Neoadjuvant moderately high-dose chemotherapy with rh-G-CSF in locally advanced breast carcinoma.

UNLABELLED: The poor results of local treatment for locally advanced breast carcinoma (LABC) justify the use of chemotherapy as primary treatment. Retrospective studies have shown a positive correlation between dose and response rate in advanced breast cancer. G-CSF has shown efficacy in achieving optimal dose intensity and ameliorating chemotherapy-induced myelosuppression. The aim of the present study was to assess the efficacy of a moderately high-dose chemotherapy regimen in terms of response rate, disease-free and overall survival and to assess the role of G-CSF in induced neutropenia. METHODS: Inclusion criteria were the following: age <65 years, WHO performance status <2, histologically proven breast carcinoma, adequate hematologic, renal and hepatic function, stage IIIA or IIIB disease, and no metastatic disease. No prior chemotherapy or radiotherapy was allowed. Three cycles of the following chemotherapy were used preoperatively: epirubicin (100 mg/m2 on day 1), cyclophosphamide (400 mg/m2 for 3 consecutive days) and rh-G-CSF (5 microg/kg/die from day 4 to day 12 every 14 days). After mastectomy or quadrantectomy plus radiotherapy, all patients were treated with 4 courses of adjuvant chemotherapy according to the CMF 1-8 schedule (methotrexate, 40 mg/m2 cyclophosphamide, 600 mg/m2; fluorouracil, 600 mg/m2; all on days 1 and 8, with recycle every 4 weeks). RESULTS: From May 1992 to June 1996, 57 patients with histologically proven LABC were preoperatively treated. Forty-four patients were premenopausal and 13 postmenopausal; the median age was 45 years (range, 29-64). Thirty-five patients had stage IIIA and 22 patients stage IIIB disease (7 with inflammatory disease). Forty-seven patients underwent radical mastectomy and 10 conservative surgery. A clinical response was noted in 93% (95% confidence interval, 83-98%) of patients (12% complete responses and 81% partial responses); 2 pathological complete remissions (3.5%) were obtained. No toxic deaths were observed. All patients had a follow-up of at least 42 months. The overall 5-year survival rate was 76% (standard error--SE), 6%) and the 5-year disease-free survival rate was 68% (SE, 6.3%). CONCLUSIONS: The 14-day regimen was well tolerated and effective in LABC patients, although not superior to standard-dose chemotherapy. To improve results the use of new drugs in controlled clinical trials seems warranted.

Pressure- and heat-induced inactivation of butyrylcholinesterase: evidence for multiple intermediates and the remnant inactivation process.

The inactivation process of native (N) human butyrylcholinesterase (BuChE) by pressure and/or heat was found to be multi-step. It led to irreversible formation of an active intermediate (I) state and a denatured state. This series-inactivation process was described by expanding the Lumry-Eyring [Lumry, R. and Eyring, H. (1954) J. Phys. Chem. 58, 110-120] model. The intermediate state (I) was found to have a K(m) identical with that of the native state and a turnover rate (k(cat)) twofold higher than that of the native state with butyrylthiocholine as the substrate. The increased catalytic efficiency (k(cat)/K(m)) of I can be explained by a conformational change in the active-site gorge and/or restructuring of the water-molecule network in the active-site pocket, making the catalytic steps faster. However, a pressure/heat-induced covalent modification of native BuChE, affecting the catalytic machinery, cannot be ruled out. The inactivation process of BuChE induced by the combined action of pressure and heat was found to continue after interruption of pressure/temperature treatment. This secondary inactivation process was termed 'remnant inactivation'. We hypothesized that N and I were in equilibrium with populated metastable N' and I' states. The N' and I' states can either return to the active forms, N and I, or develop into inactive forms, N(')(in) and I(')(in). Both active N' and I' intermediate states displayed different rates of remnant inactivation depending on the pressure and temperature pretreatments and on the storage temperature. A first-order deactivation model describing the kinetics of the remnant inactivation of BuChE is proposed.

Differential effect of pressure and temperature on the catalytic behaviour of wild-type human butyrylcholinesterase and its D70G mutant.

The combined action of temperature (10-35 degrees C) and pressure (0. 001-2 kbar) on the catalytic activity of wild-type human butyrylcholinesterase (BuChE) and its D70G mutant was investigated at pH 7.0 using butyrylthiocholine as the substrate. The residue D70, located at the mouth of the active site gorge, is an essential component of the peripheral substrate binding site of BuChE. Results showed a break in Arrhenius plots of wild-type BuChE (at Tt approximately 22 degrees C) whatever the pressure (dTt/dP = 1.6 +/- 1.5 degrees C.kbar-1), whereas no break was observed in Arrhenius plots of the D70G mutant. These results suggested a temperature-induced conformational change of the wild-type BuChE which did not occur for the D70G mutant. For the wild-type BuChE, at around a pressure of 1 kbar, an intermediate state, whose affinity for substrate was increased, appeared. This intermediate state was not seen for the mutant enzyme. The wild-type BuChE remained active up to a pressure of 2 kbar whatever the temperature, whereas the D70G mutant was found to be more sensitive to pressure inactivation (at pressures higher than 1.5 kbar the mutant enzyme lost its activity at temperatures lower than 25 degrees C). The results indicate that the residue D70 controls the conformational plasticity of the active site gorge of BuChE, and is involved in regulation of the catalytic activity as a function of temperature.

Combined pressure/heat-induced inactivation of butyrylcholinesterase.

The combined effects of pressure and temperature on the activity of butyrylcholinesterase (BuChE) were investigated in the pressure range from 10(-3) to 5 kbar and temperature range from -10 degrees C to 70 degrees C. Inactivation of the enzyme showed a complex dependence on pressure and temperature. Under moderate pressures (1-3 kbar) at temperatures 40-65 degrees C BuChE was resistant to heat inactivation; under other conditions of pressure and temperature, the action of both parameters was synergistic and caused inactivation. Results allowed to construct a pressure-temperature kinetic phase diagram for the enzyme inactivation. The elliptic diagram for the irreversible transition active-->inactive BuChE as a function of both pressure and temperature has a positive angular coefficient. This indicates that pressure acts as a stabilizer of BuChE against heat denaturation.

[Color processing of ultrasonographic images in extracorporeal lithotripsy]. / Colorisation des images échographiques en lithotritie extra-corporelle "C.I.E.L.E.C.".

A number of technical difficulties are encountered in the ultrasonographic detection of renal stones which unfortunately limit its performance. The margin of error of firing in extracorporeal shock-wave lithotripsy (ESWL) must be reduced to a minimum. The role of the ultrasonographic monitoring during lithotripsy is also essential: continuous control of the focussing of the short-wave beamand assessment if the quality of fragmentation. The authors propose to improve ultrasonographic imaging in ESWL by means of intraoperative colour processing of the stone. Each shot must be directed to its target with an economy of vision avoiding excessive fatigue. The principle of the technique consists of digitalization of the ultrasound video images using a Macintosh Mac 2 computer. The Graphis Paint II program is interfaced directly with the Quick Capture card and recovers the images on its work surface in real time. The program is then able to attribute to each of these 256 shades of grey any one of the 16.6 million colours of the Macintosh universe with specific intensity and saturation. During fragmentation, using the principle of a palette, the stone changes colour from green to red indicating complete fragmentation. A Color Space card converts the digital image obtained into a video analogue source which is visualized on the monitor. It can be superimposed and/or juxtaposed with the source image by means of a multi-standard mixing table. Colour processing of ultrasonographic images in extracoporeal shockwave lithotripsy allows better visualization of the stones and better follow-up of fragmentation and allows the shockwave treatment to be stopped earlier. It increases the stone-free performance at 6 months. This configuration will eventually be able to integrate into the ultrasound apparatus itself.

[Computer stimulation of endoscopic resection of the prostate]. / Simulateur de résection endoscopique de prostate.

The number of urologists in need of training is increasing whereas the number of resections of the prostate is falling. Patients are less and less willing to have their procedure serve for young residents to learn the technique of endoscopic resection of the prostate. Despite teachings and videoendoscopy, this procedure remains difficult to learn. We decided to develop a simulator for endoscopic resection after having seen the remarkable model of endoscopic simulation developed by French gastroenterologists and presented at the computer science workshop of the AFU symposium. The hypercard program, the laservision disk, and the CD ROM project were elected as a good introduction to this challenging although not unsurmountable problem. We had to adequate our goals to the resources of French urologists: the Macintosh II is the most sophisticated affordable computer. Computerization of the televised images of the endoscopic procedure and formalization of the gestures of the operator are required. Conventional image synthesis programs for use with the Mac II are either very slow or very limited. Conventional simulation programs are highly mathematical. Computerized images take up considerable memory space and large capacity disks or optical disks are required. The urologic laservision to which we contributed in 1986 contains few endoscopic images of the prostate but served as a basis for devising a methodology. Object programming with hypercard and animated image programs for Macintosh computers will be the starting points for our project that will benefit from the significant advances announced by Apple concerning color image file maintenance.