Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparison between universal molecular screening for Lynch syndrome and revised Bethesda guidelines in a large population-based cohort of patients with colorectal cancer

Background The selection of patients for genetic testing to rule out Lynch syndrome is currently based on fulfilment of at least one of the revised Bethesda criteria followed by mismatch repair (MMR) status analysis. A study was undertaken to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC). Methods 2093 patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumour tissue. Germline MLH1 and MSH2 mutation analysis was performed in patients whose tumours showed loss of MLH1 or MSH2 staining, respectively. MSH6 genetic testing was done in patients whose tumours showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have MSH2 mutations. PMS2 genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumours and normal or not available MMR protein expression, all four MMR genes were studied. Results A total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not. Conclusions Routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines.
Growth pattern of serous cystic neoplasms of the pancreas: observational study with long-term magnetic resonance surveillance and recommendations for treatment

Background and aims The natural history and growth pattern of pancreatic serous cystic neoplasms (SCNs) are not well understood. This study was designed in order to get insight into the growth rate of SCNs and to suggest recommendations for their management. Methods Patients with well-documented incidentally discovered or minimally symptomatic SCNs who underwent yearly surveillance MRI were analysed using a linear mixed model. The growth rate and the effects of different fixed factors (sex, personal history of other non-pancreatic malignancies, radiological pattern, clinical presentation, tumour site) and random factors (age and tumour diameter at the time of diagnosis) on tumour growth were investigated. Results Study population consisted of 145 patients. Estimated overall mean growth rate was 0.28 cm/year, but the growth curve analysis showed a different trend between the first 7 years after the baseline evaluation (growth rate of 0.1 cm/year) and the subsequent period (years 7 to 10, growth rate of 0.6 cm/year, p<0.0001). Tests for fixed effects demonstrated that an oligocystic/macrocystic pattern and a personal history of other tumours are significant predictors of a more rapid mean tumour growth (p<0.0001 and 0.022, growth rates of 0.34 cm/year). Furthermore, tumour growth significantly increased with age (p=0.0001). Conclusion Overall, SCNs grow slowly, and an initial non-operative approach is feasible in all the asymptomatic or minimally symptomatic patients. The oligocystic/macrocystic variant, a history of other non-pancreatic malignancies and patients' age impact on tumour growth. In any case, a significant growth is unlikely to occur before 7 years from the baseline evaluation. Tumour size at the time of diagnosis should not be used for decisional purposes.
Ibrutinib for chronic graft-versus-host disease after failure of prior therapy.

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials. gov as #NCT02195869.
Distributed diagnostic fault simulation for synchronous sequential circuits by dynamic fault partitioning

In this paper, a distributed diagnostic fault simulation for sequential circuits by dynamic fault partitioning is proposed, in which the indistinguishable faults for all the detectable faults are obtained from different machines. Several ISCAS89 benchmark circuits have been experimented on. For a circuit s35932, less than one hour of CPU time is spent by using 4 SUN SPARC stations II.
Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL.

Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163+ monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3-CD56hiCD16-ve NK cells had substantially higher PD-1 expression relative to CD3-CD56dimCD16+ cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163+ monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m2, bleomycin 10 000 IU/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m2, cyclophosphamide 750 mg/m2 IV, doxorubicin 50 mg/m2 IV, vincristine 1.4 mg/m2 (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1hi NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3-CD56hiCD16-ve NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3-CD56hiCD16-ve NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.
Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia.

Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials. gov as #NCT01207388.
Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease despite tremendous scientific efforts. Numerous trials have failed to improve the outcome on this deadliest of all major cancers. Potential causes include a still insufficient understanding of key features of this cancer and imperfect preclinical models for identification of active agents and mechanisms of therapeutic responses and resistance. Modern genetically engineered mouse models of PDAC faithfully recapitulate the genetic and biological evolution of human PDAC, thereby providing a potentially powerful tool for addressing tumour biological issues as well as strategies for early detection and assessment of responses to therapeutic interventions. Here, the authors will discuss opportunities and challenges in the application of genetically engineered mouse models for translational approaches in pancreatic cancer and provide a non-exhaustive list of examples with already existing or future clinical relevance.
Clinical, but not oesophageal pH-impedance, profiles predict response to proton pump inhibitors in gastro-oesophageal reflux disease

Objective Approximately 30% of patients with gastro-oesophageal reflux disease (GORD) do not achieve adequate symptom control with proton pump inhibitors (PPIs). The aim of this study was to determine whether any symptom profile or reflux pattern was associated with refractoriness to PPI therapy. Design Patients with typical GORD symptoms (heartburn and/or regurgitation) were included and had 24 h pH-impedance monitoring off therapy. Patients were considered to be responders if they had fewer than 2 days of mild symptoms per week while receiving a standard or double dose of PPI treatment for at least 4 weeks. Both clinical and reflux parameters were taken into account for multivariate analysis (logistic regression). Results One hundred patients were included (median age 50 years, 42 male), 43 responders and 57 non-responders. Overall, multivariate analysis showed that the factors associated with the absence of response were absence of oesophagitis (p=0.050), body mass index (BMI) ≤25 kg/m2 (p=0.002) and functional dyspepsia (FD) (p=0.001). In patients who reported symptoms during the recording (n=85), the factors associated with PPI failure were BMI ≤25 kg/m2 (p=0.004), FD (p=0.009) and irritable bowel syndrome (p=0.045). In patients with documented GORD (n=67), the factors associated with PPI failure were absence of oesophagitis (p=0.040), FD (p=0.003), irritable bowel syndrome (p=0.012) and BMI ≤25 kg/m2 (p=0.029). Conclusion No reflux pattern demonstrated by 24 h pH-impedance monitoring is associated with response to PPIs in patients with GORD symptoms. In contrast, absence of oesophagitis, presence of functional digestive disorders and BMI ≤25 kg/m2 are strongly associated with PPI failure.
Exploring the hidden heritability of inflammatory bowel disease

In recent years the inflammatory bowel diseases (IBD)—Crohn's disease and ulcerative colitis—have emerged as a model for all complex traits in the successful dissection of the molecular basis of inherited susceptibility by non-parametric linkage analysis1 2 and genome-wide association studies (GWAS). 3–5 The recent meta-analyses of GWAS carried out by the International Inflammatory Bowel Disease Genetics Consortium have now reported the identification of 99 susceptibility loci involved in the pathogenesis of Crohn's disease and ulcerative colitis.4 5 These successes in candidate gene discovery have provided new insights into the pathogenetic mechanisms involved in the chronic intestinal inflammation associated with IBD. These data provide strong evidence that Crohn's disease and ulcerative colitis are related complex diseases, sharing some, but not all, susceptibility loci.5 It is clear that while some pathogenic pathways are implicated in both Crohn's disease and ulcerative colitis—notably, interleukin (IL)-23 signalling6 and Th17 cell activation,7 other innate immune mechanisms appear to be implicated in Crohn's disease only (eg, autophagy, and NOD2 signalling). Similarly, aspects of the maintenance of epithelial barrier function are most strongly implicated in ulcerative colitis.8 Furthermore, it is clear that many of the genetic determinants involved in IBD are also implicated in other complex disorders, such as type I diabetes and coeliac disease ( in press ). 9 Both expected and unexpected associations are evident, and have provided avenues for further research. Along with this exciting progress, however, new challenges have emerged for researchers in this complex field. Of the estimated heritability of IBD, which has been derived from concordance rates in twin pairs, <30% …
Environmental and health impacts of Canada's bitumen industry: in search of answers.

itumen production and processing in Alberta, Canada hasbecome the world’s largest energy project. The westernCanadian sedimentary basin contains 43% of the globalbitumen reserve; Canadian production is projected to reachthree million barrels/day by 2020 and five million barrels/dayby 2030. Increasing concern about the benefits and risks ofbitumen exploitation has led to a sustained and often stridentdebate that has garnered international attention. As aconsequence, the Royal Society of Canada (RSC)
First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability, and short survival.

TO THE EDITOR: Light-chain amyloidosis (AL) is a rare systemic protein deposition disorder that belongs to the group of plasma cell dyscrasias. Approximately 10% to 22% of cases are associated with symptomatic multiple myeloma or Waldenstrom macroglobulinemia (WM). The disease is characterized by
PATOLOGIA CLÍNICA EM AVES DE PRODUÇÃO – UMA FERRAMENTA PARA MONITORAR A SANIDADE AVÍCOLA – REVISÃO

Clinical pathology has been used in veterinary medicine for many years to evaluate metabolic changes that may indicate any sign of disease in animals. Even though the use of blood parameters is routine in companion animals, it is not commonly used for avian clinical evaluation either wild or production birds. Among others, the lack of information of avian blood reference values has limited the use of this tool in avian medicine. The blood parameters in avian medicine are helpful to evaluate aspects related to animal health for wild and also production birds. Thus, this review paper presents some ways to use clinical pathology parameters to evaluate and to monitor the avian health.
An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota

Background and aims Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder that may be triggered by enteric pathogens and has also been linked to alterations in the microbiota and the host immune response. The authors performed a detailed analysis of the faecal microbiota in IBS and control subjects and correlated the findings with key clinical and physiological parameters. Design The authors used pyrosequencing to determine faecal microbiota composition in 37 IBS patients (mean age 37 years; 26 female subjects; 15 diarrhoea-predominant IBS, 10 constipation-predominant IBS and 12 alternating-type IBS) and 20 age- and gender-matched controls. Gastrointestinal and psychological symptom severity and quality of life were evaluated with validated questionnaires and colonic transit time and rectal sensitivity were measured. Results Associations detected between microbiota composition and clinical or physiological phenotypes included microbial signatures associated with colonic transit and levels of clinically significant depression in the disease. Clustering by microbiota composition revealed subgroups of IBS patients, one of which (n=15) showed normal-like microbiota composition compared with healthy controls. The other IBS samples (n=22) were defined by large microbiota-wide changes characterised by an increase of Firmicutes-associated taxa and a depletion of Bacteroidetes-related taxa. Conclusions Detailed microbiota analysis of a well-characterised cohort of IBS patients identified several clear associations with clinical data and a distinct subset of IBS patients with alterations in their microbiota that did not correspond to IBS subtypes, as defined by the Rome II criteria.
Subphenotypes of sickle cell disease in Africa.

In this issue of Blood , Dubert et al present the results of a large cohort study conducted across 3 sub-Saharan African countries (Mali, Cameroon, and Ivory Coast) to quantify differences between subphenotypes of sickle cell disease (SCD) based on markers of anemia, hemolysis, and vascular complications. 1
Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma.

In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials. gov as #NCT02572167.
Beurteilung der Lebensqualität vor und nach Implantation einer Hüft-Totalendoprothese

PURPOSE OF THE STUDY: Quality of Life of patients with Total Hip Arthroplasty is analysed before and one year after surgery. The evaluation included the functional capacity of our patients in every day life comparing the preoperative situation with the result one year after surgery. Age and duration of symptoms were analysed with respect to their influence on the success of the procedure. Finally the question should be answered, if clinical examinations and questionnaires concerning Quality of Life result in comparable data. METHOD: 101 patients with an average age of 64.2 years were included into this study. All patients were evaluated preoperatively and one year after surgery using the Harris Hip Score, questionnaires for Quality of Life of the patients included the Nottingham Health Profile and the Functional Questionnaire Hannover. RESULTS: The pre- and postoperative means of the Nottingham Health Profile showed in five of the six dimensions a significant improvement of Quality of Life (pain, mobility, energy, emotional reaction, sleep). Only the scale "social isolation" remained unchanged between the pre- and postoperative situation. The means of the functional capacity according to the Hannover questionnaire improved from 57.92 to 39.79, a highly significant result. The Harris Hip Score was poor in 97% of the preoperative evaluations. This score improved to 80.2% excellent or good, 7.9% fair and 11.9% poor at one year after surgery. Age and duration of symptoms had no influence in any parameter of Quality of Life. A classification of parameters on Quality of Life according to the Harris-Hip-Score at the 1-year results demonstrates a clear grading concerning the excellent and poor results. Based on the patients evaluations a differentiation between good and poor results is not recorded. CONCLUSIONS: The objective evaluation of results after implantation of a total hip joint-endoprosthesis should not be based only on clinical scores (f.e. Harris-Hip-Score). Subjective informations by the patients using questionnaires on Quality of Life (f.e. NHP, FFbH-R) have to be included into these evaluations. The different judgments of the outcome of surgery underline the necessity, not only to use clinical scores but also to include the patients' feeling into the interpretation of the clinical result.
VITAMIN A AND COLDS

That experimental animals which have been deprived of vitamin A are highly susceptible to respiratory infections has been demonstrated by scores of research workers. The lack of this vitamin in the dietary of man has also been observed to result in similar types of infections, including the common cold. 1 The recent studies of Green, Pindar, Davis and Mellanby 2 indicated that concentrates of vitamin A have a therapeutic value in the treatment of certain infections, for example, puerperal sepsis. Their reports as to the value of the vitamin as a prophylactic agent against infections are also convincing. McCarrison attributed the comparative freedom from respiratory infections among certain Indian tribes to the adequacy of their dietary in vitamin A. In marked contrast to these Indians, the tribes whose diets showed a definite lack of vitamin A generally suffered from respiratory infections. Recent experimental work has shown the relation between vitamin