Multi-observer concordance and accuracy of the British Thoracic Society scale and other visual assessment qualitative criteria for solid pulmonary nodule assessment using FDG PET-CT.

AIM: To compare the interobserver reliability and diagnostic accuracy of the British Thoracic Society (BTS) scale and other visual assessment criteria in the context of 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)-computed tomography (CT) evaluation of solid pulmonary nodules (SPNs). MATERIALS AND METHODS: Fifty patients who underwent FDG PET-CT for assessment of a SPN were identified. Seven reporters with varied experience at four centres graded FDG uptake visually using the British Thoracic Society (BTS) four-point scale. Five reporters also scored SPNs according to three- and five-point visual assessment scales and using semi-quantitative assessment (maximum standardised uptake value [SUVmax]). Interobserver reliability was assessed with the intra-class correlation coefficient (ICC) and weighted Cohen's kappa (κ). Diagnostic performance was evaluated by receiver operator characteristic (ROC) analysis. RESULTS: Good interobserver reliability was demonstrated with the BTS scale (ICC=0.78, 95% confidence interval [CI]: 0.69-0.85) and five-point scale (ICC=0.78, 95 CI 0.68-0.86), whilst the three-point scale demonstrated moderate reliability (ICC=0.70, 95% CI: 0.59-0.80). Almost perfect agreement was achieved between two consultants (κ=0.85), and substantial agreement between two other consultants (κ=0.78) using the BTS scale. ROC curves for the BTS and five-point scales demonstrated equivalent accuracy (BTS area under the ROC curve [AUC]=0.768; five-point AUC=0.768). SUVmax was no more accurate compared to the BTS scale (SUVmax AUC=0.794; BTS AUC=0.768, p=0.43). CONCLUSIONS: The BTS scale can be applied reliably by reporters with varied levels of PET-CT reporting experience, across different centres and has a diagnostic performance that is not surpassed by alternative scales.

Prediction of outcome in anal squamous cell carcinoma using radiomic feature analysis of pre-treatment FDG PET-CT.

PURPOSE: Incidence of anal squamous cell carcinoma (ASCC) is increasing, with curative chemoradiotherapy (CRT) as the primary treatment of non-metastatic disease. A significant proportion of patients have locoregional treatment failure (LRF), but distant relapse is uncommon. Accurate prognostication of progression-free survival (PFS) would help personalisation of CRT regimens. The study aim was to evaluate novel imaging pre-treatment features, to prognosticate for PFS in ASCC. METHODS: Consecutive patients with ASCC treated with curative intent at a large tertiary referral centre who underwent pre-treatment FDG-PET/CT were included. Radiomic feature extraction was performed using LIFEx software on baseline FDG-PET/CT. Outcome data (PFS) was collated from electronic patient records. Elastic net regularisation and feature selection were used for logistic regression model generation on a randomly selected training cohort and applied to a validation cohort using TRIPOD guidelines. ROC-AUC analysis was used to compare performance of a regression model encompassing standard clinical prognostic factors (age, sex, tumour and nodal stage-model A), a radiomic feature model (model B) and a combined radiomic/clinical model (model C). RESULTS: A total of 189 patients were included in the study, with 145 in the training cohort and 44 in the validation cohort. Median follow-up was 35.1 and 37. 9 months, respectively for each cohort, with 70.3% and 68.2% reaching this time-point with PFS. GLCM entropy (a measure of randomness of distribution of co-occurring pixel grey-levels), NGLDM busyness (a measure of spatial frequency of changes in intensity between nearby voxels of different grey-level), minimum CT value (lowest HU within the lesion) and SMTV (a standardized version of MTV) were selected for inclusion in the prognostic model, alongside tumour and nodal stage. AUCs for performance of model A (clinical), B (radiomic) and C (radiomic/clinical) were 0.6355, 0.7403, 0.7412 in the training cohort and 0.6024, 0.6595, 0.7381 in the validation cohort. CONCLUSION: Radiomic features extracted from pre-treatment FDG-PET/CT in patients with ASCC may provide better PFS prognosis than conventional staging parameters. With external validation, this might be useful to help personalise CRT regimens in the future.

Current concepts in imaging for local staging of advanced rectal cancer.

Imaging of rectal cancer has an increasingly pivotal role in the diagnosis, staging, and treatment stratification of patients with the disease. This is particularly true for advanced rectal cancers where magnetic resonance imaging (MRI) findings provide essential information that can change treatment. In this review we describe the rationale for the current imaging standards in advanced rectal cancer for both morphological and functional imaging on the baseline staging and reassessment studies. In addition the clinical implications and future methods by which radiologists may improve these are outlined relative to TNM8.

Radiologist and multidisciplinary team clinician opinions on the quality of MRI rectal cancer staging reports: how are we doing?

AIM: To evaluate the current opinion of magnetic resonance imaging (MRI) reports amongst specialist clinicians involved in colorectal cancer multidisciplinary teams (CRC MDTs). MATERIALS AND METHODS: Active participants at 16 UK CRC MDTs across a population of 5.7 million were invited to complete a questionnaire, this included 22 closed and three open questions. Closed questions used ordinal (Likert) scales to judge the subjective inclusion of tumour descriptors and impressions on the clarity and consistency of the MRI report. Open (free-text) questions allowed overall feedback and suggestions. RESULTS: A total of 69 participants completed the survey (21 radiologists and 48 other CRC MDT clinicians). Both groups highlighted that reports commonly omit the status of the circumferential resection margin (CRM; 83% versus 81% inclusion, other clinicians and radiologists, respectively, p>0.05), presence or absence of extra-mural venous invasion (EMVI; 67% versus 57% inclusion, p>0.05), and lymph node status (90% inclusion in both groups). Intra-radiologist agreement across MRI examinations is reported as 75% by other clinicians. Free-text comments included suggestions for template-style reports. CONCLUSION: Both groups recognise a proportion of MRI reports are suboptimal with key tumour descriptors omitted. There are also concerns around the presentation style of MRI reports and inter- and intra-radiologist report variability. The widespread implementation of standardised report templates may improve completeness and clarity of MRI reports for rectal cancer and thus clinical management and outcomes in rectal cancer.

Standardised reports with a template format are superior to free text reports: the case for rectal cancer reporting in clinical practice.

PURPOSE: Rectal cancer staging with magnetic resonance imaging (MRI) allows accurate assessment and preoperative staging of rectal cancers. Therefore, complete MRI reports are vital to treatment planning. Significant variability may exist in their content and completeness. Template-style reporting can improve reporting standards, but its use is not widespread. Given the implications for treatment, we have evaluated current clinical practice amongst specialist gastrointestinal (GI) radiologists to measure the quality of rectal cancer staging MRI reports. MATERIALS AND METHODS: Sixteen United Kingdom (UK) colorectal cancer multi-disciplinary teams (CRC-MDTs) serving a population over 5 million were invited to submit up to 10 consecutive rectal cancer primary staging MRI reports from January 2016 for each radiologist participating in the CRC-MDT. Reports were compared to a reference standard based on recognised staging and prognostic factors influencing case management RESULTS: Four hundred ten primary staging reports were submitted from 41 of 42 (97.6%) eligible radiologists. Three hundred sixty reports met the inclusion criteria, of these, 81 (22.5%) used a template. Template report usage significantly increased recording of key data points versus non-template reports for extra-mural venous invasion (EMVI) status (98.8% v 51.6%, p < 0.01) and circumferential resection margin (CRM) status (96.3% v 65.9%, p < 0.01). Local tumour stage (97.5% v 93.5%, NS) and nodal status (98.8% v 96.1%, NS) were reported and with similar frequency. CONCLUSION: Rectal cancer primary staging reports do not meet published standards. Template-style reports have significant increases in the inclusion of key tumour descriptors. This study provides further support for their use to improve reporting standards and outcomes in rectal cancer. KEY POINTS: • MRI primary staging of rectal cancer requires detailed tumour descriptions as these alter the neoadjuvant and surgical treatments. • Currently, rectal cancer MRI reports in clinical practice do not provide sufficient detail on these tumour descriptors. • The use of template-style reports for primary staging of rectal cancer significantly improves report quality compared to free-text reports.

FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas.

The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients.

Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1).

Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I protein arginine methyltransferase (PRMT) that catalyzes the conversion of arginine into monomethylarginine (MMA) and further into asymmetric dimethylarginine (ADMA). CARM1 methylates histone 3 arginines 17 and 26, as well as numerous non-histone proteins including CBP/p300, SRC-3, NCOA2, PABP1, and SAP49, while also functioning as a coactivator for various proteins that have been linked to cancer such as p53, NF-κß, ß-catenin, E2F1 and steroid hormone receptor ERα. As a result, CARM1 is involved in transcriptional activation, cellular differentiation, cell cycle progression, RNA splicing and DNA damage response. It has been associated with several human cancers including breast, colon, prostate and lung cancers and thus, is a potential oncological target. Herein, we present the design and synthesis of a series of CARM1 inhibitors. Based on a fragment hit, we discovered compound 9 as a potent inhibitor that displayed selectivity for CARM1 over other PRMTs.

The prevalence of NAFLD and NASH among patients with psoriasis in a tertiary care dermatology and rheumatology clinic.

BACKGROUND: Psoriasis has been linked to metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Data suggest that the prevalence of NAFLD is increased in patients with psoriasis. The aim of this study was to determine the prevalence and severity of NAFLD in this patient population. AIM: To determine the prevalence of both NAFLD and non-alcoholic steatohepatitis (NASH) in patients with psoriasis. METHODS: Patients between the ages of 18 and 70 years with a diagnosis of psoriasis or psoriatic arthritis and followed by either the Dermatology or Rheumatology Division within the Department of Medicine at San Antonio Military Medical Center were considered for enrollment. Each patient completed a questionnaire, underwent a thorough skin evaluation, and had a right upper quadrant ultrasound and fasting blood work. If the liver enzymes were elevated or fatty liver detected on imaging, percutaneous liver biopsy was recommended. RESULTS: One hundred and twenty-nine patients were enrolled and 103 completed all necessary studies. The participants were predominantly middle aged (52.7 ± 12) and overweight or obese (average BMI 30.1 ± 5.9, range: 19.8-52.5 kg/m(2)). 53% (n = 54) were male while 15% (n = 15) of participants identified themselves as being a diabetic. The overall prevalence of NAFLD was 47%. The overall prevalence of NASH was 22% in those who underwent biopsy. CONCLUSIONS: Non-alcoholic fatty liver disease is very common among our cohort of patients with psoriasis, occurring in roughly 47% of patients. The more progressive form of the disease, NASH, is found in approximately one in five patients. Health care providers should be mindful of this association given the high prevalence of both NAFLD and NASH in this cohort of patients.

Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients.

We previously identified autoantibodies to the endocytic-associated protein Huntingtin-interacting protein 1-related (HIP1R) in diffuse large B-cell lymphoma (DLBCL) patients. HIP1R regulates internalization of cell surface receptors via endocytosis, a process relevant to many therapeutic strategies including CD20 targeting with rituximab. In this study, we characterized HIP1R expression patterns, investigated a mechanism of transcriptional regulation and its clinical relevance in DLBCL patients treated with immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, R-CHOP). HIP1R was preferentially expressed in germinal center B-cell-like DLBCL (P<0.0001) and inversely correlated with the activated B-cell-like DLBCL (ABC-DLBCL) associated transcription factor, Forkhead box P1 (FOXP1). HIP1R was confirmed as a direct FOXP1 target gene in ABC-DLBCL by FOXP1-targeted silencing and chromatin immunoprecipitation. Lower HIP1R protein expression (≤ 10% tumoral positivity) significantly correlated with inferior overall survival (OS, P=0.0003) and progression-free survival (PFS, P=0.0148) in R-CHOP-treated DLBCL patients (n=157). Reciprocal expression with ≥ 70% FOXP1 positivity defined FOXP1(hi)/HIP1R(lo) patients with particularly poor outcome (OS, P=0.0001; PFS, P=0.0016). In an independent R-CHOP-treated DLBCL (n=233) microarray data set, patients with transcript expression in lower quartile HIP1R and FOXP1(hi)/HIP1R(lo) subgroups exhibited worse OS, P=0.0044 and P=0.0004, respectively. HIP1R repression by FOXP1 is strongly associated with poor outcome, thus further understanding of FOXP1-HIP1R and/or endocytic signaling pathways might give rise to novel therapeutic options for DLBCL.

Fibroepithelial polyps of the vagina in bitches: a histological and immunohistochemical study.

The histological and immunohistochemical features of 13 cases of suspected vaginal fibroepithelial polyps are reported. The characteristic microscopical features of these lesions were an abundant oedematous or fibrous stroma containing spindle-shaped and stellate cells and the presence of variable inflammation and haemorrhage. There was often a superficial layer of compressed tissue, but the stroma in the peripheral areas of the masses was generally more loosely arranged than in central areas. The connective tissue cells expressed vimentin and desmin, but did not express smooth muscle actin or calponin. Individual cases had additional changes including granulomatous inflammation, epithelial dysplasia suggestive of papillomavirus infection and a lesion resembling phyllodes tumour in women.

A survey of congenital reproductive abnormalities in rams in abattoirs in South west England.

Congenital abnormalities of the reproductive tract of male sheep were surveyed at three abattoirs in the south west of England during the period June 2000-January 2004. A total of 7307 rams were examined [6521 lambs (prepubescent) and hoggets (aged from their first autumn after birth until first shorn) and 786 adult rams mature rams that had been exposed to ewes]. A total of 156 congenital lesions were detected, 87 of which occurred in lambs. Testicular hypoplasia was the most common lesion occurring in 69 lambs as well as eight hoggets ('microtestes' were recognized in nine other animals in which the testis was disproportionately smaller than the epididymis). The second most common lesion found was notched scrotum occurring in 34 animals (27 young rams and seven adults). Some cases of notched scrotum were accompanied by hypospadias which was seen in a total of seven lambs and eight hoggets. Other lesions, detected in five or less animals (less than approximately 0.05% of the animals examined), included cryptorchidism and various abnormalities of the epididymis (segmental aplasia of the epididymis, blind efferent ducts and epididymal cyst) and congenital scrotal hernia. The overall prevalence of congenital lesions of 2.21% emphasizes the importance of undertaking breeding soundness examinations of young rams before they are put with the flock.

Haemosiderin deposition in Donkey (Equus asinus) livers: Comparison of quantitative histochemistry for iron and liver iron content.

Post mortem liver samples from 12 donkeys (Equus asinus) aged 21-57 years (4 females, 1 stallion, 7 geldings), were assessed chemically for copper and iron content on a wet weight basis and histologically for stainable iron. Chemical liver copper content ranged from 2.7 to 4.8µg/g (mean 3.5±0.05µg/g). Chemical liver iron content ranged from 524 to 5010µg/g (mean 1723±1258µg/g). Histochemical iron was measured morphometrically using a computer-based image analysis system; percentage section area staining for iron ranged from 0.84% to 26.69% (mean 10.82±8.36%). There was no clear correlation, within the wide range of iron values, between histochemically demonstrable iron and chemically measured iron content. No clear age-related increase was apparent for either parameter in these aged donkeys. The accumulation of iron in the liver of donkeys may represent a physiological haemosiderosis rather than pathological haemochromatosis.

Haemosiderin deposition in Donkey (Equusasinus) liver: Comparison of liver histopathology with liver iron content.

Histopathological examination was carried out on post mortem samples of liver from 12 donkeys (Equus asinus), aged 21-57 years (4 females, 1 stallion, 7 geldings). Variable amounts of haemosiderin were present in Kupffer cells, portal macrophages and hepatocytes in all cases. In all cases there was infiltration of connective tissue around portal tracts by variable numbers of inflammatory cells (lymphocytes, plasma cells and macrophages) but obvious portal fibrosis was present in only four animals. Subjective assessment of overall haemosiderin staining (including extent and intensity) generally reflected biochemical measurements of liver iron content (measured by an inductively-coupled plasma method) as well as quantitative histochemical measurements (using an image analysis package and sections stained with Perl's Prussian blue stain). Accumulation of hepatic iron in old donkeys was not directly related to other pathological changes and may be an incidental finding.

Expression of the forkhead box transcription factor FOXP1 is associated with oestrogen receptor alpha, oestrogen receptor beta and improved survival in familial breast cancers.

BACKGROUND: The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored. AIMS: To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival. METHODS: Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX. RESULTS: Nuclear FOXP1 expression ranged from focal weak to widespread strong expression. Expression of FOXP1 was higher in familial breast cancers (54%) compared with sporadic cancers (46%) (p<0.001). There was a significant correlation between FOXP1 with ERalpha (p = 0.038) and ERbeta (p = 0.007) in familial breast cancers. FOXP1 was more highly expressed in familial breast cancers compared with sporadic cancers for luminal (p = 0.021) and basal (p<0.001), but not HER2 and null phenotypes (both p>0.05). The absence of FOXP1 expression was associated with a shorter relapse-free (p = 0.025) and overall survival (p = 0.009) in familial breast cancer. Negativity for FOXP1 was associated with a significantly worse overall survival in BRCA2 cancers (p = 0.021) and there was a non-significant separation of the survival curves for BRCA1 cancers (p = 0.183). No differences in survival were seen for BRCAX cancers (p = 0.762). CONCLUSION: Results suggest that FOXP1 demonstrates different expression patterns in familial breast cancers than sporadic tumours, even in tumours showing similar phenotypes. They also suggest a different role of FOXP1 as a tumour suppressor in familial tumours, which is unrelated to ER expression and may impact on therapeutic options.

Pseudomonas aeruginosa transmission is infrequent in New Zealand cystic fibrosis clinics.

Pseudomonas aeruginosa is an important pathogen in cystic fibrosis (CF). Although most patients harbour unique P. aeruginosa isolates, some clinics report patients sharing common strains. The overall importance of person-to-person transmission in P. aeruginosa acquisition and whether routine patient segregation is necessary remains uncertain. The present authors therefore investigated the extent of P. aeruginosa transmission in New Zealand CF clinics. New Zealand's seven major CF centres were assessed, combining epidemiological data with computer-assisted SalI DNA fingerprinting of 496 isolates from 102 patients. One cluster of related isolates was significantly more prevalent in the largest clinic than expected by chance. The seven patients with isolates belonging to this cluster had more contact with each other than the remaining patients attending this centre. No other convincing evidence of transmission was found in any of the other smaller clinics. Three P. aeruginosa strains believed to be transmissible between patients in Australian and British CF clinics are present in New Zealand, but there was no definite evidence they had spread. Pseudomonas aeruginosa transmission is currently infrequent in New Zealand cystic fibrosis clinics. This situation could change rapidly and ongoing surveillance is required. The current results confirm that computer-assisted SalI DNA fingerprinting is ideally suited for such surveillance.

Toxicological and biochemical responses of the earthworm Lumbricus rubellus to pyrene, a non-carcinogenic polycyclic aromatic hydrocarbon.

The effects of the polycyclic aromatic hydrocarbon (PAH) pyrene on earthworms were investigated in contact and soil tests. In addition to measuring toxic effects on survival and reproduction, Ethoxyresorufin-o-deethylase (EROD) activity and catalase activity were also studied as possible biomarkers of toxic stress. The survival data indicated that LC50 values were 0.0068 mg/ml for the contact test, and 283 mg/kg in the soil test. Cocoon production rate was significantly reduced compared to controls at 160, 640 and 2560 mg/kg in the soil test. No EROD activity could be detected in preliminary studies using control and exposed animals from the contact test, so this assay was not used to the soil test. Catalase activity was shown to be significantly lower at 640 mg/kg in the soil test compared to all other treatments and the control. When compared to toxicological data for other soil invertebrates, Lumbricus rubellus has an intermediate sensitivity in respects of survival and a lower sensitivity for reproductive effects, although the soil used in this study had a higher organic content than previous studies, meaning that the sensitivity of this species may be underestimated in comparison to previous published data for other soil invertebrates.

Feline necrotising sialometaplasia: a report of two cases.

Unilateral swelling of submandibular salivary gland in two cats was diagnosed as necrotising sialometaplasia. Histological features that differentiate the disease from other salivary gland lesions, particularly neoplasia are: lobular necrosis of salivary tissue; squamous metaplasia conforming to duct and/or acinar outlines; preservation of salivary lobular morphology; and variable inflammation and granulation tissue.

A novel diffuse large B-cell lymphoma-associated cancer testis antigen encoding a PAS domain protein.

Here we report that the OX-TES-1 SEREX antigen, which showed immunological reactivity with serum from four out of 10 diffuse large B-cell lymphoma (DLBCL) patients, is encoded by a novel gene, PAS domain containing 1 (PASD1). PASD1_v1 cDNA encodes a 639 amino-acid (aa) protein product, while an alternatively spliced variant (PASD1_v2), lacking intron 14, encodes a 773 aa protein, the first 638 aa of which are common to both proteins. The PASD1-predicted protein contains a PAS domain that, together with a putative leucine zipper and nuclear localisation signal, suggests it encodes a transcription factor. The expression of PASD1_v1 mRNA was confirmed by RT-PCR in seven DLBCL-derived cell lines, while PASD1_v2 mRNA appears to be preferentially expressed in cell lines derived from non-germinal centre DLBCL. Immunophenotyping studies of de novo DLBCL patients' tumours with antibodies to CD10, BCL-6 and MUM1 indicated that two patients mounting an immune response to PASD1 were of a poor prognosis non-germinal centre subtype. Expression of PASD1 mRNA was restricted to normal testis, while frequent expression was observed in solid tumours (25 out of 68), thus fulfilling the criteria for a novel cancer testis antigen. PASD1 has potential for lymphoma vaccine development that may also be widely applicable to other tumour types.

Salivary gland basal cell adenocarcinoma: a report of cases in a cat and two dogs.

Basal cell adenocarcinoma of the salivary gland is described in a cat and two dogs; tumour tissue was characterized by cords and islands of epithelial cells with a distinct basal layer. The tumours were stained by various immunohistochemical methods. In addition to positive staining with cytokeratin 14 and pancytokeratin (CKs 5, 6, 8, 17 and 19), there was also staining with Jack bean agglutinin A (ConA) and soya bean agglutinin (SBA); this occurs in many other types of salivary gland tumours and is a feature of normal salivary gland acinar cells. In one dog there was also staining with SBA. This is the first report of this tumour in domestic animals; the immunohistochemical characteristics did not distinguish it from other salivary gland tumours.