Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study.

PURPOSE: Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin. MATERIALS AND METHODS: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. RESULTS: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. CONCLUSIONS: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.

Surgical management of the hand in Apert syndrome.

In patients with Apert syndrome, the hands demonstrate many disturbances of soft tissue and bony structures. These include a short thumb with radial clinodactyly, complex syndactyly with a bony fusion involving the index, long and ring fingers, symphalangism and simple syndactyly of the fourth web space. The soft tissue anomalies involve the intrinsic muscles, the extrinsic tendon insertions and the neurovascular bundles. We have reviewed 52 patients who underwent surgical reconstruction of their hands. The aim of this study is to propose a better surgical management in the light of recent publications and to improve our understanding of the syndrome, attempting to reduce the number of procedures and to select the best possible procedures for each patient.

[Quadruple internal distraction with early frontal-facial avancement for faciocraniodysostosis]. / Quadruple distraction interne avec avancement fronto-facial précoce pour faciocraniosténose.

INTRODUCTION: Frontofacial monobloc advancement (FFMA), known as a high risk procedure, was evaluated in combination with distraction. PATIENTS AND METHOD: Twenty patients with faciocraniosynostosis, were treated with FFMA and quadruple internal distraction. Mean age at surgery was 3.2 Years and mean follow-up was 14 Months (3-32 Months). Four distractors were used per patient in combination with complete osteotomy FFMA. Rate of distraction was classical (0.5 mm to 1mm per day) starting on day 7. The rate of short-term complications was evaluated. Correction of exorbitism and the dental occlusion relationship were assessed to evaluate achievement of advancement. Rate of relapse was evaluated by measuring the orbital bony gap on horizontal CT slices, before and 6 Months after removal of the distractor. Respiratory impairment when present was also evaluated. RESULTS: Distraction was completed in 18/20 patients. Fifteen patients completed their distraction uneventfully during the initial period. In three patients with CSF leaks, distraction was delayed at day 14 and 16, but was resumed and completed normally. Second operations were required for two patients during the early phase: the distractor failed in one requiring immediate reoperation to change the device; distraction was completed successfully. Device infection developed in two patients requiring removal of the device and abortion of distraction. One patient died the day after surgery from acute tonsillar herniation before distraction could be initiated. Exorbitism was clinically corrected in all cases in whom distraction was completed (n=18). Class I occlusion was obtained in 16/18 patients. When present, respiratory impairment was corrected in all cases. Septic frontal necrosis occurred in one patient two Months after distraction was completed and necessitated removal of the forehead flap. Distractors were easily removed through a coronal approach at 6 Months, but reossification was limited. Relapse was observed in three patients whose retaining phase was less than five Months. Rate of relapse was much lower when distraction was maintained more than six Months. DISCUSSION: Internal distraction can provide early correction of respiratory impairment due to faciocraniosynostosis in infancy and can reduce the major risks of frontofacial monobloc advancement. Morbidity is higher in patients with prior surgery before FFMA. Further evaluation is necessary to determine whether the two stage treatment strategy for faciocraniosynostosis (fronto-orbital advancement before one Year of age, and later facial Lefort III type advancement) could be replaced by a routine FFMA procedure.

Prenatal ultrasound diagnosis of fetal craniosynostosis.

OBJECTIVE: Craniosynostosis is defined as the premature closure of the calvarial sutures. The prevalence of this heterogeneous condition is 1 in 2000 and approximately 100 different forms have been described with an established genetic transmission in half of them. Prenatal diagnosis of craniosynostosis relies mainly on identification of associated anomalies and molecular analysis of fetal DNA, which is only feasible in some syndromic forms and in well-documented families. The objective of this study was to investigate the value of prenatal ultrasound examination of cranial sutures in fetuses at risk for craniosynostosis. METHODS: Forty fetuses at risk for craniosynostosis on the basis of either a family history (Group 1, n = 16) or skull deformity suspected on a first-level fetal ultrasound examination (Group 2, n = 24) were retrospectively investigated. Craniosynostosis was suspected on the basis of skull deformities when present, however the diagnosis was only made in cases where there was a loss of hypoechogenicity of the normal sutures. All infants had both clinical and radiological investigations performed postnatally. RESULTS: In Group 1, serial ultrasound examination from 12 weeks' gestation onwards led to accurate prenatal diagnosis in all 16 cases. Dysmorphism and skull deformity preceded closure of the sutures by 4 to 16 weeks. In Group 2, prenatal diagnosis was correct in 23/24 cases. There were no false-negative results in either group. CONCLUSIONS: This series questions further the uncertain genetic determinism of craniosynostosis and seems to rule out the hypothesis of a deformation sequence following primary closure of the cranial sutures. It also suggests that ultrasound examination is useful to demonstrate closure of the sutures in the third trimester of pregnancy in most affected cases.

[Treatment of intracranial cysts in children: peritoneal derivation or endoscopic fenestration?]. / Traitement des kystes intracrâniens de l'enfant: dérivation péritonéale ou fenestration endoscopique?

OBJECTIVE: The goal of this study is to evaluate the indications, benefit and complications of shunts and endoscopic fenestrations in the treatment of malformative intracranial cysts. MATERIAL AND METHOD: The records of 172 consecutive children (mean age of 4 years) were reviewed. All had a malformative cyst. Dandy Walker malformation, mega cisterna magna, and cysts from tumoral or porencephalic origin were excluded from the study. The cysts were diagnosed either in utero (n=64) or postnatally (n=108). Most of them were unique (94.8%) and localized in the posterior fossa (26.2%) or at the convexity (23.2%). Indication for surgery was based on clinical symptoms (n=101; 86.3%) or size of the lesion (n=16; 13.7%). Endoscopy was the treatment of choice when cysts were in closed relationship with enlarged ventricles. Shunting procedures were indicated when endoscopy was not feasible and craniotomies when shunt insertion was unsafe or diagnosis uncertain. Fifty children underwent an endoscopic fenestration, 55 a shunting procedure, 7 the puncture or the external drainage of a pericerebral collection and 5 a direct surgical approach. The mean follow-up was 5.5 years. Psycho-motor, intellectual and school performances were evaluated in 93 children (54%). Success was defined by both the disappearance of symptoms of increased intra cranial pressure and regression of the cyst. RESULTS: Compared to shunts, endoscopic fenestrations were more frequently successful (70% vs 61.8%), led to less complications (6% vs 61.8%) and to a lesser number of reoperations (in average 1.6 operation per child vs 2.2). Median developmental and intellectual quotients for the whole series were respectively 98 and 97 and did not depend upon the type of treatment. CONCLUSION: The study of this series shows that treatment modalities necessarily vary according to the site of the cysts but that endoscopic fenestrations are preferable to shunts whenever feasible.

Craniosynostosis and fetal exposure to sodium valproate.

OBJECT: Fetal valproate syndrome affects one in 10 children born to mothers who ingest sodium valproate regularly during pregnancy. It has been described as producing a combination of typical dysmorphic features and major organ system anomalies. Trigonocephaly is caused by premature fusion of the metopic suture and has not previously been described as a typical feature of the syndrome. The authors reviewed the cases of 2,220 children with craniosynostosis to examine the effect of maternal sodium valproate use on the fetus. METHODS: Case files of all 2,220 children were reviewed. The type and severity of each patient's craniosynostosis was assessed. Information about maternal health and medication use was obtained, and family interviews were conducted. Children underwent mental development assessment performed using standard tests both pre- and postoperatively. Detailed maternal health information was obtained in 1,676 cases. Of these, 17 mothers were found to have undergone regular treatment with sodium valproate monotherapy at the time of their pregnancies. No other antiepileptic medical regimen was found. All 17 children exhibited trigonocephaly. These patients' intelligence quotients (JQs) at the time of the most recent follow-up examination ranged from 45 to 100, with a mean of 75; IQs were significantly higher in patients who underwent surgery before reaching 6 months of age. CONCLUSIONS: Ideally any pregnancy in a woman being treated for epilepsy should be planned, and both an obstetrician and a neurologist should be consulted. In children born with fetal valproate syndrome, it is important to be aware of the possibility of metopic suture synostosis, which we believe should be considered part of the syndrome, because early surgical intervention may improve cognitive outcome.

Management of hydrocephalus in pediatric patients with posterior fossa tumors: the role of endoscopic third ventriculostomy.

OBJECT: The authors undertook a study to evaluate the effectiveness of endoscopic third ventriculostomy in the management of hydrocephalus before and after surgical intervention for posterior fossa tumors in children. METHODS: Between October 1, 1993, and December 31, 1997, a total of 206 consecutive children with posterior fossa tumors underwent surgery at Hjpital Necker-Enfants Malades in Paris. Excluded were 10 patients in whom shunts had been placed at the referring hospital. The medical records and neuroimaging studies of the remaining 196 patients were reviewed and categorized into three groups: Group A, 67 patients with hydrocephalus present on admission in whom endoscopic third ventriculostomy was performed prior to tumor removal; Group B, 82 patients with hydrocephalus who did not undergo preliminary third ventriculostomy but instead received conventional treatment; and Group C, 47 patients in whom no ventricular dilation was present on admission. There were no significant differences between patients in Group A or B with respect to the following variables: age at presentation, evidence of metastatic disease, extent of tumor resection, or follow-up duration. In patients in Group A, however, more severe hydrocephalus was demonstrated (p < 0.01): the patients in Group C were in this respect different from those in the other two groups. Ultimately, there were only four patients (6%) in Group A compared with 22 patients (26.8%) in Group B (p = 0.001) in whom progressive hydrocephalus required treatment following removal of the posterior fossa tumor. Sixteen patients (20%) in Group B underwent insertion of a ventriculoperitoneal shunt, which is similar to the incidence reported in the literature and significantly different from that demonstrated in Group A (p < 0.016). The other six patients (7.3%) were treated by endoscopic third ventriculostomy after tumor resection. In Group C, two patients (4.3%) with postoperative hydrocephalus underwent endoscopic third ventriculostomy. In three patients who required placement of CSF shunts several episodes of shunt malfunction occurred that were ultimately managed by endoscopic third ventriculostomy and definitive removal of the shunt. There were no deaths; however, there were four cases of transient morbidity associated with third ventriculostomy. CONCLUSIONS: Third ventriculostomy is feasible even in the presence of posterior fossa tumors (including brainstem tumors). When performed prior to posterior fossa surgery, it significantly reduces the incidence of postoperative hydrocephalus. The procedure provides a valid alternative to placement of a permanent shunt in cases in which hydrocephalus develops following posterior fossa surgery, and it may negate the need for the shunt in cases in which the shunt malfunctions. Furthermore, in patients in whom CSF has caused spread of the tumor at presentation, third ventriculostomy allows chemotherapy to be undertaken prior to tumor excision by controlling hydrocephalus. Although the authors acknowledge that the routine application of third ventriculostomy in selected patients results in a proportion of patients undergoing an "unnecessary" procedure, they believe that because patients' postoperative courses are less complicated and because the incidence of morbidity is low and the success rate is high in those patients with severe hydrocephalus that further investigation of this protocol is warranted.

[Distraction osteogenesis with double internal devices combined with early frontal facial advancement for the correction of facial craniosynostosis. Report of clinical cases]. / Double distraction interne avec avancement frontofacial précoce pour faciocraniosténose. A propos de cinq cas cliniques.

Frontofacial monobloc advancement is a surgical procedure which corrects at the same time both frontal and facial retrusions in faciocraniosynostosis. The high risk morbidity limited its use to major exorbitism or severe breathing impairment. We report the results of a preliminary experience in five children with a mean age of 3.8 years. All patients presented with a Crouzon or Pfeiffer syndrome. The procedure performed was a frontofacial monobloc osteotomy with peroperative mobilization. Two pairs of distractors (Martin-Medizin) were implanted. The upper pair of frontal distractors was located behind the supraorbital bar. The pair of temporo-zygomatic distractors (a modification of the MicroFrance prototypes) was implanted behind the zygomatic bone. In one patient a transfacial pin was connected to the anterior part the lower distractors, to avoid facial bipartition. Distraction was performed according to classical protocols with a 1 mm advancement per day, until sufficient advancement was obtained. The correction of exorbitism and facial retrusion was obtained in all cases. An open-bite was created by the advancement in two out of the five patients. Minor infection occurred in one patient. This combination of distractors with frontofacial advancement seemed to increase the efficacy and reduce the morbidity. This might lead to a one stage strategy for faciocraniosynostosis treatment, even if minor additive procedures will be necessary when children get older and that insufficient facial growth still reoccurs.

Mutations in the basic domain and the loop-helix II junction of TWIST abolish DNA binding in Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome is an autosomal dominant skull disorder resulting from premature fusion of coronal sutures (craniosynostosis). It is caused by mutations in the TWIST gene encoding a basic Helix-Loop-Helix transcription factor. Here we report on the identification of a novel mutation affecting a highly conserved residue of the basic domain. Unlike nonsense and missense mutations lying within helices, this mutation does not affect protein stability or heterodimerisation of TWIST with its partner E12. However, it does abolish TWIST binding capacity to a target E-box as efficiently as two missense mutations in the loop-helix II junction. By contrast, elongation of the loop through a 7 amino acid insertion appears not to hamper binding to the DNA target. We conclude that loss of TWIST protein function in Saethre-Chotzen patients can occur at three different levels, namely protein stability, dimerisation, and DNA binding and that the loop-helix II junction is essential for effective protein-DNA interaction.

[Diagnosis of facial and craniofacial asymmetry]. / Diagnostic d'une asymétrie faciale et crânio-faciale.

Craniofacial asymmetry is caused by various aetiologies but clinical examination remains the most important criteria since minor asymmetry is always present. The diagnosis can be confirmed by anthropometric measurements and radiological examinations but only severe asymmetries or asymmetries with an associated functional impairment should be treated. The treatment depends on the cause, and on the time of appearance. Congenital asymmetries might be treated early, during the first year of life if a craniosynostosis is present. Hemifacial microsomia are treated later if there is no breathing impairment. Since the pediatricians have recommended the dorsal position for infant sleeping, an increasing number of posterior flattening of the skull has been appearing, and could be prevented by adequate nursing. Other causes of craniofacial asymmetries are rare and should be adapted to the cause (tumors, atrophies, neurological paralysis, hypertrophies) by a specialized multidisciplinar team.