This article applies formal detection and attribution techniques to investigate the nature of observed shifts in the timing of streamflow in the western United States. Previous studies have shown ...that the snow hydrology of the western United States has changed in the second half of the twentieth century. Such changes manifest themselves in the form of more rain and less snow, in reductions in the snow water contents, and in earlier snowmelt and associated advances in streamflow “center” timing (the day in the “water-year” on average when half the water-year flow at a point has passed). However, with one exception over a more limited domain, no other study has attempted to formally attribute these changes to anthropogenic increases of greenhouse gases in the atmosphere. Using the observations together with a set of global climate model simulations and a hydrologic model (applied to three major hydrological regions of the western United States—the California region, the upper Colorado River basin, and the Columbia River basin), it is found that the observed trends toward earlier “center” timing of snowmelt-driven streamflows in the western United States since 1950 are detectably different from natural variability (significant at thep< 0.05 level). Furthermore, the nonnatural parts of these changes can be attributed confidently to climate changes induced by anthropogenic greenhouse gases, aerosols, ozone, and land use. The signal from the Columbia dominates the analysis, and it is the only basin that showed a detectable signal when the analysis was performed on individual basins. It should be noted that although climate change is an important signal, other climatic processes have also contributed to the hydrologic variability of large basins in the western United States.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Elderly patients have largely been excluded from randomized trials for glioblastoma multiforme (GBM). We reviewed the results of treatment approaches, which included surgery, chemotherapy, and ...radiation in this group of patients. Patients were treated during the period 1979-2007 and were 70 years of age and older with histologically confirmed GBM. Overall survival (OS) was the primary endpoint of this retrospective study. Two hundred six patients 70 years of age and older were identified. Median age was 75 years (range 70-90). Median OS time was 4.5 months. Univariate analysis showed that OS was significantly impacted by KPS score (1.8 months for KPS ≤50 to 17.2 months for KPS ≥90, P < .001), age at diagnosis (5.1 months for age 70-79 versus 3.1 months for age ≥80, P < .001), and extent of disease (worse for bilateral disease P = .003, multifocal disease P = .005, and multicentric disease P = .02). On multivariate analysis, higher KPS score (P = .006), surgical resection (any surgery beyond biopsy) (P < .001), radiation therapy (P < .001), and chemotherapy (P < .001) were all found to be independently associated with improved OS. In this study of newly diagnosed glioblastoma patients over the age of 70 years, aggressive treatment with radiation, chemotherapy, and surgery is associated with OS.
Pathobiology of brain metastases Nathoo, N; Chahlavi, A; Barnett, G H ...
Journal of Clinical Pathology,
03/2005, Volume:
58, Issue:
3
Journal Article, Book Review
Peer reviewed
Open access
Brain metastasis is a major cause of systemic cancer morbidity and mortality. Many factors participate in the development and maintenance of brain metastases. The survival of the metastasis depends ...upon crucial interactions between tumour cells and the brain microenvironment during its development at the new site. This review focuses on the pathobiological mechanisms involved in the establishment and regulation of brain metastases. Developments in molecular biology have vastly expanded our knowledge about the mechanisms of invasion, proliferation, metastatic cell signalling, and angiogenesis in brain metastases. Advances in this understanding of the pathobiology of brain metastasis may lead to novel targeted treatment paradigms and a better prognosis for patients with brain metastatic disease.
Gliomas are the most common primary tumours of the central nervous system, with nearly 15,000 diagnosed annually in the United States and a lethality approaching 80% within the first year of ...glioblastoma diagnosis. The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression; however, the precise molecular mechanisms underlying the regulation of brain tumour growth and angiogenesis remain unresolved. Here we report that a candidate tumour suppressor gene, ING4, is involved in regulating brain tumour growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours. We show that ING4 physically interacts with p65 (RelA) subunit of nuclear factor NF-κB, and that ING4 regulates brain tumour angiogenesis through transcriptional repression of NF-κB-responsive genes. These results indicate that ING4 has an important role in brain tumour pathogenesis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma multiforme (GBM), the most common and malignant central nervous system tumor in humans, is highly proliferative and resistant to apoptosis. Stat3, a latent transcription factor being ...activated by aberrant cytokine or growth factor signaling, acts as a suppressor of apoptosis in a number of cancer cells. Here we report that GBM tumors and cell lines contain high levels of constitutively activated Stat3 when compared with normal human astrocytes, white matter, and normal tissue adjacent to tumor. The persistent activation of Stat3 is in part, attributable to an autocrine action of interleukin-6 in the GBM cell line U251. Janus kinase inhibitor AG490 inhibits Stat3 activation with a concomitant reduction in steady-state levels of Bcl-X(L), Bcl-2 and Mcl-1 proteins and induces apoptosis in U251 cells as revealed by Poly (ADP-ribose) polymerase cleavage and Annexin-V staining. Expression of a dominant negative mutant Stat3 protein or treatment with AG490 markedly reduces the proliferation of U251 cells by inhibiting the constitutive activation of Stat3. These results provide evidence that constitutive activation of Stat3 contributes to the pathogenesis of glioblastoma by promoting both proliferation and survival of GBM cells. Therefore, targeting Stat3 signaling may provide a potential therapeutic intervention for GBM.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ABSTRACT
Background: Evidence for a link between periodontal disease and several systemic diseases is growing rapidly. The infectious and inflammatory burden of chronic periodontitis is thought to ...have an important systemic impact. Current evidence suggests that periodontitis is associated with an increased likelihood of coronary heart disease and may influence the severity of diabetes.
Scope: This paper represents a UK and Ireland cross-specialty consensus review, undertaken by a group of physicians and dentists. The consensus group reviewed published evidence (PubMed search for review and original articles), focusing on the past 5 years, on the contributory role of periodontal disease to overall health. In particular, evidence relating to a role for periodontal disease in cardiovascular disease and in diabetes was considered.
Findings: Initial studies of large epidemiological data sets have sought to find links between periodontitis and systemic disease outcomes, but a causal relationship still needs to be demonstrated between periodontal disease, cardiovascular disease and diabetes through prospective studies. There is a need for prospective studies assessing the association between periodontal disease and patients at particular risk of cardiovascular events which will allow assessment of both cardiovascular disease clinical endpoints and surrogate markers of cardiovascular risk. Of note, periodontal disease is also often more severe in subjects with diabetes mellitus, a group at already increased risk for cardiovascular events.
Conclusions: While further research is needed to define the population-attributable risk of periodontal disease to both cardiovascular diseases and to diabetes control and progression, health education to encourage better oral health should be considered as part of current healthy lifestyle messages designed to reduce the increasing health burden of obesity, cardiovascular disease and diabetes.
The United Kingdom is a diverse society with 7.9% of the population from black and minority ethnic groups (BMEGs). The causes of the excess cardiovascular disease (CVD) and stroke morbidity and ...mortality in BMEGs are incompletely understood though socio-economic factors are important. However, the role of classical cardiovascular (CV) risk factors is clearly important despite the patterns of these risk factors varying significantly by ethnic group. Despite the major burden of CVD and stroke among BMEGs in the UK, the majority of the evidence on the management of such conditions has been based on predominantly white European populations. Moreover, the CV epidemiology of African Americans does not represent well the morbidity and mortality experience seen in black Africans and black Caribbeans, both in Britain and in their native African countries. In particular, atherosclerotic disease and coronary heart disease are still relatively rare in the latter groups. This is unlike the South Asian diaspora, who have prevalence rates of CVD in epidemic proportions both in the diaspora and on the subcontinent. As the BMEGs have been under-represented in research, a multitude of guidelines exists for the 'general population.' However, specific reference and recommendation on primary and secondary prevention guidelines in relation to ethnic groups is extremely limited. This document provides an overview of ethnicity and CVD in the United Kingdom, with management recommendations based on a roundtable discussion of a multidisciplinary ethnicity and CVD consensus group, all of whom have an academic interest and clinical practice in a multiethnic community.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
BACKGROUND
Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and ...prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases.
MATERIAL AND METHODS
In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method.
RESULTS
118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN.
CONCLUSION
Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.
Patients
with newly diagnosed gliomas were treated with adoptive transfer of
ex vivo activated T lymphocytes, derived from lymph
nodes (LNs) draining autologous tumor vaccines, to determine the
...long-term toxicity of this treatment. Twelve consecutive patients were
enrolled: 2 with grade II astrocytoma, 4 with anaplastic gliomas, and 6
with glioblastoma multiforme. Patients were injected intradermally with
short-term cultured autologous irradiated tumor cells, admixed with
granulocyte macrophage colony-stimulating factor, to stimulate draining
LNs. The LN cells were activated with staphylococcal enterotoxin
A for 48 h and then cultured in medium containing
interleukin 2 for an additional 6–8 days and subsequently transferred
i.v. to the patients. The number of cells obtained from the LNs ranged
from 9 × 10 7 to 1.1 × 10 9 , and the
median cell proliferation was 41-fold. The dose of T cells infused
ranged from 0.6 to 5.5 × 10 10 with a median of
1.1 × 10 10 , the majority of which were CD
4 + (mean, 71%). The entire treatment was performed as
outpatient therapy and was associated with a toxicity of grade 2 or
less, consisting mainly of fever, nausea, and myalgias during the first
24 h. There were no indications of late adverse events from this
treatment even among three patients with follow-up greater than 2 years
post T cell transfer. Moreover, four patients demonstrated partial
regression of residual tumor. This Phase I clinical trial of adoptive
immunotherapy for patients with newly diagnosed malignant gliomas
demonstrates feasibility, lack of long-term toxicity, and several
objective clinical responses.
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