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Resume Les inhibiteurs de tyrosine kinase (TKI) de l’EGFR (erlotinib et gefitinib) sont utilises dans le cancer bronchique non a petites cellules (CBNPC) de stade IV en 2 e et 3 e ligne de traitement, et pour le gefitinib en premiere ligne en cas de mutation activatrices de l’EGFR. Ces drogues sont particulierement efficaces en presence de ces mutations, avec des taux de reponse d’environ 60–70%. Les donnees pharmacologiques in vitro et in vivo chez l’animal suggerent un effet equivalent de l’erlotinib et du gefitinib. Une seule etude de phase II a compare directement les deux molecules en 2 e ligne, avec un avantage non significatif en termes de reponse et de survie sans progression pour le gefitinib. Par contre le profil de tolerance cutanee etait statistiquement superieur avec le gefitinib. Les comparaisons indirectes des deux produits dans les differents essais de phase III ou ils sont compares a des chimiotherapies en 1 re ligne sont delicates, avec notamment un impact important du bras controle sur le hazard ratio pour la survie sans progression ou pour la survie globale. Cependant, les taux de reponse semblent similaires. Les etudes de cohortes et les etudes de phase IV montrent une absence de difference significative de reponse et de survie, et un profil de tolerance similaire.

Resume Pemetrexed est un nouvel antimetabolite multicible, intervenant dans le cycle des folates, mecanisme metabolique indispensable a la synthese de l’ADN. Cet antifolate multicible, contrairement aux antifolates classiques (methotrexate, raltitrexed et lometrexol), inhibe les trois enzymes cles : la Thymidilate Synthetase (TS), la Dihydrofolate Reductase (DHFR) et la GlycinAmide Ribonucleotide FormylTransferase (GARFT). Son activite va dependre de sa penetration a l’interieur de la cellule grâce a differents systemes de transport ainsi que de sa polyglutamation.

L’incidence de recidives cerebrales est de l’ordre de 5 % dans les lymphomes. Elle peut atteindre plus de 30 % dans le traitement du cancer du sein par trastuzumab [7] ou apres la prescription de chimiotherapies ne passant pas la barriere hematomeningee comme dans l’association doxorubicine plus docetaxel [3]. Que l’incidence soit faible ou elevee, cette complication est grave et de mauvais pronostic avec une issue fatale dans la majorite des cas. La radiotherapie est le traitement de choix des metastases cerebrales des tumeurs solides. Dans les lymphomes, la mise en place d’une prophylaxie systematique chez tous les patients ne se justifie pas car l’incidence reste faible. L’identification de sous-groupes de patients pour lesquels une prophylaxie aurait un interet majeur reste donc interessante et l’index pronostique international ajuste a l’âge (aa-IPI) pourrait etre utile dans ce cadre. L’ifosfamide est un anticancereux largement utilise. La forme active moutarde isophosphoramide (IFM) a un effet alkylant sur l’ADN. L’ifosfamide est metabolise par voie hepatique par la chaine oxydative des cytochromes P450. Comme la majorite des agents anticancereux, l’ifosfamide a des effets toxiques dont une neurotoxicite connue et due au catabolite chloroacetaldehyde. L’incidence de la neurotoxicite est tres faible lorsque la molecule est administree en perfusion continue. L’ifosfamide (IFO) et son metabolite actif (IFM) possedent tous deux la capacite de traverser la barriere hematoencephalique: un traitement a base d’IFO est, donc, a priori efficace dans la prevention des rechutes cerebrales chez les patients souffrant de lymphomes a haut rique de rechute. Le rapport benefice/risque pour de tels patients merite d’etre evalue.

Les effets secondaires toxiques sont indissociables de la chimiotherapie anticancereuse. Mais aujourd’hui, nous nous trouvons devant un phenomene nouveauqui est l’administration orale de ces medicaments anticancereux. Des effets secondaires qui pouvaient passer pour anodins lors de l’administration intraveineuse de ces produits, nausees-vomissements de grades 1 ou 2 par exemple, donc non susceptibles d’arreter le traitement, deviennent, avec la multiplication des formes orales, un reel probleme. Beaucoup de ces formes orales sont des nouvelles formulations de cytotoxiques classiquesque l’on sait, pour nombre d’entre eux, etre emetisants. L’engouement pour ces formes orales est louable: l’objectif est de maintenir les patients dans leur cadre de vie afin d’eviter de trop frequents sejours a l’hopital, surtout pour les sujets âges. Mais, quid de l’autoprise en charge de ces memes patients lors de la survenue, a domicile, d’effets secondaires, faut-il reprendre une capsule, une gelule ou pas ? Lespetites molecules ciblees ont l’avantage de ne pas ou peu presenter ce genre d’inconvenient. Elles sont dans l’ensemble moins problematiques, meme si d’autres types de toxicites, en particulier dermatologiques, sont quasiment constants.

Protein kinase C (PKC) family enzymes participate in several cell-signaling pathways by controlling proliferation, differentiation, senescence, invasion, and apoptosis both in normal and in cancer cells. The PKC family consists of serine/threonine kinases including 12 isoforms, which could be divided in three groups based on their interactions with calcium and diacylglycerol. Studies have suggested that PKCs play a role in carcinogenesis and maintenance of malignant phenotype. Potentiation of malignant phenotype may be mediated by activation of selective PKC isoenzymes and/or through altered isoenzyme expression profile compared to the originating tissue. PKC-δ is thought to mediate anticancer effects and PKC-α has often been linked to malignant phenotype. During the past few years, preclinical and clinical data with first generation PKC inhibitors/ activators provided insights that PKCs may indeed represent attractive targets for the discovery of small molecules with new anticancer properties. This review focuses on current knowledge on regulation of PKC-δ and PKC-α in cancer progression highlighting the potential role of those kinases as targets for anticancer therapeutics.

The low temperature horizontal tube multi-effect desalination (MED) process is thermodynamically the most efficient of all thermal distillation processes. A comprehensive multi-disciplinary development and design approach resulted in prevention of corrosion and scale formation on the plant’s heat transfer surfaces. It also allows the successful and most economical use of aluminum alloys for heat transfer tubes, as well as carbon steel epoxy coated shells for the evaporator body. The ability to use economically low grade heat, such as waste heat, exhaust steam from power station turbines as the primary heat source for MED, yields very low specific energy costs for sea water desalination. Recent developments of very economical low temperature deep pool nuclear heat reactors, when acting as the primary energy source for large MED plants, yield very low specific desalination energy costs. The combination of economical specific MED plant costs with low energy cost, together with the inherent durability of low temperature MED avoiding the necessity of comprehensive sea water pretreatment (such as with RO plants) make the MED process one of the best candidates for safe and durable large capacity economical desalination options. This paper describes the design principles and various energy considerations that result in this uniquely economical MED process and plant. It also provides an overview of various cases of waste heat utilization, and cogeneration MED plants operating for many years.

Epiphyseal involvement of a simple bone cyst (SBC) is uncommon. Eight patients are reported in whom an SBC was found to cross the growth plate, involving the epiphysis in seven patients and the apophysis in one. All patients had more than two pathologic fractures. In seven patients growth disturbance was found. Functional impairment did not develop in any patient. Radiographically, all lesions presented a characteristic involvement of the epiphysis and metaphysis in various proportions. Only one of four cysts treated with methyl-prednisolone acetate injections showed incomplete healing; the others failed to respond. After percutaneous grafting of autologous bone marrow, three of seven cysts healed and the others attained incomplete healing. Epiphyseal involvement of SBC should be considered a more aggressive form of an active lesion.

Club foot can be diagnosed by ultrasound of the fetus in more than 60% of cases. We have correlated the accuracy of the prenatal findings in 281 ultrasound surveys with the physical findings after birth and the subsequent treatment in 147 children who were born with club foot. The earliest week of gestation in which the condition was diagnosed with a high degree of confidence was the 12th and the latest was the 32nd. Not all patients were diagnosed at an early stage. In 29% of fetuses the first ultrasound examination failed to detect the deformity which subsequently became obvious at a later examination. Club foot was diagnosed between 12 and 23 weeks of gestation in 86% of children and between 24 and 32 weeks of gestation in the remaining 14%. Therefore it can be considered to be an early event in gestation (45% identified by the 17th week), a late event (45% detected between 18th and 24th weeks) or a very late event (10% recognised between 25th and 32nd weeks). We cannot exclude, however, the possibility that the late-onset groups may have been diagnosed late because earlier scans were false-negative results. The prenatal ultrasonographic findings were correlated with the physical findings after birth and showed that bilateral involvement was more common than unilateral. There was no significant relationship between the prenatal diagnosis and the postnatal therapeutic approach (i.e., conservative or surgical), or the degree of rigidity of the affected foot.

Primary subacute epiphyseal osteomyelitis is a rare disease. Owing to its insidious onset, mild symptoms, and inconsistent supportive laboratory data, diagnosis and treatment are usually delayed. The authors report a retrospective review of 16 patients with hematogenous osteomyelitis primarily affecting the epiphysis. In all of these patients an osteolytic lesion developed. In eight patients it was confined to the epiphysis or apophysis alone; in the other patients there was contiguous involvement of the adjacent metaphysis. Complete clinical and radiologic healing was observed in all patients after antibiotic therapy alone. Based on this experience, in view of the controversy in the literature, the authors recommend a conservative treatment policy in the management of both epiphyseal and epiphyseal-metaphyseal subacute osteomyelitis as the treatment of choice. Surgery should be reserved for persistent infection that does not respond to appropriate antibiotic therapy or when bone lesions cannot be distinguished from bone tumors by use of all available imaging modalities.

Geleophysic dysplasia is a rare skeletal dysplasia characterised by 'happy natured' facies, short stature with short limbs, brachydactyly, and joint contractures. This report describes a case of a patient with unilateral Legg-Calvé-Perthes-like changes associated with dysplastic proximal capital femoral epiphysis, typical to geleophysic dysplasia.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garre's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garre's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garré's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garré's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.

Subungual exostosis is a benign osteochondral tumor usually involving the distal phalanx of the great toe. The lesion most frequently occurs in the second and third decades of life and is rare before the age of 10 years. There are few reports of its occurrence in children, and most of them advocate partial or complete nail excision to treat this lesion successfully. We report our experience with six children and adolescents using a simple surgical technique that involves approaching the exostosis under the nail to preserve nail coverage. Rapid recovery and excellent cosmetic appearance were achieved immediately after the operation.

Resume La chimiotherapie sous exclusion vasculaire permet d’obtenir localement de tres fortes concentrations en substances cytotoxiques, sans effet secondaire systemique important. But de l’etude : Apprecier la faisabilite, la toxicite et la pharmacocinetique d’une chimiotherapie par perfusion isolee du foie, avec du melphalan. Materiel et methode : Six porcs (50–60 kg) ont eu une perfusion isolee du foie avec du Ringer lactate non oxygene, additionne d’un bolus de 15 mg de melphalan qui circulait pendant 30 minutes. L’effluent sus-hepatique, recueilli grâce a une sonde a double ballonnet placee dans la veine cave retro-hepatique, etait reinjecte par l’artere gastroduodenale, tandis que l’artere hepatique commune et la veine porte etaient clampees. Resultats : Apres l’injection, les concentrations en melphalan, dans le perfusât decrivaient un pic a 30 000 ng/mL puis suivaient une decroissance bi-exponentielle (n = 3). Les concentrations dans le sang peripherique ne depassaient pas 500 ng/mL. A la fin de l’intervention, les concentrations tissulaires en melphalan etaient d’environ 2 000 ng/g dans le foie et etaient indetectables dans le muscle. Le suivi postoperatoire pendant 14 jours (n = 2) n’a pas montre de modifications importantes des tests biologiques, ni de l’histologie hepatique. Conclusion : Suivant ce mode d’administration, le melphalan est capte tres rapidement par le foie, sans toxicite importante intra- ou extra-hepatique. L’utilisation d’une sonde de clampage endovasculaire est compatible avec une exclusion satisfaisante de la veine cave inferieure.

Simple bone cyst (SBC) is an enigma to the radiologist, pathologist and the orthopaedic surgeon. The etiology of this asymptomatic lesion that frequently causes pathological fracture is still unknown. It is probably self limited in nature, seen in children but rare among adults. The biological behavior is unpredictable as is the clinical course in various anatomical sites. This reflects on the high recurrence rate that has been associated with various treatment modalities. The clinical, radiological and biological features are discussed together with comparative review of treatment options from resection, curettage, and bone grafting to steroid injection and the latest experience of the use of percutaneous autologous marrow grafting in SBC.

We prospectively evaluated the percutaneous injection of autogenous bone marrow for the treatment of active simple bone cysts in ten consecutive children with cysts in the proximal humerus, proximal femur or tibia. The treatment included percutaneous biopsy, aspiration of fluid and the injection of autogenous bone marrow aspirated from the iliac crest. All the patients became painfree after a mean of two weeks and resumed full activities within six weeks. All ten cysts consolidated radiologically and showed remarkable remodelling within four months. Review at 12 to 48 months showed satisfactory healing without complications. Percutaneous injection of autologous bone marrow appears to be an effective treatment for active simple bone cysts.

Penetration of ceftriaxone into heart tissues (valves, myocardium, auricles, and pericardium) and mediastinal tissues (fat and sternal bone) was evaluated after two regimens of ceftriaxone administration. Ten patients (group 1) were given 1,000 mg of ceftriaxone intravenously 30 min before anesthesia. Ten other patients (group 2) received the same dose and then a second 1,000-mg dose at the time of initiation of cardiopulmonary bypass. Similar and very satisfactory penetrations of ceftriaxone into tissue were observed for both groups. During opening and closure of the thorax, mean ceftriaxone concentration was in excess of the MIC at which 90% of the potential pathogens were inhibited (> or = 4 micrograms/g) in the thoracic fat, the sternal bone, and the pericardium. No significant differences between the two administration regimens in penetration of ceftriaxone into tissue were observed. During cardiopulmonary bypass, the ceftriaxone concentration was > or = 4 micrograms/g in the myocardium, the endocardium, and the auricle. The regimen of ceftriaxone administration did not significantly influence penetration of the drug into heart tissues. However, for some patients in the two groups and mainly in the sternal bone at the time of thorax closure (6 patients in group 1 and 5 patients in group 2), ceftriaxone levels in tissues were less than the MICs (4 micrograms/g) for some potential pathogens (methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis). During the different steps of the surgical procedures, all (10 of 10) patients in each group had tissue ceftriaxone levels greater than the MICs for gram-negative aerobic bacilli (0.1 microgram/g), except for Pseudomonas spp.

Une distinction apparait, de facon tres nette, dans la therapeutique anticancereuse moderne, entre, les medicaments « classiques » qui sont tous des cytotoxiques, c’est-a-dire qui detruisent les cellules par action sur le noyau cellulaire, et une nouvelle classe de medicaments qui sont des cytostatiques qui vont freiner la croissance cellulaire en bloquant des facteurs de croissance ou des oncogenes. Il existe donc des therapeutiques ciblees en opposition aux therapeutiques « conventionnelles », ces nouvelles molecules ciblees font l’objet d’un chapitre specifique dans ce livre.

Dans le cancer du sein, l’apparition de metastases est signe d’incurabilite et releve d’un traitement medical dont deux modalites, l’hormonotherapie et la chimiotherapie, sont utilisees depuis des decennies et une, l’immunotherapie, d’utilisation recente, annonce les therapies ciblees. L’efficacite des traitements disponibles constatee quotidiennement est temporaire, modeste individuellement mais somme toute benefique par leur diversite.

We describe a five-year-old child with neurofibromatosis type I who developed a Charcot knee. Infiltration of the joint by tissue associated with the disease caused damage to the proprioceptive mechanism and resulted in severe joint instability, accelerated destruction and development of neuropathic arthropathy.

The incidence of central nervous system (CNS) recurrence in patients with lymphoma is about 5%. Nevertheless, this complication is very serious because it is almost always fatal. Its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The identification of subgroups for whom CNS prophylaxis may be of benefit is therefore important and the age-adjusted international prognostic index (aa-IPI) may be useful in this respect. Ifosfamide (IFO) is a widely used antitumor agent, requiring activation to isophosphoramide mustard (IPM) for DNA alkylation. IFO anabolism occurs through the hepatic microsomal cytochrome P450 system. As with the majority of antineoplastic agents, IFO has toxic side-effects. These include neurotoxicity due to the chloroacetaldehyde (CAA) catabolite. However, the incidence of neurotoxicity is low when IFO is administered as a continuous intravenous infusion. Both inactive IFO and active IPM cross the blood-brain barrier, making IFO treatment effective in the prevention of CNS metastasis in lymphoma patients at high risk of recurrence. The benefit/risk ratio for such patients should evaluated.

To study the longitudinal variations of plasma B-type natriuretic peptide (BNP) with reference to left ventricular ejection fraction (LVEF) during and after chemotherapy with cardiotoxic drugs.We prospectively measured plasma BNP using an immunoradiometric assay in 12 anthracycline-treated breast cancer patients monitored for a mean time of 880+/-293 days (pilot group). Prior to each cycle and throughout the following year, LVEF and cardiac output were measured by radionuclide ventriculography. Anthracycline pharmacokinetics was studied during the first cycle. Relationships between serial observations were analysed with the general linear mixed effects model. Identical methods were subsequently applied to a test group of 67 anthracycline or trastuzumab-treated patients.Five out of 70 (6.33%) patients developed anthracycline-induced heart failure. BNP concentrations were found to be positively correlated to anthracycline cumulative dose and negatively to LVEF values. Variables entering the mixed models were cumulative anthracycline dose, time and cardiac output.An infra-clinical cardiotoxicity of anthracyclines as defined by BNP elevation is frequent but reversible. Patients who developed heart failure showed a continuous BNP increase and concentrations over 100 ng/ml.

The marrow stromal cells (MSC) are essential for regulation of bone remodeling and hematopoiesis. It is of prime importance to isolate MSC and to expand the proliferating cells ex vivo. In this study, we analyzed cultured MSC for various cellular parameters, including cell morphology, cell cycle, and expression of cell surface antigens by flow cytometry. MSC were divided based on cell size to small (S-cells) and large (L-cells) and were visualized by light and electron microscope. The S-cells were proliferating cells correlated with G0/G1 phase of cell cycle, and expressed cFOS. The expression of surface markers CD-34, -44, -51, -61, -62E, -62P, -62L was quantified using flow cytometry. CD-44 was ubiquitously expressed by S and L cells, CD-51 and -61 were expressed by 30%–38% of S-cells. CD-34 and -62 expressed 20% positive of the analyzed cells that were of the proliferating progenitors (S-cells). This study enables the identification of subpopulations from MSC with special attention paid to the proliferating cells from ex vivo cultures of marrow stroma. J. Cell. Biochem. 87: 51–57, 2002. © 2002 Wiley-Liss, Inc.

Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase II study is worthwhile in ovarian cancer patients.

The treatment of malignancies in transplanted patients has become an emerging issue. The anticancer agent CPT-11 is hydrolysed to the active metabolite SN-38 and many drugs interact with its metabolism and toxicity.We studied the clinical and pharmacological interactions between CPT-11 and FK506 in a liver transplant patient. Serial plasma samples of FK506, CPT-11, SN-38 and SN-38 glucuronide were assayed by high-performance liquid chromatography.While no CPT-11 toxicity was observed pre-operatively, several post-operative cycles of CPT-11 were complicated with severe diarrhea. No change in FK506 plasma concentrations was noted in the presence of CPT-11 but the pharmacokinetics of CPT-11 was altered in the presence of FK506. SN-38 glucuronidation was reduced for up to 12 hours following CPT-11 infusion. This increase in plasmatic exposure to unbound SN-38 might account for diarrhea.The starting dose of CPT-11 should be reduced in FK506-treated liver transplant patients.

Human cells with osteogenic capacity were studied for differential gene expression. In the first part of the study we compared gene expression of marrow stroma cells (MSC) in comparison to matured osteoblasts cultured from trabecular bone (TBC) that were analyzed by RT-PCR for series of messages. High expression was detected for PTH-r, TGFb1 and biglycan in TBC compared to MSC's. The messages for c-MYC, IL-6, IL-11, M-CSF, osteonectin, and osteocalcin were expressed at the same level in the two populations of cells. In the second part of the study, we analyzed gene expression within the MSC derived from 25 donors (2.5–49 years old) with respect to donors' age and gender. Increased message levels for M-CSF and biglycan were measured in correlation with age of the donors. Gender differences did not affect the expression of cytokines studied (IL-6, IL-11, MCSF, TGFb1). We investigated the effect of Dexamethasone treatment on MSC and monitored an increased expression of IL-11, M-CSF, biglycan, and osteocalcin messages. This study employs primary cell systems (MSC and TBC) to illustrate differential gene expression by osteoblastic cells. The expression was correlated with maturation status of the cells with respect to differences between donors. J. Cell. Biochem. 83: 547–553, 2001. © 2001 Wiley-Liss, Inc.

The conventional osteotomies used to treat infantile tibia vara (Blount’s disease) may require internal fixation and its subsequent removal. These techniques, which carry the risk of traction injury, and potential problems of stability and consolidation, do not always succeed in correcting the rotational deformity which accompanies the angular deformity. We have used a new surgical approach, the serrated W/M osteotomy of the proximal tibia, to correct infantile tibia vara in 15 knees of 11 patients. We present the results in 13 knees of nine patients who have been followed up for a mean of eight years. The mean angular correction achieved after operation was 18 ± 5.8°. The mean femorotibial shaft angle was corrected from 14.2 ± 3.7° of varus to 4.6 ± 4.4° of valgus. At the last follow-up, the mean angular correction had reduced to 1.3 ± 4.9° of valgus without compromising the rotational correction and the overall good clinical results. All the patients and parents were satisfied, rating the result as excellent or good. There were no major postoperative complications and no reoperations. Eight patients were free from pain and able to perform physical activities suitable for their age. One complained of occasional pain. This procedure has the advantage of allowing both angular and rotational correction with a high degree of success without the need for internal fixation.

Very high concentrations of cytotoxic drug may be obtained with chemotherapy performed with vascular exclusion.To study the pharmacokinetics and toxicity of melphalan during in situ isolated liver perfusion, and to test an endovascular occlusion catheter.Isolated liver perfusion with melphalan (15 mg bolus) was performed in 6 pigs (50-60 kg) for 30 min, with non-oxygenated Ringer's solution. Hepatic outflow, collected by a double balloon catheter inserted into the retrohepatic inferior vena cava, was pumped into the gastroduodenal artery, while the common hepatic artery and portal vein were clamped.A maximum concentration of 30,000 ng/mL was obtained in the circuit before an exponential decrease, while the concentration in systemic blood was less than 500 ng/mL (n = 3). Before closing the abdomen, melphalan concentrations were about 2,000 ng/mg in the liver, and undetectable in the muscle. Postoperative course (2 weeks, n = 2) was uneventful with minor alterations in blood tests and hepatic histology.This method of local chemotherapy with melphalan appears to be safe with minor leakage and minimal toxicity.

Since the discovery of the superiority of the combination 5-fluorouracil (5FU)-folinic acid (FA) in comparison to 5FU alone in the treatment of gastrointestinal cancers, the interest of this association has been demonstrated in many other tumors. In the treatment of advanced colorectal carcinoma, FA is usually administered in 1 or 2 h infusion before 5FU. In treatment of other cancers, the two drugs are generally mixed together in the same container and administered as a continuous intravenous infusion over several days. Many studies have demonstrated the stability of 5FU alone in different vials, but results about compatibility of 5FU with AF in racemate (d,l) or levogyre (l) forms are conflicting. The aim of our study was to determine the influence of the container, the concentrations of the two drugs and the form of folinic acid (d, l or l) on the stability of the 5 FU-FA admixtures. Based on drug concentrations corresponding to current 5FU-FA chemotherapeutic protocols, 5FU was used at 50 mg/ml and 6.5 mg/ml in association with equitherapeutic and equimolar doses of FA respectively. Each association has been studied in three types of containers. For all combinations with 5FU 50 mg/ml, flocculation was noted, whatever form or concentration of FA which associated. No influence of the type of containers was noted. No precipitate was observed with the combinations 5FU 6.5 mg/ml. The evolution of the concentrations of 5FU and FA with time have been compared with a regression straight corresponding to a loss of product of 10% in 96 h. The mixtures 5FU 6.5 mg/ml with FA (d,l) 4 mg/ml and FA (l) 2 and 4 mg/ml remained stable in the three types of container. When a precipitate was noted (with 5FU 50 mg/ml), the concentration of 5FU decreased with time, whereas FA was stable in racemate and levogyre forms. Analysis of the precipitate showed that principally 5FU and equal parts of FA and calcium constituted it. Our results allowed to conclude that 5FU mixed with FA (d,l or l) 2 mg/ml and 4 mg/ml remained stable during 96 h in glass vials, PVC infusion bags and cassettes for portable pump in normal conditions of temperature and light. A precipitate of 5FU appears systematically with the concentration 50 mg/ml. These findings do not confirm those obtained in previously published studies. It seems that the precipitation is more a result of the decline of 5FU solubility at high concentrations than the form of folinic acid associated.

Pharmacokinetics, which is the study of the drug becoming in the body, is an important approach of new drug evaluation. Anticancer drugs have mostly a very narrow therapeutic index which leads to a delicate clinical use. Pharmacokinetics permits the prediction of the occurrence of iatrogenic toxicities taking into account the interpatient variability of the pharmacokinetic parameters.

The clinical pharmacokinetics of irinotecan (CPT11) can be described by a 2 or 3 compartment model, a mean terminal half-life of 12 hours, a volume of distribution at steady state of 168 l/m2 and a total body clearance of 15 l/m2/h. Irinotecan is 65% bound to plasma proteins. The areas under the plasma concentration-time curve (AUC) of both irinotecan and active metabolite SN38 increase proportionally to the administered dose, although interpatient variability is important. SN38 levels achieved in humans are about 100-fold lower than corresponding irinotecan levels, but these concentrations are important since SN38 is 100- to 1,000-fold more cytotoxic than the parent compound. SN38 is 95% bound to plasma proteins. SN38 plasma decay follows closely that of the parent compound. Irinotecan is extensively metabolized in the liver. The bipiperidinocarbonylxy group of irinotecan is first removed by a carboxyesterase to yield the corresponding carboxylic acid and SN38. This metabolite can be converted into SN38 glucuronide by UDP-glucuronyltransferase (1.1 isoform). A recently identified metabolite is the 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC), which is formed by the action of cytochrome P450 3A4. Numerous other unidentified metabolites are detected in bile and urine. The mean 24 h irinotecan urinary excretion represents 17-25% of the administered dose, whereas SN38 and its glucuronide recovery in urine is minimal (0.5 and 6%, respectively). Irinotecan and SN38 pharmacokinetics are not influenced by prior exposure to the parent drug. Irinotecan and SN38 AUCs correlate significantly with leuko-neutropenia and sometimes with the intensity of diarrhea. Increased bilirubin levels appear to influence irinotecan total body clearance. The observation that most tumor responses were seen at the highest doses administered in phase I trials suggest a dose-response relationship with this drug. These pharmacokinetic-pharmacodynamic relationships may prove useful for a better clinical management of this drug aimed at a better control of toxicities and a better prediction of tumor response for the benefit of the individual patient.

Simple bone cyst (SBC) is an enigma to the radiologist, pathologist and the orthopaedic surgeon. The etiology of this asymptomatic lesion that frequently causes pathological fracture is still unknown. It is probably self limited in nature, seen in children but rare among adults. The biological behavior is unpredictable as is the clinical course in various anatomical sites. This reflects on the high recurrence rate that has been associated with various treatment modalities. The clinical, radiological and biological features are discussed together with comparative review of treatment options from resection, curettage, and bone grafting to steroid injection and the latest experience of the use of percutaneous autologous marrow grafting in SBC.

This is a case report of osteochondritis of the medial plantar apophysis of the calcaneus presenting as medial plantar heel pain in a 15-year-old basketball player. The lesion was detected radiographically and by increased focal uptake on bone scan. Conservative treatment resulted in complete pain relief and normal calcaneal appearance with union of the osteochondral fragment. No recurrence was noted during 3 years of follow-up.

Basic fibroblast growth factor (bFGF) was shown to enhance rat stromal bone marrow cells in culture to produce mineralized bone-like tissue in response to dexamethasone (Dex) treatment (Pitaru et al., J Bone Miner Res 8:919; 1993). The purpose of this study was to explore the effect of bFGF on Dex-treated human stromal bone marrow cells (hSBMC) in culture. Human SBMC from 6 patients were cultured for 14 days (P 0 ) and then subcultured and grown for 28 days in the presence of Dex (10 −8 mol/L). The effect of bFGF on cell proliferation at P 0 and protein content, DNA content, alkaline phosphatase activity (ALP), osteocalcin secretion, and formation of mineralized bone-like tissue (MBT) at P 1 was analyzed. bFGF treatment resulted in a 2.4-fold increase in cell number at P 0 and a concentration-dependent increase in [ 3 H]-thymidine incorporation at P 1 , reaching a maximum increase of 3.7-fold at a concentration of 0.3 ng/mL. Furthermore, bFGF significantly increased both DNA content (two- to threefold), protein content (five- to sixfold), and the amount of MBT (up to 20-fold) at P 1 cultures. Morphological evaluation of the MBT at the electron microscope level revealed a mineralization process along collagen fibrils similar to the natural process. The osteogenic nature of the bFGF-treated cultures was further shown by their ALP activity, as well as osteocalcin secretion in response to 1,25-dihydroxyvitamin D 3 . In conclusion, bFGF demonstrated a stimulatory effect on the proliferation of Dex-treated hSBMC-derived osteoprogenitors while maintaining their capacity to fully differentiate and form bone-like tissue in culture.

We describe a five-year-old child with neurofibromatosis type I who developed a Charcot knee. Infiltration of the joint by tissue associated with the disease caused damage to the proprioceptive mechanism and resulted in severe joint instability, accelerated destruction and development of neuropathic arthropathy.

Irinotecan (CPT-11) is an analogue of 20(S)-camptothecin with promising activity against several tumor types. In patients, CPT-11 is metabolized to 7-ethyl-10-hydroxycamptothecin (SN-38) and to the beta-glucuronide of SN-38. Recently, we identified an additional metabolite of CPT-11, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC; L. P. Rivory et al. , Cancer Res., 56: 3689-3694, 1996). The aim of this study was to investigate the interrelationships of all four compounds to identify factors that might be responsible for the large interpatient variability in CPT-11 and SN-38 kinetics. The plasma kinetics of CPT-11, SN-38, the beta-glucuronide of SN-38, and APC were studied in 19 patients for a total of 33 cycles (115-600 mg/m2). Although the area under the concentration curves (AUCs) of all compounds studied increased with dose, there was considerable variability. Ratios of the AUCs of the appropriate compounds were used as estimates of the major routes of metabolism (conversion of CPT-11 to SN-38, metabolism of CPT-11 to APC, and glucuronidation of SN-38). Each ratio varied more than 10-fold across the patient population, and the apparent extent of conversion of CPT-11 to SN-38 was highest at the 115 mg/m2 dose level. Interestingly, AUCSN-38 was greater in patients with both high AUCCPT-11 and AUCAPC. We conclude that the variability of the pharmacokinetics of CPT-11 and SN-38 is likely to be due to extensive interpatient differences in the pathways implicated in the metabolism of CPT-11.

PURPOSE A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.

Ceftriaxone penetration into heart tissues (valves, myocardium, auricles and pericardium) and mediastinal tissues (fat and sternal bone) was evaluated after two regimens of ceftriaxone administration. Ten patients were given 1,000 g intravenously of ceftriaxone 30 min. before anesthesia. Ten other patients received the same dose and then a second 1,000 mg dose at the time of initiation of cardiopulmonary bypass. Similar and very satisfactory ceftriaxone tissue penetrations were observed in both groups. However, for some patients in the two groups and mainly in the sternal bone at the time of thorax closure, ceftriaxone levels in tissues were less than the MICs for some potential pathogens (Methicillin susceptible Staphylococcus aureus and Staphylococcus epidermidis). During the different steps of the surgical procedures all patients in both groups had tissue levels greater than the MICs for Gram negative aerobic bacilli, except for Pseudomonas spp.

S 12363 is a new Vinca alkaloid derivative, characterized by the grafting of an alpha-aminophosphonate, onto the Vinca nucleus, facilitating drug penetration and increasing intracellular drug retention. As a high cytotoxic activity had been demonstrated in in vitro and in vivo models recommended by the National Cancer Institute, a phase I trial was initiated in cancer patients. In order to quantify S 12363 systemic levels in humans, two monoclonal antibody-based immunoassays, RIA (radio-) and EIA (enzyme immunoassay) were developed. The gamma-emitting probe used in the RIA, 125I-(deacetyl-O4-vinblastine)-tyramine, bound very tightly to the monoclonal antibody (dissociation constant, Kd = 2.5 x 10(-11) M), demonstrating a high affinity mainly directed toward the catharantine nucleus (vindesine, vincristine, vinblastine, 100% cross-reactivity; vinorelbine, 0.3% cross-reactivity). In the EIA, a deacetyl O4-vinblastine/ovalbumine conjugate was used as the competing antigen. Its binding to the monoclonal antibody was revealed by an anti-mouse immunoglobulin G conjugated to biotin which interacts with streptavidin labeled with alkaline phosphatase. This method permitted obtaining nearly the same sensitivity and reproducibility with EIA as with RIA, their respective minimum quantitation limits being 0.100 and 0.040 ng/ml (106 and 42 pM) of S 12363 in plasma. These assays allowed the study of S 12363 systemic pharmacokinetics in cancer patients during a phase I trial up to 72 h after dosing. As determined by RIA, the S 12363 plasma profile was triphasic with a terminal half-life; t1/2 gamma = 49 +/- 16 h, a plasma clearance, CL = 0.14 +/- 0.04 liter/h/kg, and a volume of distribution at steady state, Vdss = 5.0 +/- 2.8 liter/kg. The pharmacokinetics of S 12363 is linearly related to dose when increased from 0.08 up to 0.84 mg/m2 in humans. Its plasma profile and pharmacokinetic parameters are close to those of other Vinca alkaloids with clearance and terminal half-life being intermediate between those of vinblastine and vincristine. Therapeutic doses are 4 to 10 times lower and should be a direct consequence of the higher uptake and retention by the cells of this new aminophosphonate Vinca alkaloid derivative.

To assess plasma acyclovir levels in pregnant women given oral acyclovir during late gestation and to determine the role and effect of oral acyclovir on asymptomatic shedding of virus in cases of recurrent genital herpes.Five pregnant women with proven genital herpes isolate (herpes simplex virus [HSV] 2) after 37 weeks' gestation were studied. Oral acyclovir was administered every 8 hours at dosages of 300, 400, and 300 mg in two subjects, and 200 mg five times daily in the other three until delivery. Plasma acyclovir peak and trough levels were determined. Viral cultures were obtained from both the mothers and neonates at delivery.There was no difference in acyclovir plasma levels among the patients. Furthermore, acyclovir levels were comparable to those of nonpregnant adults. The drug failed to suppress asymptomatic shedding of virus and transmission of HSV 2 to the neonate in one of five of the patients.Our study suggests that asymptomatic shedding of virus is not prevented by use of oral acyclovir during late gestation in proven recurrent genital herpes even though plasma acyclovir levels were within the normal range.

The effects of diclofenac, a nonsteroidal antiinflammatory drug, on the biliary and urinary excretion of ceftriaxone were evaluated in subjects with a T drain in the common bile duct. The kinetic study was carried out on the sixth postoperative day of treatment with ceftriaxone alone (2 g intravenously; group 1) or ceftriaxone combined with diclofenac (50 mg every 12 h orally from postoperative days 3 to 6; group 2). A significant increase in the elimination half-life of ceftriaxone was observed in group 2 patients. Diclofenac caused a significant rise in ceftriaxone biliary excretion. This increase was not sufficient to balance the significant deficit of urinary excretion of ceftriaxone.

Varicella occurs in 0.7 to 0.13% of pregnant women. The risk of transmission of the varicella-zoster virus to the fetus is small. The virus causes malformations (cutaneous scars and above all central nervous system anomalies). Mother-to-offspring transmission is more common during the perinatal period (20%), when mild or severe (fatal in 20% of cases) congenital varicella may occur. Prevention of transmission of the varicella-zoster virus from the mother to her fetus or neonate rests on detection of fetal varicella (antenatal ultrasonography, fetal IgM assays) and on administration of both specific anti-VZ virus immune globulins and acyclovir to the mother and neonate during the perinatal period.

1. A novel anticancer vinca alkaloid derivative (I) has been given as an i.v. bolus to cancer patients, using four different dosage regimens with dose levels ranging from 0.04 to 0.84 mg/m2 (equivalent to between 0.12 and 1.35 mg per dose), and the pharmacokinetics determined up to 72 h after dosing. In addition, secondary effects of leukopenia and neutropenia, were related to drug exposure using a sigmoid Emax model. 2. Plasma levels of I declined in a triphasic manner with a terminal half-life of approximately 50 h; most drug elimination (55%) being associated with the terminal phase. 3. Clearance of I was relatively low (245 +/- 160 ml/min) and remained constant with increasing doses. Initial distribution volume was low (approximately 71) but once distribution was complete, it was comparatively high (327 +/- 2121). 4. Both leukopenia and neutropenia were fitted successfully to a sigmoid Emax model showing that these effects were related to the total exposure to the drug. The Hill constant was less than 1, indicating a relatively shallow exposure/response curve and a predictable, graded increase in response with increasing I exposure, rather than a sudden quantal response. 5. Pharmacokinetically, I shows some similarities to other vinca alkaloids in its plasma level decline profile, although there are some notable differences which can be exploited clinically. In addition, the ability to model both leukopenia and neutropenia to the exposure to I, provides a valuable tool in the design of the most appropriate dosage regimen for the drug, as well as for dose adjustment taking into account inter-individual variations.

907 patients were operated on for fracture of the proximal femur in 1986-1987 and were then followed for an average of 7 months. There was a relatively high rate of complications in those over the age of 71, in whom mortality reached 15.5%, while the overall mortality was 6.8%. There was also a high rate of complications in those operated 3 or more days after the fracture had occurred. In those up to the age of 60, the ratio of males to females was almost 1 to 1, but in those over 80 the ratio was 1 to 4. The mortality of males was higher (9.2%) than that of females (5.5%). In trochanteric fractures treated by various methods of rigid fixation there were no problems of union or delayed union. Early mobilization and early discharge from hospital reduced mortality and complications.