No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma.

Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.

BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors.

The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells. We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors.

Accidental deep hypothermia with cardiopulmonary arrest: extracorporeal blood rewarming in 11 patients.

Sixteen patients (age 13-53 years) with accidental deep hypothermia have been rewarmed in our clinic during the last 10 years, 14 by femoro-femoral cardiopulmonary bypass (CPB) of whom 11 had a cardiopulmonary arrest (asystole in 5 and ventricular fibrillation in 6). On admission, the latter were clinically dead showing wide non-reactive pupils and being supported by ventilation and external heart massage. In the survivors, the mean length of cold exposure was 4.4 h (2-5.5 h) and mean arrest interval until initiation of CPB was 2.5 h (1.4-3.7 h). Rectal temperature on admission ranged from 17.5 degrees C to 26 degrees C (mean 22.5 degrees C). The causes for hypothermia were fall into a crevasse (5), avalanche (1), drowning (2) and cold exposure (3) including 2 suicide attempts. Results are summarized in the following table: [table: see text] Eight of the 11 patients with deep hypothermia and cardiac arrest were rewarmed and resuscitated successfully with CPB. Three patients, including 2 cases of asphyxia (avalanche and drowning), could not be weaned from CPB despite adequate rewarming. The other drowned patient (53 years) died on the 3rd postoperative day (POD) from ARDS. The main complication was pulmonary edema (57%) and transient neurological deficits. All survivors became conscious during the first POD and resumed, their professional activity. We conclude that patients with accidental deep hypothermia and even prolonged cardiopulmonary arrest should be rewarmed and resuscitated rapidly by cardiopulmonary bypass. These measures are very promising particularly if the cause of accident and the circumstances suggest that cardiopulmonary arrest was induced by hypothermia alone without other asphyxiating mechanisms.

[Differential diagnosis of circulatory failure in hypothermic avalanche victims: retrospective analysis of 32 avalanche accidents]. / Differentialdiagnose des Kreislaufstillstands hypothermer Lawinenopfer: retrospektive Analyse von 32 Lawinenunfällen.

In avalanche accidents the cause of cardio-respiratory arrest (asphyxia, hypothermia, trauma) is difficult to determine in the field but may be important (high number of victims, limited number of rewarming places). 32 avalanche accidents (16 survivors/16 deaths) were therefore reviewed retrospectively. In 19 patients with cardiorespiratory arrest, asphyxia was frequent (17 patients, 89%) hypothermia was rare (two patients, 11%). The cooling rate between the accident and the arrival at the hospital was 3.0 degrees C/h. (range 0.75-5.8). The core temperature at arrival in the hospital was dependent on the time spent buried under the snow (survivors) and total time (nonsurvivors). The maximal cooling rate under the snow was estimated at 8 degrees C/h. Cardiorespiratory arrest in hypothermic patients without asphyxia seems only to be possible after being buried for at least 1 h. under the snow. Serum potassium was elevated in most cases of asphyxia.

[Accidental hypothermia in Switzerland (1980-1987)--case reports and prognostic factors]. / Akzidentelle Hypothermie in der Schweiz (1980-1987)--Kasuistik und prognostische Faktoren.

This retrospective study comprises 234 cases of accidental hypothermia (core temperature less than 35 degrees C) hospitalized in 95 Swiss clinics between 1980 and 1987. The most frequent accidents were alpine (n = 78) in origin, followed by cold exposure after injuries (n = 63) and suicide attempts (n = 43). Hypothermia was induced by cold air in 129 cases and by water in 47 cases. Patients were divided evenly between the degree of hypothermia: 75 mild (32-35 degrees C), 79 moderate (28-32 degrees C) and 66 severe (less than 28 degrees C). Among the survivors the coldest patient had a core temperature of 17.5 degrees C and the longest cardiac arrest with a favourable outcome lasted 4.75 hours. Out of the 234 patients 68 died (29%). We assessed all variables relative to outcome, in particular the mechanism of the accident, the mode of cooling, temperature, circulation, age and sex, underlying diseases, rewarming methods, medication and complications during the hospital course. All variables were tested in two multiple regression analysis models (retrospective model n = 181: prospective model n = 128) with regard to significance (p less than 0.05) and survival. Results are expressed with ODD's ratios (OR). The negative survival factors are asphyxia (OR 30), invasive rewarming methods (OR 20), slow rate of cooling (OR 10), asystole on arrival (OR 9), pulmonary edema or ARDS during hospitalization (OR 8), elevated serum potassium (OR 2/mmol/l) and age (OR 1.03/year). The positive survival factors are rapid cooling rate (OR 10), presence of ventricular fibrillation in cardiac arrest patients (OR 9) and presence of narcotics and/or alcohol during hypothermia (OR 5).(ABSTRACT TRUNCATED AT 250 WORDS)