Arnold Knijn

EUROCARE-3: survival of cancer patients diagnosed 1990–94—results and commentary

EUROCARE-4 analysed about three million adult cancer cases from 82 cancer registries in 23 European countries, diagnosed in 1995-1999 and followed to December 2003. For each cancer site, the mean European area-weighted observed and relative survival at 1-, 3-, and 5-years by age and sex are presented. Country-specific 1- and 5-year relative survival is also shown, together with 5-year relative survival conditional to surviving 1-year. Within-country variation in survival is analysed for selected cancers. Survival for most solid cancers, whose prognosis depends largely on stage at diagnosis (breast, colorectum, stomach, skin melanoma), was highest in Finland, Sweden, Norway and Iceland, lower in the UK and Denmark, and lowest in the Czech Republic, Poland and Slovenia. France, Switzerland and Italy generally had high survival, slightly below that in the northern countries. There were between-region differences in the survival for haematologic malignancies, possibly due to differences in the availability of effective treatments. Survival of elderly patients was low probably due to advanced stage at diagnosis, comorbidities, difficult access or lack of availability of appropriate care. For all cancers, 5-year survival conditional to surviving 1-year was higher and varied less with region, than the overall relative survival.

Survival patterns in lung and pleural cancer in Europe 1999-2007: Results from the EUROCARE-5 study.

BACKGROUND Survival of patients diagnosed with lung and pleura cancer is a relevant health care indicator which is related to the availability and access to early diagnosis and treatment facilities. Aim of this paper is to update lung and pleural cancer survival patterns and time trends in Europe using the EUROCARE-5 database. METHODS Data on adults diagnosed with lung and pleural cancer from 87 European cancer registries in 28 countries were analysed. Relative survival (RS) in 2000-2007 by country/region, age and gender, and over time trends in 1999-2007 were estimated. RESULTS Lung cancer survival is poor everywhere in Europe, with a RS of 39% and 13% at 1 and 5years since diagnosis, respectively. A geographical variability is present across European areas with a maximum regional difference of 12 and 5 percentage points in 1-year and 5-year RS respectively. Pleural cancer represents 4% of cases included in the present study with 7% 5-year RS overall in Europe. Most pleural cancers (83%) are microscopically verified mesotheliomas. Survival for both cancers decreases with advancing age at diagnosis for both cancers. Slight increasing trends are described for lung cancer. Survival over time is higher for squamous cell carcinoma and adenocarcinomas than for small and large cell carcinoma; and better among women than men. CONCLUSIONS Despite the generalised although slight increase, survival of lung and pleural cancer patients still remains poor in European countries. Priority should be given to prevention, with tobacco control policies across Europe for lung cancer and banning asbestos exposure for pleural cancer, and in early diagnosis and better treatment. The management of mesothelioma needs a multidisciplinary team and standardised health care strategies.

Detection of polyol accumulation in a new ovarian carcinoma cell line, CABA I: a 1 H NMR study

Ovarian carcinomas represent a major form of gynaecological malignancies, whose treatment consists mainly of surgery and chemotherapy. Besides the difficulty of prognosis, therapy of ovarian carcinomas has reached scarce improvement, as a consequence of lack of efficacy and development of drug-resistance. The need of different biochemical and functional parameters has grown, in order to obtain a larger view on processes of biological and clinical significance. In this paper we report novel metabolic features detected in a series of different human ovary carcinoma lines, by 1H NMR spectroscopy of intact cells and their extracts. Most importantly, a new ovarian adenocarcinoma line CABA I, showed strong signals in the spectral region between 3.5 and 4.0 p.p.m., assigned for the first time to the polyol sorbitol (39±11 nmol/106 cells). 13C NMR analyses of these cells incubated with [1-13C]-D-glucose demonstrated labelled-sorbitol formation. The other ovarian carcinoma cell lines (OVCAR-3, IGROV 1, SK-OV-3 and OVCA432), showed, in the same spectral region, intense resonances from other metabolites: glutathione (up to 30 nmol/106 cells) and myo-inositol (up to 50 nmol/106 cells). Biochemical and biological functions are suggested for these compounds in human ovarian carcinoma cells, especially in relation to their possible role in cell detoxification mechanisms during tumour progression.

Potential Role of in vitro 1H Magnetic Resonance Spectroscopy in the Definition of Malignancy Grading of Human Neuroepithelial Brain Tumours

The increasing sensitivity of neuro-imaging in the diagnosis of brain expanding lesions is not directly related to biopathological specificity and new technological approaches are under study. In particular Magnetic Resonance Spectroscopy (MRS) allows evaluation of some biochemical pathways whose metabolic alterations may be correlated with the nature and malignancy grading of primary brain tumours. In the present study the author performed an in vitro high field 1H MRS (9.4 and 14.1 T) analysis of specimens obtained from stereotactic biopsy or microsurgical removal of primary brain tumours. Different samples derived from heterogeneous areas and/or infiltrated perilesional regions were examined. This study was principally focused on malignancy grading of gliomas and its correlation with the ratio (R) between the resonance band arising from choline containing compounds (between 3.14 and 3.35 ppm) and the total creatine signal (3.0 ppm). Analyses allowed significant discrimination between astrocytomas (R = 2.4 +/- 0.6) and glioblastoma (GBM) (R = 4.4 +/- 1.3) [p < 0.002]; however the results did not allow discrimination between differentiated and anaplastic astrocytomas. The GBM showed the largest spread of values corresponding to their higher level of tissue heterogeneity and de-differentiation. Studies on non astrocytic brain tumours indicated that even higher R values were exhibited by oligodendrogliomas, even in well differentiated forms (p < 0.02 with respect to GBM). Moreover, preliminary observations indicated that signals arising from other metabolites may also contribute to a differential diagnosis of different oncotypes. Among these glycine appears particularly relevant, since higher levels were measured for this amino acid in GBM with respect to both astrocytomas and oligodendrogliomas.

Absolute metabolite quantification by in vivo NMR spectroscopy: V. multicentre quantitative data analysis trial on the overlapping background problem

The goal of this study was to establish the best approach for quantifying nuclear magnetic resonance (NMR) lines, that in the frequency domain are overlapping with broad, unwanted background features. To perform the quantitative data analysis in a controlled way, test signals were designed and utilised, derived from two different real-world in vivo nuclear magnetic resonance signals. One of the main conclusions of the study was that the quantification methods currently available to the biomedical research groups can deliver the correct values of the quantitative parameters, but that great care should be taken in using optimal input parameters for the computer programs concerned.

Absolute metabolite quantification by in vivo NMR spectroscopy: IV. multicentre trial on MRSI localisation tests

The difference between the experimental and theoretical spatial response function (SRF) of a narrow tube with water is used for a localization test for magnetic resonance spectroscopic imaging (MRSI). From this difference a quantitative performance parameter is derived for the relative amount of signal within a limited region in the field of view. The total signal loss by the MRSI experiment and eddy currents is described by a parameter SL derived from the signal intensities of two echoes. Results of a European multi-centre trial show that this approach is suited for assessment of MRSI localization performance.

Evaluation of signal processing methods for the quantification of a multi-exponential signal: the glycogen 13C-1 NMR signal

The 13C‐1 NMR peak in proton‐decoupled spectra of liver glycogen solution was quantitatively analyzed by three types of model‐function fitting algorithms: iterative line‐fitting in the frequency domain (MDCON); iterative least‐squares fitting (VARPRO) in the time‐domain; and noniterative singular value decomposition‐based analysis (HTLS), also in the time domain. Quantification results were compared with manual integration values. Performance of the algorithms was tested at various signal‐to‐noise ratios (S/N) of the glycogen C‐1 peak. This was achieved by varying the number of scans summed prior to analysis. Since T2 relaxation in glycogen has been shown to be multiexponential [Overloop, K. et al. Magn. Reson. Med. 36, 45‐51 (1996)], the exact quantification of the C‐1 glycogen signal requires a model function comprising a sum of Lorentzian components, each with a different broadening at the glycogen frequency. This paper focuses on the performance of the above methods to fit such a multicomponent resonance line. In the frequency domain, VARPRO performs better than HTLS because fixed values can be imposed to the linewidth of the components at the common C‐1 frequency, thereby reducing convergence problems at low S/N.

Double-resonance J-edited 1H-NMR detection of [6-13C]-D-2-deoxyglucose uptake in glioma cells

The C6 methylene protons were selectively detected in 1H‐NMR spectra of intact glioma cells incubated with [6‐13C]‐D‐2‐deoxyglucose ([6‐13C]‐2dG), a 13C‐enriched glucose analog that is suitable for monitoring glucose utilization in brain tumors. Spectral editing via 1H–13C scalar coupling was performed with twin spin‐echo double resonance (T‐SEDOR), a pulse sequence which combines chemical specificity and high sensitivity, requires no solvent pre‐saturation, and can easily be adapted to imaging protocols. This work demonstrates the suitability of the pulse sequence for monitoring [6‐13C]‐2dG uptake in living cells in vitro, in spite of line‐broadening and the occurrence of other strong signals in the spectral region of interest (3.5–4.4 ppm). Copyright

1H NMR detection of 13C–1H bonds by double 13C editing: application to the discrimination of glucose metabolites

Abstract The discrimination of chemical groups based on the J selectivity of the 13 C – 1 H bonds ( J -editing or X-filter) may be dramatically enhanced by introducing selective 13 C pulses, which exploit the large 13 C chemical shift range. The double resonance pulse sequence presented in this paper, besides allowing indirect, selective 13 C detection with high signal to noise ratio, may also be used for imaging purposes. Results are presented on the efficacy of the method in selective glucose metabolite detection in aqueous solution.

Metagenomic Characterization of the Human Intestinal Microbiota in Fecal Samples from STEC-Infected Patients

The human intestinal microbiota is a homeostatic ecosystem with a remarkable impact on human health and the disruption of this equilibrium leads to an increased susceptibility to infection by numerous pathogens. In this study, we used shotgun metagenomic sequencing and two different bioinformatic approaches, based on mapping of the reads onto databases and on the reconstruction of putative draft genomes, to investigate possible changes in the composition of the intestinal microbiota in samples from patients with Shiga Toxin-producing E. coli (STEC) infection compared to healthy and healed controls, collected during an outbreak caused by a STEC O26:H11 infection. Both the bioinformatic procedures used, produced similar result with a good resolution of the taxonomic profiles of the specimens. The stool samples collected from the STEC infected patients showed a lower abundance of the members of Bifidobacteriales and Clostridiales orders in comparison to controls where those microorganisms predominated. These differences seemed to correlate with the STEC infection although a flexion in the relative abundance of the Bifidobacterium genus, part of the Bifidobacteriales order, was observed also in samples from Crohns disease patients, displaying a STEC-unrelated dysbiosis. The metagenomics also allowed to identify in the STEC positive samples, all the virulence traits present in the genomes of the STEC O26 that caused the outbreak as assessed through isolation of the epidemic strain and whole genome sequencing. The results shown represent a first evidence of the changes occurring in the intestinal microbiota of children in the course of STEC infection and indicate that metagenomics may be a promising tool for the culture-independent clinical diagnosis of the infection.