Purpose The 70-gene prognosis signature (van't Veer et al., Nature 415(6871):530-536, 2002) may improve the selection of lymph node-negative breast cancer patients for adjuvant systemic therapy. ...Optimal validation of prognostic classifiers is of great importance and we therefore wished to evaluate the prognostic value of the 70-gene prognosis signature in a series of relatively recently diagnosed lymph node negative breast cancer patients. Methods We evaluated the 70-gene prognosis signature in an independent representative series of patients with invasive breast cancer (N = 123; <55 years; pT1-2N0; diagnosed between 1996 and 1999; median follow-up 5.8 years) by classifying these patients as having a good or poor prognosis signature. In addition, we updated the follow-up of the node-negative patients of the previously published validation-series (Van de Vijver et al., N Engl J Med 347(25):1999-2009, 2002; N = 151; median follow-up 10.2 years). The prognostic value of the 70-gene prognosis signature was compared with that of four commonly used clinicopathological risk indexes. The endpoints were distant metastasis (as first event) free percentage (DMFP) and overall survival (OS). Results The 5-year OS was 82 ± 5% in poor (48%) and 97 ± 2% in good prognosis signature (52%) patients (HR 3.4; 95% CI 1.2-9.6; P = 0.021). The 5-years DMFP was 78 ± 6% in poor and 98 ± 2% in good prognosis signature patients (HR 5.7; 95% CI 1.6-20; P = 0.007). In the updated series (N = 151; 60% poor vs. 40% good), the 10-year OS was 51 ± 5% and 94 ± 3% (HR 10.7; 95% CI 3.9-30; P < 0.01), respectively. The DMFP was 50 ± 6% in poor and 86 ± 5% in good prognosis signature patients (HR 5.5; 95% CI 2.5-12; P < 0.01). In multivariate analysis, the prognosis signature was a strong independent prognostic factor in both series, outperforming the clinicopathological risk indexes. Conclusion The 70-gene prognosis signature is also an independent prognostic factor in node-negative breast cancer patients for women diagnosed in recent years.
Atrophy is regarded a sensitive marker of neurodegenerative pathology. In addition to confirming the well-known presence of decreased global grey matter and hippocampal volumes in Alzheimer's ...disease, this study investigated whether deep grey matter structure also suffer degeneration in Alzheimer's disease, and whether such degeneration is associated with cognitive deterioration. In this cross-sectional correlation study, two groups were compared on volumes of seven subcortical regions: 70 memory complainers (MCs) and 69 subjects diagnosed with probable Alzheimer's disease. Using 3T 3D T1 MR images, volumes of nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus were automatically calculated by the FMRIB's Integrated Registration and Segmentation Tool (FIRST)—algorithm FMRIB's Software Library (FSL). Subsequently, the volumes of the different regions were correlated with cognitive test results. In addition to finding the expected association between hippocampal atrophy and cognitive decline in Alzheimer's disease, volumes of putamen and thalamus were significantly reduced in patients diagnosed with probable Alzheimer's disease. We also found that the decrease in volume correlated linearly with impaired global cognitive performance. These findings strongly suggest that, beside neo-cortical atrophy, deep grey matter structures in Alzheimer's disease suffer atrophy as well and that degenerative processes in the putamen and thalamus, like the hippocampus, may contribute to cognitive decline in Alzheimer's disease.
Coastal food webs can be supported by local benthic or pelagic primary producers and by the import of organic matter. Distinguishing between these energy sources is essential for our understanding of ...ecosystem functioning. However, the relative contribution of these components to the food web at the landscape scale is often unclear, as many studies lack good taxonomic and spatial resolution across large areas. Here, using stable carbon isotopes, we report on the primary carbon sources for consumers and their spatial variability across one of the world's largest intertidal ecosystems (Dutch Wadden Sea; 1460 km2 intertidal surface area), at an exceptionally high taxonomic (178 species) and spatial resolution (9,165 samples from 839 locations). The absence of overlap in δ13C values between consumers and terrestrial organic matter suggests that benthic and pelagic producers dominate carbon input into this food web. In combination with the consistent enrichment of benthic primary producers (δ13C –16.3‰) relative to pelagic primary producers (δ13C –18.8) across the landscape, this allowed the use of a two-food-source isotope-mixing model. This spatially resolved modelling revealed that benthic primary producers (microphytobenthos) are the most important energy source for the majority of consumers at higher trophic levels (worms, molluscs, crustaceans, fish, and birds), and thus to the whole food web. In addition, we found large spatial heterogeneity in the δ13C values of benthic primary producers (δ13C –19.2 to –11.5‰) and primary consumers (δ13C –25.5 to –9.9‰), emphasizing the need for spatially explicit sampling of benthic and pelagic primary producers in coastal ecosystems. Our findings have important implications for our understanding of the functioning of ecological networks and for the management of coastal ecosystems.
The clinical outcome of contralateral prophylactic mastectomy (CPM) in women with a BRCA1 or BRCA2 mutation and a personal history of invasive breast cancer is unknown. We identified a cohort of 148 ...female BRCA1 or BRCA2 mutation carriers (115 and 33, respectively) who previously were treated for unilateral invasive breast cancer stages I-IIIa. In all, 79 women underwent a CPM, while the other women remained under intensive surveillance. The mean follow-up was 3.5 years and started at the time of CPM or at the date of mutation testing, whichever came last, that is, on average 5 years after diagnosis of the first breast cancer. One woman developed an invasive contralateral primary breast cancer after CPM, whereas six were observed in the surveillance group (P<0.001). Contralateral prophylactic mastectomy reduced the risk of contralateral breast cancer by 91%, independent of the effect of bilateral prophylactic oophorectomy (BPO). At 5 years follow-up, overall survival was 94% for the CPM group vs 77% for the surveillance group (P=0.03), but this was unexpectedly mostly due to higher mortality related with first breast cancer and ovarian cancer in the surveillance group. After adjustment for BPO in a multivariate Cox analysis, the CPM effect on overall survival was no longer significant. Our data show that CPM markedly reduces the risk of contralateral breast cancer among BRCA1 or BRCA2 mutation carriers with a history of breast cancer. Longer follow-up is needed to study the impact of CPM on contralateral breast cancer-specific survival. The choice for CPM is highly correlated with that for BPO, while only BPO leads to a significant improvement in overall survival so far.
Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and ...histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.
Background
Advance care planning (ACP) is a process in which professionals, patients and their relatives discuss wishes and options for future care. ACP in the palliative phase reduces the chance ...that decisions have to be taken suddenly and can therefore improve the quality of life and death. The primary aim of this study is to explore how ACP takes place in cases of people with intellectual disabilities (ID).
Method
Medical files were analysed, and interviews were held in six care organisations for people with mild to severe ID. The data concerned people with ID (n = 30), 15 in the palliative phase, identified using the ‘surprise question’, and 15 who had died after an identifiable period of illness. Additional pre‐structured telephone interviews were conducted with their relatives (n = 30) and professionals (n = 33).
Results
For half of the people with ID who had died, the first report in their file about palliative care (needs) was less than 1 month before their death. Professionals stated that ACP was started in response to the person's deteriorating health situation. A do‐not‐attempt‐resuscitation order was recorded for nearly all people with ID (93%). A smaller group also had other agreements between professionals and relatives documented in their files, mainly about potentially life‐sustaining treatments (43%) and/or hospitalisation admissions (47%). Relatives and professionals are satisfied with the mutual cooperation in ACP in the palliative phase. Cognitive and communication disabilities were most frequently mentioned by relatives and professionals as reasons for not involving people with ID in ACP.
Conclusions
Advance care planning in the palliative phase of people with ID focuses mainly on medical issues at the end of life. Specific challenges concern a proactive identification of changing needs, fear to initiate ACP discussions, documentation of ACP in medical files and the involvement of people with ID in ACP. It is recommended that relatives and professionals should be informed about the content of ACP and professionals should be trained in communicating in advance about wishes for future care.
To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a ...genotype-phenotype relationship for mutations in the ATM gene.
Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity.
Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum alpha-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations.
Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype-phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.
The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited ...statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Streptococcus (S.) pneumoniae strains vary considerably in their ability to cause invasive disease in humans, which is at least in part determined by the capsular serotype. Platelets have been ...implicated as sentinel cells in the circulation for host defence. One of their utensils for this function is the expression of Toll-like receptors (TLRs). We here aimed to investigate platelet response to S. pneumoniae and a role for TLRs herein. Platelets were stimulated using four serotypes of S. pneumonia including an unencapsulated mutant strain. In vitro aggregation and flow cytometry assays were performed using blood of healthy volunteers, or blood of TLR knock out and WT mice. For in vivo pneumonia experiments, platelet specific Myd88 knockout (Plt-Myd88-/-) mice were used. We found that platelet aggregation was induced by unencapsulated S. pneumoniae only. Whole blood incubation with all S. pneumoniae serotypes tested resulted in platelet degranulation and platelet-leukocyte complex formation. Platelet activation was TLR independent, as responses were not inhibited by TLR blocking antibodies, not induced by TLR agonists and were equally induced in wild-type and Tlr2-/-, Tlr4-/-, Tlr2/4-/-, Tlr9-/- and Myd88-/- blood. Plt-Myd88-/- and control mice displayed no differences in bacterial clearance or immune response to pneumonia by unencapsulated S. pneumoniae. In conclusion, S. pneumoniae activates platelets through a TLR-independent mechanism that is impeded by the bacterial capsule. Additionally, platelet MyD88-dependent TLR signalling is not involved in host defence to unencapsulated S. pneumoniae in vivo.
Thrombocytopenia is a common finding in sepsis and associated with a worse outcome. We used a mouse model of pneumonia-derived sepsis caused by the human pathogen Klebsiella pneumoniae to study the ...role of platelets in host response to sepsis. Platelet counts (PCs) were reduced to less than a median of 5 × 109/L or to 5 to 13 × 109/L by administration of a depleting antibody in mice infected with Klebsiella via the airways. Thrombocytopenia was associated with strongly impaired survival during pneumonia-derived sepsis proportional to the extent of platelet depletion. Thrombocytopenic mice demonstrated PC-dependent enhanced bacterial growth in lungs, blood, and distant organs. Severe thrombocytopenia resulted in hemorrhage at the primary site of infection, but not in distant organs. PCs of 5 to 13 × 109/L were sufficient to largely maintain hemostasis in infected lungs. Thrombocytopenia did not influence lung inflammation or neutrophil recruitment and did not attenuate local or systemic activation of coagulation or the vascular endothelium. PCs <5 × 109/L even resulted in enhanced coagulation and endothelial cell activation, which coincided with increased proinflammatory cytokine levels. In accordance, low PCs in whole blood enhanced Klebsiella-induced cytokine release in vitro. These data suggest that platelets play an important role in host defense to Klebsiella pneumosepsis.
•Severe thrombocytopenia is associated with a strongly impaired host defense during pneumonia-derived Klebsiella pneumoniae sepsis.•Platelet counts between 5 and 13 × 109/L of normal prevent bleeding and confer protection against distant organ damage during gram-negative sepsis.
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