The right dose in the right place: an overview of current prescription, instruction and application modalities for topical psoriasis treatments.

BACKGROUND: Compared to treatment success with oral medications, treatment success with topical treatments is currently difficult to achieve. AIM: To assess and compare existing methods of lesion size evaluation, prescription habits, instruction and application modalities of topical medications. METHODS: Review of current and new procedures to estimate the body surface area, to calculate the most adequate quantity of medication to be prescribed, to instruct patients and to assess the individual dosing procedures of topical treatments. RESULTS: The most accurate method to assess the body surface area remains the rule of nine, allowing, together with a recently developed calculation disc, to estimate the most adequate quantity of topical treatment (here calcitriol 3 g/g ointment) to be prescribed. Precise instructions to the patient are other important elements for the successful treatment of dermatoses. Dosing devices, such as a spatula, may help patients to dose their daily topical treatment, avoiding over- and underdosing of the medication. CONCLUSION: A correct evaluation of the lesions sizes, a precise calculation of the treatments quantity to be prescribed, clear instructions and treatment-specific individual dosing devices may help to achieve higher patient compliance and treatment success.

'Parcours de Femme 2001': a French opinion survey on overall disease and everyday life management in 1870 women presenting with gynecological or breast cancer and their caregivers.

PURPOSE: The aim of the survey 'Parcours de Femmes 2001' was to evaluate the overall management and care of women with female cancers and to determine their needs. METHODS: Women with breast or gynecological cancer who had either received at least 3 months of treatment or had completed treatment <1 year before the study were enrolled in this cross-sectional, observational study. RESULTS: From February to November 2001, 2839 questionnaires were distributed; 1870 were returned (66% response rate), mainly by breast cancer patients (87%). While 92% of women reported having received information at diagnosis, 34% of relapsed patients complained of lack of information concerning their disease and treatment. Only 18% of patients were included in the treatment decision process and 66% of women obtained complementary information from the media, patients and care professionals. Fatigue was the most severe problem quoted (78% of cases) and was poorly managed by caregivers due to diagnostic and treatment difficulties. Problems relating to family and to affective and socio-professional life were poorly identified and remained largely unmanaged. CONCLUSIONS: Information given to female cancer patients must be improved in relapsed patients, particularly regarding the adverse effects of treatment. Psychosocial management requires a more holistic approach through new channels, together with the coordination of existing structures.

Phase II trial of a paclitaxel-carboplatin combination in recurrent squamous cell carcinoma of the head and neck.

OBJECTIVE: Twenty-seven patients with recurrent squamous cell carcinoma of the head and neck were entered in a multicenter study to determine the efficacy of the paclitaxel-carboplatin association. METHODS: Standard eligibility criteria applied, i.e. measurable disease, and chemotherapy given as induction treatment or concomitant chemoradiotherapy was allowed if completed more than 6 months prior to the study. Every 21 days, paclitaxel 175 mg/m(2) and carboplatin AUC 6 were administered. The patient group included 3 females and 24 males with a median age of 61 years (range 39-75 years). RESULTS: All patients were assessable for toxicity and 24 for responses. Main grade 3-4 toxicities were: neutropenia (62.9%), febrile neutropenia (18.5%), anemia (11.1%), thrombocytopenia (14.8%), mucositis (7.4%) and vomiting (7.4%). Among the intent-to-treat population, 29.6% of patients had an objective response, with a median response duration of 4.2 months (range 1-5.7 months). Stable and progressive disease were observed in 11.1 and 48.1% of patients, respectively. The median overall survival was 7.2 months (range 0.5-10.9 months). CONCLUSION: From these data, paclitaxel-carboplatin seems to have an activity in recurrent squamous cell carcinoma of the head and neck, but the high level of toxicity highlights the need to search for a safer chemotherapy combination.

T-helper-cell proliferative responses to whole-killed human immunodeficiency virus type 1 (HIV-1) and p24 antigens of different clades in HIV-1-infected subjects vaccinated with HIV-1 immunogen (Remune).

The discovery of multiple subtypes of human immunodeficiency virus type 1 (HIV-1) worldwide has created new challenges for the development of both therapeutic and preventive AIDS vaccines. We examined T-helper proliferative responses to HIV-1 clade A, B, C, G, and E whole-killed virus and to HIV-1 clade G and B core (p24) antigens in HIV-1-infected subjects taking potent antiviral drugs who received HIV immunogen (Remune) therapeutic vaccination. Subjects who were immunized mounted strong proliferative responses to both whole virus and core antigens of the different clades. These results suggest that a whole-killed immunogen may have broad applications as a therapeutic as well as a preventive vaccine in the current multiclade HIV-1 pandemic.

HIV-1-Specific CD4 helper function in persons with chronic HIV-1 infection on antiviral drug therapy as measured by ELISPOT after treatment with an inactivated, gp120-depleted HIV-1 in incomplete Freund's adjuvant.

OBJECTIVE: We hypothesized that treatment of HIV-1-seropositive study subjects receiving potent antiviral therapy with an HIV-specific immune-based therapy would increase HIV-1-specific T-helper immune function. DESIGN: 10 HIV-1-seropositive study subjects receiving antiretroviral therapy were treated with an inactivated, gp120-depleted immunogen in IFA (HIV-1 immunogen, Remune) at baseline, week 12, and week 24. METHODS: The frequency of HIV-1 antigen-stimulated interferon-gamma (IFN-gamma)-producing cells was determined by the ELISPOT assay. RESULTS: Study subjects significantly increased their frequency of HIV-1-stimulated (p <. 001) or p24 antigen-stimulated (p <.01) IFN-gamma-producing cells after one, two, and three treatments of HIV-1 immunogen. Depletion of CD4 cells resulted in the strongest abrogation of the IFN-gamma response. The frequency of HIV-1 (r = 0.64; p =.0002) and p24 (r = 0. 72; p <.001) antigen-stimulated IFN-gamma-producing cells in the CD8-depleted population before and after treatment was associated with the lymphocyte-proliferative response. CONCLUSIONS: Treatment with HIV-1 immunogen significantly enhanced the frequency of HIV-1-specific IFN-gamma-producing cells. Studies are ongoing to determine the relationship between this reversal of HIV-specific anergy and virologic outcomes.

CXCR4 and CCR5 expression on CD4+ T cells in vivo and HIV-1 antigen beta-chemokine production in vitro after treatment with HIV-1 immunogen (REMUNE).

BACKGROUND: The chemokine receptors CXCR4 and CCR5 have been identified as the major coreceptors for HIV-1 on CD4+ cells and macrophages. The natural ligands for these receptors are SDF-1 and the beta-chemokines (MIP-1alpha, MIP-1beta, RANTES), respectively, and are the products of a variety of immune cells, including CD8+ T lymphocytes. STUDY DESIGN/METHODS: We hypothesized that the ability to stimulate the natural ligands for these receptors using an immune based therapy might influence in vivo chemokine receptor expression. RESULTS: In vivo CXCR4 expression remained stable after treatment with an HIV-1 Immunogen (REMUNE), whereas CCR5 expression on CD4+ T cells decreased (p < .05). Furthermore, HIV-1 antigen-specific production of beta-chemokines in vitro was also augmented (P < .05). CONCLUSIONS: These preliminary results suggest that this HIV-1-specific immune-based therapy can stimulate antigen-specific beta-chemokine production in vitro and downregulate CCR5 receptor expression on CD4 cells in vivo.

Cell-mediated immune responses to autologous virus in HIV-1-seropositive individuals after treatment with an HIV-1 immunogen.

OBJECTIVE: We hypothesized that cell mediated immune responses to an HIV-1 immunogen (whole-killed, gp120-depleted HIV-1 in IFA, REMUNE) would include those to autologous virus. METHODS: Five chronically HIV-1 infected individuals were examined for HIV-specific immune responses to their own virus (autologous viral antigen) after treatment with an HIV-1 immunogen. RESULTS: Subjects had low proliferative responses to HIV and p24 antigens prior to immunization and mounted strong lymphocyte proliferative responses to the immunizing HIV-1 virus, native p24, and autologous viral antigen post immunization. Similarly, subjects produced low amounts of interferon-gamma in response to HIV and p24 antigens prior to immunization and increased their interferon-gamma production in response to HIV-1, native p24, and to autologous antigen post-immunization. Furthermore, beta-chemokine responses measured as migratory inhibitory protein-1beta production were low at baseline in response to HIV-1 and native p24 antigens and were enhanced post immunization to HIV-1, native p24, and autologous antigen. CONCLUSIONS: In this study HIV-specific immune responses to autologous virus were observed after treatment with an HIV-specific immunogen.

[Trisomy 18: ultrasound aspects. Report of 40 cases]. / Trisomie 18: aspects échographiques. A propos de 40 observations.

OBJECTIVE: We describe the different ultrasound findings suggestive of trisomy 18. PATIENTS AND METHODS: We conducted a retrospective study in 40 cases of trisomy 18 diagnosed in the department of obstetrics at the Lille University Hospital between 1988 and 1998. RESULTS: Eighty percent of the women in this series were multiparous. Mean maternal age at discovery of the trisomy as 33.2 years and the mean gestational age was 20.4 weeks. Fifty-five percent of the cases were discovered during the second trimester of pregnancy, 22.5% during the third trimester and 22.5% during the first trimester. One ultrasound abnormality, at least, was detected in 36/40 cases (90%) a percentage that reached 96.8% taking into consideration the ultrasound examinations performed during the second and third trimesters (30/31 cases). The most frequently detected ultrasound abnormalities were: intra uterine growth retardation (IUGR: 50%), poly-hydramnios (42.5%), limb abnormalities (42.5%), cardiac defects (30%), facial abnormalities (37.5%), meningomyelocele (32.5%), digestive abnormalities (32.5%), urinary tract abnormalities (27.5%), lymphangiectasia and cystic hygroma (15%), and single umbilical artery (12.5%). Medical termination of pregnancy (TOP) was performed in 28 cases. There was one spontaneous miscarriage at 8 weeks and one in utero death (IUD) at 39 weeks in a patient who desired to continue her pregnancy. In 6 cases, the issue of the pregnancy was unknown because the patients were lost to follow-up. In 4 cases (10%), pregnancy was continued to delivery of live babies that only survived a few minutes to 7 days. CONCLUSION: The ultrasound signs suggestive of trisomy 18 change according to the term of pregnancy. At the first trimester, most of the signs are nonspecific, such as cystic hydroma or lymphangiectasia, and do not suggest the need for a karyotype. At the end of the second trimester, an association of various signs that alone would not be highly suspect suggest the need for further exploration in search of other signs: early IUGR, associated or not with poly-hydramnios, limb abnormalities, cardiac defects, omphalocele, diaphragmatic hernia, meningomyelocele, enlarged cisterna magna, choroid plexus cysts, single umbilical artery, facial dysmorphism, facial cleft, hydronephrosis.

[Reliability of the response rate in oncology: analysis of the causes for variation]. / Fiabilité des taux de réponses en oncologie: analyse des causes de variation.

We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. Major disagreements occurred in 43% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.

HIV-Specific CD4(+) and CD8(+) immune responses are generated with a gp120-depleted, whole-killed HIV-1 immunogen with CpG immunostimulatory sequences of DNA.

We examined the adjuvant effects of a synthetic CpG oligodeoxynucleotide immunostimulatory sequence (ISS) using a whole-killed, gp120-depleted HIV antigen (HIV-1 antigen) in a Lewis rat model. We hypothesized that HIV-1-specific CD4(+) T helper (Th) immune responses could be enhanced when an ISS was combined with an HIV-1 antigen in incomplete Freund's adjuvant (IFA). We also reasoned that if such Th responses were sufficient, such a combination might also induce HIV-specific CD8(+) T cell immune responses. Here we demonstrate that the HIV-1 antigen in IFA combined with ISS stimulates both CD4(+) and CD8(+) HIV-specific immune responses as measured by interferon-gamma (IFN-gamma) in the ELISPOT assay. A strong correlation between these CD4(+) and CD8(+) responses was demonstrated. Furthermore, we found that the HIV-1 antigen in IFA with ISS as an adjuvant stimulated strong antibody responses to core antigen (p24). These studies suggest that the combination of the whole-killed, gp120-depleted HIV-1 antigen in IFA with ISS may be an ideal candidate to test in nonhuman primates and in human studies as a preventive HIV-1 vaccine.

Cytokines in metastatic renal cell carcinoma: is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Français d'Immunothérape.

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNalpha2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNalpha2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNalpha2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 10(6) IU/m(2)/d), and IFNalpha2a was administered three times weekly at 18 x 10(6) IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNalpha2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNalpha2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNalpha2a. CONCLUSION: Cross-over after failure of IL-2 or IFNalpha2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.

Phenotypic analysis of human immunodeficiency virus (HIV) type 1 cell-mediated immune responses after treatment with an HIV-1 immunogen.

It was hypothesized that immune recognition could be stimulated with combined immune-based and potent antiviral drug therapies. This study examined human immunodeficiency virus type 1 (HIV-1)-specific lymphocyte proliferation before and after treatment with an inactivated HIV-1 immunogen in 15 chronically infected HIV-1 seropositive subjects. Lymphocyte proliferation to the immunizing antigen (gp120-depleted HIV-1; P<.001), purified native p24 (P<.001), and recombinant p24 (P<.05) increased after treatment with the HIV-specific immune-based therapy. By HIV-1 antigen-specific flow cytometry, T helper CD4 lymphocytes, CD8 lymphocytes, and NK cells (all P<.001) were the predominant cell types proliferating in vitro after treatment. Additional phenotyping of proliferating cells revealed predominantly CD4 and CD8 memory (both P<.001) phenotypes. This study supports the concept that in vitro lymphocyte proliferation to HIV-1 antigens, augmented after treatment with an inactivated HIV-1 immunogen, involves primarily CD4 and CD8 cell memory immune responses.

Excision repair defect in Rothmund Thomson syndrome.

Rothmund Thomson syndrome is a rare autosomal recessive skin disorder. The main clinical feature is poikiloderma appearing in early childhood associated with skeletal abnormalities. Early occurrence of malignancies is another relevant feature. Here we describe the clinical features of 2 patients with Rothmund Thomson syndrome who were investigated for the in vitro DNA repair capacities of blood cells following UVC radiation exposure. DNA excision repair, assessed with unscheduled DNA synthesis following UVC exposure, was decreased in both patients. Such a defect might explain the patients' sensitivity to sunlight and the relatively high risk of cancer associated with this syndrome.

Clinical evaluation of the cutaneous phototoxicity of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin.

The cutaneous phototoxic reaction induced by intravenous injection of 5,-10,-15,-20-tetra(m-hydroxyphenyl)chlorin (mTHPC) has been clinically evaluated in patients undergoing photodynamic therapy. These tests were performed on the backs of 23 patients with a solar simulator at various times after drug administration ranging from 5 h to 57 days. The mTHPC doses ranged from 0.1 to 0.3 mg/kg, and the illuminations lasted from 30 s up to 8 min. These tests have shown that the duration of the skin photosensitization induced after a typical therapeutic dose of mTHPC (0.15 mg/kg) is less important than with Photofrin (2 mg/kg). The level of mTHPC in the skin was also assessed in vivo and at times corresponding to the irradiations using an optical fiber-based spectrofluorometer. This study indicates that the light-induced fluorescence spectroscopy of mTHPC enables prediction of the degree of photosensitivity of the skin.

A primer on HIV type 1-specific immune function and REMUNE.

The ability to recognize HIV antigens is lost early in HIV-1 infection. Individuals with nonprogressive HIV disease have been observed to mount strong immune responses against the virus and have become a paradigm to emulate with immune-based therapies. Highly active antiviral drug therapy (HAART) has now become the standard of care for HIV-1-infected individuals. Because HIV-specific anergy occurs early in HIV infection, HAART initiated after primary infection may not reconstitute HIV-specific immune function. We have been investigating the effects of an immune-based therapy, called REMUNE, in HIV-1-seropositive individuals. REMUNE has been observed to stimulate HIV-1-specific immune function measured by delayed-type hypersensitivity, lymphocyte proliferation, Th1 cytokine, and beta-chemokine production. Multiple Phase II studies and a Phase III clinical end-point study are ongoing in thousands of seropositive individuals in order to test the clinical utility of REMUNE. The clinical testing of REMUNE and other promising immune-based therapies may provide additional treatment modalities useful in the chronic management of HIV-1.

Photodynamic therapy of early squamous cell carcinomas of the esophagus: a review of 31 cases.

BACKGROUND AND STUDY AIMS: Patients with cancers of the head and neck have a strong tendency to develop early synchronous and metachronous carcinomas of the esophagus. In many of these patients, whose general condition is poor as a result of alcohol and tobacco abuse, the second primary cancers require minimally invasive treatment. The aims of this study were to evaluate the efficacy of photodynamic therapy for the treatment of early esophageal carcinomas and to compare the results obtained with three different photosensitizers (hematoporphyrin derivative), porfimer sodium (Photofrin II), and meta-(tetrahydroxyphenyl)chlorin (m-THPC). PATIENTS AND METHODS: Thirty-one early squamous cell carcinomas (Tis or T1a) of the esophagus were treated by photodynamic therapy in 24 patients. Nine tumors were treated with hematoporphyrin derivative, eight with Photofrin II and 14 with m-THPC. RESULTS: The early cancers were cured in 84% of patients after a mean follow-up period of 2 years. Because the number of cases included in each group was small, the differences in recurrence rates for the different photosensitizers could not be evaluated statistically, but m-THPC was more phototoxic, induced a shorter period of photosensitization of the skin, and had better selectivity than either of the other photosensitizers. There were four major complications: two stenoses and two esophagotracheal fistulas. CONCLUSIONS: Photodynamic therapy eradicates early squamous cell carcinomas (Tis and T1a) of the esophagus efficiently. Transmural necroses leading to fistulas can be avoided by using a low-penetrating wavelength of laser light (green light at 514.5 m instead of red light at 630 or 652 nm). Stenoses always result from circumferential irradiation of the esophageal wall, and this can be avoided by using a 180 degrees or 240 degrees windowed cylindrical light distributor.

Characterization of highly purified, inactivated HIV-1 particles isolated by anion exchange chromatography.

This report characterizes inactivated, gp120 depleted, HIV-1 particles purified by an anion exchange chromatography production process. This antigen formulated with incomplete Freund's adjuvant constitutes Remune, which is being evaluated in a phase III clinical endpoint trial to determine the effect of this immune-based therapy on clinical progression of HIV-1 seropositive patients. Multiple production lots of the inactivated HIV-1 antigen strain HZ321, isolated by anion exchange chromatography, exhibit purity of > 95% by gel filtration. These findings are corroborated by thin section electron microscopy showing a homogenous field of intact particles. Analyses of the purified virus particles for protein, lipid, carbohydrate and RNA show structural retention of the envelope proteins, lipid bilayer and core components after large scale processing. The qualitative identification of at least 85% of total HIV-1 protein is determined by ELISA, Western blot, HPLC and amino acid sequencing analyses. Quantitative values are assigned to 50% of these proteins. The data confirm the presence of virally encoded proteins p6, p7, pI15, p17, p24, p32, pI39Gag, gp41, pp55Gag, p66/51, Vpr, Vif and Nef. Excellent consistency between production lots and equivalency to HIV-1 preparations purified by sucrose density gradient sedimentation has been established for protein and lipid composition, and overall purity. These findings further establish that non-viral encoded proteins and lipids are integral structural components of the intact virion and are not contaminants unique to a particular isolation method. The data confirm the presence of multicomponent antigens in the viral particles for stimulating a broad HIV-1 specific immune response. Finally, the work demonstrates that the two inactivation procedures (beta-propiolactone and gamma irradiation), which achieve efficient viral inactivation meeting US FDA guidelines, do not damage the protein antigens of the viral particles.

Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie.

BACKGROUND: Recombinant human interleukin-2 (aldesleukin) and recombinant human interferon alfa can induce notable tumor regression in a limited number of patients with metastatic renal-cell carcinoma. We conducted a multicenter, randomized trial to determine the effect of each cytokine independently and in combination, and to identify patients who are best suited for this treatment. METHODS: Four hundred twenty-five patients with metastatic renal-cell carcinoma were randomly assigned to receive either a continuous intravenous infusion of interleukin-2, subcutaneous injections of interferon alfa-2a, or both. The main outcome measure was the response rate; secondary outcomes were the rates of event-free and overall survival. Predictive factors for response and rapid progression were identified by multivariate analysis. RESULTS: Response rates were 6.5 percent, 7.5 percent, and 18.6 percent (P<0.01) for the groups receiving interleukin-2, interferon alfa-2a, and interleukin-2 plus interferon alfa-2a, respectively. At one year, the event-free survival rates were 15 percent, 12 percent, and 20 percent, respectively (P=0.01). There was no significant difference in overall survival among the three groups. Toxic effects of therapy were more common in patients receiving interleukin-2 than in those receiving interferon alfa-2a. Response to treatment was associated with having metastasis to a single organ and with receiving the combined treatment. The probability of rapid progression of disease was at least 70 percent for patients with at least two metastatic sites, liver metastases, and a period of less than one year between the diagnosis of the primary tumor and the appearance of metastases. CONCLUSIONS: Cytokines are active in a few patients with metastatic renal-cell carcinoma. The higher response rate and longer event-free survival obtained with a combination of cytokines must be balanced against the toxicity of such treatment.

Response rate accuracy in oncology trials: reasons for interobserver variability. Groupe Français d'Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: We evaluated the impact of an evaluation committee (EC) on patients' overall response status in a large multicenter trial in oncology. We identified reasons for disagreements between investigators and the EC. MATERIALS AND METHODS: The Cancer Renal Cytokine (CRECY) study was a French multicenter trial that tested cytokine therapy in 489 patients with metastatic renal cell carcinoma. Objective response (OR) evaluation included medical imaging and was studied according to international guidelines. A blinded peer review of all responders and litigious cases was performed by an EC. RESULTS: Major disagreements occurred in 40% and minor disagreements in 10.5% of the reviewed files. The number of significant tumor responses was reduced by 23.2% after review by the EC. Reasons for disagreements included errors in tumor measurements, errors in selection of measurable targets, intercurrent diseases, and radiologic technical problems. These reasons for disagreements are analyzed and discussed. CONCLUSION: We conclude that all therapeutic trial results should be reviewed by peer analysis of all presumed responders by an EC. International guidelines for response evaluation should be updated by including more reliable methods of measurements and definition of minimal imaging procedures.