated. Two patients in the first triplet had G3-G4 local toxicity, so that the scheduled F dosage was halved. At drug levels of 12.5, 15.6 and 18.2 mg/l, local toxicity decreased, but only one of eight patients showed CR. The trial was then interrupted due to the low tolerability and poor efficacy of this perfusion regimen. At present, F ILP after DTIC chemosensitization should not be recommended for the treatment of locally advanced limb melanoma.