The MOSA study (Maastricht Observational study of late effects after Stem cell trAnsplantation) aims to study the prevalence of adverse health effects in hematopoietic stem cell transplantation (HCT) ...survivors compared to a matched cohort, representing the general population.
The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Participants of The Maastricht Study serve as a reference group matched on age, gender, and education to compare MOSA participants to the general population. In both studies, the same study protocol and extensive phenotyping measurements are used.
HCT Survivors: Five hundred and thirty nine survivors were invited of which, so far, 123 (23%) participants completed the study assessments. Data will be analyzed and published separately. Reference Group: For each MOSA participant, four reference cases were matched. After matching, both groups are comparable with respect to age, gender, and education.
To our knowledge, this is the first study conducting such detailed phenotyping in HCT survivors. Comparison with a large reference group provides essential information about late effects of HCT and associated risk factors. This may improve screening and prevention strategies, potentially leading to a positive impact on morbidity, mortality, and quality of life.
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•A cohort study with a large reference group matched on age, gender, and education representing the general population to study long-term adverse effects in hematopoietic stem cell transplantation (HCT) survivors.•The first study conducting extensive in-depth phenotyping in HCT survivors including assessment of relevant outcomes of cardiovascular, neurological, respiratory, and musculoskeletal diseases.•HCT survivors and the reference group undergo the same measurements. The reference group enables detection of somatic diseases, mental disorders, and functional limitations that occur earlier or more frequently than expected.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gene-expression profiling (GEP) is used to study the molecular biology of lymphomas. Here, advancing insights from GEP studies in diffuse large B-cell lymphoma (DLBCL) lymphomagenesis are discussed. ...GEP studies elucidated subtypes based on cell-of-origin principles and profoundly changed the biological understanding of DLBCL with clinical relevance. Studies integrating GEP and next-generation DNA sequencing defined different molecular subtypes of DLBCL entities originating at specific anatomical localizations. With the emergence of high-throughput technologies, the tumor microenvironment (TME) has been recognized as a critical component in DLBCL pathogenesis. TME studies have characterized so-called "lymphoma microenvironments" and "ecotypes". Despite gained insights, unexplained chemo-refractoriness in DLBCL remains. To further elucidate the complex biology of DLBCL, we propose a novel targeted GEP consortium panel, called BLYM-777. This knowledge-based biology-driven panel includes probes for 777 genes, covering many aspects regarding B-cell lymphomagenesis (f.e., MYC signature, TME, immune surveillance and resistance to CAR T-cell therapy). Regarding lymphomagenesis, upcoming DLBCL studies need to incorporate genomic and transcriptomic approaches with proteomic methods and correlate these multi-omics data with patient characteristics of well-defined and homogeneous cohorts. This multilayered methodology potentially enhances diagnostic classification of DLBCL subtypes, prognostication, and the development of novel targeted therapeutic strategies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CCAAT/enhancer binding protein alpha (CEBPA) double mutations (CEBPAdm) versus single mutations (CEBPAsm) ...in 1182 cytogenetically normal acute myeloid leukemia (AML) patients (16-60 years of age). We identified 151 (12.8%) patients with CEBPA mutations (91 CEBPAdm and 60 CEBPAsm). The incidence of germline mutations was 7% (5 of 71), including 3 C-terminal mutations. CEBPAdm patients had a lower frequency of concurrent mutations than CEBPAsm patients (P < .0001). Both, groups were associated with a favorable outcome compared with CEBPAwt (5-year overall survival OS 63% and 56% vs 39%; P < .0001 and P = .05, respectively). However, in multivariable analysis only CEBPAdm was a prognostic factor for favorable OS outcome (hazard ratio HR 0.36, P < .0001; event-free survival, HR 0.41, P < .0001; relapse-free survival, HR 0.55, P = .001). Outcome in CEBPAsm is dominated by concurrent NPM1 and/or FLT3 internal tandem duplication mutations. Unsupervised and supervised GEP analyses showed that CEBPAdm AML (n = 42), but not CEBPAsm AML (n = 18), expressed a unique gene signature. A 25-probe set prediction signature for CEBPAdm AML showed 100% sensitivity and specificity. Based on these findings, we propose that CEBPAdm should be clearly defined from CEBPAsm AML and considered as a separate entity in the classification of AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To detect Schmallenberg virus (SBV) infections in ruminants and to perform SBV epidemiological studies a cost-effective serological test is required. For these purposes an indirect whole virus ...Enzyme-linked Immunosorbent Assay (ELISA) for detection of SBV specific antibodies in ruminant blood samples was developed. Schmallenberg virus antigen was produced by propagation on Vero cells, partly purified and coated onto ELISA plates. The indirect ELISA procedure included the subsequent incubation of diluted samples, protein-G-HRP conjugate and TMB substrate solution. Net Optical Densities (OD) values were calculated and expressed as a sample to positive percentage (S/P%) by comparison of the average net OD with the OD of the positive control. Validation of this assay was performed using 633 samples from SBV-free sheep, goats and cattle, and 141 samples from SBV suspect ruminants. The diagnostic specificity was 98.8%. Test results of 86 ruminant serum samples using both the SBV-ELISA and an SBV virus neutralization test (VNT), designated as the gold standard serological test for SBV, showed good correlation: at an S/P cut-off of 15% only one VNT positive sample tested negative in the SBV ELISA. The diagnostic sensitivity of the ELISA, relative to the VNT, was 98.8% (95% CI: 93.3–100.0%). The ELISA showed a high repeatability (cv=6.5%) and reproducibility (100% agreement). It was concluded that this ELISA is a suitable test method for the detection of SBV antibodies in sera from cows, sheep and, possibly, goats.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Among the different mycotoxin reducing methods, we should not declare that one individual method is unconditionally effective to eliminate mycotoxin contamination in crops or to prevent the ...consequent impacts on animal health.•Prevention strategies and cleaning and sorting methods are widely applied because they work as first-line barriers to free materials from various contaminants, including mycotoxins.•Mycotoxin reducing effects of other feed manufacturing technologies, like milling, dehulling and thermal methods, could be inconsistent and limited by various practical conditions. In addition, the evident reducing effects of some physical removal methods requires the costs of high grain mass loss, which could be a dilemma from the aspect of practical manufacturing.•Feed additive products specifically against mycotoxins are promising but still in their babyhood, since in vitro functioning of some products are inconsistent, and their in vivo functioning need more proof.•As for biotransformation, understanding the reaction for the detoxification of mycotoxins, attention in research on the toxicity of transformation by enzymes and their end-products should emphasize the possibilities of the use of micro-organisms or enzymes towards safe properties in animal feed ingredients.•This literature review generally agrees with the discussion of Jouany (2007): ‘Prevention strategies are essential, since it is impossible for other technologies to completely decontaminate the mycotoxin-contaminated feed samples once they are present’.
Mycotoxins are the secondary metabolites of fungi, especially moulds. They have over 300 types and can be easily produced ubiquitously by moulds. Many mycotoxins have been found to be toxic to most farmed animals through the diets. With the globalization of feed ingredient trade and the rapid climate changes, occurrence of mycotoxins become increasingly difficult to be predicted. Thus, the unnoticeable mycotoxin hazards can directly impact the animal production systems. Preventing or minimizing mycotoxins in feed ingredients has become an important topic from the aspect of feed manufacturing industry. The aim of this literature review is to summarize the effective strategies for feed manufacturers to minimize the mycotoxin hazards. Prevention methods, including pre-harvest field management and post-harvest storage management, are still the most effective strategies, since mycotoxins are hardly to be eliminated once they are present in the ingredients. Moreover, mycotoxin reducing effects of several feed manufacturing technologies are also reviewed. In this review, the mycotoxin reducing methods are mainly categorized into 4 methodologies: physical methods, thermal methods, chemical methods, and mycotoxin controlling feed additives. The first three methodologies mainly focus on how to reduce mycotoxins in feed ingredients during processes, while the last one on how to compensate the adverse impacts of mycotoxin-contaminated diets in animal bodies. The results showed that most of the methods reviewed show evident mycotoxin reducing effects, but of different consistencies. On the other hand, many practical factors that can affect the feasibility of each method in practical manufacturing are also discussed in this review. In conclusion, mycotoxin prevention management and the processing stage of cleaning and sorting are still the most efficient strategies to control mycotoxin hazards in current feed manufacturing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•We implemented a high-throughput 384-wells version of the functional FIS assay to screen a large number of PDIOs for compounds that enhance CFTR function.•We found that PDE4 inhibitors are potent ...CFTR function inducers when residual CFTR function is either present or created by additional compound exposure.•We show that CFTR modulators can be beneficial for CF patients with CFTR mutations that are not eligible for CFTR modulators at present-day.•Our study demonstrates how preclinical studies using PDIOs can be used to initiate drug repurposing efforts, paving the way for patient stratification in the upcoming era of personalized medicine.
Preclinical cell-based assays that recapitulate human disease play an important role in drug repurposing. We previously developed a functional forskolin induced swelling (FIS) assay using patient-derived intestinal organoids (PDIOs), allowing functional characterization of CFTR, the gene mutated in people with cystic fibrosis (pwCF). CFTR function-increasing pharmacotherapies have revolutionized treatment for approximately 85% of people with CF who carry the most prevalent F508del-CFTR mutation, but a large unmet need remains to identify new treatments for all pwCF.
We used 76 PDIOs not homozygous for F508del-CFTR to test the efficacy of 1400 FDA-approved drugs on improving CFTR function, as measured in FIS assays. The most promising hits were verified in a secondary FIS screen. Based on the results of this secondary screen, we further investigated CFTR elevating function of PDE4 inhibitors and currently existing CFTR modulators.
In the primary screen, 30 hits were characterized that elevated CFTR function. In the secondary validation screen, 19 hits were confirmed and categorized in three main drug families: CFTR modulators, PDE4 inhibitors and tyrosine kinase inhibitors. We show that PDE4 inhibitors are potent CFTR function inducers in PDIOs where residual CFTR function is either present, or created by additional compound exposure. Additionally, upon CFTR modulator treatment we show rescue of CF genotypes that are currently not eligible for this therapy.
This study exemplifies the feasibility of high-throughput compound screening using PDIOs. We show the potential of repurposing drugs for pwCF carrying non-F508del genotypes that are currently not eligible for therapies.
We screened 1400 FDA-approved drugs in CF patient-derived intestinal organoids using the previously established functional FIS assay, and show the potential of repurposing PDE4 inhibitors and CFTR modulators for rare CF genotypes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Combined laparoscopic resection of liver metastases and colorectal cancer (LLCR) may hold benefits for selected patients but could increase complication rates. Previous studies have ...compared LLCR with liver resection alone. Propensity score-matched studies comparing LLCR with laparoscopic colorectal cancer resection (LCR) alone have not been performed.
Methods
A multicenter, case-matched study was performed comparing LLCR (2009–2016, 4 centers) with LCR alone (2009–2016, 2 centers). Patients were matched based on propensity scores in a 1:1 ratio. Propensity scores were calculated with the following preoperative variables: age, sex, ASA grade, neoadjuvant radiotherapy, type of colorectal resection and T and N stage of the primary tumor. Outcomes were compared using paired tests.
Results
Out of 1020 LCR and 64 LLCR procedures, 122 (2 × 61) patients could be matched. All 61 laparoscopic liver resections were minor hepatectomies, mostly because of a solitary liver metastasis (
n
= 44, 69%) of small size (≤ 3 cm) (
n
= 50, 78%). LLCR was associated with a modest increase in operative time 206 (166–308) vs. 197 (148–231) min,
p
= 0.057 and blood loss 200 (100–700) vs. 75 (5–200) ml,
p
= 0.011. The rate of Clavien–Dindo grade 3 or higher complications 9 (15%) vs. 13 (21%),
p
= 0.418, anastomotic leakage 5 (8%) vs. 4 (7%),
p
= 1.0, conversion rate 3 (5%) vs. 5 (8%),
p
= 0.687 and 30-day mortality 0 vs. 1 (2%),
p
= 1.0 did not differ between LLCR and LCR.
Conclusion
In selected patients requiring minor hepatectomy, LLCR can be safely performed without increasing the risk of postoperative morbidity compared to LCR alone.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose We compared the nodal yield after histopathological examination of extended bilateral pelvic lymph node dissection specimens for bladder cancer at 2 hospitals. Surgery at each hospital was ...done by the same 4 staff urologists using a standardized extended bilateral pelvic lymph node dissection template. Materials and Methods All consecutive patients with bladder cancer who underwent extended bilateral pelvic lymph node dissection from January 1, 2007 to December 31, 2009 were included in this study. Specimens were sent for pathological evaluation in a minimum of 2 packages per side. At the 2 pathology departments specimens were processed according to institutional protocols. Results A total of 174 patients with a mean age of 62.7 years were included in analysis. At hospital 1 a mean of 16 lymph nodes were found after dissection vs a mean of 28 reported at hospital 2 (p <0.001). No significant differences were found in the number of tumor positive lymph nodes (p = 0.65). Mean lymph node density at hospitals 1 and 2 was 9.3% and 3.9%, respectively (p = 0.056). Conclusions Despite equal anatomical clearance by the same experienced surgeons we report a statistically significant difference between 2 pathology departments where the number of lymph nodes was evaluated after extended bilateral pelvic lymph node dissection for bladder cancer. Unless standardized methods are agreed on by pathologists, the number of reported lymph nodes as an indicator of surgical quality and lymph node density as a prognostic factor should be used cautiously.
Although cognitive problems can recover over time, a subgroup of hematopoietic stem cell transplantation (HCT) survivors experience persistent cognitive problems in the long term. Despite these ...implications, studies assessing cognitive functioning in HCT survivors are limited. The aim of the present study was (1) to quantify the prevalence of cognitive impairment in patients treated with HCT who survived at least 2 years and to compare these with a matched reference group representing the general population; (2) to identify potential determinants of cognitive functioning within the HCT survivor group. Within the single-center Maastricht Observational study of late effects after Stem cell trAnsplantation, cognitive performance was assessed by a neuropsychological test battery divided into 3 cognitive domains: memory, information processing speed, and executive function and attention. An overall cognition score was calculated as the average of the domain scores. A total of 115 HCT survivors were group-matched on a 1:4 ratio to the reference group by age, sex, and level of education. Regression analyses adjusted for different sets of covariates including demographic and health- and lifestyle-related factors were used to test for differences in cognition between HCT survivors and the reference group resembling the general population. A limited set of clinical characteristics (diagnosis, type of transplant, time since treatment, conditioning regimen with total body irradiation and age at time of transplantation) were assessed as potential determinants of neurocognitive dysfunction among HCT survivors. Cognitive impairment was defined as scores in the cognitive domains < −1.5 standard deviation (SD) from what can be expected based on someone's age, sex, and education. The mean age at time of transplantation was 50.2 (SD ± 11.2) years, and the mean number of years after transplant was 8.7 (SD ± 5.7) years. The majority of HCT survivors were treated with autologous HCT (n = 73 64%). The prevalence of cognitive dysfunction was 34.8% in HCT survivors and 21.3% in the reference group (p = .002.) When adjusted for age, sex, and level of education, HCT survivors had a worse overall cognition score (b = −0.35; 95% confidence interval CI, −0.55 to −0.16; p < .001), translating into 9.0 years of higher cognitive age. Analyses of specific cognitive domain scores showed that HCT survivors scored worse on memory (b = −0.43; 95% CI, −0.73 to −0.13; p = .005), information processing speed (b = −0.33; 95% CI, −0.55 to −0.11; p = .003), and executive function and attention (b = −0.29; 95% CI, −.55 to −.03; p = .031) than the reference group. The odds of cognitive impairment were on average 2.4 times higher among HCT survivors than the reference group (odd ratio = 2.44; 95% CI, 1.47-4.07; p = .001). Within the HCT survivor group none of the tested clinical determinants of cognitive impairment were significantly associated with cognition. This cohort study showed evidence for worse cognitive functioning in HCT survivors encompassing all three cognitive domains, respectively memory, information processing speed, and executive and attention compared to a reference group that represents the general population translating into nine years of faster cognitive ageing in HCT survivors than can be expected based on their chronological age. It is important to increase awareness for signs of neurocognitive dysfunction after HCT in clinicians and HCT survivors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Minimally invasive surgery (MIS) is quickly becoming mainstream in hepato-pancreato-biliary surgery because of presumed advantages. Surgery for perihilar cholangiocarcinoma (PHC) is highly demanding ...which may hamper the feasibility and safety of MIS in this setting. This study aimed to systematically review the existing literature on MIS for PHC. A systematic literature review was performed according to the PRISMA statement. The PubMed and EMBASE databases were searched and all studies describing MIS in patients with PHC were included. Data extraction and risk of bias were assessed by two independent researchers. Overall, 21 studies reporting on a total of 142 MIS procedures for PHC were included. These included 82 laparoscopic, 59 robot-assisted and 1 hybrid procedure(s). Risk of bias was deemed substantial. Pooled conversion rate was 7/142 (4.9%), pooled morbidity 30/126 (23.8%), and pooled mortality rate 4/126 (3.2%). The only comparative study, comparing 10 robot-assisted procedures to 32 open procedures, reported a significant increased operative time and higher morbidity rate with MIS. The available evidence on MIS for PHC is limited and generally of poor quality. This systematic review shows that the implementation of MIS for patients with PHC is still in its infancy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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