[Muir-Torre syndrome and Turcot syndrome]. / Syndrome de Muir-Torre et syndrome de Turcot.

INTRODUCTION: Lynch syndrome (LS) is a syndrome that carries a genetic predisposition to certain cancers associating, either in a single individual or in a family, a visceral tumour, mainly colorectal, with a high risk of other synchronous or metachronous cancers. LS is linked with mutations in the genes coding for proteins in the DNA repair system. Phenotypic variants of SL exist, including Muir-Torre syndrome (MTS) and Turcot syndrome (TS), both of which predispose to colorectal cancer. They may be distinguished by the presence of benign or malignant sebaceous tumours in MTS, and tumours of the central nervous system in TS. PATIENTS AND METHODS: A 59-year-old man, with a history of right colon cancer at the age of 36 years, consulted for a nose lesion shown by histopathological examination to be a sebaceous tumour. Immunohistochemistry revealed loss of expression of proteins MSH2 and MSH6, strongly suggesting a diagnosis of MTS. Eight years earlier, the man's son had developed a fatal glioblastoma; given the paternal phenotype of MTS, the hypothesis of TS in the son is probable. DISCUSSION: This case suggests that several variants of Lynch syndrome may be seen within the same family. It raises the issue of screening for cerebral tumours in patients with MTS and in their family members, even though such a recommendation does not exist; current recommendations in fact consist primarily of gastrointestinal and gynaecological monitoring.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Therapeutic properties of glass-ionomer cements: Their application to orthodontic treatment.

Fluoride has been shown to be an effective agent in the prevention of caries during orthodontic treatment. Resin-modified glass-ionomer cements possess therapeutic anticariogenic properties acting as a fluoride reservoir and releasing fluoride into the environment, particularly at low pH where there is a threat of enamel demineralisation and white spot lesions (WSL's). Patient compliance to instructions in standard oral hygiene measures limits the success of caries prevention and the routine use of glass-ionomer cements can mitigate the lack of compliance, although RMGIC's are not a panacea against WSL's. The adhesion of GIC's to the enamel surface is a physicochemical bond rather than a mechanical bond which reduces the risk of iatrogenic damage to the enamel when bonding and debonding attachments. RMGIC's can be recommended as a bonding adhesive for all attachments but one needs to be selective when bonding molar attachments to avoid occlusal interferences as masticatory forces can be high in these areas.

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

Obesity and iron status in menstruating women.

The relationship between iron stores and obesity in menstruating women was studied in 20 obese and 20 nonobese women matched for age and contraception. Although no difference was observed in serum iron or total-iron-binding capacity, the obese group showed significantly higher hemoglobin (137 +/- 9 vs 10 g/L, mean +/- SD; P less than 0.01), hematocrit (0.41 +/- 0.02 vs 0.39 +/- 0.03, P less than 0.05), and serum ferritin concentrations (48.0 +/- 44.3 vs 25.8 +/- 19.5 micrograms/L, P less than 0.05). There was no difference between obese and nonobese women in either the menstrual-cycle interval or the duration of the menstrual flow. Iron intake was significantly higher in the obese group (15.9 +/- 2.9 vs 14.1 +/- 2.9 mg/d, P less than 0.05). These results suggest that obese menstruating women are at low risk of depleting iron stores, possibly because of high iron intake. Iron-fortification programs might thus be undesirable in such subjects.

Fat-free mass estimation by the two-electrode impedance method.

In 202 healthy subjects (81 men, 121 women) aged 12-71 y, impedance (Z) was measured with a two-electrode analyzer. Fat-free mass was assessed by hydrodensitometry (FFMd). This population was randomized into two groups for cross-validation. In group 1 the relationship between ht2/Z at 1 MHz and FFMd was highly significant (r = 0.85, P less than 0.001). The equation for predicting FFMd from impedance, height2, weight, and age obtained in group 1 (r = 0.97) was applied to group 2 (r = 0.96) without reduction in r value. The accuracy of this equation was not different between men and women or between active and sedentary people. These data indicate that the two-electrode impedance method is a reliable and valid approach not only for the determination of extracellular water (as previously shown) but also for that of FFM.

Energy-metabolism adaptation in obese adults on a very-low-calorie diet.

In this study, six obese women received a very-low-calorie diet (VLCD) for 3 wk. At day 0, body composition was assessed with a bioelectric impedance analyzer. The evolution in lean body mass (LBM) during the VLCD was estimated from nitrogen balance, measuring urine and fecal losses and taking into account skin, nitrate, and menstrual losses to avoid underestimation bias that could explain the decreased ratio of resting metabolic rate (RMR) to LBM previously reported. RMR was measured at days 0, 3, 5, and 21. The RMR-LBM ratio declined significantly during the VLCD period and decreased faster during the first week; the day 3, day 5, and day 21 ratio values were 94%, 91%, and 82%, respectively, of the original. The RMR-LBM ratio decrease after 21 d of a VLCD was near that found in chronic undernutrition. Results of previous studies that did not find any drop in the RMR-LBM ratio in obese adults on VLCDs might be explained by their LBM-assessment methods.

Comparing the effects of aspartame and sucrose on motivational ratings, taste preferences, and energy intakes in humans.

This study compared the effects of four breakfast preloads on motivational ratings, taste preferences, and energy intakes of 24 normal-weight nondieting young men and women. The preloads, composed of creamy white cheese (fromage blanc), were either plain or sweetened with aspartame or sucrose. Their energy value was either 1255 or 2929 kJ (300 or 700 kcal). Taste preferences were measured before and 150 min after breakfast. Motivational ratings were obtained at 30-min intervals. The subjects ate lunch, snack, and dinner meals in the laboratory. The consumption of low-energy as opposed to high-energy breakfasts, regardless of sweetness, led to elevated motivational ratings and increased energy intakes at lunch. However, intakes at subsequent meals were the same for all preloads, and no overall compensation in energy was observed. Aspartame did not promote hunger or lead to increased energy intakes in normal-weight subjects.

Lack of association between dietary alcohol and HDL-cholesterol concentrations in obese women.

The relationships of alcohol intake and corpulence to HDL-cholesterol were studied in 653 women taking medical advice about body weight. The body mass index (BMI) was positively correlated with triglyceride and negatively with HDL-cholesterol. The relation between BMI and HDL-cholesterol was discontinuous. Total cholesterol, triglycerides and diastolic blood pressure were increased for alcohol intakes greater than 10 g/d regardless of body weight. Alcohol intake was associated with higher concentrations of HDL-cholesterol (P = 0.006) in non obese (BMI = 25.2 +/- 1.5 kg/m2) subjects, but not in mildly (27.3 less than or equal to BMI less than 32.3) or massively (BMI greater than or equal to 32.3) obese subjects. The fact that HDL concentrations were not associated with alcohol intake in obese patients suggests that (1) alcohol acts on the HDL pool through one of the pathways which are perturbed in obesity, possibly lipolysis, (2) obesity is one of the reasons for the differences in individual responses of HDL-cholesterol to alcohol, (3) myocardial infarction might not be inversely correlated with alcohol intake in the obese as it is in the non-obese population.

Effects of ovarian steroids on energy balance in rats fed a highly palatable diet.

The effects of progesterone and estradiol on body weight, energy intake, energy expenditure, body composition, and brown adipose tissue activity were investigated in female rats fed a highly palatable diet (association of chow and full milk with sugar), which, by itself, induced an increase in food intake and energy expenditure. Progesterone and estradiol were administered in the form of implants. Ovariectomized animals were used in the estradiol studies. Energy expenditure was assessed through oxygen consumption, body composition through carcass analysis, brown adipose tissue activity through measurements of uncoupling-protein, guanosine diphosphate (GDP) binding capacity, and assay of uncoupling-protein mRNA. Body weight and food intake were increased by progesterone and decreased by estradiol. Energy expenditure was not altered by progesterone. Indirect evidence showed that estradiol increased energy expenditure, but direct measurements showed no modification. Changes in body weight under progesterone or under estradiol were not due to brown adipose tissue activity. The results indicate that ovarian hormones act on energy balance mainly by altering food intake, and possibly in the case of estradiol by increasing energy expenditure. These effects persist in rats fed a highly palatable diet, despite increases in energy intake and expenditure induced by the diet alone.

Adjuvant tamoxifen in breast-cancer-treatment in postmenopausal women - occurrence of thromboembolic complications.

Of 441 postmenopausal breast cancer patients who received adjuvant tamoxifen, 19 had thromboembolic accidents (4.3%). All were in remission when thrombosis occurred. One patient died of bilateral pulmonary embolism. In the other cases, thromboembolic disorders were found to be reversible after the withdrawal of tamoxifen and anticoagulant treatment. Some patients had a history of vascular disorders, and others required prolonged bed rest which may have contributed as an aggravating circumstance to thrombotic events. Our study suggests that thromboembolic risk factors as well as potential vascular disorders induced by aggravating conditions have to be carefully examined in postmenopausal patients treated by adjuvant tamoxifen therapy. This is especially true in women with lobular breast cancer and aged more than 60 years.

Permanent administration of d-fenfluramine in rats: paradoxical effects.

In order to test the hypothesis of Levitzky that d-fenfluramine (d-F) acts by modifying the ponderal set-point, we compared the effects of a permanent infusion of d-F on food intake and body weight (BW). The effect on the weight persisted as long as the infusion; the clear-cut anorectic effect lasted only a few days. This paradox is compatible with the set-point hypothesis. In rats rendered overweight by insulin treatment, the d-F-induced decrease in BW was approximately four times smaller than in controls. In rats rendered overweight by a cafeteria diet, the decrease in BW was twice as large in permanently cafeteria fed rats as in cafeteria, then, ad lib fed rats. In rats rendered underweight by a restricted chow diet and then returned to an ad lib feeding, the final BW depended only on the doses of d-F (0.6 or 12 mg/kg BW/day), whatever the weight at the beginning of infusion. Thus, the underweight paradigm fits well with the set-point hypothesis; the overweight paradigm fits only partially.

Thymulin activity during very-low-calorie diet.

The potential use of thymulin levels as a sensitive and functional marker of energy deficiency was investigated in 13 obese women during a 3-week very-low-calorie diet. Mean weight loss was 8.92 +/- 0.52 kg after 21 days of treatment. The patients were free from infection as assessed by serum orosomucoid and C-reactive protein measurements. Serum albumin levels were not decreased throughout the experiment whereas transthyretin concentrations fell significantly during the first 2 weeks and remained fairly stable thereafter. Orosomucoid levels dropped only after 3 weeks of dieting. Serum zinc concentrations were within the normal range on admission and at the end of the experiment. Thymulin activity was not altered throughout the study, suggesting that this thymic hormone cannot be used as a functional marker of short-term energy restriction.

Penalizing recidivist drunk drivers in Indiana: impediments to implementation.

In 1983, Indiana enacted a law mandating that anyone convicted a second or subsequent time of Operating While Intoxicated (OWI) receive a minimum of 48 consecutive hours in jail or 10 days of community service. A representative random sample of Indiana counties was used to determine the extent of implementation of this law by the courts in 1984 and 1985. Analysis of the 1984 data concluded that nearly 70% of the cases did comply with the law in its first year of implementation. However, 13.8% of the recidivists received neither jail nor community service. Another 17.6% served some jail time and/or community service, but not of a sufficient length to comply with the law. Overall compliance increased to 75% in 1985, while the proportion who received neither jail nor community service increased to 17%. Several specific causes for noncompliance are identified and recommendations for their correction are offered. It is felt that the Indiana experience described in this paper will prove instructive to other states with newly-strengthened OWI laws.

[Thromboembolic accidents in postmenopausal patients with adjuvant treatment by tamoxifen. Frequency, risk factors and prevention possibilities]. / Accidents thromboemboliques chez les patientes ménopausées sous traitement adjuvant par tamoxifène. Fréquence, facteurs de risque et possibilités de prévention.

Tamoxifen is the anti-estrogen the most widely used in breast cancer. The duration of its prescription, as adjuvant treatment, tends to increase (5 years, and even more) and now it is used in chemoprevention. A slight increase of thromboembolic complications was noted in some studies. This article evaluates the frequency of thromboembolic accidents (TEA) in 441 postmenopausal patients treated by an association of conservative radiosurgery, tamoxifen +/- chemotherapy, for a breast carcinoma T0, T1T2 < 4 cm. Nineteen patients (4.3%), all in remission, presented a TEA, between 1 and 44 months after the beginning of the tamoxifen treatment. We observed seven pulmonary embolisms (PE), 11 deep venous thromboses (DVT) and an acute arterial ischemia. Two patients aged 74 and 80 years died, the others had a favourable evolution under anticoagulant treatment. Among these 19 patients, six presented known risks factors (phlebitis, cardiovascular disorders) and ten had a "favouring circumstance" aggravating the risk of TEA (surgical operation, severe infection, fracture). Their median age was 65 years (61 for all the 441 patients). We noted eight cases of breast lobular cancer (42%) among these 19 patients (11% for all the patients). Among postmenopausal patients, the indication of tamoxifen must be evaluated according to the benefits expected in those with high risk factors of TEA (history of heart failure, obesity, spread varix, age > 65 years). In case of DVT and/or PE, this treatment seems contra-indicated. In case of "favouring circumstances", a hypocoagulant or systematic anticoagulant treatment must be proposed. In case of combined chemotherapy, it is better to start tamoxifen at the end of the treatment. These simple prophylactic measures should allow to reduce significantly the risk of TEA in postmenopausal patients with adjuvant anti-estrogenotherapy.

[Germ-line mutations of the BRCA1 gene in northeastern France]. / Mutations germinales du gène BRCA1 dans le Nord-Est de la France.

Thirty-seven breast/ovarian or breast-only cancer families selected on a regional basis have been analyzed for mutations at BRCA1. By combining direct sequence analysis and protein truncation test, mutations were detected in 14 families (38%). We found seven different mutations, two of which have not been described before. Mutations at BRCA1 were present in 60% of breast/ovarian and 32% of breast-only cancer families. Mutations were frequent in families with at least one breast cancer case before age 40 (44%) and/or one bilateral breast cancer case (54%). Two mutations, namely 3600del11 and G1710X, are frequent in the population native from northeastern France. Oriented BRCA1 analysis should facilitate carrier detection in breast and/or ovarian cancer families stemming from this French area.

[Li-Fraumeni syndrome: update, new data and guidelines for clinical management]. / Le syndrome de Li-Fraumeni: mise au point, données nouvelles et recommandations pour la prise en charge.

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

[Preliminary results of a randomized trial comparing the efficacy of standard heparin with that of fragmine, a low molecular weight heparin, in the prevention of postoperative thrombosis in cancer surgery]. / Résultats préliminaires d'un essai randomisé comparant l'efficacité d'une héparine standard à celle de la fragmine, une héparine de bas poids moléculaire, dans la prophylaxie des thromboses post-opératoires en chirurgie oncologique.

Low molecular weight heparins have stimulated much interest because of their supposedly more selective action on Xa factor. A randomized study in 50 patients compared efficacy of low doses of a standard heparin, calciparin (5,000 IU/8 h) with that of a low molecular weight heparin, fragmine (Kabi 2165) (5,000 anti-Xa U/24 h), in the prophylaxis of postoperative thrombosis after oncologic surgery. Three of 25 patients receiving calciparin developed pulmonary embolism, as against one of 25 treated with fragmine who developed a periphlebitis. Hemorrhagic complications were comparable in the two groups. Anti-Xa activity was significantly higher in the fragmine group, whereas platelet counts, cephalin times with activator and anti-IIa activity were similar. These findings indicate equal efficacy of fragmine and calciparin in the prophylaxis of post-oncology surgery venous thrombosis.

The effects of temperature on the setting of glass ionomer (polyalkenoate) cements.

Glass ionomer (polyalkenoate) cements have proved to be superior to zinc phosphate cements as orthodontic luting agents. Setting behaviours at different temperatures were recorded by an oscillating rheometer under controlled conditions. The working time of these cements can be increased by mixing on a chilled glass slab with setting time at mouth temperatures remaining rapid. Where more than one orthodontic band is cemented per mix, the authors recommend refrigeration of the glass slab for at least one hour prior to mixing the cement.