Pancreatic tumors in multiple endocrine neoplasia type 1: Clinical presentation and surgical treatment

Among 33 patients with endocrine pancreatic tumors due to multiple endocrine neoplasia type 1 (MEN-1), 19 (58%) patients had hypergastrinemia, 7 (21%) patients had hyperinsulinism, and 7 (21%) patients had clinically non-functioning lesions. At least one gross tumor was found in all patients undergoing pancreatic surgery, including those with negative localization studies prior to operation. The patients also had additional macroscopic tumors as well as numerous microadenomas, and the lesions frequently were positive for immunostaining with multiple hormones, mainly pancreatic polypeptide, insulin, glucagon, and somatostatin. Duodenal endocrine lesions were found in 4 of 5 investigated patients and stained with gastrin and somatostatin antibodies. Distal, mainly subtotal pancreatic resection, was performed in 18 patients, eventually combined with caput tumor enucleation or duodenotomy, while a few patients underwent only tumor enucleation or a Whipple procedure. The long-erm outcome of operation was most favorable in patients with hyperinsulinism; only 1 patient had clinical recurrence. Patients with hypergastrinemia experienced only transitory lowering of serum gastrin values after pancreatic surgery and 47% of them had or developed metastases. Such tumor spread was seen in 57% of the patients with non-functioning lesions. Nine patients died from progressive tumor disease during follow-up. Consistent with previous studies, we found that surgery is indicated in MEN-1 patients with hyperinsulinism even if a lesion is not visualized by radiology. In addition, these indications should be extended to also include patients with only biochemical markers of disease, including elevations of gastrin, as these indicate the presence of gross tumors. This strategy should be applied especially in patients with aggressive family histories to possibly reduce the risk of malignant tumor progression.

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Resumen Entre 33 individuos con tumores pancréaticos endocrinos como componente del síndrome de neoplasia endocrina múltiple tipo 1 (NEM-1), 19 pacientes (58%) tenían hipergastrinemia, 7 (21%) hiperinsulinismo y 7 (21%) lesiones clínicas no funcionantes. En la totalidad de los pacientes sometidos a cirugía pancreática fue hallado por lo menos un tumor, incluso en aquellos con examenes de localización negativos anteriores a la operación. Estos pacientes también albergaban tumores macroscópicos, así como numerosos microadenomas; con frecuencia las lesiones demostraron inmunocoloración con diferentes hormonas, principalmente polipéptido, insulina, glucagón y somatostatina. Se encontraron lesiones endocrinas duodenales en 4 de cada 5 pacientes investigados, las cuales colorearon con gastrina y anticuerpos a la somatostatina. Se practicó resección pancreática distal (principalmente resección subtotal) en 18 pacientes, eventualmente combinada con enucleación del tumor (cuando éste se hallaba ubicado en la cabeza del páncreas) o duodenectomía; solamente unos pocos pacientes fueron sometidos a simple enucleación del tumor o al procedimiento de Whipple. El resultado a largo plazo fue más favorable en los pacientes con hiperinsulinismo, puesto que sólo uno presentó recurrencia clínica. Los pacientes con hipergastrinemia exhibieron apenas una disminución transitoria de los valores de gastrina sérica luego de la cirugía pancreática. Cuarenta y siete por ciento del conjunto tuvo o desarrolló metástasis, en tanto que la extensión local del tumor se presentó en 57% de los casos con lesiones no funcionantes. Nueve pacientes murieron por progresión de la neoplasia en el curso del seguimiento. En acuerdo con sugerencias previas, se considero quo la cirugía está indicada en pacientes con NEM-1 e hiperinsulinismo, aún en los casos en que no se visualiza radiológicamente la lesión, pero que la indicación puede ser ampliada para incluir también pacientes con sólo marcadores bioquímicos, tales como niveles elevados de gastrina, indicativos de la presencia de tumores macroscópicos. Esta estrategia debe ser aplicada principalmente en aquellos pacientes con historia familiar agresiva, con lo cual tal vez se reduce el riesgo de progesión maligna del tumor.

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Résumé Parmi 33 patients ayant une tumeur pancréatique endocrine due à une néoplasie endocrine multiple de type 1 (MEN-1), 19 (58%) avaient une hypergastrinémie, 7 (21%) un hyperinsulinisme et 7 (21%) une lésion cliniquement muette. On a mis en évidence au minimum une grosse tumeur chez tous les patients, y compris chez ceux dont les examens préopératoires de dépistage tumoral étaient négatifs. Les patients étaient également porteurs de tumeurs macroscopiques et de nombreux microadénomes. Les lésions montraient souvent un immunomarquage positif pour de multiples hormones, principalement le polypeptide pancréatique, l'insuline, le glucagon et la somatostatine. Des lésions endocrines duodénales furent retrouvées chez 4 des 5 patients explorés; elles montraient un immunomarquage avec les anticorps angigastrine et anti-somatostatine. Une résection pancréatique distale, le plus souvent subtotale, a été réalisée chez 18 patients. Elle était éventuellement complétée par une énucléation tmorale de la tête ou par une duodénotomie. Peu de patients ont bénéficié d'une simple énucléation ou d'une intervention de Whipple. L'évolution postopératoire à long terme a été plus favorable en cas d'insulinome puisque seul un patient a eu une récidive clinique. Les patients atteints de gastrinome n'ont présenté que transitoirement une diminution des taux sériques de gastrine après la chirurgie pancréatique. Quarante sept pour cent de ces patients avaient ou ont développé des métastases contre 57% des patients porteurs de lésions sans traduction clinique. Neuf patients sont décédés en raison de l'extension tumorale au cours du suivi. Conformément à des suggestions antérieures, la chirurgie semble indiquée chez les patients atteints de MEN-1 avec hyperinsulinisme même si la radiologie ne visualise pas de lésion. Mais cette indication peut être élargie aux patients dont seuls les paramètres biologiques sont en faveur d'une grosse tumeur (dont l'hypergastrinémie). Cette stratégie pourrait convenir particulièrement aux patients ayant des antécédents familiaux importants; elle permettrait peut-être de réduire le risque d'extension tumorale.

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Presented at the International Association of Endocrine Surgeons in Stockholm, Sweden, August, 1991.     

Developmentally Regulated Expression of HDNF/NT-3 mRNA in Rat Spinal Cord Motoneurons and Expression of BDNF mRNA in Embryonic Dorsal Root Ganglion

Northern blot analysis was used to demonstrate high levels of hippocampus-derived neurotrophic factor/neurotrophin-3 (HDNF/NT-3) mRNA in the embryonic day (E) 13 - 14 and 15 - 16 spinal cord. The level decreased at E18 - 19 and remained the same until postnatal day (P) 1, after which it decreased further to a level below the detection limit in the adult. In situ hybridization revealed that the NT-3 mRNA detected in the developing spinal cord was derived from motoneurons and the decrease seen at E18 - 19 was caused by a reduction in the number of motoneurons expressing NT-3 mRNA. The distribution of NT-3 mRNA-expressing cells in the E15 spinal cord was very similar to the distribution of cells expressing choline acetyltransferase or nerve growth factor receptor (NGFR) mRNA. Moreover, a striking similarity between the developmentally regulated expression of NT-3 and NGFR mRNA was noted in spinal cord motoneurons. A subpopulation of all neurons in the dorsal root ganglia expressed brain-derived neurotrophic factor (BDNF) mRNA from E13, the earliest time examined, to adulthood. These results are consistent with a trophic role of NT-3 for proprioceptive sensory neurons innervating the ventral horn, and imply a local action of BDNF for developing sensory neurons within the dorsal root ganglia.     

The costs of treating hypertension--an analysis of different cut-off points

In this article the effects of different cut-off points for hypertension treatment are analysed, with respect to treatment costs. A theoretical blood pressure distribution is used to calculate the potential annual cost of treating all persons in Sweden above certain cut-off points for drug treatment. A lowering of the cut-off point from 105 mm Hg to 100 mm Hg diastolic blood pressure could potentially lead to an increase in annual costs of approximately 80m pounds. Further lowering from 100 to 95 mm Hg in turn could increase annual costs by about 110m pounds. The potential annual cost of treating all persons (roughly 1.6 million) with a diastolic blood pressure of greater than or equal to 95 mm Hg with drugs is calculated as being roughly 40 pounds per inhabitant in Sweden. The Swedish cut-off point for treatment (95 mm Hg) can be expected to lead to roughly 50 per cent higher treatment costs than the British cut-off point (100 mm Hg).     

Plasma concentrations of valproate during maintenance therapy in epileptic children

Summary A total of 20 children with various types of epilepsy were treated with valproate, 11 with monotherapy and 9 with valproate in combination with phenobarbitone, phenytoin, or carbamazepine. Valproate was given either every 8 or 12 h. At least two different dose levels were tried in each patient. The pharmacokinetics of valproate during the interval between doses was determined using a gas chromatographic technique. The clinical effect of the treatment was assessed by interviewing the parents.The plasma concentrations showed considerable fluctuation during the intervals between doses. The mean increase from pre-administration to peak level was 82% when the dose interval was 12 h, and 62% when it was 8 h. The mean plasma half-life of valproate, using a one-compartment model, was 10.9±1.3 h (mean±SD). The plasma half-life of valproate was decreased when the drug was combined with the other anti-epileptics. The calculated area under the concentration versus time curve was linearly related to dose, both in a single patient on four dose levels and when different patients were compared. The clinical effect of valproate monotherapy was best in patients with absences, usually good in myoclonus and less favourable in other types of epilepsy. For children with absences, the optimal dose range of valproate was between 20 and 40 mg/kg/24 h. In comparison, the myoclonic types of epilepsy needed a slightly higher dose level, between 30 and 60 mg/kg/24 h. In the latter group a therapeutic window seems to exist, since patients below and above the suggested dose levels were not well-controlled. Therapeutic monitoring of valproate does not appear meaningful when the drug is used as monotherapy. However, in combination therapy, determination of the plasma levels of all anti-convulsants used may be helpful. The large fluctuations of valproate during a dose interval must be taken into consideration when the clinical effects are analysed.Supported by the Swedish Medical Research Council (Project No. 522), Stiftelsen Margarethahemmet, and Sällskapet Barnavård     

The influence of different technique factors on image quality of lumbar spine radiographs as evaluated by established CEC image criteria

In this study we have investigated the image quality of lumbar spine radiographs taken after recording technical and physical parameters. Two technical parameters were altered, tube voltage (70 kV and 90 kV for the anteroposterior (AP) projection and 77 kV and 95 kV for the lateral projection) and sensitivity of the film-screen system (sensitivity class 400 and 600). In total, 85 images were included in the study. Entrance surface dose (ESD) was measured using thermoluminescent dosemeters. The mean value of ESD for the different technique groups varied between 1.9 mGy (90 kV, sensitivity class 400) and 4.6 mGy (70 kV, sensitivity class 400) for the AP projection, and between 6.4 mGy (95 kV, sensitivity class 600) and 20.4 mGy (70 kV, sensitivity class 400) for the lateral projection. Image criteria given in the "European Guidelines on Quality Criteria for Radiographic Images" were used to assess image quality. Two evaluation methods have been employed. A straightforward scoring of fulfilled image criteria, and visual grading analysis using the structures defined in the image criteria. The latter method provided a sharper distinction between groups of images taken using different radiographic techniques. The average number of fulfilled image criteria for the AP projections varied between 0.74 (90 kV, sensitivity class 400) and 0.87 (70 kV, sensitivity class 400). For the lateral projection this number varied between 0.79 (95 kV, sensitivity class 600) and 0.84 (77 kV, sensitivity class 600). This study shows that image criteria are useful tools in clinical studies of image quality.     

Subjective xerostomia in long-term surviving children and adolescents after pediatric bone marrow transplantation

BACKGROUND: The aim of the present investigation was to evaluate whether the subjective symptoms of dry mouth in long-term-surviving pediatric bone marrow transplant (BMT) patients are associated with low unstimulated salivary secretion rates (USSR) and with stimulated whole salivary secretion rates (SSSR). METHODS: Fifty-three patients surviving > or =2 years after pediatric allogeneic BMT were included. USSR, SSSR, and the change in salivary secretion rates since the previous year were estimated. A questionnaire regarding subjective symptoms of xerostomia was answered. RESULTS: The mean USSR and SSSR were 0.24+/-0.17 and 0.90 +/- 0.58 ml/min, respectively. Salivary gland dysfunction, defined as USSR < or =0.1 ml/min or SSSR < or =0.5 ml/min, was present in 35% of the patients. Seventy-nine percent of the patients expressed one or more symptom of dry mouth, and 49% gave at least two answers indicating dry mouth. The number of complaints increased with age at examination (P<0.05). Both USSR (P<0.01) and SSSR (P<0.01) were inversely correlated to the total number of complaints of xerostomia. A reduction in SSSR compared with the year before was correlated to two or more complaints of xerostomia (P<0.01). The presence of dry mouth at night or on awakening was indicative of both low USSR (P<0.01) and SSSR (P<0.001). Patients reporting dryness during the day had significantly lower SSSR (P<0.05). CONCLUSION: The expression of subjective complaints of xerostomia among long-term surviving pediatric BMT patients is correlated to salivary gland dysfunction and age. It is very important to identify these patients with salivary gland dysfunction to relieve their symptoms and prevent secondary complications.     

Organ-specific acellular matrix for reconstruction of the urinary tract

In urology, replacement of organs or organ segments has proved problematic. Current techniques do not replicate complete organ function, and they cause well-known complications. With the acellular organ-specific matrix we have found a way to regenerate tissue components seen in the normal lower urinary tract. The time required for regeneration depends on the matrix size and function. The matrix is covered by urothelium migrating from the host, after which neovascularization occurs, followed by formation of smooth-muscle cells and nerves. In our studies, normal muscle lining and nerves providing functional tissue were demonstrable and no sign of antigenicity was evident, even after heterologous grafting. The regenerated rat bladder was evaluated by organ bath as well as by in vivo functional tests and demonstrated properties and functions similar to those of host tissue. Besides our obtaining encouraging results in the rat bladder, we also studied the organ-specific acellular matrix in other species (dog and rabbit) and other organ segments (ureter and urethra).     

Reduction of epileptiform activity in response to low-dose clonazepam in children with epilepsy: a randomized double-blind study

PURPOSE: To evaluate the effect of low-dose clonazepam (CZP) on the amount of epileptiform activity in children with focal and generalized epilepsy. METHODS: In a single-blind pilot study, followed by a double-blind, placebo-controlled, randomized, crossover study, 15 children with epilepsy were evaluated by using 24-h long-term EEG recordings during baseline days and days after injections of placebo and CZP. The drug was given as a single i.m. injection of 0.02 mg/kg BW. Blood samples were obtained regularly for analysis of plasma concentrations of CZP. The number of epileptiform discharges was determined during corresponding periods with the individual child in the same state of alertness, the same real time of day, and with concomitant antiepileptic drugs (AEDs) unchanged. RESULTS: In the double-blind study, low-dose CZP produced a highly significant (p = 0.0015) decrease in the amount of epileptiform activity (mean, -69% vs. placebo, -2%) obtained during periods when median plasma concentrations ranged from 18 to <14 nM. The maximal plasma level (median, 24 nM) was reached before the start of the analysis periods. The pilot study showed reductions of epileptiform discharges within the same range as the double-blind study. In the children with daily seizures, a parallel decrease in seizures and the number of epileptiform discharges was seen after the administration of CZP. CONCLUSIONS: Our data demonstrate a significant reduction of epileptiform discharges on long-term EEGs after a single low dose of CZP with concomitant low plasma levels, which were considerably lower than the doses and plasma levels usually recommended. A concomitant reduction of seizures also was seen.     

Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery

BACKGROUND: The aim was to evaluate the use of clevidipine, a new vascular selective, ultra-short-acting calcium antagonist for blood pressure control after coronary artery bypass grafting (CABG). METHODS: The effects of clevidipine on central hemodynamics, myocardial blood flow and metabolism were studied at two different phases after CABG. In phase 1 (n=13), the hypertensive phase, the effects of clevidipine were compared to those of sodium nitroprusside (SNP) when used to control postoperative hypertension. In phase 2 (n=9), the normotensive phase, a clevidipine dose-response relationship was established. RESULTS: At a target mean arterial pressure (MAP) of 75 mmHg, systemic vascular resistance (SVR) and heart rate (HR) were lower, preload, stroke volume (SV) and pulmonary vascular resistance (PVR) were higher, while there were no differences in myocardial lactate metabolism or oxygen extraction with clevidipine compared to SNP. In the normotensive phase, clevidipine induced a dose-dependent decrease in MAP (-19%), SVR (-27%) and PVR (-15%), accompanied by an increase in SV (10%), but no reflex increase in HR or changes in cardiac preload. Clevidipine caused a direct coronary vasodilation, as indicated by a decrease in myocardial oxygen extraction from 54% to 45%. Myocardial lactate metabolism was unaffected by clevidipine. The blood clearance of clevidipine was 0.05 l x min(-1) x kg(-1), the volume of distribution at steady state was 0.08 l x kg(-1) and the initial and terminal half-lives were <1 min and 4 min, respectively. CONCLUSIONS: Clevidipine rapidly reduced MAP and induced a systemic, pulmonary and coronary vasodilation with no effect on venous capacitance vessels or HR. Clevidipine caused no adverse effects on myocardial lactate metabolism. Clevidipine thus appears suitable to control blood pressure after CABG.     

Satisfaction of caregivers of patients with schizophrenia in Finland

OBJECTIVE: The aims of the study were to determine whether the caregivers of discharged patients with schizophrenia were satisfied with their situation in general and with psychiatric services in particular and to examine the factors associated with caregiver satisfaction. METHODS: The data were drawn from a national project designed to study the treatment and life situation of deinstitutionalized schizophrenia patients in Finland. The patients were discharged from psychiatric hospitals in 1986, and both the patients (N=775) and their caregivers (N=545) were interviewed after a three-year follow-up. RESULTS: One-fifth of the caregivers were dissatisfied with the situation in general, and one-third were dissatisfied with the psychiatric services the patient received. Caregivers were more likely to be dissatisfied with the situation if they lived with the patient and if the patient's functional state was poor or the patient's use of services, particularly medication and rehabilitation, was low. Caregivers were likely to be dissatisfied with the psychiatric services if the patient had severe psychotic symptoms and poor "maintenance of grip on life" or if the patient was given less psychiatric care and rehabilitation or used more social services. CONCLUSIONS: The satisfaction of caregivers of persons with mental illness appears to have two dimensions. First, caregivers need to be accepted and treated as active partners in the patients' care and rehabilitation. Second, the burden on the families of persons with mental illness can be alleviated with long-term rehabilitation and care to help patients gain as high a functional state as possible.