141 research outputs found
Serratierte LĂ€sionen im Kolorektum â ein pathologisches Problem oder ein Problem der Pathologen?
Serratierte LĂ€sionen im Kolorektum stellen eine Problemzone fĂŒr Kliniker und Pathologen dar; dies liegt zum einen an der noch nicht allgemein bekannten Nomenklatur, zum anderen an dem noch nicht abschlieĂend geklĂ€rten Progressionsrisiko der verschiedenen serratierten Polypen. Mittlerweile gilt als akzeptiert, dass neben der klassischen Adenom-Karzinom-Sequenz ein alternativer serratierter und ein sogenannter gemischter Karzinogeneseweg existiert; diese Karzinogenesewege sind in Bezug auf die prĂ€invasiven Vorstufen, die molekularen Pfade und die Prognose der Karzinome heterogen. Bei den serratierten Adenokarzinomen lassen sich ein Niedrigrisiko-Subtyp (HĂ€ufigkeit 70%) sowie ein Hochrisiko-Subtyp (HĂ€ufigkeit >80%, mit meist distaler Lokalisation, dem traditionellen serratierten Adenom als VorlĂ€uferlĂ€sion, KRAS-Mutation, niedriger MikrosatelliteninstabilitĂ€t/mikrosatellitenstabil, CpG-Methylierung/ p53-Akkumulation und einer 5-Jahres-Ăberlebens-Rate von 70%) and a high-risk subtype (frequency >80%, often with distal location, the traditional serrated adenoma as a precursor lesion, KRAS mutation, low microsatellite instability/microsatellite stable, CpG methylation/ p53 accumulation and a 5-year survival rate of <30%). The evaluation of the microsatellite status as well as the detection of BRAF or KRAS mutations together with immunohistochemistry for hMLH1 and p53 will allow a discrimination between these two subtypes and will become increasingly important in the future.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugĂ€nglich
Silenced ZNF154 Is Associated with Longer Survival in Resectable Pancreatic Cancer
Pancreatic cancer has become the third leading cause of cancer-related death in the Western world despite advances in therapy of other cancerous lesions. Late diagnosis due to a lack of symptoms during early disease allows metastatic spread of the tumor. Most patients are considered incurable because of metastasized disease. On a cellular level, pancreatic cancer proves to be rather resistant to chemotherapy. Hence, early detection and new therapeutic targets might improve outcomes. The detection of DNA promoter hypermethylation has been described as a method to identify putative genes of interest in cancer entities. These genes might serve as either biomarkers or might lead to a better understanding of the molecular mechanisms involved. We checked tumor specimens from 80 patients who had undergone pancreatic resection for promoter hypermethylation of the zinc finger protein ZNF154. Then, we further characterized the effects of ZNF154 on cell viability and gene expression by in vitro experiments. We found a significant association between ZNF154 hypermethylation and better survival in patients with resectable pancreatic cancer. Moreover, we suspect that the cell growth suppressor SLFN5 might be linked to a silenced ZNF154 in pancreatic cancer
DNA copy number changes define spatial patterns of heterogeneity in colorectal cancer
Genetic heterogeneity between and within tumours is a major factor determining
cancer progression and therapy response. Here we examined DNA sequence and DNA
copy-number heterogeneity in colorectal cancer (CRC) by targeted high-depth
sequencing of 100 most frequently altered genes. In 97 samples, with primary
tumours and matched metastases from 27 patients, we observe inter-tumour
concordance for coding mutations; in contrast, gene copy numbers are highly
discordant between primary tumours and metastases as validated by fluorescent
in situ hybridization. To further investigate intra-tumour heterogeneity, we
dissected a single tumour into 68 spatially defined samples and sequenced them
separately. We identify evenly distributed coding mutations in APC and TP53 in
all tumour areas, yet highly variable gene copy numbers in numerous genes. 3D
morpho-molecular reconstruction reveals two clusters with divergent copy
number aberrations along the proximalâdistal axis indicating that DNA copy
number variations are a major source of tumour heterogeneity in CRC
On the Benefit of Dual-domain Denoising in a Self-supervised Low-dose CT Setting
Computed tomography (CT) is routinely used for three-dimensional non-invasive
imaging. Numerous data-driven image denoising algorithms were proposed to
restore image quality in low-dose acquisitions. However, considerably less
research investigates methods already intervening in the raw detector data due
to limited access to suitable projection data or correct reconstruction
algorithms. In this work, we present an end-to-end trainable CT reconstruction
pipeline that contains denoising operators in both the projection and the image
domain and that are optimized simultaneously without requiring ground-truth
high-dose CT data. Our experiments demonstrate that including an additional
projection denoising operator improved the overall denoising performance by
82.4-94.1%/12.5-41.7% (PSNR/SSIM) on abdomen CT and 1.5-2.9%/0.4-0.5%
(PSNR/SSIM) on XRM data relative to the low-dose baseline. We make our entire
helical CT reconstruction framework publicly available that contains a raw
projection rebinning step to render helical projection data suitable for
differentiable fan-beam reconstruction operators and end-to-end learning.Comment: This work has been submitted to the IEEE for possible publication.
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Noise2Contrast: Multi-Contrast Fusion Enables Self-Supervised Tomographic Image Denoising
Self-supervised image denoising techniques emerged as convenient methods that
allow training denoising models without requiring ground-truth noise-free data.
Existing methods usually optimize loss metrics that are calculated from
multiple noisy realizations of similar images, e.g., from neighboring
tomographic slices. However, those approaches fail to utilize the multiple
contrasts that are routinely acquired in medical imaging modalities like MRI or
dual-energy CT. In this work, we propose the new self-supervised training
scheme Noise2Contrast that combines information from multiple measured image
contrasts to train a denoising model. We stack denoising with domain-transfer
operators to utilize the independent noise realizations of different image
contrasts to derive a self-supervised loss. The trained denoising operator
achieves convincing quantitative and qualitative results, outperforming
state-of-the-art self-supervised methods by 4.7-11.0%/4.8-7.3% (PSNR/SSIM) on
brain MRI data and by 43.6-50.5%/57.1-77.1% (PSNR/SSIM) on dual-energy CT X-ray
microscopy data with respect to the noisy baseline. Our experiments on
different real measured data sets indicate that Noise2Contrast training
generalizes to other multi-contrast imaging modalities
Randomised, double-blind, placebo-controlled trial of oral budesonide for prophylaxis of acute intestinal graft-versus-host disease after allogeneic stem cell transplantation (PROGAST)
Background Gastrointestinal graftâversus-host disease (GvHD) is a potentially
life-threatening complication after allogeneic stem cell transplantation
(SCT). Since therapeutic options are still limited, a prophylactic approach
seems to be warranted. Methods In this randomised, double-blind-phase III
trial, we evaluated the efficacy of budesonide in the prophylaxis of acute
intestinal GvHD after SCT. The trial was registered at
https://clinicaltrials.gov webcite, number NCT00180089. Patients were randomly
assigned to receive either 3 mg capsule three times daily oral budesonide or
placebo. Budesonide was applied as a capsule with pH-modified release in the
terminal ileum. Study medication was administered through day 56, follow-up
continued until 12 months after transplantation. If any clinical signs of
acute intestinal GvHD appeared, an ileocolonoscopy with biopsy specimens was
performed. Results The crude incidence of histological or clinical stage 3â4
acute intestinal GvHD until day 100 observed in 91 (n =48 budesonide, n =43
placebo) evaluable patients was 12.5% (95% CI 3-22%) under treatment with
budesonide and 14% (95% CI 4-25%) under placebo (pâ=â0.888). Histologic and
clinical stage 3â4 intestinal GvHD after 12 months occurred in 17% (95% CI
6-28%) of patients in the budesonide group and 19% (CI 7-32%) in the placebo
group (pâ=â0.853). Although budesonide was tolerated well, we observed a trend
towards a higher rate of infectious complications in the study group (47.9%
versus 30.2%, pâ=â0.085). The cumulative incidences at 12 months of intestinal
GvHD stage >2 with death as a competing event (budesonide 20.8% vs. placebo
32.6%, pâ=â0.250) and the cumulative incidence of relapse (budesonide 20.8%
vs. placebo 16.3%, pâ=â0.547) and non-relapse mortality (budesonide 28% (95%
CI 15-41%) vs. placebo 30% (95% CI 15-44%), showed no significant difference
within the two groups (pâ=â0.911). The trial closed after 94 patients were
enrolled because of slow accrual. Within the limits of the final sample size,
we were unable to show any benefit for the addition of budesonide to standard
GvHD prophylaxis. Conclusions Budesonide did not decrease the occurrence of
intestinal GvHD in this trial. These results imply most likely that
prophylactic administration of budenoside with pH-modified release in the
terminal ileum is not effective
Budesonide as induction therapy for incomplete microscopic colitis: A randomised, placeboâcontrolled multicentre trial
Background and aims: Incomplete microscopic colitis (MCi) is a subtype of microscopic colitis (MC). Budesonide is recommended as a first-line treatment for MC. However, randomised trials on efficacy of treatment in MCi are missing. We therefore performed a randomised, placebo-controlled trial to evaluate budesonide as induction therapy for MCi. Methods: Patients with active MCi were randomly assigned to either budesonide 9 mg once daily or placebo for 8 weeks in a double-blind, double-dummy design. The primary endpoint was clinical remission, defined as a mean of <3 stools/day and a mean of <1 watery stool/day in the 7 days before week 8. Results: Due to insufficient patient recruitment, the trial was discontinued prematurely. The intention-to-treat analysis included 44 patients (21 budesonide and 23 placebo). The primary endpoint of clinical remission at week 8 was obtained by 71.4% on budesonide and 43.5% on placebo (p = 0.0582). All clinical secondary endpoints were in favour of budesonide. Budesonide decreased the number of soft or watery stools (16.3 vs. 7.7, p = 0.0186) and improved health-related quality of life for all four dimensions of the short health scale. Adverse events with a suspected relation to study drug were reported in one patient in the budesonide group and two patients in the placebo group. Neither serious nor severe adverse events occurred during the double-blind phase. Conclusions: Budesonide decreased the frequency of soft or watery stools and improved the patients' quality of life significantly in MCi, but the primary endpoint was not met due to the low sample size (type 2 error). Budesonide was safe and well tolerated during the 8-weeks treatment course
Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks
<p>Abstract</p> <p>Background</p> <p>The identification of genomic signatures of colorectal cancer for risk stratification requires the study of large series of cancer patients with an extensive clinical follow-up. Multicentric clinical studies represent an ideal source of well documented archived material for this type of analyses.</p> <p>Methods</p> <p>To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours.</p> <p>Results</p> <p>The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes.</p> <p>Conclusion</p> <p>Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.</p
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