Evaluating different breast tumor progression models using screening data.

BACKGROUND: Mammography screening is used to detect breast cancer at an early treatable stage, reducing breast cancer mortality. Traditionally, breast cancer has been seen as a disease with only progressive lesions, and here we examine the validity of this assumption by testing if incidence levels after introducing mammography screening can be reproduced assuming only progressive tumors. METHODS: Breast cancer incidence data 1990-2009 obtained from the initially screened Norwegian counties (Akershus, Oslo, Rogaland and Hordaland) was included, covering the time-period before, during and after the introduction of mammography screening. From 1996 women aged 50-69 were invited for biennial public screening. Using estimates of tumor growth and screening sensitivity based on pre-screening and prevalence screening data (1990-1998), we simulated incidence levels during the following period (1999-2009). RESULTS: The simulated incidence levels during the period with repeated screenings were markedly below the observed levels. The results were robust to changes in model parameters. Adjusting for hormone replacement therapy use, we obtained levels closer to the observed levels. However, there was still a marked gap, and only by assuming some tumors that undergo regressive changes or enter a markedly less detectable state, was our model able to reproduce the observed incidence levels. CONCLUSIONS: Models with strictly progressive tumors are only able to partly explain the changes in incidence levels observed after screening introduction in the initially screened Norwegian counties. More complex explanations than a time shift in detection of future clinical cancers seem to be needed to reproduce the incidence trends, questioning the basis for many over-diagnosis calculations. As data are not randomized, similar studies in other populations are wanted to exclude effect of unknown confounders.

Bias in Observational Studies of the Association between Menopausal Hormone Therapy and Breast Cancer.

BACKGROUND: During the period 1985-2000 the breast cancer incidence rates increased 50% in the age group invited to mammography screening in Norway and Sweden. Simultaneously, use of hormone replacement treatment therapy (HT) increased 5 times. Several influential observational studies showed that HT was associated with 50% to 100% increased risk of breast cancer and most for those using combined (estrogen plus progestin) hormone replacement therapy (CHT). In contrast, the randomized WHI trial reported that CHT increased the risk by 10% for those not having previously used hormones and 24% when including previous users in the analyses. In another randomized trial, estrogen use only was not associated with any increased risk at all. After the WHI trial was published in 2003, use of HT dropped 70% within 5 years in Norway and Sweden while breast cancer rates were essentially unchanged. After 2008, HT use has dropped further and breast cancer incidence rates have started increasing again. The study objective is to calculate and to explain potential bias in the observational study design. METHODS AND FINDINGS: Here we use data from the randomized WHI trial and analyze these data as done in the observational studies to calculate the magnitude of the potential biases in the observational study design. Time varying effect of hormones and categorization of the follow-up time may increase the hazard ratio for long-term users from 1.10 to 1.48. Selective retrospective reporting of hormone use may further increase the hazard ratio to 1.68. CONCLUSIONS: We suggest that the mechanism causing higher hazard ratio of breast cancer (compared to the observational studies) is the time-varying effect of CHT on the breast cancer risk and selective retrospective reporting of hormone use. Other risk factors for the increase in breast cancer risk in the age group 50-69 years should be considered, for example, overdiagnosis.

Breast cancer stromal elastosis is associated with mammography screening detection, low Ki67 expression and favourable prognosis in a population-based study.

BACKGROUND: Mammography screen-detected breast cancers have a better prognosis than predicted from established prognostic markers. A search for additional features that are characteristic for these tumours and their prognosis is needed to reduce overtreatment, a recognized challenge in breast cancer patient management today. Here, we have investigated the occurrence and importance of tumour elastosis. METHODS: We performed a population based retrospective study of breast cancers detected in the Norwegian Breast Cancer Screening Programme in Vestfold County during 2004-2009. In total, 197 invasive screen-detected cancers and 75 interval cancers in patients aged 50-69 years were compared with regard to standard clinico-pathological parameters and tumour shape, as well as ER, PR, HER2 and Ki67 expression. In particular, the presence of elastotic material in tumours was graded on a 4-tiered scale (score 0-3). RESULTS: Screen-detected cancers had a significantly higher content of stromal elastosis than interval cancers (p < 0.001). High content of elastosis (score 3) correlated strongly with stellate tumour shape, low histological grade, and ER+/HER2- status. Further, high elastosis score was significantly associated with lower Ki67 expression. In survival analyses, cases with high elastosis demonstrated increased recurrence free (p = 0.03) and disease-specific survival (p = 0.11) compared to cases with low elastosis. CONCLUSION: There is a strong correlation between the presence of tumour elastosis, stellate tumour shape and mammography detection of breast cancers. To our knowledge, this is the first time elastosis has been studied in relation to breast cancer detection method. Presence of elastosis is associated with low tumour cell proliferation (Ki67) and a good prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_230.

Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells.

Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1(gt/gt) mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1(gt/gt) liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1(gt/gt) Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1(gt/gt) mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.

Postmortem heart weight: relation to body size and effects of cardiovascular disease and cancer.

BACKGROUND: Gender, body weight, and cardiovascular disease (CVD) are all variables known to influence human heart weight. The impact of cancer is less studied, and the influence of age is not unequivocal. We aimed to describe the relationship between body size and heart weight in a large autopsy cohort and to compare heart weight in patients with cancer, CVD, and other diseases. METHODS AND RESULTS: Registered information, including cause of death, evidence of cancer and/or CVD, heart weight, body weight, and height, was extracted from the autopsy reports of 1410 persons (805 men, mean age 66.5 years and 605 women, mean age 70.6 years). The study population was divided in four groups according to cause of death; cancer (n=349), CVD (n=470), mixed group who died from cancer and CVD and/or lung disease (n=263), and a reference group with patients who did not die from any of these conditions (n=328). In this last group, heart weight correlated only slightly better with body surface area than body weight, and nomograms based on body weight are presented. Compared to the reference group (mean heart weight: 426 g and 351 g in men and women, respectively), heart weight was significantly lower (men: P<.05, women: P<.001) in cancer patients (men: 392 g, women: 309 g) and higher (P<.001) in patients who died from CVD (men: 550 g, women: 430 g). Similar results were obtained in linear regression models adjusted for body weight and age. Among CVD, heart valve disease had the greatest impact on heart weight, followed by old myocardial infarction, coronary atherosclerosis, and hypertension. Absolute heart weight decreased with age, but we demonstrated an increase relative to body weight. CONCLUSION: The weight of the human heart is influenced by various disease processes, in addition to body weight, gender, and age. While the most prevalent types of CVD are associated with increased heart weight, patients who die from cancer have lower average heart weight than other patient groups. The latter finding, however, is diminished when adjusting for body weight. SUMMARY: The present study demonstrates that the weight of the human heart is influenced by various disease processes like cancer and CVD, in addition to body weight, gender and, possibly, age.

Hormone therapy use and breast cancer incidence by histological subtypes in Sweden and Norway.

Mammography screening and postmenopausal hormone therapy (HT) both influence breast cancer incidence. While breast cancer incidence increased by around 50% during the introduction of screening, a smaller decline in incidence has been reported in several countries after 2002 when the sales of HT started to decline. Data suggest that HT increases the risk of the second most common type of breast cancer, invasive lobular carcinoma (ILC) but not the most common, invasive ductal carcinoma (IDC). Breast cancer incidences stratified on histological subtypes were obtained from the national cancer registries. HT sales data from drug consumption statistics and information on the county-level introduction of mammography screening were combined, and breast cancer incidence trends were estimated using Poisson regression models, focusing on the period after 2002. From 2002 to 2007 the annual decrease in breast cancer incidence rates for women aged 50-69 was 1.5% (95% CI -2.3% to -0.7%) in Sweden and 0.8% (95% CI -2.8% to 1.2%) in the part of Norway not confounded by prevalence screening. Most of the decline was in the rates of ILC which dropped by 4.7% (95% CI -6.6% to -2.7%) and 7.0% (95% CI -12.8% to -0.9%) per year, respectively. The rates of IDC were stable in this period. Breast cancer incidence has declined in Sweden and Norway since 2002, but the reduction is moderate compared with the large increase that occurred during the introduction of mammography screening. Declining rates of ILC, but not of IDC, support the hypothesis that the drop in breast cancer incidence is associated with reduced HT use.

Overdiagnosis of breast cancer after 14 years of mammography screening.

BACKGROUND: In 2004 we wrote in Tidsskriftet that mammography screening resulted in massive over-diagnosis and over-treatment of breast cancer. Our study was criticised because we had only five years of follow-up time and did not take account of the fact that increased use of hormone replacement therapy could lead to more breast cancer. We have now been screening women for 14 years, and during a period when the use of hormones has fallen by 70 %. MATERIAL AND METHOD: Age-specific incidence rates, detection rates and interval rates for breast cancer in the period 1991-2009 have been computed for 40-79 year-old women. Incidence trends have been calculated using Poisson regression. RESULTS: The incidence of breast cancer in the age group 40-49 was stable throughout the period, but rose by 50 % in the age group 50-69 years immediately after the start of screening. There was no significant reduction in the incidence of breast cancer in the age group 70-74. The number of new cases of breast cancer in the period increased from around 2000 to 2750. About 300 cases of ductal carcinoma in situ (DCIS) were also diagnosed. Today a total of some 1050 more women have been diagnosed than before screening started. Our calculations indicate that in the absence of screening, around 800 of these women would never have become breast cancer patients. INTERPRETATION: The figures from 14 years of mammography screening indicate that all increase in the incidence of breast cancer is due to over-diagnosis: findings of tumours that in the absence of screening would never have given rise to clinical illness.

Why mammography screening has not lived up to expectations from the randomised trials.

We analysed the relation between tumour sizes and stages and the reported effects on breast cancer mortality with and without screening in trials and observational studies. The average tumour sizes in all the trials suggest only a 12% reduction in breast cancer mortality, which agrees with the 10% reported in the most reliable trials. Recent studies of tumour sizes and tumour stages show that screening has not lowered the rate of advanced cancers. In agreement with this, recent observational studies of breast cancer mortality have failed to find an effect of screening. In contrast, screening leads to serious harms in healthy women through overdiagnosis with subsequent overtreatment and false-positive mammograms. We suggest that the rationale for breast screening be urgently reassessed by policy-makers. The observed decline in breast cancer mortality in many countries seems to be caused by improved adjuvant therapy and breast cancer awareness, not screening. We also believe it is more important to reduce the incidence of cancer than to detect it 'early.' Avoiding getting screening mammograms reduces the risk of becoming a breast cancer patient by one-third.

Natural history of breast cancers detected in the Swedish mammography screening programme: a cohort study.

BACKGROUND: The natural history of screen-detected breast cancers is not well understood. A previous analysis of the incidence change during the introduction of the Norwegian screening programme in the late 1990s suggested that the natural history of many screen-detected invasive breast cancers is to regress spontaneously but the study was possibly confounded by use of hormone replacement therapy in the population. We did a similar analysis of data collected during an earlier period when few women were exposed to hormone replacement therapy. METHODS: We compared cumulative breast cancer incidence in age-matched cohorts of women living in seven Swedish counties before and after the initiation of public mammography screening between 1986 and 1990. Women aged 40-49 years were invited to screening every year and women aged 50-74 years were invited every 2 years. A screened group including all women aged 40-69 years (n=328,927) was followed-up for 6 years after the first invitation to the programme. A control group including all women in the same age range (n=317,404) was also followed-up for 6 years--4 years without screening and 2 years when they entered the screening programme. Screening attendance was much the same in both groups (close to 80%). Counts of incident invasive breast cancers were obtained from the Swedish Cancer Registry (in-situ cancers were excluded). FINDINGS: Before the age-matched controls were invited to be screened at the end of their follow-up period, the 4-year cumulative incidence of invasive breast cancer was significantly higher in the screened group (982 per 100,000) than it was in the control group (658 per 100,000) (relative risk [RR] 1·49, 95% CI 1·41-1·58). Even after prevalence screening in the control group, the screened group had higher 6-year cumulative incidence of invasive breast cancer (1443 per 100,000 vs 1269 per 100,000; RR 1·14, 1·10-1·18). INTERPRETATION: Because the cumulative incidence among controls did not reach that of the screened group, we believe that many invasive breast cancers detected by repeated mammography screening do not persist to be detected by screening at the end of 6 years, suggesting that the natural course of many of the screen-detected invasive breast cancers is to spontaneously regress. FUNDING: None.

Effect of mammography screening on surgical treatment for breast cancer in Norway: comparative analysis of cancer registry data.

OBJECTIVE: To determine the effect of mammography screening on surgical treatment for breast cancer. DESIGN: Comparative analysis of data from Norwegian cancer registry. SETTING: Mammography screening, Norway (screening of women aged 50-69 was introduced sequentially from 1996 to 2004). PARTICIPANTS: 35,408 women aged 40-79 with invasive breast cancer or ductal carcinoma in situ treated surgically from 1993 to 2008. MAIN OUTCOME MEASURES: Rates of breast surgery (mastectomy plus breast conserving treatment) and rates of mastectomy for three age groups of women: 40-49, 50-69, and 70-79. Changes in rates from pre-screening period (1993-5) to introduction of screening phase (1996-2004) and then to screening period (2005-8) are presented as hazard ratios in invited and non-invited women. RESULTS: The annual rate for breast surgery from the pre-screening period (1993-5) to screening period (2005-8) in Norway increased by 70% (hazard ratio 1.70, 95% confidence interval 1.62 to 1.78), from 180 to 305 per 100,000 women in the invited age group (50-69 years). In the younger, non-invited age group (40-49 years), however, the increase was only 8% (1.08, 1.00 to 1.16), from 133 to 144 per 100,000 women per year, whereas in the older, non-invited age group (70-79 years) the rate decreased by 8% (0.92, 0.86 to 1.00), from 227 to 214 per 100,000 women per year. The rates for mastectomy decreased similarly from the pre-screening period to screening period in invited and non-invited women. From the pre-screening period to the introduction phase of screening (1996-2004), however, the annual mastectomy rate in women aged 50-69 invited to screening increased by 9% (1.09, 1.03 to 1.14), from 156 to 167 per 100,000 women, and in the younger non-invited women declined by 17% (0.83, 0.78 to 0.90), from 109 to 91 per 100,000 women. In consequence, the mastectomy rate was 31% (1.31, 1.20 to 1.43) higher in the invited than in the non-invited younger age group. CONCLUSIONS: Mammography screening in Norway was associated with a noticeable increase in rates for breast cancer surgery in women aged 50-69 (the age group invited to screening) and also an increase in mastectomy rates. Although over-diagnosis is likely to have caused the initial increase in mastectomy rates and the overall increase in surgery rates in the age group screened, the more recent decline in mastectomy rates has affected all age groups and is likely to have resulted from changes in surgical policy.

Surgical mortality at 30 days and complications leading to recraniotomy in 2630 consecutive craniotomies for intracranial tumors.

BACKGROUND: In order to weigh the risks of surgery against the presumed advantages, it is important to have specific knowledge about complication rates. OBJECTIVE: To study the surgical mortality and rate of reoperations for hematomas and infections after intracranial surgery for brain tumors in a large, contemporary, single-institution consecutive series. METHODS: All adult patients from a well-defined population of 2.7 million inhabitants who underwent craniotomies for intracranial tumors at Oslo University Hospital from 2003 to 2008 were included (n = 2630). The patients were identified from our prospectively collected database and their charts studied retrospectively. Follow-up was 100%. RESULTS: The overall surgical mortality, defined as death within 30 days of surgery, was 2.3% (n = 60). The mortality rates for high- and low-grade gliomas, meningiomas, and metastases were 2.9%, 1.0%, 0.9%, and 4.5%, respectively. Age >60 (odds ratio 1.84, P < 0.05) and biopsy compared with resection (odds ratio 4.67, P < 0.01) were significantly positively associated with increased surgical mortality. Hematomas accounted for 35% of the surgical mortality. Postoperative hematomas needing evacuation occurred in 2.1% (n = 54). Age >60 was significantly correlated to increased risk of postoperative hematomas (odds ratio 2.43, P < 0.001). A total of 39 patients (1.5%) were reoperated for postoperative infection. Meningiomas had an increased risk of infections compared with high-grade gliomas (odds ratio 4.61, P < 0.001). CONCLUSION: The surgical mortality within 30 days of surgery was 2.3%, with age >60 and biopsy vs resection being the 2 factors significantly associated with increased mortality. Postoperative hematomas caused about one third of the surgical mortality.

Brain pathology in fatal serotonin syndrome: presentation of two cases.

Serotonin syndrome is a potentially life-threatening reaction that occurs in patients using drugs that elevate the serotonin level in the body. Excess serotonergic activity in the CNS and peripheral serotonin receptors results in neuromuscular hyperactivity, mental changes and autonomic symptoms. Hyperthermia is a characteristic feature of the syndrome. We describe neuropathological findings from two cases of lethal serotonin syndrome, both patients presenting with hyperthermia and neuromuscular symptoms. One of the patients had been taking amitriptylin and mirtazapin and the other had used amitriptylin and citalopram. They died, respectively, 10 days and 2½ months after the onset of serotonin syndrome symptoms. Post-mortem examination of the brains showed subtotal loss of cerebellar Purkinje cells in both cases. In the case with shorter survival time, areas with partial loss of cerebellar granule cells were observed, whereas in the case with longer survival time general and extensive loss of granule cells was found. Cells in other areas of the brain known to be sensitive to hypoxic injury were not affected. Selective loss of Purkinje cells has previously been described in neuroleptic malignant syndrome and heatstroke, conditions that are characterized by hyperthermia. This suggests that hyperthermia may be a causative factor of brain damage in serotonin syndrome. This is the first report describing neuropathological findings in serotonin syndrome.

Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors.

BACKGROUND: Brain metastases and primary high-grade gliomas, including glioblastomas multiforme (GBM) and anaplastic astrocytomas (AA), may be indistinguishable by conventional magnetic resonance (MR) imaging. Identification of these tumors may have therapeutic consequences. PURPOSE: To assess the value of MR spectroscopy (MRS) using short and intermediate echo time (TE) in differentiating solitary brain metastases and high-grade gliomas on the basis of differences in metabolite ratios in the intratumoral and peritumoral region. MATERIAL AND METHODS: We performed MR imaging and MRS in 73 patients with histologically verified intraaxial brain tumors: 53 patients with high-grade gliomas (34 GBM and 19 AA) and 20 patients with metastatic brain tumors. The metabolite ratios of Cho/Cr, Cho/NAA, and NAA/Cr at intermediate TE and the presence of lipids at short TE were assessed from spectral maps in the tumoral core, peritumoral edema, and contralateral normal-appearing white matter. The differences in the metabolite ratios between high-grade gliomas/GBM/AA and metastases were analyzed statistically. Cutoff values of Cho/Cr, Cho/NAA, and NAA/Cr ratios in the peritumoral edema, as well as Cho/Cr and NAA/Cr ratios in the tumoral core for distinguishing high-grade gliomas/GBM/AA from metastases were determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Significant differences were noted in the peritumoral Cho/Cr, Cho/NAA, and NAA/ Cr ratios between high-grade gliomas/GBM/AA and metastases. ROC analysis demonstrated a cutoff value of 1.24 for peritumoral Cho/Cr ratio to provide sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 100%, 88.9%, 80.0%, and 100%, respectively, for discrimination between high-grade gliomas and metastases. By using a cutoff value of 1.11 for peritumoral Cho/NAA ratio, the sensitivity was 100%, the specificity was 91.1%, the PPV was 83.3%, and the NPV was 100%. CONCLUSION: The results of this study demonstrate that MRS can differentiate high-grade gliomas from metastases, especially with peritumoral measurements, supporting the hypothesis that MRS can detect infiltration of tumor cells in the peritumoral edema.

Tuberculin status, socioeconomic differences and differences in all-cause mortality: experience from Norwegian cohorts born 1910-49.

BACKGROUND: From 1948 to 1975, Norway had a mandatory tuberculosis (TB) screening programme with Pirquet testing, X-ray examinations and BCG vaccination. Electronic data registration in 1963-75 enabled the current study aimed at revealing (i) the relations between socioeconomic factors and tuberculosis infection and (ii) differences in later all-cause mortality according to TB infection status. METHODS: TB screening data were linked to information from the Norwegian Cause of Death Registry (1975-98) and the National Population and Housing Censuses (1960, 1970 and 1980). Analyses were done for 10 years cohorts born 1910-49, separately for men (approximately 534,000 individuals) and women (608,000), using logistic and Cox regressions. RESULTS: TB infection and X-ray data confirmed the strong regional pattern seen for TB mortality, with the highest rates in the three northernmost counties and higher rates in urban than rural areas. High socioeconomic status relates to lower odds both for TB infection and TB-related chest X-ray findings (odds ratios 0.6-0.7 for highest vs lowest educational groups). Those infected by TB, and especially those with chest X-ray findings, have increased all-cause mortality in at least a 20 years period following determination of tuberculin status (hazard ratios approximately 1.15 and 1.30, respectively, higher for late than early cohorts). CONCLUSIONS: TB particularly affected lower socioeconomic strata, but even those in higher strata were at high risk. The differences in all-cause mortality could partly be attributed to socioeconomic factors, but we hypothesize that developing TB infection may also indicate biological frailness.

The natural history of invasive breast cancers detected by screening mammography.

BACKGROUND: The introduction of screening mammography has been associated with sustained increases in breast cancer incidence. The natural history of these screen-detected cancers is not well understood. METHODS: We compared cumulative breast cancer incidence in age-matched cohorts of women residing in 4 Norwegian counties before and after the initiation of biennial mammography. The screened group included all women who were invited for all 3 rounds of screening during the period 1996 through 2001 (age range in 1996, 50-64 years). The control group included all women who would have been invited for screening had there been a screening program during the period 1992 through 1997 (age range in 1992, 50-64 years). All women in the control group were invited to undergo a 1-time prevalence screen at the end of their observation period. Screening attendance was similar in both groups (screened, 78.3%, and controls, 79.5%). Counts of incident invasive breast cancers were obtained from the Norwegian Cancer Registry (in situ cancers were excluded). RESULTS: As expected, before the age-matched controls were invited to be screened at the end of their observation period, the cumulative incidence of invasive breast cancer was significantly higher in the screened group than in the controls (4-year cumulative incidence: 1268 vs 810 per 100 000 population; relative rate, 1.57; 95% confidence interval, 1.44-1.70). Even after prevalence screening in controls, however, the cumulative incidence of invasive breast cancer remained 22% higher in the screened group (6-year cumulative incidence: 1909 vs 1564 per 100 000 population; relative rate, 1.22; 95% confidence interval, 1.16-1.30). Higher incidence was observed in screened women at each year of age. CONCLUSIONS: Because the cumulative incidence among controls never reached that of the screened group, it appears that some breast cancers detected by repeated mammographic screening would not persist to be detectable by a single mammogram at the end of 6 years. This raises the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress.

Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum.

High-potency glucocorticoids (GC) are used in the prophylaxis and treatment of neonatal bronchopulmonal dysplasia, but there is concern about side effects on the developing brain. Recently, the low-potency GC hydrocortisone (HC) has been suggested as an alternative to high-potency GC. We compared the neurotoxic effects of HC with the high-potency GC dexamethasone (DEX) in chicken cerebellum. A single dose of GC was injected into the egg at embryonic day 16 and the death of granule neurons in histologic sections of the cerebellar cortex was examined 24 h later. DEX and HC showed a similar dose-dependent induction of morphological apoptosis and caspase-3 activation in the internal granular layer. A doubling of the apoptosis rate compared to the basal rate was seen for the highest dose of DEX (5 mg/kg) and medium dose of HC (1 mg/kg). In cultures of embryonic chicken cerebellar granule cells, DEX and HC increased cell death and induced rapid caspase-3 activation in a similar dose-dependent manner. Transfection of granule cells with a luciferase reporter gene revealed that the dose needed for the activation of gene transcription (classical signalling pathway) with DEX was much lower than for HC. In conclusion, HC does not present itself as a safer drug than DEX in this model. In addition, it appears that DEX and HC induce apoptosis in immature granule neurons via a non-genomic (non-classical) mechanism.