[Frameless trigeminal neuralgia radiosurgery with a dedicated linear accelerator: From equipment commissioning to initial clinical results]. / Radiochirurgie des névralgies trigéminales avec accélérateur linéaire dédié sans cadre invasif : de la mise en service de l'appareil aux premiers résultats cliniques.

PURPOSE: Radiosurgery for the treatment of trigeminal neuralgia delivers a very high dose in a single fraction, over a few millimeters, at a single isocenter placed along the nerve. We present here the different steps that have been performed to validate small beams by conical collimators, and report the clinical results of the first patients treated on Novalis Tx®, frameless. MATERIAL AND METHODS: First, the geometric accuracy of 4 and 6mm conical collimators was evaluated using Winston-Lutz tests; then dosimetric data acquisition was performed using high spatial resolution detectors (PTW 60019 microdiamond and a PTW 60017 E-diode). The corrective factors of the TRS 483 report were applied to calculate the collimator aperture factors. These dosimetric data were then compared with the data implemented in the iPlan® treatment planning system. Then end-to-end tests were performed to control the entire treatment process using an anthropomorphic phantom "STEEV". Between 2020 and 2022, 18 patients were treated for refractory trigeminal neuralgia on Novalis Tx®, frameless, with Exactrac® repositioning. A total of 17 patients were evaluated (one was lost to follow-up) using the BNI score for pain assessment and MRI with a median follow-up of 12 months. RESULTS: The quality criteria of geometric and dosimetric accuracy were met for the 6-mm cone but not for the 4-mm cone. All patients were treated with a 6-mm cone with a dose of 90Gy prescribed at the isocenter at the root entry zone. Initial pain control was obtained in 70.5% of our patients, and 53% maintained pain control with a median follow-up of 12 months. All recurrences occurred within 3 to 6 months after radiosurgery. No brainstem toxicity was observed. Six patients had non-disabling facial hypoesthesia, half of whom already had pretreatment hypoesthesia. CONCLUSION: The treatment of trigeminal neuralgia on a dedicated linear accelerator is a highly technical treatment whose accuracy and safety are paramount. The physical measurements allowed the commissioning of the technique with a 6mm cone. Our first clinical results are in accordance with the literature.

Hypofractionated stereotactic radiotherapy for large brain metastases: Optimizing the dosimetric parameters.

PURPOSE: Stereotactic radiotherapy plays a major role in the treatment of brain metastases (BM). We aimed to compare the dosimetric results of four plans for hypofractionated stereotactic radiotherapy (HFSRT) for large brain metastases. MATERIAL AND METHODS: Ten patients treated with upfront NovalisTx® non-coplanar multiple dynamic conformal arcs (DCA) HFSRT for≥25mm diameter single BM were included. Three other volumetric modulated arc therapy (VMAT) treatment plans were evaluated: with coplanar arcs (Eclipse®, Varian, VMATcEclipse®), with coplanar and non-coplanar arcs (VMATncEclipse®), and with non-coplanar arcs (Elements Cranial SRS®, Brainlab, VMATncElements®). The marginal dose prescribed for the PTV was 23.1Gy (isodose 70%) in three fractions. The mean GTV was 27mm3. RESULTS: Better conformity indices were found with all VMAT techniques compared to DCA (1.05 vs 1.28, P<0.05). Better gradient indices were found with VMATncElements® and DCA (2.43 vs 3.02, P<0.001). High-dose delivery in healthy brain was lower with all VMAT techniques compared to DCA (5.6 to 6.3 cc vs 9.4 cc, P<0.001). Low-dose delivery (V5Gy) was lower with VMATncEclipse® or VMATncElements® than with DCA (81 or 94 cc vs 110 cc, P=0.02). CONCLUSIONS: NovalisTx® VMAT HFSRT for≥25mm diameter brain metastases provides the best dosimetric compromise in terms of target coverage, sparing of healthy brain tissue and low-dose delivery compared to DCA.

[Concurrent chemoradiotherapy for head neck cancers. Should organs at risk dose constraints be revisited ?] / Chimioradiothérapie concomitante des cancers des voies aérodigestives supérieures. Faut-il revoir les contraintes de dose dans les organes à risque ?

Concurrent chemoradiotherapy improves the outcome of locally advanced head and neck cancers and the current reference chemotherapy is cisplatin. These results are obtained at the cost of increased toxicities. To limit the risk of toxicity, organ at riskdose constraints have been established starting with 2D radiotherapy, then 3D radiotherapy and intensity-modulated radiotherapy. Regarding grade ≥3 acute toxicities, the scientific literature attests that concurrent chemoradiotherapy significantly increases risks of mucositis and dysphagia. Constraints applied to the oral mucosa volume excluding the planning target volume, the pharyngeal constrictor muscles and the larynx limit this adverse impact. Regarding late toxicity, concurrent chemoradiotherapy increases significantly the risk of postoperative neck fibrosis and hearing loss. However, for some organs at risk, concurrent chemotherapy appears to increase late radiation induced effect, even though the results are less marked (brachial plexus, mandible, pharyngeal constrictor muscles, parotid gland). This additional adverse impact of concomitant chemotherapy may be notable only when organs at risk receive less than their usual dose thresholds and this would be vanished when those thresholds are exceeded as seems to be the situation for the parotid glands. Until the availability of more robust data, it seems appropriate to apply the principle of delivering dose to organs at risk as low as reasonably achievable.

[Radionecrosis following stereotactic radiotherapy of a 3-cm brain metastasis: Can we improve the dosimetric results?] / Radionécrose après radiothérapie stéréotaxique d'une métastase cérébrale de 3cm : la technique peut-elle améliorer les résultats dosimétriques ?

Stereotactic radiotherapy is a major issue in the management of brain metastases. Radionecrosis is a major concern, especially for large lesions. Optimizing dosimetric parameters is essential to allow optimal local control rate while minimizing potential toxicity. We report the case of a 30-mm brain metastases treated with stereotactic radiotherapy after initial whole brain radiotherapy, complicated with symptomatic radionecrosis. A dose of 24Gy in three fractions on the 80% isodose were delivered using a dynamic conformal arc technique (Novalis TX®). We realized a dosimetric comparison with: (i) optimization of initial conformal arc plan, (ii) volumetric modulated arctherapy with coplanar arcs and (iii) volumetric modulated arctherapy with coplanar and non-coplanar arcs. The optimal dose planning in terms of planning target volume coverage (99.2%) and normal brain sparing (V24Gy=0.4cm3, V18Gy=6.5cm3, V10Gy=25.4cm3, V5=83.9cm3) was obtained with volumetric modulated arctherapy with coplanar and non-coplanar arcs. Volumetric modulated arctherapy-based stereotactic irradiation with coplanar and non-coplonar arcs seems an interesting option for the treatment of large brain metastases to optimize dosimetric parameters.

Molecular Epidemiology of High-Risk Human Papillomavirus in High-Grade Cervical Intraepithelial Neoplasia and in Cervical Cancer in Parakou, Republic of Benin.

Human papilloma virus (HPV) infection remains a worldwide concern, especially in Sub-Saharan Africa where cervical cancer is the leading cause of cancer death in women. The aim of the study was to determine the prevalence and genotypic distribution of High-Risk HPV (HR-HPV) involved in Cervical Intraepithelial Neoplasia (CIN) II and III and in cervical cancer in Parakou. Out of a total of 149 samples of cervical tissues archived, fixed and paraffin-embedded, 78 samples with histological diagnosis of CIN-II, CIN-III and cervical cancer went through deparaffinization with xylene, followed by an extraction of HPV DNA and the detection of HR-HPV by real-time multiplex PCR. The average age of the women was 40.05±13.99 years. The samples were positive to at least one HR-HPV genotype in 76.92% (50/65) of cases. The HR-HPV genotypes which are most common in the cervical cancer and in CIN-II and III were, respectively HPV-39 (38 and 37.50%), HPV-18 (35 and 31.30%), HPV-45 (35 and 31.30%), HPV-35 (9 and 25%) and HPV-52 (9 and 12.50%). The HPV-16 was absent. This study helped to detect (in samples archived, fixed and paraffin-embedded tissues) HR-HPV involved in high-grade precancerous lesions and in cervical cancer in Parakou, some of which are not covered by currently available vaccines.

Should the angiotensin II antagonists be discontinued before surgery?

UNLABELLED: Angiotensin II antagonists (AIIA) are part of a new rational treatment of hypertension. Because adverse circulatory effects during anesthesia can occur in patients chronically treated with angiotensin-converting enzyme inhibitors, some clinicians discontinue them at least 24 h before operation. No data are available concerning AIIA administration in patients scheduled for vascular surgery performed under general anesthesia. The aim of this prospective randomized study was to compare hemodynamics during induction of anesthesia in patients chronically treated with AIIA and those of patients not receiving this drug on the morning before operation. Thirty-seven patients chronically treated with AIIA for hypertension were randomly assigned to two groups: Group I: AIIA discontinued on the day before surgery (n = 18); Group II: AIIA given 1 h before anesthesia (n = 19). Patients received sufentanil 0.4 microg/kg, propofol 1.5 mg/kg, and atracurium 0.5 mg/kg. During the procedure, the anesthesiologist was required to maintain systolic blood pressure and heart rate within 30% of baseline values using intravascular fluid administration and vasoconstric- tors (e.g. , ephedrine, phenylephrine, or terlipressin). Hemodynamic variables were recorded each 1 min. Hemodynamic study ended at incision. The number and duration of hemodynamic events were collected, and total doses of vasoactive drugs were noted in each group. Systolic arterial pressure was significantly decreased in Group II at 5, 15 and 23 min after induction of anesthesia (*P < 0.05). In this group, the decrease in systolic arterial pressure was associated with more frequent episodes of hypotension (AIIA withdrawn: 1 +/- 1; AIIA given: 2 +/- 1; P < 0.01), with a larger number of patients developing at least 1 episode of hypotension (AIIA withdrawn: 12; AIIA given: 19; P < 0.01), and a longer duration of an episode of hypotension (AIIA withdrawn: 3 +/- 4 min; AIIA given: 8 +/- 7 min; P < 0.01), and an increased need for vasoactive drugs. In conclusion, blockade of the renin-angiotensin system increases the potential hypotensive effect of anesthetic induction. A severe hypotensive episode, requiring vasoconstrictor treatment, occurs after induction of general anesthesia in patients chronically treated with AIIA. Recommendations to discontinue AIIA drugs on the day before the surgery may be justified. IMPLICATIONS: This prospective randomized study demonstrated that more severe hypotensive episodes, requiring vasoconstrictor treatment, occur after induction of general anesthesia in patients chronically treated with AIIA and receiving this drug on the morning before operation, in comparison with those in whom AIIA were discontinued on the day before operation. Recommendations to discontinue these drugs on the day before the surgery may be justified.

[Trisomy 18: ultrasound aspects. Report of 40 cases]. / Trisomie 18: aspects échographiques. A propos de 40 observations.

OBJECTIVE: We describe the different ultrasound findings suggestive of trisomy 18. PATIENTS AND METHODS: We conducted a retrospective study in 40 cases of trisomy 18 diagnosed in the department of obstetrics at the Lille University Hospital between 1988 and 1998. RESULTS: Eighty percent of the women in this series were multiparous. Mean maternal age at discovery of the trisomy as 33.2 years and the mean gestational age was 20.4 weeks. Fifty-five percent of the cases were discovered during the second trimester of pregnancy, 22.5% during the third trimester and 22.5% during the first trimester. One ultrasound abnormality, at least, was detected in 36/40 cases (90%) a percentage that reached 96.8% taking into consideration the ultrasound examinations performed during the second and third trimesters (30/31 cases). The most frequently detected ultrasound abnormalities were: intra uterine growth retardation (IUGR: 50%), poly-hydramnios (42.5%), limb abnormalities (42.5%), cardiac defects (30%), facial abnormalities (37.5%), meningomyelocele (32.5%), digestive abnormalities (32.5%), urinary tract abnormalities (27.5%), lymphangiectasia and cystic hygroma (15%), and single umbilical artery (12.5%). Medical termination of pregnancy (TOP) was performed in 28 cases. There was one spontaneous miscarriage at 8 weeks and one in utero death (IUD) at 39 weeks in a patient who desired to continue her pregnancy. In 6 cases, the issue of the pregnancy was unknown because the patients were lost to follow-up. In 4 cases (10%), pregnancy was continued to delivery of live babies that only survived a few minutes to 7 days. CONCLUSION: The ultrasound signs suggestive of trisomy 18 change according to the term of pregnancy. At the first trimester, most of the signs are nonspecific, such as cystic hydroma or lymphangiectasia, and do not suggest the need for a karyotype. At the end of the second trimester, an association of various signs that alone would not be highly suspect suggest the need for further exploration in search of other signs: early IUGR, associated or not with poly-hydramnios, limb abnormalities, cardiac defects, omphalocele, diaphragmatic hernia, meningomyelocele, enlarged cisterna magna, choroid plexus cysts, single umbilical artery, facial dysmorphism, facial cleft, hydronephrosis.

[Digestive carcinoid tumors: often undiagnosed endocrine tumors (a case report)]. / Tumeurs carcinoïdes digestives: tumeurs endocrines souvent méconnues (à propos d'un cas).

The authors reported a case of a carcinoid tumor of the ileum with nodal metastasis. Diagnosis was made by histological examination of the tumor after its removal. Immunohistochemistry demonstrated the presence of serotonin, synaptophysin, chromogranin and neuron-specific enolase (NSE) in the tumor cells. The patient was followed up for 15 months. Tumor ablation resulted in the total cessation of bronchospastic episodes in the patient, suggesting that these symptoms were mediated by tumor secretion. We also present a review of the literature concerning clinical, paraclinical and treatment aspects of gastrointestinal carcinoid tumors.

Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.

In familial hypercholesterolemia (FH), the efficacy of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase shows considerable interindividual variation, and several genetic and environmental factors can contribute to explaining this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG-CoA reductase inhibitor, was conducted in 63 children and adolescents with heterozygous FH. The patients were grouped according to known LDL receptor genotype. After 6 weeks of treatment with 20 mg/d simvastatin, the mean reduction in plasma LDL cholesterol in patients with the W66G mutation (n=14) was 31%, whereas in the deletion>15 kb (n=23) and the C646Y mutation groups (n=10), it was 38% and 42%, respectively (P<0.05). After treatment with simvastatin, HDL cholesterol levels were increased in all groups, and triglyceride concentrations were significantly reduced. Multiple regression analyses suggested that 42% of the variation of the LDL cholesterol response to simvastatin can be attributed to variation in the mutant LDL receptor locus, apolipoprotein E genotype, and body mass index, while 35% of the variation in HDL cholesterol response was explained by sex and baseline HDL cholesterol. These results show that simvastatin was an effective and well-tolerated therapy for FH in the pediatric population for all LDL receptor gene mutations. Moreover, the nature of LDL receptor gene mutations and other genetic and constitutional factors play a significant role in predicting the efficacy of simvastatin in the treatment of FH in children and adolescents.

Geographic distribution of French-Canadian low-density lipoprotein receptor gene mutations in the Province of Quebec.

A total of 35 homozygous and 1320 heterozygous patients with familial hypercholesterolemia (FH) was screened for the presence of six low-density lipoprotein receptor (LDLR) gene mutations previously reported among French-Canadians. The geographic distribution of patients' birthplaces and the relative prevalence of these six mutations in the LDLR gene in the province of Quebec were compared. For this purpose, the 16 administrative regions of the province of Quebec were grouped into seven geographic regions. The relative frequency of the six mutations differed in the seven regions: the > 15 kb deletion (delta > 15 kb) had the highest relative frequency in the Bas St-Laurent/Gaspésie region, and the point mutation in exon 3 had the highest relative frequency in the Saguenay-Lac-St-Jean/Côte-Nord region. In the Montreal area, the delta > 15 kb and the mutation in exon 3 had prevalence rates of 71.2% and 13.0%, respectively, whereas the relative frequencies of the delta > 15 kb and the point mutation in exon 3 in the Quebec city region were 57.5 and 21.8%, respectively. Finally, in Saguenay-Lac-St-Jean/Côte-Nord, the relative frequency of the delta > 15 kb only reached 31.5% and the point mutation in exon 3, 59.2%. Thus, on the north shore of the St. Lawrence River, the prevalence of the delta > 15 kb decreases from west to north-east, whereas the relative frequency of the mutation in exon 3 appears to increase. These observations provide a better characterization of FH among French-Canadians of Quebec, a Canadian province with a high prevalence of this inherited disease.

Heterozygous familial hypercholesterolemia in children: low-density lipoprotein receptor mutational analysis and variation in the expression of plasma lipoprotein-lipid concentrations.

The phenotypic expression of heterozygous familial hypercholesterolemia (FH) is variable form biochemical and clinical standpoints and several genetic and environmental factors could contribute to explain this variability. We have compared, in a cohort of 266 heterozygous FH children and adolescents (1-19 years), the variation in plasma lipoprotein-lipid levels among patients defined by three mutations in the low density lipoprotein receptor (LDLR) gene. Comparison of the plasma total and LDL-cholesterol (LDL-C) levels among the three mutation groups revealed significant differences. Plasma total and LDL-C levels were significantly higher (P < 0.05) in the group bearing the French-Canadian delta > 15 kb null allele mutation (8.17 +/- 1.45 and 6.58 +/- 1.42 mmol/l) and in the group with the defective allele C646Y missense mutation (8.18 +/- 1.53 and 6.65 +/- 1.50 mmo/l) compared to the group with the defective allele W66G missense mutation (7.19 +/- 1.23 and 5.62 +/- 1.16 mmol/l). Comparisons of other lipoprotein-lipid parameters between FH heterozygotes and normolipemic (n = 120) children indicated that all mutation groups had significantly (P = 0.0001) lower plasma HDL-cholesterol (HDL-C) levels and a higher total cholesterol (TC) to HDL-C ratio (P < 0.05). Among FH heterozygote groups, the W66G group had the lowest TC to HDL-C ratio. Multivariate analyses revealed that in FH heterozygotes as well as in controls, HDL-C levels contributed to a greater proportion of the variation in TC to HDL-C ratio than TC. In order to examine the age effect, control and FH heterozygote delta > 15 kb groups were then subdivided into four groups (1-4; 5-8; 9-13, and 14-19 years). The variation in HDL-C and triglycerides with age in heterozygous FH children showed a pattern which was similar to the one noted in the control group. In conclusion, the present study demonstrated that the overall contribution of age to variation in the lipoprotein profile of heterozygous FH children is similar to the effect observed among healthy children. The effect of LDLR gene in FH is dominant and there was no difference in plasma TC and LDL-C due to gender. Finally, this study indicates that the LDLR gene type mutations are a modulator of the magnitude of the increase in plasma TC and LDL-C levels noted among FH heterozygote children.

Primary lipoprotein-lipase-activity deficiency: clinical investigation of a French Canadian population.

We examined 56 French Canadians, aged 1 week to 54 years, from eastern Quebec who were referred to the Laval University Lipid Research Centre and in whom coincidental finding (in 46% of the cases), abdominal pain (in 32%) or family screening (in 22%) led to the diagnosis of primary lipoprotein-lipase-activity deficiency (familial hyperchylomicronemia). Half of the patients had one or more of the following signs: lipemia retinalis, eruptive xanthomas, splenomegaly and hepatomegaly; the plasma triglyceride concentrations were significantly higher (greater than 40 mmol/L) among these patients than among those without clinical signs (mean 21.7 [standard deviation 13.5] mmol/L). The prevalence rate of this disorder was 30 times higher than the previously published rate and was highest in the counties of Charlevoix and Saguenay-Lac-St-Jean (200 and 100 cases per million respectively) because of the distinct demographic history of these areas. Because of a founder effect an autosomal recessive gene involved in lipoprotein-lipase expression or activation has probably been disseminated among this isolated French Canadian population.

Severe lipemia induced by tamoxifen.

A 61-year-old woman was treated with tamoxifen for breast cancer and had marked hyperlipoproteinemia: high plasma triglyceride levels (2790 mg/dl); increased very low density lipoprotein (VLDL) cholesterol levels (241 mg/dl); and high VLDL apoprotein B levels (126 mg/dl). Low density lipoprotein (LDL) cholesterol was decreased (104 mg/dl) and LDL apoprotein B was at 107 mg/dl. A low activity of both postheparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (h-TGL) was also noted. All these observations were reversed following tamoxifen withdrawal. Plasma triglyceride levels fell to 361 mg/dl. VLDL cholesterol and VLDL apoprotein B decreased to 41 mg/dl (83%) and 21 mg/dl (83%), respectively. Meanwhile, LDL cholesterol rose to 194 mg/dl (86%) and LDL apoprotein B increased to 138 mg/dl (29%). LPL and h-TGL activities did increase following tamoxifen withdrawal. Our observations show that, in some patients, the previously described weak hypertriglyceridemic effect of tamoxifen is amplified. That observation supports the concept and helps to explain that, in such severe induced lipemia, reduction of the activities of LPL and h-TGL might impede the conversion of VLDL to LDL, thus causing an amplification of the effect.

Long term treatment of two familial hypercholesterolemic heterozygote patients with batch affinity chromatography (BAC).

Two familial hypercholesterolemic heterozygote patients were treated for a period of 2 years using an extracorporeal technique involving batch affinity chromatography. In both cases LDL-cholesterol levels were drastically lowered and HDL-cholesterol levels were normalized. No untoward side effects were noted during the 2 year experimental period. These results confirm the safety and simplicity of this technique to lower considerably LDL-cholesterol levels in whole blood of familial hypercholesterolemic patients who do not adequately respond to conventional medical treatment.

Effects of dextrothyroxine on the pituitary-thyroid axis in hypercholesterolemic children and goitrous adults.

To evaluate the effects of dextrothyroxine (D-T4) on the pituitary-thyroid axis, we have measured the secretion of TSH in response to TRH in six goitrous adults and six euthyroid children with familial hypercholesterolemia. Since the effects of thyroid hormones appear to be mediated by specific nuclear receptors, the binding affinity of D-T4 was also studied. In both groups of subjects, D-T4 completely abolished the expected TRH stimulation of TSH and T3 secretion. The in vitro binding of D-T4 to rat pituitary nuclear receptors is only 3% that of L-T3, but the binding of D-T3 was similar to that of L-T4 (13% and 11%, respectively). The high circulating levels of D-T4 and possibly of D-T3 after chronic administration of D-T4 may be responsible for the saturation of pituitary nuclear T3 receptors, resulting in the suppression of the TRH-induced TSH response. During the treatment period, total cholesterol, low density lipoprotein cholesterol, and high density lipoprotein cholesterol were significantly decreased by 18%, 18%, and 19%, respectively. Plasma triglyceride levels and the ratio of total to high density lipoprotein cholesterol were not affected. Although D-T4 lowers cholesterol levels, in view of its suppressive effect on the pituitary-thyroid axis, caution must be exercised with regard to its long term use in children.

Evaluation of the daily amount of ascorbic acid supplied by food in France.

The food consumption of a sample of 10,000 French households has been under constant study by the Institut National des Statistiques et Etudes Economiques. Based on the data obtained, a representative model of the daily food consumption has been established with the help of the Nutrition Section of the Institut National de la Santé et de la Recherche Médicale. A composition table was used to define the theoretical amount of natural ascorbic acid contained in these foodstuffs, to this quantity was added the amounts of ascorbic acid incorporated as an additive in these foodstuffs. The latter amount was obtained using the maximum authorized amounts. Natural ascorbic acid plus additive gives the maximum theoretical amount of vitamin C supplied through food consumption. The mean value obtained is approximately 170-200 mg/day between 1965-1974 period. Interesting as they may be, from a nutritional point of view, it would be unrealistic to build upon these theoretical values. A critical analysis of these values based on the results of a food survey we carried out and the technological role played by ascorbic acid, led to the conclusion that food content, with this model of food intake, was somewhat between 56 to 91 mg/day and more probably between 56 to 69 mg/day. Kallner and al. in 1979 suggested that in the healthy non-smoking man the recommended dietary allowance should be 100 mg/day. In connection with this work and with nutritional studies undertaken in various industrial countries, the present study brings up the question of the level of vitamin C supply in certain groups of the French population (old people, pregnant women...).