Jan Mæhlen

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.

Quantitative Apparent Diffusion Coefficients in the Characterization of Brain Tumors and Associated Peritumoral Edema

Background: Conventional magnetic resonance (MR) imaging has a number of limitations in the diagnosis of the most common intracranial brain tumors, including tumor specification and the detection of tumoral infiltration in regions of peritumoral edema. Purpose: To prospectively assess if diffusion-weighted MR imaging (DWI) could be used to differentiate between different types of brain tumors and to distinguish between peritumoral infiltration in high-grade gliomas, lymphomas, and pure vasogenic edema in metastases and meningiomas. Material and Methods: MR imaging and DWI was performed on 93 patients with newly diagnosed brain tumors: 59 patients had histologically verified high-grade gliomas (37 glioblastomas multiforme, 22 anaplastic astrocytomas), 23 patients had metastatic brain tumors, five patients had primary cerebral lymphomas, and six patients had meningiomas. Apparent diffusion coefficient (ADC) values of tumor (enhancing regions or the solid portion of tumor) and peritumoral edema, and ADC ratios (ADC of tumor or peritumoral edema to ADC of contralateral white matter, ADC of tumor to ADC of peritumoral edema) were compared with the histologic diagnosis. ADC values and ratios of high-grade gliomas, primary cerebral lymphomas, metastases, and meningiomas were compared by using ANOVA and multiple comparisons. Optimal thresholds of ADC values and ADC ratios for distinguishing high-grade gliomas from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Statistically significant differences were found for minimum and mean of ADC tumor and ADC tumor ratio values between metastases and high-grade gliomas when including only one factor at a time. Including a combination of in total four parameters (mean ADC tumor, and minimum, maximum and mean ADC tumor ratio) resulted in sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 72.9, 82.6, 91.5, and 54.3% respectively. In the ROC curve analysis, the area under the curve of the combined four parameters was the largest (0.84), indicating a good test. Conclusion: Our results suggest that ADC values and ADC ratios (minimum and mean of ADC tumor and ADC tumor ratio) may be helpful in the differentiation of metastases from high-grade gliomas. It cannot distinguish high-grade gliomas from lymphomas, and lymphomas from metastases. ADC values and ADC ratios in peritumoral edema cannot be used to differentiate edema with infiltration of tumor cells from vasogenic edema when measurements for high-grade gliomas, lymphomas, metastases, and meningiomas were compared.

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.

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.

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

Background The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals. Conclusions/Significance Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

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.

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.

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.

In Situ Deposition of Complement in Human Acute Brain Ischaemia

Experimental animal models indicate that complement contributes to tissue damage during brain ischaemia and stroke, but limited data are available for a role of the complement in human stroke. We, therefore, evaluated whether acute ischaemia leads to complement activation in human brain. Indirect immunohistochemical staining was performed on paraffin‐embedded, formalin‐fixed human brain from 10 patients and 10 controls. Complement components C1q, C3c and C4d were detected in all ischaemic lesions, suggesting activation via the classical pathway. C9, C‐reactive protein and IgM were detected in necrotic zones. Marked CD59 and weak CD55 expression were found in normal brains, but these complement regulators were virtually absent in ischaemic lesions. Modest amounts of mannose‐binding lectin (MBL), MBL‐associated serine protease‐2 and factor B were found in both ischaemic lesions and controls. These data suggest that increased deposition of complement components combined with decreased expression of complement regulators is a possible mechanism of tissue damage during ischaemia in human brain.

Brain stem encephalitis in listeriosis.

Serious infection with the bacterium L. monocytogenes mainly manifests as sepsis and/or meningitis. A particular entity is Listeria brain stem encephalitis, which is characterized by progressive brain stem deficits. The condition is fatal unless early treated. The purpose of the present study was to assess the incidence of brain stem encephalitis in a population-based listeriosis material. Medical records from 212 of the 240 patients with serious listeriosis reported in Norway from 1977 to 2000, as well as autopsy material from 8 of these patients, were available. This material was searched for clinical and neuropathological evidence of brain stem infection. Findings indicating brain stem encephalitis were present in 19 of the 172 patients with adult listeriosis (11%) but none of the 40 pregnancy-related listeriosis cases. None of the 19 patients had been diagnosed with Listeria brain stem infection originally. We conclude that brain stem encephalitis is relatively common in this Norwegian listeriosis material.