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.

The importance of histologic grade in long-term prognosis of breast cancer: a study of 1,010 patients, uniformly treated at the Institut Gustave-Roussy.

In a study of 1,010 patients with solitary, unilateral, nonmetastatic breast cancer, the histologic grade, assessed by a multifactorial analysis (Cox model) to study its significance with other prognostic factors, was found to be an important, independent factor. For 612 operable patients, two laboratory characteristics, the number of histologically positive nodes and the histologic grade, were the most valuable predictors. These two factors alone form a predictive index that may be an excellent and simple guide for the clinical decision of subsequent therapy. For 398 patients with inoperable breast cancer (ie, tumor greater than or equal to 7 cm, N2-3, inflammatory, skin fixation, and clinically rapidly growing forms), the histologic grade (performed on drill or cutting needle biopsy) was again a most important (and with inflammatory forms the most important) predictor of prognosis in these patients. Our data support that performing our modified histoprognostic grading of Scarff and Bloom is simple, reproducible, incurs no additional cost, may be carried out in the simplest histology laboratory, and finally, defines an important risk factor in all patients. It should be routine for all breast cancer specimens. Furthermore, studies of adjuvant therapy should stratify patients for this variable.

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.

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.

Twenty years experience of interstitial iridium brachytherapy in the management of soft tissue sarcomas.

From February 1968 to February 1988, 50 patients above 10 years of age with a soft tissue sarcoma were treated with interstitial brachytherapy, combined with a wide excision. After pathologic review, 48 were included in the final analysis. A pathological grading was made possible in 41, which showed a majority of high grades (2 + 3 = 86%). Patients presented mainly with small (less than 5 cm: 36) or mid-size lesions (greater than 5 cm: 12). The tumor was located in the limbs (32), trunk (9), and head and neck (7). Four patients had metastases at the time of treatment. Brachytherapy was part of the initial treatment in 22 cases, and of a salvage procedure after previous excision(s) combined or not with another form of treatment in 26. A uniform technique of iridium 192 wires after-loaded in plastic tubing was used. Sixty Gy median doses were delivered with brachytherapy alone (44) or combined with external beam (4). Sixteen patients also received an adjuvant chemotherapy. Follow up ranged from 16 months to 20 years (median 82 months). At the time of analysis, two patients (4%) only had failed in the irradiated volume, but the marginal failures rate (14:31%) was unexpectedly high. Seven of the patients who failed (43%) were salvaged by a second similar procedure. The 5-year survival was 62% in non-previously treated patients and 56.5% in previously treated ones (pNS). By multivariate analysis, only the tumor location appeared predictive of LF (p less than 0.01), which in turn was strongly correlated with the metastatic outcome (p less than 0.01). Necroses were observed in 17 cases (35%) and associated with a benign course in most of them. High dose brachytherapy combined with conservative surgery is highly effective in small and mid-size soft tissue sarcomas located in the extremities and head and neck, whereas in trunk and in recurrent tumors, the adjunction of large fields external radiotherapy and/or possibly polychemotherapy appears necessary.

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.

[Local and regional lymph node invasion in breast cancer]. / L'envahissement ganglionnaire loco-régional des cancers du sein

The significance and the pronostic value of nodal involvement were studied in patients suffering from mammary carcinoma over the past fifteen years at the Institute Gustave-Roussy. An average of eighteen lymph nodes per patient were examined by routine methods. In 70% of the cases there was axillary involvement as well as in 42% of the cases classified as NO. Such involvement seems to proceed step by step from the lower lymph nodes to the upper ones and is significantly more frequent when the tumor is located externally or centraly (70%) than when the tumor is located in an internal quadrant (55%). Involvement of the interpectoral chain of Rotter was found in only 12% of these cases and practically never in an isolated manner. Internal mammary chain involvement, present 25% of the cases, did not seem to be connected to a median or lateral location of the tumor. The number of involved nodes has great prognostic significance, much more so than the presence of capsular rupture or sinus histiocytosis. The prognosis is much poorer if three or more nodes are involved: the seven year survival is about 85% when 0, 1 or 2 nodes are involved, and falls to 44% when three or more are involved.

[Neurosarcoma associated with Von Recklinghausen disease: apropos of 25 cases observed at the Gustave Roussy Institute from 1967 to 1990]. / Neurosarcome associé à une maladie de Von Recklinghausen: à propos de 25 cas observés à l'Institut Gustave-Roussy de 1967 à 1990.

In the absence of systematic immunohistochemistry investigations, only 25 cases (out of 69) clearly diagnosed as neurosarcoma due to the association with Von Recklinghausen disease (ie, neurofibromatosis type 1) and treated at the Institut Gustave Roussy were included in the present study. Neurosarcoma consists of a neurocristopathy whose cells migrate to several parts of the body in order to constitute neuroglia, Schwann cells, pigmented and endocrinal tissues. From 1967 to 1990, 25 cases of such neurosarcomas associated with a neurofibromatosis type 1 were seen at our institute. Three different histological terms exist for this tumour: malignant schwannoma, neurosarcoma, and more recently, malignant peripheral nerve sheath tumours (MPNST). The median age (23 years) of the patients with neurofibromatosis type 1 is lower than that of patient with isolated neurosarcoma. Their sex ratio is 2/1. Primary tumour surgical exeresis was performed in all cases, with poor results in 7. Post-operative radiation therapy was not systematically used in this series. It was administered only in cases with incomplete surgical exeresis or when a local recurrence occurred. Adjuvant CYVADIC (doxorubicin, procarbazine, cyclophosphamide, vincristine) chemotherapy was administered in 5 cases, of in cases of relapse (8). All cases but 2 (the most recent ones) relapsed within 1 to 226 months (median 7 months). In addition, 13 patients developed metastases. Overall, the 2-year and 4-year survival rates were 41% and 18%, respectively. Our observations confirm the very poor prognosis for the association of neurofibromatosis type 1 and neurosarcoma. This finding should lead to systematically associate radical surgical exeresis, post-operative irradiation and adjuvant chemotherapy in the treatment of these patients.

[Mesenchymal breast sarcomas. Apropos of 25 cases]. / Les sarcomes mammaires mésenchymateux. A propos de 25 cas.

Breast sarcoma are rare, representing 1% of all malignant breast tumours. This is a retrospective study of 25 patients with a breast sarcoma, treated at Institut Gustave Roussy from 1954 to 1981. Thirty six per cent of these arose in a cystosarcoma phyllodes. A variety of histologies were found, the main one being malignant fibrohistiocytoma (44%). Nodal involvement was rare (4%) and, as in other sarcoma, hematogenous spread of metastases was more usual. Local recurrence occurred in 44% of cases and distant metastases (usually pulmonary) in 24%. The 3 year disease-free survival was 60% and the major prognostic factor was the mitotic index. Surgery is the treatment of choice of these tumours, supplemented by local irradiation in those cases where only a tumorectomy has been performed. The role of adjuvant chemotherapy remains undefined.

[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.

[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.

Clinical results of a 15-filter digital auditory prosthesis using selective amplification and compression.

Classical hearing aid efficiency was compared with that of a 15-filter digital auditory prosthesis in 23 patients suffering from partial sensorineural hearing loss. This device contains a microprocessor 320C25 from TEXAS Instruments. The sound signal is analysed at a sampling rate of 16 kHz. With the use of a Fast Fourier Transform (FFT), it provides the system with 15 energy levels at frequencies ranging from 0 to 8 kHz. The energy of each frequency band is multiplied by a coefficient stored in the device memory and directly dependent on the patient's audiometric specificities. The 15 signals are then synthesized by inverse FFT and mixed in a loudspeaker. The prosthesis is a rechargable battery powered 4 x 10 x 15 cm box programmable through a PC. The clinical results obtained with this 15-filter digital prosthesis are discussed and compared with the performances of present classical hearing aids.

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.

[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.

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.

[Alveolar soft part sarcomas. Apropos of 6 cases and review of the literature]. / Les sarcomes alvéolaires des parties molles. A propos de 6 cas et revue de la littérature.

This is a clinicopathologic study of 6 cases of alveolar soft-part sarcoma. The patients age ranges from 8 to 47 years. All patients are women. In 5 cases the localization of the primary tumor is the lower extremities. Histologically the tumors have a distinctive organoid pattern outlined by thin-walled capillaries and are composed of nests of large polyhedral cells with abundant finely granular, acidophilic cytoplasm. Two tumors, among the 4 tested cases, have cytoplasmic PAS positive diastase-resistant crystalline structures. Electron microscopic study of one tumor shows intracytoplasmic glycogen, small membrane-bound electron-dense granules, Golgi lamellae and crystalline structures. Immunoperoxidase study performed in one case reveals a positivity with antikeratin and anti-enolase (NSE) antibodies. The prognosis of this tumor is poor. The main metastasis are in the lung and in the brain. Often the patients develop metastasis before detection of the primary tumor. The histogenesis of alveolar soft part sarcoma and the identity of the characteristic crystalloids remain open for discussion.

[Elastofibroma dorsi. Apropos of 5 cases]. / Elastofibrome dorsal. A propos de cinq observations.

Elastofibroma is a rare tumor mainly found under the scapula. Based on a recent study of five cases, we would like to stress the importance of making the diagnosis of elastofibroma, as this lesion simply consists of dysplasia of the elastic fibres and is not malignant as could be suggested by clinical examination.

[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.

[The value of magnetic resonance imaging in the surveillance of fibromatosis. A study of 10 cases]. / Intérêt de l'imagerie par résonance magnétique dans la surveillance des fibromatoses. Etude de 10 cas.

Retrospective study of 10 patients followed for fibromatosis after initial treatment by magnetic resonance imaging. There is a close correlation between an intense signal on weighted T2 images and tumour recurrence. Inversely, a low signal on the weighted T2 image indicated fibrotic sequelae without tumour recurrence. The examination should commence with the weighted T2 sequence. The injection of contrast medium may be an alternative.

[Conservative surgical treatment of osteogenic sarcoma of the limbs. Technics and functional results]. / Traitement chirurgical conservateur des sarcomes ostéogéniques des membres. Techniques et résultats fonctionnels.

Sixty-three osteogenic sarcomata of the limbs in patients aged between 10 and 20 years were treated by en bloc resection combined with chemotherapy. A review was made after an average follow-up of less than four years, which is too short a time to assess the carcinologic value of this type of treatment but sufficiently long to assess functional results and surgical technique. The resection was made through apparently normal tissues, thanks to meticulous pre-operative investigation and an appreciation of the extent of the tumour at operation. The tissues contaminated by a biopsy were removed. Three local recurrences were seen and in three other cases further extension in the operated limb was due to metastases. Reconstruction almost always utilised inert prosthetic implants often made during the pre-operative phase of chemotherapy. In cases of resection of the upper tibia an original procedure was developed to reconstruct the quadriceps using muscle-plasties. In 32 out of 39 knees, the immediate functional result was good. Only 10 still survived after two years, with nine good functional results. The authors conclude that en bloc resection is preferable to amputation in young patients both for those who will have a limited survival and those who will have long survival because of improvements in chemotherapy treatment. The risk of secondary loosening requires the use of more grafting procedures in reconstruction.