Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Incidence and survival of intracranial meningioma patients in Norway 1963-1992.

The age-adjusted incidence rate for intracranial meningiomas increased from 0.6 patients per 100,000 population in the period 1963-1972 to 1.5 in 1983-1992 for males and correspondingly from 1.0 to 2.8 for females. An incidence fall-off after 70 years of age was evident, presumably because many older patients with small and asymptomatic meningiomas were undiagnosed due to the low autopsy rate in the population. The prognosis for survival in meningioma patients improved over the study period and was related to type of tumor histology and age at diagnosis.

The incidence of primary central nervous system neoplasms before and after computerized tomography availability.

The observed incidence of primary intracranial neoplasms has increased dramatically among the elderly over the past several years. It is unclear to what extent this increase can be attributed to improved detection by new imaging technology and what portion might represent a true increase in incidence. The first computerized tomography (CT) scanner was operative in Norway in 1975 and became available in all geographical regions within 4 years. The author analyzed incidence data from the population-based Cancer Registry of Norway, placing particular emphasis on the basis for diagnosis (histological, imaging, or clinical findings) for the registrations. In the decade from 1983 to 1992, when the use of CT was widespread, incidence rates of primary intracranial neoplasms for individuals aged 55 to 74 and above 74 years were, respectively, 1.76 (95% confidence interval (CI), 1.63-1.90) and 3.35 (95% CI, 2.70-4.15) times the rates in 1963 to 1972 before CT was available. For persons older than 74 years, the relative incidence increase was 1.98-fold (95% CI, 1.53-2.56) for histologically verified tumors; 15.20 (95% CI, 7.80-29.61) when based on imaging (without histological evidence); and 3.33 (95% CI, 1.93-5.76) when based on clinical diagnosis (without imaging or histological evidence). In this age group, the increase for gliomas was 1.77 (95% CI, 1.18-2.65) and 2.28 (95% CI, 1.53-3.39) for meningioma patients. The present study demonstrates that new imaging technology has improved the diagnostic yield of primary intracranial neoplasms. For those older than 74 years, a large part of the three-fold incidence increase from the pre-CT decade 1963 to 1972 to the post-CT decade 1983 to 1992 can be attributed to improved tumor detection.

Endocrine and metabolic characteristics of polyoma large T transgenic mice that develop ACTH-producing pituitary tumors.

The authors have analyzed several endocrine and metabolic parameters in polyoma large T transgenic mice (PyLT-1) that develop adrenocorticotropic hormone (ACTH)-immunoreactive pituitary tumors and in nontransgenic mice with tumor transplants. All clinically ill PyLT-1 mice (13 to 16 months of age) had pituitary macroadenomas and elevated plasma ACTH levels. Compared to PyLT-1 transgenic mice, the ACTH plasma concentrations in immunocompetent mice with transplant tumors were markedly raised. In these animals, a secondary effect of hypercorticotropism was documented by a moderate hyperglycemia. Furthermore, mice with transplant tumors had a pathological weight increase from the time the tumor was palpable. The present study supports and extends the authors' previous morphological documentation of the similarity between the ACTH-producing tumors in this mouse model and human Cushing's disease.

Mortality among seamen with special reference to work on tankers.

BACKGROUND: Several studies demonstrate a high mortality among seamen but this has not been related to different types of work on board. This study examined a possible relationship between work on tankers and mortality. Tankers differ from other ships by carrying different types of oil, oil products and other chemicals. METHODS: Mortality was studied in 1687 men who were captains and mates during the period 1970-1987, and were registered by a Norwegian census in 1970. The data were linked to the Norwegian Register of Death Certificates. In all 181 deaths were found. Each case was age-matched at time of death to three individuals from the rest of the population alive at this date. Information about the seamen's work on different ships was obtained for cases and controls. The data were analysed using multivariate conditional logistic regression. RESULTS: Seamen working on tankers had a higher mortality rate ratio (RR = 2.43, 95% confidence interval [CI]: 1.65-3.60) than seamen who had not been working on tankers. The increased risk was especially related to death from cancer and from accidents, while no significantly increased mortality due to cardiovascular diseases was found. Employment as a mate on tankers showed the highest all-causes risk of death (RR = 3.14, 95% CI: 2.04-4.82) as well as for cancer (RR = 4.24, 95% CI: 2.02-8.88) and accidents (RR = 5.85, 95% CI: 1.66-20.60). Employment as a captain on tankers showed no significantly increased mortality. CONCLUSION: Exposure to chemicals on tankers may be related to the increased mortality, as this is the major difference between tankers and other ships and mates are exposed to chemical agents, while captains are not.

Nude rat models for human tumor metastasis to CNS. Procedures for intracarotid delivery of cancer cells and drugs.

Models for hematogenous spread of human cancer to the central nervous system (CNS) were established by injecting human tumor cells into the internal carotid artery of nude rats. With 4 out of 10 cell lines, belonging to four different tumor types, metastases developed in all injected animals. Tumor growth manifested clinically as neurological symptoms which appeared after a median latency ranging from 19-87 days for the different tumors. The H-146 and DMS-273 small cell lung cancers and the LOX melanoma almost exclusively gave meningeal tumors, whereas with FEMX-I melanoma cells bone metastases in the skull dominated. For these tumor types a correlation was found between the capacity for experimental metastasis formation and the s.c. tumorigenicity. In agreement with clinical experience, none of the 2 sarcoma and 2 glioblastoma lines gave CNS metastases. With a modified microsurgical technique, allowing for repeated ipsilateral intracarotid injections, we analyzed the drug concentrations obtained in tumor and surrounding brain tissue after i.v. treatment with doxorubicin. The concentration in the LOX tumor reached therapeutic levels and was approximately 100 x higher than in normal brain tissue, both with and without intraarterial pretreatment with arabinose. In the same model, the tissue concentrations of 9.2.27-abrin immunotoxin 10 min after intracarotid injection were examined. Although the levels were low, a tumor to brain concentration ratio of up to 9 was achieved. The data demonstrate that clinically relevant tumor models can be established with the techniques described, and these models may successfully be used to evaluate the pharmacokinetics and effect of intravenous or intraarterial therapy.

[Intracranial tumors in adults (over 15 years)]. / Intrakraniale svulster hos voksne (> 15 år).

Primary intracranial tumours develop in 420 adult Norwegians each year. Of these tumours, gliomas are the most frequent, followed by meningiomas, pituitary adenomas and acoustic neurinomas. Glioblastomas represent more than 50% of the gliomas. Less than 10% of the patients with glioblastoma survive for two years, despite aggressive therapy (surgery, radiotherapy and chemotherapy). The prognosis for low grade gliomas is much better. In the case of meningiomas, 95% of the tumours are benign. The primary treatment for meningiomas is surgery. If surgery is impossible, radiosurgery should be considered. Pituitary adenomas are often hormone-secreting (e.g. prolactin, growth hormone, adrenocorticotrophic hormone). Many prolactinomas are treated with bromocriptine alone. The rest of the pituitary adenomas are treated by microsurgery and radiotherapy. The prognosis for patients with pituitary adenomas is good. Acoustic neurinomas, which in most cases are benign, are treated by microsurgery or radiosurgery. Postoperative morbidity due to cochlear nerve and facial nerve dysfunction is a problem. Brain metastases are far more frequent than primary intracranial tumours. Solitary metastases in patients with stable systemic disease should be treated by surgery or radiosurgery.

Alcohol abstainers: a low-risk group for cancer--a cohort study of Norwegian teetotalers.

Groups with assumed health-protective life-styles have been studied for several decades, in search of causes for cancer. We have analyzed cancer incidence, total mortality, and cause-specific mortality in Norwegian teetotalers to assess the possible health gains from an alcohol-abstaining life-style. A cohort of 5332 members of the International Organization of Good Templars was followed for 10 years from 1980. The cancer incidence and the cause-specific mortality of the cohort has been compared to that of the total Norwegian population. The standardized incidence ratio (SIR) for all cancer sites was 74 [95% confidence interval (CI), 64-80] for men and 72 (95% CI, 61-84) for women. For possible alcohol-associated cancers, such as cancer of the oral cavity, pharynx, esophagus, liver, and larynx, the SIR was 43 (95% CI, 17-88) for both sexes combined. For lung cancer the SIR was 57 (95% CI, 37-90) for men and 10 (95% CI, 0-57) for women. When all alcohol- and tobacco-associated cancers were excluded, the SIR for both sexes combined was 79 (95% CI, 69-87). The standardized mortality ratio for total mortality was 81 (95% CI, 65-74). This significant decrease in total mortality was caused by reduced risks for all major causes of death. The study indicates that members of the Norwegian chapter of the International Organization of Good Templars are a low-risk group not only regarding alcohol- and tobacco-associated cancers, but also regarding all other cancers.

[Transgenic mice as animal model of Cushing's syndrome]. / Transgene mus som dyremodell for Cushings sykdom.

Transgenic mice were generated with the polyoma early region promoter linked to cDNA encoding polyoma large T antigen (PyLT). Light microscopic examination showed up to 5 mm large pituitary adenomas in clinically ill transgenic mice. The tumour cells showed positive ACTH immuno-reactivity. The adrenal glands of clinically ill mice showed an increase in weight and exhibited medullary hyperplasia. These findings were unexpected, and might have been caused by transgene expression in the neuroendocrine cells of the adrenal medulla. Plasma ACTH measurements showed significantly increased levels in clinically ill PyLT-1 transgenic mice.

ACTH-producing pituitary tumors in transgenic mice. An ultrastructural and immunoelectron microscopic study.

Ultrastructural and electron microscopic immunohistochemical features of corticotropic pituitary tumors arising in polyoma large T transgenic mice and the corresponding tumor transplants in non-transgenic mice are reported. Spherical, irregular and drop-shaped secretory granules measuring 150-450 nm in diameter, were seen in all tumors. Both in tumors from transgenic mice and in tumor transplants immunoreactivity for adrenocorticotropic hormone (ACTH) and beta-endorphin was expressed in the majority of the secretory granules, whereas growth hormone (GH) immunoreactivity was demonstrated only in a small number of cells in tumors from transgenic mice. In addition, positive immunostaining for neuron-specific enolase (NSE) and synaptophysin was found in the two pituitary tumor transplants tested. The study shows that the pituitary tumors from transgenic mice and their tumor transplants have features similar to human corticotropic pituitary tumors, and may therefore be a valuable model for experimental studies of the tumorigenesis.

Transgenic mice that develop pituitary tumors. A model for Cushing's disease.

Transgenic mice that developed adrenocorticotropic hormone (ACTH)-producing pituitary tumors were generated with the polyoma early region promotor linked to a cDNA encoding polyoma large T antigen (PyLT). Light microscopic examination of the pituitaries showed normal morphology at 4 months of age, either unremarkable morphology or microadenoma formation at 9 months of age, and up to 5 mm large adenomas in clinically ill transgenic mice at 13-16 months of age. At age 9 months, transgenic mice weighed significantly more than corresponding control mice, but they began wasting at approximately 1 year of age. The adrenal glands of these older PyLT-1 mice showed a weight increase and exhibited a medullary hyperplasia. Subcutaneous transplants of transgenic pituitary tumors to nontransgenic, immunocompetent mice resulted in tumors with a morphology and ACTH immunoreactivity similar to the primary tumor. The effects of hypercorticotropism were more enhanced and occurred with a shorter latency in the mice carrying transgene pituitary transplants than in the PyLT-1 transgenic mice themselves. Moreover, these transplanted mice showed a weight increase with an axial deposition pattern and hypertrophy of the adrenal cortex that resembled the findings in human Cushing's disease. Plasma ACTH levels were significantly increased in clinically ill transgenic mice and even higher levels were found in the transplant mice. Thus, both murine models should be useful for studying Cushing's disease.

Cancer incidence in Norwegian Seventh-Day Adventists 1961 to 1986. Is the cancer-life-style association overestimated?

Standardized incidence ratio for cancer in Norwegian Seventh-Day Adventists compared with the general population was not significantly different from unity (men 91, women 97). Persons converting late in life had a higher incidence than those converting at an earlier age. Respiratory cancers (standardized incidence ratio [SIR] 59, 95% CI = 36 to 91) and cancers with an unspecified site (SIR 53, 95% CI = 25 to 97) were rarer and cancer of the uterine corpus (SIR 164, 95% CI = 109 to 237) was more common in Seventh-Day Adventists before the age of 75 years. Inclusion of all registered Seventh-Day Adventists regardless of religious activity and the relatively low cancer incidence rates in the Norwegian population could contribute to the nonsignificant result with regard to total cancer. Main etiologic factors in cancer development in Norway should be sought in areas where Seventh-Day Adventists do not differ from the general population.

[Cancer among captains and mates on Norwegian tankers]. / Kreft blant kapteiner og styrmenn på norske tankship.

1,687 registered captains and mates from a Norwegian census in 1970 were monitored up to 1987. By matching the data from the census with data from the Norwegian Cancer Registry we discovered 104 cases of cancer. A control group of 376 was chosen among those without cancer. A nested case-control study design was used. The material was analysed using multivariate logistic regression. Increased risk of developing cancer was found in the group of seamen who had been working on tankers, especially among seamen who had been working as mate on these tankers. Exposure to chemicals is the major factor distinguishing tankers from other ships. Mates are exposed to chemicals while captains are not. The study indicates the presence of carcinogenic agents on these tankers.

Cancer among captains and mates on Norwegian tankers.

A cohort of 1687 registered captains and mates from a Norwegian census in 1970 was followed until 1987 using a historical prospective design. By matching the data from the census to the Norwegian Cancer Registry, 104 cases of cancer were found. A control group of 376 was chosen among non-cases at baseline (1970). Information about the seamen's work on different ships was obtained from the National Register of Norwegian Seamen. The material was analysed using multivariate logistic regression. An increased risk of developing cancer was found in the group of seamen who had been working on tankers, especially oil tankers (OR = 6.47, 95%CI: 1.14, 7.24). The increased risk was found to be significantly correlated to working as mate on these tankers (OR = 6.95, 95%CI: 3.70, 13.04), whereas working as captain showed a much lower risk (OR = 1.42, 95%CI: 0.64, 3.15). Chemical exposure is the major factor separating tankers from other ships. Mates are exposed to chemicals while captains are not. The study indicates the presence of several carcinogenic agents on these tankers.

Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients.

A survey of all patients (173 males and 294 females) registered with primary intraspinal neoplasms in the Norwegian Cancer Registry from 1955 through 1986 is presented. Annual age-adjusted incidence rates of new tumors per one million population were three for males and five for females. Altogether, 89% of the tumors were verified histologically. Meningioma was the most common tumor type, followed by ependymoma and neurilemoma. Intraspinal ependymomas accounted for 34.5% of all 223 ependymomas of the central nervous system, whereas only 0.2% of the 3046 glioblastomas were found intraspinally. Patients with intraspinal meningioma had a better life expectancy than those with intracranial meningioma. The 5-year relative survival rate for patients with intraspinal ependymoma was 88.9% in contrast to 24.4% for patients with intracranial ependymoma.

Neoplasms of the central nervous system in Norway. V. Meningioma and cancer of other sites. An analysis of the occurrence of multiple primary neoplasms in meningioma patients in Norway from 1955 through 1986.

The association between meningioma and a primary malignant neoplasm at another site was studied. The data from the population-based Norwegian Cancer Registry were analysed according to whether the meningioma occurred before or after the malignant neoplasm. Male patients with meningioma showed a raised risk for developing a subsequent renal cancer. A significant association was found between meningioma and subsequent breast cancer in females 50-64 years old at time of meningioma diagnosis and between breast cancer and subsequent occurrence of meningioma. Breast cancer patients with symptoms of an intracranial neoplasm may therefore have a potentially curable meningioma and female meningioma patients over 50 years should be considered for breast cancer screening programmes.

Neoplasms of the central nervous system in Norway. IV. A population-based epidemiological study of meningiomas.

All 1632 cases of meningioma reported to the Norwegian Cancer Registry from 1955 to 1986 have been studied: a) 96% appeared in patients over 30 years of age, b) 95% were histologically benign, c) 88% were located intracranially, and d) 66% occurred in females. The female predominance manifested itself in the middle age period. Eighty-seven percent of the intraspinal meningiomas presented in females, but the ratio between intracranial and intraspinal meningiomas was significantly lower in females (5.4) than in males (20.4). Increased incidence rates of meningioma in females are revealed for the birth-cohorts after 1930. The reason for this change is unclear so both environmental and hormonal factors should be explored. Based upon the epidemiological data, it appears that female sex hormone(s) could act as a growth stimulus in the development of meningiomas, but are neither sufficient nor necessary for tumourigenesis.