Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Biomechanics of locomotion in Asian elephants.

Elephants are the biggest living terrestrial animal, weighing up to five tons and measuring up to three metres at the withers. These exceptional dimensions provide certain advantages (e.g. the mass-specific energetic cost of locomotion is decreased) but also disadvantages (e.g. forces are proportional to body volume while supportive tissue strength depends on their cross-sectional area, which makes elephants relatively more fragile than smaller animals). In order to understand better how body size affects gait mechanics the movement of the centre of mass (COM) of 34 Asian elephants (Elephas maximus) was studied over their entire speed range of 0.4-5.0 m s(-1) with force platforms. The mass-specific mechanical work required to maintain the movements of the COM per unit distance is approximately 0.2 J kg(-1) m(-1) (about 1/3 of the average of other animals ranging in size from a 35 g kangaroo rat to a 70 kg human). At low speeds this work is reduced by a pendulum-like exchange between the kinetic and potential energies of the COM, with a maximum energy exchange of approximately 60% at 1.4 m s(-1). At high speeds, elephants use a bouncing mechanism with little exchange between kinetic and potential energies of the COM, although without an aerial phase. Elephants increase speed while reducing the vertical oscillation of the COM from about 3 cm to 1 cm.

Cholesterol depletion perturbs calcium handling by rat submandibular glands.

The sensitivity to cholesterol depletion of calcium handling by rat submandibular glands was investigated. The glands were digested with collagenase. After homogenization, the lysate was extracted at 4 degrees C with 0.5% Triton X-100 and the extract was submitted to an ultracentrifugation in a sucrose discontinuous gradient. A population of detergent-resistant membranes (DRM) was collected at the 5%-35% interface. The DRM had a higher content of cholesterol, saturated and long-chain fatty acids. Caveolin-1 and alpha(q/11) were located in these membranes. They were more ordered than vesicles from total cellular lysate as determined by anisotropy measurement. They disappeared after cholesterol extraction with methyl-beta-cyclodextrin (MCD). Exposure of the cellular suspension with MCD nearly abolished the response to carbachol, epinephrine, and substance P and inhibited the activation of phospholipase C (PLC) by these agonists and by sodium fluoride. MCD did not affect the mobilization of intracellular pools of calcium by thapsigargin. It increased the uptake of extracellular calcium or barium and did not inhibit the uptake of calcium after depletion of the intracellular stores of this ion. From these results, it is concluded that Triton X-100 can extract a fraction of membrane resistant to detergents. Treatment of the cells with MCD disrupts these membranes. The coupling between the heterotrimeric GTP-binding protein G(q/11) and poly-phosphoinositide-specific PLC is affected by disruption of these membrane fractions. At the opposite, the store-operated calcium channel (SOCC) is not affected by DRM-disruption.

Assessment of an electron-impact GC-MS method for organic acids and glycine conjugates in amniotic fluid.

We assessed the reliability of a method designed for common electron-impact GC-MS systems to determine in a single run most organic acids and glycine conjugates of clinical interest in amniotic fluid. Suitable sensitivity was achieved by dividing the selected-ion chromatogram into 12 time segments during which the monitoring dwelt on specific ions. Twelve metabolites were simultaneously quantified in amniotic fluid, with performances ranging from very good to clinically acceptable. The total coefficient of variation was 2.5-14.1% and the detection limit was well below the lower value of the physiological range. For five other metabolites, the precision was lower and/or the detection limit was near the physiological range. The method was clinically assessed by the prenatal detection of three cases of tyrosinaemia type I and one case of propionic acidaemia. Analytical and clinical evaluation of the method showed that GC-MS with electron-impact fragmentation can be an informative analytical approach for low-level organic acids in physiological fluids. Apart from the case of glycine conjugates, the method shows a fair reliability for amniotic fluid analysis, which might warrant its use for prenatal diagnosis of organic acidurias. However, this method cannot replace procedures using isotopic internal standards, nor GC-MS based on chemical ionization fragmentation, which remain confirmatory analytical methods of choice.

EXOCAM: Mars in a box to simulate soil-atmosphere interactions.

We present the principle of the EXOCAM chamber, devoted to the study of physical-chemical interactions between the atmosphere and the surface and subsurface in Mars conditions. The purpose of this experiment is to reach a better knowledge of the physical and chemical processes that altered the atmosphere-soil coupled system. We describe the scientific goals of EXOCAM, the multiple fields that will benefit from this experiment and the instrumentation that is devoted to the analysis of the results. We also give a description of the chamber and its main devices.

Postoperative radiotherapy in the management of adult soft tissue sarcoma of the extremities: results with two different total dose, fractionation, and overall treatment time schedules.

PURPOSE: This retrospective study was performed to evaluate two postoperative radiotherapy schedules in terms of dose, fractionation, and overall treatment time in soft tissue sarcoma (STS) of the extremities. METHODS AND MATERIALS: Between January 1984 and December 1993, 62 patients with newly diagnosed localized STS of the extremities were treated with maximal conservative surgery and postoperative radiotherapy (RT). Forty-five patients received 50 Gy with conventional fractionation plus a boost dose (5 to 20 Gy). Seventeen patients had hyperfractionated accelerated radiotherapy (HFART) up to a dose of 45 Gy in 3 weeks. RESULTS: With a median follow-up of 72 months, the 5-year local failure rate was 25%, the 5-year disease-free and overall survival rates were respectively 42% and 62%. The 3-year local relapse, disease-free, and overall survival rates were respectively 16%, 44%, and 70% in the conventional radiotherapy group, and 36%, 47%, and 82% in the HFART group (NS). No factor significantly influenced local control with a trend, however, in favor of conventional RT (p = 0.10). CONCLUSION: HFART at the dose of 45 Gy does not seem to be superior to the standard RT schedule, neither in terms of local control, survival, nor in terms of long-term side effects. However this dose could be considered too low as well as the power of comparison between the two groups to draw definitive conclusions.

[Primary cutaneous leiomyosarcoma: 32 cases]. / Léiomyosarcomes cutanés primitifs: 32 cas.

BACKGROUND: Superficial leiomyosarcomas are rare tumors, which may be confined to the dermis or extend to subcutaneous tissues. PATIENTS AND METHODS: We report the results of a retrospective study of 32 patients treated for leiomyosarcomas through a twenty-two year period (from 1975 to 1997). RESULTS: Mean age was 45 years, with 50 p. 100 of patients less than 35 years of age. Forty seven percent of the tumors were located on the lower limbs and mean diameter was 2.8 cm. Three clinical types have been isolated: nodule beneath normal epidermis (50 p. 100), purple nodule ulcerated or not (28 p. 100), swelling tumor (22 p. 100). Sixteen percent were intradermal, whereas sixty nine percent involved subcutaneous tissues. With regard to tumor grade, 37 p. 100 of tumors were grade I, 44 p. 100 of tumors were grade II, and 19 p. 100 were grade III. Immunohistochemical staining showed positive reactions for all tumors with anti-vimentin and anti-alpha smooth muscle actin. Main treatment was complete surgical excision. Follow-up informations were available for all patients and 75 p. 100 of them had a follow up period longer than a year. Five patients with leiomyosarcomas involving the subcutis developed local recurrences, and two of them died of the disease. DISCUSSION: Leiomyosarcomas can occur at any age without predominant sex-ratio. Main prognostic factors are tumor size, distal location, depth of tumor invasion and pathological grade. Immunohistological staining with anti-alpha smooth muscle actin is more sensitive and specific than with anti-desmin or anti-HHF 35. Main treatment is surgical excision with wide margins.

[Chondrosarcoma in Ollier's disease. Apropos of 2 cases and review of the literature]. / Les chondrosarcomes sur maladie d'Ollier. A propos de deux cas et revue de la littérature.

Ollier's disease is a rate affliction (not more than approximately 100 cases have been reported over a 30-year period) characterized by bone dysplasia in which evolution to degenerative neoplasia has been described. Diagnosis of chondrosarcoma is delicate in these cases. It is a kind of slowly evolving low grade malignant tumor. Surgery is the primary treatment course, and can lead to remission. Prognosis, depending on the number and dimension of the lesions, their localization and metastasis prevention, is usually good, but relapses are relatively frequent: 25 to 50%. In case of relapse, radiotherapy and chemotherapy were tested but their efficacy is limited. We report here two clinical cases and discuss literature data.

[Digital multi-filter auditory prosthesis: study of its efficiency in function of number of filters and their programming]. / Prothèse auditive numérique multifiltres: étude de l'efficacité en fonction du nombre de filtres et de leur programmabilité.

We designed a prototype of a 7-filter digital auditory prosthesis table prototype. For each of these filters frequency band width, amplification and compression were programmable in order to adapt these parameters to the deaf patient's audiometric particularities. We compared the hearing improvement it was possible to obtain either with the 3-analogue-filter auditory prosthesis Triton 3004 from Siemens, or with our prototype as a function of the number of filters (3, 4 or 7) and their frequency band width programmability. We tested 21 patients suffering from middle or severe neurosensory hearing loss. This study allows to demonstrate that to overpass the present analogue T004 device a 7 programmable-width-filter strategy seems to be the most appropriate. Further studies benefiting with material improvement of our prototype and finer audiometric adjustment of filter strategies as well as long term clinical studies have to be carried out.

Auditory performances of a 3-4-7 programmable numeric filter hearing aid.

We designed a non-portable prototype seven-filter digital auditory hearing aid. For each of the filters, frequency bandwidth, amplification and compression were programmable in order to adapt these parameters to the deaf patient's audiometric characteristics. We compared the hearing improvement it was possible to obtain either with the three-analogue filter auditory prosthesis Triton 3004 hearing aid from Siemens or with our prototype as a function of the number of filters (three, four or seven) and their frequency bandwidth programmability. We tested 21 patients suffering from moderate to severe sensorineural hearing loss. This study allowed us to demonstrate that a seven programmable-width filter strategy seems to be more effective than the present analogue T004 device. Further studies with improvement of our prototype and finer audiometric adjustment of filter strategies, together with long-term clinical studies, need to be carried out.

Asynchronous interleaved stimulation (AIS): a new speech coding strategy for cochlear implant.

Cochlear implants use a fixed or F0 dependent stimulation rate, whatever the sound analysed (vowel or consonant) or procedure (fixed filters or FFT). We present a procedure which varies as a function of the input signal. This method is based on FFT analysis using a variable width analysis window. Short windows are applied on the transient part of the signal, providing poor frequency resolution but good time resolution; they permit us to accurately follow the speech signal in time during its fast temporal variations. Large windows are applied on the stationary parts of the signal, providing better frequency resolution but poor time resolution. Transient parts of the speech order this window switching; they are detected using the statistical properties of the FFT; moreover, the narrow windowing is coupled to an increase of the stimulation frequency. This strategy has been implemented using the DIGISONIC cochlear implant software, and clinically assessed in 6 regular cochlear implant users, on the basis of a consonant-vowel-consonant test. This Asynchronous-Interleaved-Stimulation (AIS) strategy provides the patients with better discrimination than fixed window FFT analysis. The coding protocol will be described and results presented.

[Angiosarcoma of the breast. Apropos of 8 cases and review of the literature]. / Les angiosarcomes du sein. Etude de 8 cas et revue de la littérature.

The 8 cases of primary breast angiosarcoma which were diagnosed, treated and had their follow-up at the Gustave-Roussy Institute between 1954 and 1995 are reported. The age at presentation ranged from 32 to 68 years. In 4 patients the vascular nature of their mammary lesion was conspicuous by a violaceous discolorations of the overlying skin. No patient had enlarged ipsilateral axillary lymph nodes. One patient had metastases. In 2 out of 5 patients who had a partial surgical or fine-needle biopsy before treatment, the diagnosis was missed, and adequate treatment was unduly delayed. The tumor most often presents as an ill defined area made of dense endothelium-lined papillae. A remarkable picture of "soap bubbles" has been identified in 4 cases. The "meshes" of fatty areas appear to be reinforced as they are infiltrated by tumor cells. This appearance may be specific of mammary angiosarcoma. By the French Cancer Centers' grading system for soft tissue sarcomas in general, grade is III in 3 tumors, II in 2 tumors, I in 3 tumors. Five tumors were treated by total mastectomy only. In 3 cases a total mastectomy was followed by radiation therapy to the chest wall. At diagnosis a chemotherapy was administered only to the patient who had metastases. Median disease-free survival was 9 months. Median overall survival was 13 months. From a review of the literature a simple mastectomy appears to be necessary as well as enough for local treatment. Patients with a grade III angiosarcoma of the breast should be included into a therapeutical trial of adjuvant chemotherapy for soft tissue sarcomas in general.

[Asynchronous sequential stimulation. A new signal treatment for cochlear implants]. / Stimulation séquentielle asynchrone. Un nouveau traitement du signal pour les implants cochléaires.

Cochlear implants use a fixed or FO dependent stimulation rate, whatever the sound analysed (vowel or consonant) and its analysis procedure (fixed filters or FFT). We present a procedure which varies as a function of the nature of the input signal. This method is based on FFT analysis using a variable with analysis window. Short windows are applied on the transient part of the signal, providing poor frequency resolution but good time resolution; they accurately permit to follow the speech signal in time during its fast temporal variations. Large windows are applied on the stationary parts of the signal, providing better frequency resolution, but poor time resolution. Transient parts of the speech order this window switching; they are detected using the statistical properties of the FFT; moreover the narrow windowing is coupled with an increase of the stimulation frequency. This strategy has been implemented using the Digisonic cochlear implant software, and clinically assessed on 6 regular cochlear implant users, owing to a consonant-vowel-consonant test. This Asynchronous-Interleaved-Stimulation (AIS) strategy provides the patients with better discrimination than fixed window FFT analysis. The coding protocol are described and results presented.

Objective evaluation of vowel identification with the Digisonic cochlear implant.

Perceptual assessment of speech recognition performance with cochlear implants is confronted with problems raised by patients' availability and specificity. These problems can be avoided by using objective evaluation methods based on automatic classification of speech sounds. In the present report, different tuning strategies for the Digisonic cochlear implant were evaluated by discriminant analysis. The results presented here concern the correct classification of vowels. A set of 600 vocalic items, corresponding to 10 vowel categories and produced by 20 French speakers, were processed by the Digisonic DX10 with two different strategies. In the linear strategy, center frequencies of the 15 Digisonic channels were almost equally spaced in acoustic units (Hz). In the mel strategy, center frequencies were almost equally spaced in psychoacoustic units. For each strategy, energy levels of the frequency channels were quantified for each vocalic item and processed by statistical discriminant analysis for classification into 10 vowel categories. Results mainly show that the percent correct classification (PCC) is larger for the mel strategy and that the improvement is due to a higher concentration of frequency channels below 4 kHz. Implications of these results for the tuning of cochlear implants are discussed.

High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.

PURPOSE: The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen. PATIENTS AND METHODS: Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity. RESULTS: One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months. CONCLUSION: The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

[Liposarcoma of the spermatic cord: apropos of a case with review of the literature]. / Liposarcome du cordon spermatique: à propos d'un cas avec revue de la littérature.

We report a case of spermatic cord liposarcoma in a 72-year-old man. Local disease progression was observed in spite of multinodal treatment, including repeated wide surgical excision, radiotherapy and chemotherapy. The literature and the treatment modalities of spermatic cord liposarcomas are reviewed.

MR imaging in the follow-up of malignant and aggressive soft-tissue tumors: results of 511 examinations.

PURPOSE: To present magnetic resonance (MR) imaging findings from 511 follow-up examinations of aggressive soft-tissue tumors. MATERIALS AND METHODS: One hundred eighty-two patients with aggressive soft-tissue tumours underwent postoperative T1- and T2-weighted imaging; 41 also underwent 51 gadolinium-enhanced T1-weighted examinations, and five underwent dynamic gadolinium-enhanced subtraction imaging. RESULTS: Twenty-four of 25 patients (101 of 102 examinations) without high signal intensity (HSI) at T2-weighted imaging had no recurrence. Among 79 patients (321 examinations) who demonstrated HSI without a mass, only two tumors recurred within 1 year. An HSI mass was found in 88 studies of 78 patients and represented recurrence (n = 60), hygroma (n = 24), or a radiation-induced pseudomass (n = 4). Hygromas did not enhance, while recurrences enhanced at 1-3 minutes and postirradiation change enhanced at 4-7 minutes. CONCLUSION: T2-weighted imaging can be used to identify possible recurrence of aggressive soft-tissue tumors, while gadolinium-enhanced imaging can be used to differentiate recurrences from hygromas and inflammatory change.

[Desmoid tumors or intra-abdominal fibromatoses]. / Tumeurs desmoïdes ou fibromatoses intra-abdominales.

Intraabdominal desmoid tumour or fibromatosis, recurrent but non-metastatic, invasive, fibroblastic proliferations, are rare tumours. From 1968 to 1989, 16 patients were treated at Gustave Roussy Institute. They were associated with familial adenomatous polyposis in 10% of cases. These tumours, observed mainly in young women (70 to 85% of cases), are aggravated by pregnancy, and spontaneous regression can occur at menopause, proving their hormonal dependence. Although histologically benign, they are serious lesions due to their invasive character; their excision is complete in only 50% of cases. They recur in 30% to 75% of cases and cause death of the patient in 30% of cases. Treatment is surgical but due to their often very slow course, and their spontaneous stabilisation in some cases, a mutilating surgical treatment (extensive small intestine resection) does not seem to be justified. Radiotherapy is effective only at doses incompatible with the site of these tumours (35 to 60 Gy). Chemotherapy has never been shown to be effective.