Purpose Acute trauma-related rotator cuff tears are believed to have better healing potential than chronic tears due to less degenerative changes of the tendons. However, the histopathological condition of tendons from trauma-related tears is not well investigated. The purpose of this study was to explore specific histopathological features in tendons from acute trauma-related full-thickness rotator cuff tears and to compare them to findings in tendons from nontraumatic, chronic tears. Methods In a prospective cohort study, 62 previously asymptomatic patients [14 women, median age 61 years (range 42-75)] with trauma-related full-thickness rotator cuff tears were consecutively included. Arthroscopic repair was performed within 30 (median, IQR 25-37) days after the injury. During surgery, tissue biopsies were harvested from the supraspinatus tendons in 53 (86%) of the patients. In addition, similar biopsies were harvested from 10 patients undergoing surgery for chronic tears without history of trauma. All tissue samples were examined by a well-experienced pathologist under light microscope. Tendon degeneration was determined using the Bonar score whereas immunostaining was used for proliferation (Ki67), inflammation (CD45), apoptosis (p53) and haemosiderin staining to study traces of bleeding. Results The median (IQR) Bonar score for the acute trauma-related biopsies was 10.5 (7.5-14.5) compared to 11 (5-12.8) for the control group with no statistically significant difference between the groups. No statistically significant between-group difference was found for the inflammatory index whereas tendons from patients with trauma-related full-thickness rotator cuff tears had statistically significantly higher apoptosis [3.1 (0.5-8.9) vs. 0.1 (0-1.5), p = 0.003] and proliferation [4.0 (1.8-6.9) vs. 0.4 (0-2.0), p = 0.001) indices than those undergoing surgery for chronic tears. Positive haemosiderin staining was found in 34% of tissue samples from patients with trauma-related tears compared to 10% in the control group (n.s). Conclusion This study suggests that there is no difference with regard to degenerative changes between supraspinatus tendons harvested from patients with acute, trauma-related rotator cuff tears and patients with nontraumatic, chronic tears.

Background: Healing failure after rotator cuff repair is a challenging problem. Acute, trauma-related tears are considered a separate entity and are often treated surgically. The aim of this study was to identify factors associated with healing failure in previously asymp-tomatic patients with trauma-related rotator cuff tears treated with early arthroscopic repair. Methods: This study included 62 consecutively recruited patients (23% women; median age, 61 years; age range, 42-75 years) with acute symptoms in a previously asymptomatic shoulder and a magnetic resonance imaging-verified full-thickness rotator cuff tear after shoulder trauma. All patients were offered, and underwent, early arthroscopic repair, during which a biopsy specimen was har-vested from the supraspinatus tendon and analyzed for signs of degeneration. Of the patients, 57 (92%) completed 1-year follow-up and underwent assessment of repair integrity on magnetic resonance images according to the Sugaya classification. Risk factors for heal-ing failure were investigated using a causal-relation diagram where age, body mass index, tendon degeneration (Bonar score), diabetes mellitus, fatty infiltration (FI), sex, smoking, tear location regarding integrity of the rotator cable, and tear size (number of ruptured tendons and tendon retraction) were included and analyzed. Results: Healing failure at 1 year was identified in 37% of patients (n = 21). A high degree of FI of the supraspinatus muscle (P = .01), a tear location including disruption of rotator cable integrity (P = .01), and old age (P = .03) were associated with healing failure. Tendon degeneration as determined by histopathology was not associated with healing failure at 1-year follow-up (P = .63). Conclusion: Older age, increased FI of the supraspinatus muscle, and a tear including disruption of the rotator cable increased the risk of healing failure after early arthroscopic repair in patients with trauma-related full-thickness rotator cuff tears. Level of evidence: Level I; Prospective Cohort Design; Prognosis Study

Background

No previous studies have investigated what biopsychosocial factors are associated with self‐reported work ability in conservatively managed patients with cervical radiculopathy.

Objective

To develop a theoretical model of factors and potential processes associated with variation in work ability based on a thorough assessment of biopsychosocial variables in conservatively managed patients with cervical radiculopathy.

Design

Cross‐sectional observational study.

Setting

Tertiary neurosurgery clinic.

Patients

A total of 144 conservatively managed patients with cervical pain and radiculopathy participated in the study.

Methods

From 64 biopsychosocial candidate variables, significant (P < .05) bivariate correlators with Work Ability Index (WAI) were entered as independent variables in a categorical regression. Elastic net regularization maintained the most parsimonious set of independent variables significantly associated with variation in WAI as the dependent variable. Process analysis of significant independent variable associations with WAI was performed.

Main Outcome Measurement

WAI.

Results

From 42 bivariate correlates of WAI, multivariate regression displayed a total of seven variables that were significantly (F [25,98] = 5.74, P < .05) associated with 65.8% of the variation in WAI. The Neck Disability Index (NDI) and Fear‐Avoidance Beliefs Questionnaire Work subscale (FABQ‐W) were significant individual factors within the final regression model. Process analysis displayed FABQ‐W having a significant specific indirect association with the direct association between NDI and WAI, with the model associated with 77% of the variability in WAI (F [2,84] = 141.17, P < .001).

Conclusion

Of 64 candidate biopsychosocial factors, NDI and FABQ‐W were the most significant multivariate correlates with work ability. FABQ‐W has a significant indirect association with baseline NDI scores and perceived work ability. This warrants future research trialing work‐related fear avoidance interventions in conservatively managed patients with cervical radiculopathy.

Level of Evidence

III

Background and purpose - Swedish clinical guidelines for osteoarthritis (OA) prioritize patient education, exercise, and-if necessary-weight reduction before considering adjunct pharmacological intervention. Contrariwise, we investigated the proportion and type of dispensed analgesic prescriptions in Sweden received by patients during 3 years before commencing non-pharmacological primary care interventions for OA (2008-2016) compared with the general population. Furthermore, we analyzed the proportion of analgesic prescriptions dispensed before (2008-2012) compared with after (2012-2016) guideline publication in terms of concordance with clinical guideline recommendations. Patients and methods - Patients with hip or knee OA (n = 72,069) from the Better Management of OA national quality register receiving non-pharmacological interventions in primary care between 2008 and 2016 were included (OA cohort). An age, sex, and residence matched reference cohort (n = 216,207) was formed from the Swedish Total Population Register. Based on a period 3 years prior to inclusion in the OA cohort, Swedish Prescribed Drug Register data was linked to both the OA and reference cohorts. Results - Compared with the reference cohort, a distinctly larger proportion of the OA cohort had dispensed prescriptions for most types of analgesics, increasing exponentially each year prior to commencing non-pharmacological intervention. Since guideline publication, the proportion of the OA cohort having no dispensed prescription analgesics prior to non-pharmacological primary care intervention concordantly increased by 5.0% (95% CI 4.2-5.9). Furthermore, dispensed prescriptions concordantly decreased for non-selective NSAIDs -8.6% (CI -9.6 to -7.6), weak opioids -6.8% (CI -7.7 to -5.9), glucosamine -9.5% (CI -9.8 to -8.8). and hyaluronic acid -1.6% (CI -1.8 to -1.5) but discordantly increased for strong opioids 2.8% (CI 2.1-3.4) and glucocorticoid intra-articular injection for hip OA 2.1% (CI 1.0-3.1). Interpretation - In Sweden, dispensed prescription of analgesics commonly occurred before initiating non-pharmacological primary care interventions for OA but reduced modestly after guideline publication, which prioritizes non-pharmacological before pharmacological interventions. Additional modest improvements occurred in the stepped-care prioritization of analgesic prescription types. However, future strategies are required to curb an increase of strong opioids prescription for OA and glucocorticoid intra-articular injection for hip OA.

BACKGROUND CONTEXT: The development of muscle fat infiltration (MFI) in the neck muscles is associated with poor functional recovery following whiplash injury. Custom software and time-consuming manual segmentation of magnetic resonance imaging (MRI) is required for quantitative analysis and presents as a barrier for clinical translation. PURPOSE: The purpose of this work was to establish a qualitative MRI measure for MFI and evaluate its ability to differentiate between individuals with severe whiplash-associated disorder (WAD), mild or moderate WAD, and healthy controls. STUDY DESIGN/SETTING: This is a cross-sectional study. PATIENT SAMPLE: Thirty-one subjects with WAD and 31 age-and sex-matched controls were recruited from an ongoing randomized controlled trial. OUTCOME MEASURES: The cervical multifidus was visually identified and segmented into eighths in the axial fat/water images (C4-C7). Muscle fat infiltration was assessed on a visual scale: 0 for no or marginal MFI, 1 for light MFI, and 2 for distinct MFI. The participants with WAD were divided in two groups: mild or moderate and severe based on Neck Disability Index % scores. METHODS: The mean regional MFI was compared between the healthy controls and each of the WAD groups using the Mann-Whitney U test. Receiver operator characteristic (ROC) analyses were carried out to evaluate the validity of the qualitative method. RESULTS: Twenty (65%) patients had mild or moderate disability and 11 (35%) were considered severe. Inter- and intra-rater reliability was excellent when grading was averaged by level or when frequency of grade II was considered. Statistically significant differences (pamp;lt;.05) in regional MFI were particularly notable between the severe WAD group and healthy controls. The ROC curve, based on detection of distinct MFI, showed an area-under-the curve of 0.768 (95% confidence interval 0.59-0.94) for discrimination of WAD participants. CONCLUSIONS: These preliminary results suggest a qualitative MRI measure for MFI is reliable and valid, and may prove useful toward the classification of WAD in radiology practice. (C) 2017 Elsevier Inc. All rights reserved.

BACKGROUND amp; AIMS: Patients with ulcerative colitis (UC) have an increased risk of rectal cancer, therefore reconstruction with an ileal pouch-anal anastomosis (IPAA) generally is preferred to an ileorectal anastomosis (IRA) after subtotal colectomy. Similarly, completion proctectomy is recommended for patients with ileostomy and a diverted rectum, although this approach has been questioned because anti-inflammatory agents might reduce cancer risk. We performed a national cohort study in Sweden to assess the risk of rectal cancer in patients with UC who have an IRA, IPAA, or diverted rectum after subtotal colectomy.

METHODS: We collected data from the Swedish National Patient Register for a cohort of 5886 patients with UC who underwent subtotal colectomy with an IRA, IPAA, or diverted rectum from 1964 through 2010. Patients who developed rectal cancer were identified from the Swedish National Cancer Register. The risk of rectal cancer was compared between this cohort and the general population by standardized incidence ratio analysis.

RESULTS: Rectal cancer occurred in 20 of 1112 patients (1.8%) who received IRA, 1 of 1796 patients (0.06%) who received an IPAA, and 25 of 4358 patients (0.6%) with a diverted rectum. Standardized incidence ratios for rectal cancer were 8.7 in patients with an IRA, 0.4 in patients with an IPAA, and 3.8 in patients with a diverted rectum. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio, 6.12), and colonic severe dysplasia or cancer before subtotal colectomy in patients with a diverted rectum (hazard ratio, 3.67).

CONCLUSIONS: In an analysis of the Swedish National Patient Register, we found that the risk for rectal cancer after colectomy in patients with UC is low, in relative and absolute terms, after reconstruction with an IPAA. An IRA and diverted rectum are associated with an increased risk of rectal cancer, compared with the general population, but the absolute risk is low. Patients and their health care providers should consider these findings in making decisions to leave the rectum intact, perform completion proctectomy, or reconstruct the colon with an IRA or IPAA.

BACKGROUND: With a lifelong perspective, 12% of ulcerative colitis patients will need a colectomy. Further reconstruction via ileo-rectal anastomosis or pouch can be affected by patients' perspective of their quality of life after surgery.

AIM: To assess the function and quality of life after restorative procedures with either ileo-rectal anastomosis or ileal pouch-anal anastomosis in relation to the inflammatory activity on endoscopy and in biopsies.

METHOD: A total of 143 UC patients operated with subtotal colectomy and ileo-rectal anastomosis or pouches between 1992 and 2006 at Linköping University Hospital were invited to participate. Those who completed the validated questionnaires (Öresland score, SF-36, Short Health Scale) were offered an endoscopic evaluation including multiple biopsies. Associations between anorectal function and quality of life with type of restorative procedure and severity of endoscopic and histopathologic grading of inflammation were evaluated.

RESULTS: Some 77 (53.9%) eligible patients completed questionnaires, of these 68 (88.3%) underwent endoscopic evaluation after a median follow-up of 12.5 (range 3.5-19.4) years after restorative procedure. Patients with ileo-rectal anastomosis reported better overall Öresland score: median = 3 (IQR 2-5) for ileo-rectal anastomosis (n = 38) and 10 (IQR 5-15) for pouch patients (n = 39) (p < 0.001). Anorectal function (Öresland score) and endoscopic findings (Baron-Ginsberg score) were positively correlated in pouch patients (tau: 0.28, p = 0.006).

CONCLUSION: Patients operated with ileo-rectal anastomosis reported better continence compared to pouches. Minor differences were noted regarding the quality of life. Ileo-rectal anastomosis is a valid option for properly selected ulcerative colitis patients if strict postoperative endoscopic surveillance is carried out.

BackgroundWhereas the literature has demonstrated an acceptable safety profile of stapled anastomoses when compared to the hand-sewn alternative in open surgery, the choice of intestinal anastomosis using sutures or staples remains inadequately investigated in robotic surgery. The purpose of this study was to compare the surgical outcomes of both anastomotic techniques in robotic-assisted radical cystectomy.MethodsA retrospective analysis of patients with urinary bladder cancer undergoing cystectomy with urinary diversion and with ileo-ileal intestinal anastomosis at a single tertiary centre (2012–2018) was undertaken. The robotic operating time, hospital stay and GI complications were compared between the robotic-sewn (RS) and stapled anastomosis (SA) groups. The only difference between the groups was the anastomosis technique; the other technical steps during the operation were the same. Primary outcomes were GI complications; the secondary outcome was robotic operation time.ResultsThere were 155 patients, of which 112 (73%) were male. The median age was 71 years old. A surgical stapling device was used to create 66 (43%) separate anastomoses, while a robot-sewn method was employed in 89 (57%) anastomoses. There were no statistically significant differences in primary and secondary outcomes between RS and SA.ConclusionsCompared to stapled anastomosis, a robot-sewn ileo-ileal anastomosis may serve as an alternative and cost-saving approach. 

Objective To study how patients with urinary bladder cancer (UBC) with previous or concomitant other primary cancers (OPCs) were treated, and to investigate their prognosis. Patients And Methods Using nationwide population-based data in the Bladder Cancer Data Base Sweden (BladderBaSe), we analysed the probability of treatment with curative intent, and UBC-specific and overall survival (OS) in patients with UBC diagnosed in the period 1997-2014 with or without OPC. The analyses considered the patients characteristics, UBC tumour stage at diagnosis, and site of OPC. Results There were 38 689 patients, of which 9804 (25%) had OPCs. Those with synchronous OPCs more often had T2 and T3 tumours and clinically distant disease at diagnosis than those with UBC only. Patients with synchronous prostate cancer, female genital cancer and lower gastro-intestinal cancer were more often treated with curative intent than patients with UBC only. When models of survival were adjusted for age at diagnosis, marital status, education, year of diagnosis, Charlson Comorbidity Index and T-stage, UBC-specific survival was similar to patients with UBC only, but OS was lower for patients with synchronous OPC, explained mainly by deaths in OPC primaries with a bad prognosis. Conclusions OPC is common in patients with UBC. Treatment for UBC, after or in conjunction with an OPC, should not be neglected and carries just as high a probability of success as treatment in patients with UBC only. The needs of patients with UBC and OPC, and optimisation of their treatment considering their complicated disease trajectory are important areas of research.

Purpose: To investigate the clinical management and outcome of patients with muscle-invasive bladder cancer with clinical lymph node involvement, using longitudinal nationwide population-based data. Methods: In the Bladder Cancer Data Base Sweden (BladderBaSe), treatment and survival in patients with urinary bladder cancer clinical stage T2-T4 N + M0 diagnosed between 1997 and 2014 was investigated. Patients characteristics were studied in relation to TNM classification, curative or palliative treatment, cancer-specific (CSS) and overall survival (OS). Age at diagnosis was categorised as amp;lt;= 60, 61-70, 71-80 and amp;gt;80 years, and time periods were stratified as follows: 1997-2001, 2002-2005, 2006-2010 and 2011-2014. Results: There were 786 patients (72% males) with a median age of 71 years (interquartile range = 64-79 years). The proportion of patients with high comorbidity increased over time. Despite similar low comorbidity, curative treatment was given to 44% and to 70% of those in older (amp;gt;70 years) and younger age groups, respectively. Curative treatment decreased over time, but chemotherapy and cystectomy increased to 25% during the last time period. Patients with curative treatment had better survival compared to those with palliative treatment, both regarding CSS and OS in the whole cohort and in all age groups. Conclusions: The low proportion of older patients undergoing treatment with curative intent, despite no or limited comorbidity, indicates missed chances of treatment with curative intent. The reasons for an overall decrease in curative treatment over time need to be analysed and the challenge of coping with an increasing proportion of node-positive patients with clinically significant comorbidity needs to be met.

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with &gt;10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.

Women with dense breast tissue on mammography are at higher risk of developing breast cancer but the underlying mechanisms are not well understood. De-regulation of microRNAs (miRNAs) has been associated with the onset of breast cancer. miRNAs in the extracellular space participate in the regulation of the local tissue microenvironment. Here, we recruited 39 healthy postmenopausal women attending their mammography-screen that were assessed having extreme dense or entirely fatty breasts (nondense). Microdialysis was performed in breast tissue and a reference catheter was inserted in abdominal subcutaneous fat for local sampling of extracellular compounds. Three miRNAs, associated with tumor suppression, miR-193b, miR-365a, and miR-452 were significantly down-regulated in dense breast tissue compared with nondense breast tissue. In addition, miR-452 exhibited significant negative correlations with several pro-inflammatory cytokines in vivo, which was confirmed in vitro by overexpression of miR-452 in breast cancer cells. No differences were found of miR-21, -29a, -30c, 146a, -148a, -203, or -451 in breast tissue and no miRs were different in plasma. Extracellular miRNAs may be among factors that should be included in studies of novel prevention strategies for breast cancer.

Extracellular circulating microRNAs (miRNAs) have been suggested to be biomarkers for disease monitoring but data are inconsistent, one reason being that blood miRNA is of heterogeneous origin. Here, we sampled extracellular microRNAs locally in situ using microdialysis. Three different cohorts of women were included; postmenopausal women with ongoing breast cancer investigated within the cancer and in normal adjacent breast tissue, postmenopausal women investigated in their normal healthy breast and subcutaneous fat before and after six weeks of tamoxifen therapy, premenopausal women during the menstrual cycle. Samples were initially screened using TaqMan array cards with subsequently absolute quantification. 124 miRNA were expressed in microdialysates. After absolute quantifications extracellular miRNA-21 was found to be significantly increased in breast cancer. In addition, the levels were significantly higher in pre-menopausal breast tissue compared with postmenopausal. In breast tissue of pre-menopausal women miRNA-21 exhibited a cyclic variation during the menstrual cycle and in postmenopausal women six weeks of tamoxifen treatment decreased miRNA-21 suggesting that this miRNA may be important for breast carcinogenesis. None of these changes were found in plasma or microdialysates from subcutaneous fat. Our data revealed tissue specific changes of extracellular circulating miRNAs that would be otherwise unraveled using blood samples.

High mammographic density, associated with increased tissue stiffness, is a strong risk factor for breast cancer per se . In postmenopausal women there is no differences in the occurrence of ductal carcinoma in situ (DCIS) depending on breast density. Preliminary data suggest that dense breast tissue is associated with a pro -inflammatory microenvironment including infiltrating monocytes. However, the underlying mechanism(s) remains largely unknown. A major roadblock to understanding this risk factor is the lack of relevant in vitro models. A biologically relevant 3D model with tunable stiffness was developed by cross -linking hyaluronic acid. Breast cancer cells were cultured with and without freshly isolated human monocytes. In a unique clinical setting, extracellular proteins were sampled using microdialysis in situ from women with various breast densities. We show that tissue stiffness resembling high mammographic density increases the attachment of monocytes to the cancer cells, increase the expression of adhesion molecules and epithelia-mesenchymal-transition proteins in estrogen receptor (ER) positive breast cancer. Increased tissue stiffness results in increased secretion of similar pro-tumorigenic proteins as those found in human dense breast tissue including inflammatory cytokines, proteases, and growth factors. ER negative breast cancer cells were mostly unaffected suggesting that diverse cancer cell phenotypes may respond differently to tissue stiffness. We introduce a biological relevant model with tunable stiffness that resembles the densities found in normal breast tissue in women. The model will be key for further mechanistic studies. Additionally, our data revealed several pro-tumorigenic pathways that may be exploited for prevention and therapy against breast cancer.

The inflammatory microenvironment affects breast cancer progression. Proteins that govern the inflammatory response are secreted into the extracellular space, but this compartment still needs to be characterized in human breast tissues in vivo. Dense breast tissue is a major risk factor for breast cancer by yet unknown mechanisms and no non-toxic prevention for these patients exists. Here, we used the minimal invasive technique of microdialysis for sampling of extracellular proteins in live tissues in situ in breast cancers of women before surgery and in healthy women having dense or non-dense breast tissue on mammography. Proteins were profiled using a proximity extension assay. Out of the 32 proteins assessed, 26 exhibited similar profiles in breast cancers and dense breast tissues; CCL-4, -7, -8, -11, -15, -16, -22, -23, and -25, CXCL-5, -8, -9, -16 as well as sIL-6R, IL-18, vascular endothelial growth factor, TGF-a, fibroblast growth factor 19, matrix metalloproteinase (MMP)-1, -2, -3, and urokinase-type plasminogen activator were all increased, whereas CCL-3, CX3CL1, hepatocyte growth factor, and MMP-9 were unaltered in the two tissues. CCL-19 and -24, CXCL-1 and -10, and IL-6 were increased in dense breast tissue only, whereas IL-18BP was increased in breast cancer only. Our results provide novel insights in the inflammatory microenvironment in human breast cancer in situ and define potential novel therapeutic targets. Additionally, we show previously unrecognized similarities of the pro-inflammatory microenvironment in dense breast tissue and breast cancer in vivo suggesting that anti-inflammatory breast cancer prevention trials for women with dense breast tissue may be feasible.

Metabolic reprogramming is a hallmark of cancer. Nutrient availability in the tissue microenvironment determines cellular events and may play a role in breast carcinogenesis. High mammographic density is an independent risk factor for breast cancer. Whether nutrient availability differs in normal breast tissues with various densities is unknown. Therefore we investigated whether breast tissues with various densities exhibited differences in nutrient availability. Healthy postmenopausal women from the regular mammographic screening program who had either predominantly fatty breast tissue (nondense), n = 18, or extremely dense breast tissue (dense), n = 20, were included. Microdialysis was performed for the in vivo sampling of amino acids (AAs), analyzed by ultra-high performance liquid chromatography with tandem mass spectroscopy, glucose, lactate and vascular endothelial growth factor (VEGF) in breast tissues and, as a control, in abdominal subcutaneous (s.c.) fat. We found that dense breast tissue exhibited significantly increased levels of 20 proteinogenic AAs and that 18 of these AAs correlated significantly with VEGF. No differences were found in the s.c. fat, except for one AA, suggesting tissue-specific alterations in the breast. Glucose and lactate were unaltered. Our findings provide novel insights into the biology of dense breast tissue that may be explored for breast cancer prevention strategies.

Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.

Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.

The results of a randomised trial with bisphosphonate-coated dental implants have been reported previously. Each patient received one coated and one uncoated implant in a double-blind split-mouth design study. After 6 months of osseointegration, resonance frequency analysis indicated better fixation of the coated implants. Reduced marginal bone resorption was also shown. However, it was not known whether the advantage of the bisphosphonate coating would persist over time. The radiographic results at 5 years after implant installation are reported herein. A blinded investigator measured marginal resorption on fresh radiographs obtained for 14 of the 16 patients (two had died) and compared these with the post-implantation images. Non-parametric statistics were used. All implants functioned well. The median marginal bone loss for control implants was found to be 0.70 mm, which is less than usually reported in the literature. The bisphosphonate-coated implants showed even less resorption (median 0.20 mm). The median difference within each pair of implants after 5 years of use was 0.34 mm (95% confidence interval 0.00-0.75 mm; P = 0.04). The present data suggest that bisphosphonate-coated implants enable prolonged preservation of the marginal bone.

OBJECTIVES: The objective of this clinical study was to evaluate the effect of a bisphosphonate coating on a titanium implant on the implant stability quotient (ISQ) and the radiographic marginal bone levels at implants during early healing (2-8 weeks).

MATERIALS AND METHODS: In a randomized double-blind trial with internal controls, 16 patients received a dental implant coated with zoledronate and one uncoated implant as a control. The coated and uncoated implants which were visually indistinguishable were bone level titanium implants with a moderately rough surface and a microthreaded neck. ISQ values were obtained at insertion and at 2, 4, 6, and 8 weeks. Radiographs were obtained at insertion and at 8 weeks. The primary outcome was the difference in ISQ values between the coated implants and the control implants at 4 and 6 weeks, corrected for insertion values. The secondary outcome was loss of marginal bone level from insertion to 8 weeks.

RESULTS: Implant stability quotient values remained largely constant over the 8 weeks, and there was no significant difference between coated and uncoated implants at any time point. There was 0.12 (SD 0.10) mm marginal bone loss at the control implants and 0.04 (SD 0.08) mm at the coated implants. The difference was 0.17 mm; SD 0.14; p < 0.006). On blind qualitative scoring, 13 of the 15 control implants and two of 15 coated implants showed small marginal bone defects (p = 0.003).

CONCLUSIONS: There were no statistically significant differences observed in ISQ values between the coated and uncoated implants during the early healing. There was less marginal bone loss at the coated implants.

ObjectivesTo perform a descriptive analysis of a series of patients with recurrent macroscopic haematuria after a primary standard evaluation including computed tomography urography (CTU) and cystoscopy negative for urinary bladder cancer (UBC) and upper tract urothelial cancer (UTUC) and to identify potential factors associated with occurrence of recurrent macroscopic haematuria.MethodsAll patients older than 50 years who underwent urological investigation for macroscopic haematuria with both cystoscopy and CTU 2015-2017 were retrospectively reviewed. A descriptive analysis of the primary and later investigations for recurrent macroscopic haematuria was performed. To investigate the association between explanatory variables and the occurrence of recurrent macroscopic haematuria, a Poisson regression analysis was performed.ResultsA total of 1395 eligible individuals with primary standard investigation negative for UBC and UTUC were included. During a median follow-up of 6.2 (IQR 5.3-7) years, 248 (18%) patients had recurrent macroscopic haematuria, of whom six patients were diagnosed with UBC, two with prostate cancer, one with renal cell carcinoma and one had a suspected UTUC at the repeated investigation. Within 3 years, 148 patients (11%) experienced recurrent macroscopic haematuria, of whom two patients were diagnosed with low-grade UBC (TaG1-2), one with T2G3 UBC and one with low-risk prostate cancer. The presence of an indwelling catheter, use of antithrombotic medication, pathological findings at CTU or cystoscopy or history of pelvic radiotherapy were all statistically significant independent predictors for increased risk for recurrent macroscopic haematuria.ConclusionIn the case of recurrent macroscopic haematuria within 3 years of primary standard evaluation for urinary tract cancer, there was a low risk of later urological malignancies in patients initially negative for UBC and UTUC. Therefore, waiting 3 years before conducting another complete investigation in cases of recurrent macroscopic haematuria might be appropriate.

Objective: To evaluate whether artificial intelligence (AI) based automatic image analysis utilising convolutional neural networks (CNNs) can be used to evaluate computed tomography urography (CTU) for the presence of urinary bladder cancer (UBC) in patients with macroscopic hematuria. Methods: Our study included patients who had undergone evaluation for macroscopic hematuria. A CNN-based AI model was trained and validated on the CTUs included in the study on a dedicated research platform (Recomia.org). Sensitivity and specificity were calculated to assess the performance of the AI model. Cystoscopy findings were used as the reference method. Results: The training cohort comprised a total of 530 patients. Following the optimisation process, we developed the last version of our AI model. Subsequently, we utilised the model in the validation cohort which included an additional 400 patients (including 239 patients with UBC). The AI model had a sensitivity of 0.83 (95% confidence intervals [CI], 0.76-0.89), specificity of 0.76 (95% CI 0.67-0.84), and a negative predictive value (NPV) of 0.97 (95% CI 0.95-0.98). The majority of tumours in the false negative group (n = 24) were solitary (67%) and smaller than 1 cm (50%), with the majority of patients having cTaG1-2 (71%). Conclusions: We developed and tested an AI model for automatic image analysis of CTUs to detect UBC in patients with macroscopic hematuria. This model showed promising results with a high detection rate and excessive NPV. Further developments could lead to a decreased need for invasive investigations and prioritising patients with serious tumours.

Background To evaluate the diagnostic accuracy of computed tomography-urography (CTU) to rule out urinary bladder cancer (UBC) and whether patients thereby could omit cystoscopy. Methods All patients evaluated for macroscopic hematuria with CTU with cortico-medullary phase (CMP) and cystoscopy at our institute between 1(st) November 2016 and 31(st) December 2019 were included. From this study cohort a study group consisting of all UBC patients and a control group of 113 patients randomly selected from all patients in the study cohort without UBC. Two radiologists blinded to all clinical data reviewed the CTUs independently. CTUs were categorized as positive, negative or indeterminate. Diagnostic accuracy and proportion of potential omittable cystoscopies were calculated for the study cohort by generalizing the results from the study group. Results The study cohort consisted of 2195 patients, 297 of which were in the study group (UBC group, n = 207 and control group, n = 90). Inter-rater reliability was high (kappa 0.84). Evaluation of CTUs showed that 174 patients were assesessed as positive (showing UBC), 46 patients as indeterminate (not showing UBC but with limited quality of CTU), and 77 patients as negative (not showing UBC with good quality of CTU). False negative rate was 0.07 (95%, CI 0.04-0.12), false positive rate was 0.01 (95% CI 0.0-0.07) and negative predictive value was 0.99 (95% CI 0.92-1.0). The area under the curve was 0.93 (95% CI 0.90-0.96). Only 2.9% (3/102) with high-risk tumors and 11% (12/105) with low- or intermediate-risk tumors had a false negative CTU. Cystoscopy could potentially have been omitted in 57% (1260/2195) of all evaluations. Conclusions CTU with CMP can exclude UBC with high accuracy. In case of negative CTU, it might be reasonable to omit cystoscopy, but future confirmative studies with possibly refined technique are needed.

Objectives To compare time intervals to diagnosis and treatment, tumor characteristics, and management in patients with primary urinary bladder cancer, diagnosed before and after the implementation of a standardized care pathway (SCP) in Sweden. Materials and methods Data from the Swedish National Register of Urinary Bladder Cancer was studied before (2011-2015) and after (2016-2019) SCP. Data about time from referral to transurethral resection of bladder tumor (TURBT), patients and tumor characteristics, and management were analyzed. Subgroup analyses were performed for cT1 and cT2-4 tumors. Results Out of 26,795 patients, median time to TURBT decreased from 37 to 27 days after the implementation of SCP. While the proportion of cT2-T4 tumors decreased slightly (22-21%, p &lt; 0.001), this change was not stable over time and the proportions cN + and cM1 remained unchanged. In the subgroups with cT1 and cT2-4 tumors, the median time to TURBT decreased and the proportions of patients discussed at a multidisciplinary team conference (MDTC) increased after SCP. In neither of these subgroups was a change in the proportions of cN + and cM1 observed, while treatment according to guidelines increased after SCP in the cT1 group. Conclusion After the implementation of SCP, time from referral to TURBT decreased and the proportion of patients discussed at MDTC increased, although not at the levels recommended by guidelines. Thus, our findings point to the need for measures to increase adherence to SCP recommendations and to guidelines.

Objectives To evaluate whether the implementation of standardized care pathway (SCP) for patients with suspected urinary bladder cancer (UBC) was associated with changes in tumour characteristics. Additionally, the study aims to explore whether there was a shift in the selection of patients prioritized for immediate evaluation regarding suspicion of UBC.Materials and Methods The study included all patients diagnosed with UBC in the NU Hospital Group between 2010 and 2019. To evaluate changes associated with SCP, patients were divided into two diagnostic time periods, either before (2010-2015) or during (2016-2019) the implementation of the SCP. To evaluate which patients were prioritized for prompt evaluation within 13 days, logistic regression analysis was performed on all patients before and during SCP.Results Median time to transurethral resection of the tumour in urinary bladder (TURBT) decreased from 29 days (interquartile range [IQR] 16-48) before SCP to 12 days (IQR 8-19) during SCP (p &lt; 0.001) with a clear break from 2016. The proportion of cT2 + tumours decreased during SCP from 26% to 20% (p = 0.035). In addition, tumours detected during SCP were smaller (p = 0.023), but with more multiple lesions (p = 0.055) and G3 tumours (p = 0.007). During SCP, there was no statistically significant difference between the groups of patients with TURBT within or after 13 days. In contrast, before SCP, a majority of the patients treated within 13 days had advanced tumours and were admitted from the emergency ward.Conclusions The implementation of an SCP for suspected UBC was associated with improved tumour characteristics. Interestingly, during SCP, there were no substantial differences in patients' or tumours' characteristics among those who underwent TURBT within or after 13 days. This indicates that the 13-day timeframe for TURBT might be prolonged, especially in less urgent cases in order to facilitate a prioritization of more severe cases with treatable disease.

Background and objective: Our objective was to assess whether GeneXpert BC can be used as a triage test to exclude urinary bladder cancer (UBC) for patients with macroscopic hematuria. Methods: We conducted a prospective study that include consecutive patients being evaluated for macroscopic hematuria between September 2020 and December 2022. Before cystoscopy, study participants provided a voided urine sample for GeneXpert BC analysis according to a case-control design with an emphasis on UBC detection. Descriptive statistics are reported for patient and tumor characteristics. To assess the diagnostic accuracy of the GeneXpert BC test, the sensitivity, specificity, and negative predictive value (NPV) were calculated, using the histopathologically proven UBC as the ground truth. Key findings and limitations: In total, 1505 subjects presenting with macroscopic hematuria were enrolled in the study. After randomization and exclusions, GeneXpert BC testing was carried out for 312 participants. Of these, 151 patients from the case arm had UBC, 122 patients from the control arm (random 10%) were negative for UBC, and 39 patients from the case arm did not have malignancy. Using a predefined linear discriminant analysis (LDA) threshold of &gt;= 0.22, the test had sensitivity of 0.94 (95% confidence interval [CI] 0.90-0.97), specificity of 0.52 (95% CI 0.42-0.59), and NPV of 0.99 (95% CI 0.98-0.99). All false-negative tumors were of low grade (Ta grade 1-2). Cystoscopy and computed tomography urography could have been omitted in 44% of the patients with macroscopic hematuria. At a secondary LDA threshold of &gt;= 0.45, the test had sensitivity of 0.79 (95% CI 0.73-0.86), specificity of 0.83 (95% CI 0.76-0.89), and NPV of 0.97 (95% CI 0.96- 0.98).

This article is the second in a series of two publications relating to the European Crohns and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohns disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohns disease and an update of previous guidelines.

Background and Aims: Diagnosis and management of inflammatory bowel diseases [IBD] requires a lifelong multidisciplinary approach.The quality of medical reporting is crucial in this context.The present topical review addresses the need for optimised reporting in endoscopy, surgery, and histopathology. Methods: A consensus expert panel consisting of gastroenterologists, surgeons, and pathologists, convened by the European Crohns and Colitis Organisation, performed a systematic literature review. The following topics were covered: in endoscopy: [i] general IBD endoscopy; [ii] disease activity and surveillance; [iii] endoscopy treatment in IBD; in surgery: [iv] medical history with surgical relevance, surgical indication, and strategy; [v] operative approach; [vi] intraoperative disease description; [vii] operative steps; in pathology: [viii] macroscopic assessment and interpretation of resection specimens; [ix] IBD histology, including biopsies, surgical resections, and neoplasia; [x] IBD histology conclusion and report. Statements were developed using a Delphi methodology incorporating two consecutive rounds. Current practice positions were set when &gt;= 80% of participants agreed on a recommendation. Results: Thirty practice positions established a standard terminology for optimal reporting in endoscopy, surgery, and histopathology. Assessment of disease activity, surveillance recommendations, advice to surgeons for operative indication and strategies, including margins and extent of resection, and diagnostic criteria of IBD, as well as guidance for the interpretation of dysplasia and cancer, were handled. A standardised report including a core set of items to include in each specialty report, was defined. Conclusions: Interdisciplinary high-quality care requires thorough and standardised reporting across specialties.This topical review offers an actionable framework and practice recommendations to optimise reporting in endoscopy, surgery, and histopathology.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO Guidelines.

n/a

Post-traumatic and post-operative stiffness of the elbow joint is relatively common and may in pronounced cases markedly interfere with normal upper extremity function.Soft-tissue contractures and heterotopic bone formation are two major causes of limited movement.Extensive recent research has elucidated many of the pathways contributing to these conditions, but the exact mechanisms are still unknown.In the early phase of soft-tissue contractures conservative treatment may be valuable, but in longstanding cases operative treatment is often necessary.Several different options are available depending on the severity of the condition and the underlying offending structures. Surgical treatment may allow significant gains in movement but rarely complete restoration, and complications are not uncommon.The following presentation reviews the recent literature on pathomechanisms and treatment alternatives. Cite this article: EFORT Open Rev 2018;3 DOI: 10.1302/2058-5241.3.170062.

The gleno-humeral joint is by far the most mobile in the human body but also afflicted by dislocations, predominantly anterior. Surgical stabilisation is often successful but failures not uncommon. The following review describes potential causes of failure and highlights the need of adapting surgical methods to pathomorphology.

Background: The majority of simple elbow dislocations (no associated fractures) can be treated nonoperatively with a short period of immobilization followed by guided aftercare. This case series describes the soft tissue injuries in a rare subset of patients in whom the elbow redislocated despite adequate immobilization. Methods: During a 6-year period, 8 patients were identified. They were all treated with reduction and casting in 90 degrees of flexion or more. At 1 week of follow-up, redislocation had occurred in all patients and open soft tissue repair was performed. The injuries were documented and the patients were followed up clinically and with radiographs. Results: Extensive soft tissue injuries, including both collateral ligament injuries and muscle origin avulsions from either or both sides, were found in all patients. The functional result at follow-up was satisfactory in all patients. Conclusion: Vast soft tissue injuries including both collateral ligaments and muscle origins should be expected in the event of early severe instability of a dislocated elbow joint. (C) 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

Background

Fruit has since long been advocated as a healthy source of many nutrients, however, the high content of sugars in fruit might be a concern.

Objectives

To study effects of an increased fruit intake compared with similar amount of extra calories from nuts in humans.

Methods

Thirty healthy non-obese participants were randomized to either supplement the diet with fruits or nuts, each at +7 kcal/kg bodyweight/day for two months. Major endpoints were change of hepatic fat content (HFC, by magnetic resonance imaging, MRI), basal metabolic rate (BMR, with indirect calorimetry) and cardiovascular risk markers.

Results

Weight gain was numerically similar in both groups although only statistically significant in the group randomized to nuts (fruit: from 22.15±1.61 kg/m2 to 22.30±1.7 kg/m2, p = 0.24 nuts: from 22.54±2.26 kg/m2 to 22.73±2.28 kg/m2, p = 0.045). On the other hand BMR increased in the nut group only (p = 0.028). Only the nut group reported a net increase of calories (from 2519±721 kcal/day to 2763±595 kcal/day, p = 0.035) according to 3-day food registrations. Despite an almost three-fold reported increased fructose-intake in the fruit group (from 9.1±6.0 gram/day to 25.6±9.6 gram/day, p<0.0001, nuts: from 12.4±5.7 gram/day to 6.5±5.3 gram/day, p = 0.007) there was no change of HFC. The numerical increase in fasting insulin was statistical significant only in the fruit group (from 7.73±3.1 pmol/l to 8.81±2.9 pmol/l, p = 0.018, nuts: from 7.29±2.9 pmol/l to 8.62±3.0 pmol/l, p = 0.14). Levels of vitamin C increased in both groups while α-tocopherol/cholesterol-ratio increased only in the fruit group.

Conclusions

Although BMR increased in the nut-group only this was not linked with differences in weight gain between groups which potentially could be explained by the lack of reported net caloric increase in the fruit group. In healthy non-obese individuals an increased fruit intake seems safe from cardiovascular risk perspective, including measurement of HFC by MRI.

Objective

To analyze associations of maternal, fetal, gestational, and perinatal factors with necrotizing enterocolitis in a matched case-control study based on routinely collected, nationwide register data.

Study design

All infants born in 1987 through 2009 with a diagnosis of necrotizing enterocolitis in any of the Swedish national health care registers were identified. For each case up to 6 controls, matched for birth year and gestational age, were selected. The resulting study population consisted of 720 cases and 3,567 controls. Information on socioeconomic data about the mother, maternal morbidity, pregnancy related diagnoses, perinatal diagnoses of the infant, and procedures in the perinatal period, was obtained for all cases and controls and analyzed with univariable and multivariable logistic regressions for the whole study population as well as for subgroups according to gestational age.

Results

In the study population as a whole, we found independent positive associations with necrotizing enterocolitis for isoimmunization, fetal distress, cesarean section, neonatal bacterial infection including sepsis, erythrocyte transfusion, persistent ductus arteriosus, cardiac malformation, gastrointestinal malformation, and chromosomal abnormality. Negative associations were found for maternal weight, preeclampsia, maternal urinary infection, premature rupture of the membranes, and birthweight. Different patterns of associations were seen in the subgroups of different gestational age.

Conclusion

With some interesting exceptions, especially in negative associations, the results of this large, population based study, are in keeping with earlier studies. Although restrained by the limitations of register data, the findings mirror conceivable pathophysiological processes and underline that NEC is a multifactorial disease.

Objective To explore the relative importance of risk factors, treatments, and blood counts for the occurrence of vascular complications and their impact on life expectancy in essential thrombocythemia (ET) and polycythemia vera (PV). Methods Nested case-control study within the Swedish MPN registry. From a cohort of 922 ET patients and 763 PV patients, 71 ET and 81 PV cases with vascular complications were compared with matched controls. Results Incidence of vascular complications was 2.0 and 3.4 events per 100 patient-years in ET and PV, respectively. At diagnosis, no significant risk factor differences were observed between cases and controls in neither of the diseases. At the time of vascular event, ET complication cases did not differ significantly from controls but in PV, cases had significantly higher WBCs and were to a lesser extent treated with anti-thrombotic and cytoreductive therapy. Life expectancy was significantly decreased in both ET and PV cases compared with controls. Conclusions The risk of vascular complications is high in both ET and PV, and these complications have a considerable impact on life expectancy. The protective effect of anti-thrombotic and cytoreductive therapy for vascular complications in PV underscores the importance of avoiding undertreatment.

Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturers recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.

Knowledge of concomitant autoimmune liver diseases (AILD) is more detailed in primary Sjogrens syndrome (pSS) compared to systemic lupus erythematosus (SLE). Herein, the prevalence of autoantibodies associated with autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) was investigated in stored sera from patients with SLE (n = 280) and pSS (n = 114). Antibodies against mitochondria (AMA), liver-kidney microsomal (LKM) antigen, smooth muscle (SMA) and anti-nuclear antibodies (ANA) were analysed with immunofluorescence microscopy. In addition, AILD-associated autoantibodies were tested with immunoblot. Prior to sampling, eight SLE (2 center dot 9%) and three pSS (2 center dot 6%) cases were diagnosed with AILD. Among SLE-cases without known AILD (n = 272), 26 (9 center dot 6%) had PBC-associated autoantibodies, 15 (5 center dot 5%) AIH-associated autoantibodies (excluding ANA) and one serological overlap. Most subjects with PBC-associated autoantibodies had liver enzymes within reference limits (22 of 27, 81%) or mild laboratory cholestasis (two of 27, 7 center dot 4%), while one fulfilled the diagnostic PBC-criteria. AMA-M2 detected by immunoblot was the most common PBC-associated autoantibody in SLE (20 of 272, 7 center dot 4%). The prevalence of SMA (4 center dot 4%) was comparable with a healthy reference population, but associated with elevated liver enzymes in four of 12 (25%), none meeting AIH-criteria. The patient with combined AIH/PBC-serology had liver enzymes within reference limits. Among pSS cases without known AILD (n = 111), nine (8 center dot 1%) had PBC-associated, 12 (10 center dot 8%) AIH-associated autoantibodies and two overlapped. PBC-associated autoantibodies were found as frequently in SLE as in pSS but were, with few exceptions, not associated with laboratory signs of liver disease. Overall, AILD-associated autoantibodies were predominantly detected by immunoblot and no significant difference in liver enzymes was found between AILD autoantibody-negative and -positive patients.

Background and Objective: Brachytherapy is a form of radiation therapy using sealed radiation sources inserted within or in the vicinity of the tumor of, e.g., gynecological, prostate or head and neck cancers. Accurate dose calculation is a crucial part of the treatment planning. Several reviews have called for clinical software with model-based algorithms that better take into account the effects of patient individual distribution of tissues, source-channel and shielding attenuation than the commonly employed TG-43 formalism which simply map homogeneous water dose distributions onto the patient. In this paper we give a comprehensive and thorough derivation of such an algorithm based on collapsed cone point-kernel superposition, and describe details of its implementation into a commercial treatment planning system for clinical use. Methods: A brachytherapy version of the collapsed-cone algorithm using analytical raytraces of the primary photon radiation followed by successive scattering dose calculation for once and multiply scattered photons is described in detail, including derivation of the corresponding set of recursive equations for energy transport along cone axes/transport lines and the coupling to clinical source modeling. Specific implementation issues for setting up of the calculation grid, handling of intravoxel gradients and voxels partly containing non patient applicator material are given. Results: Sample runs for two clinical cases are shown, one being a gynecological application with a tungsten-shielded applicator and one a breast implant. These two cases demonstrate the impact of improved dose calculation versus TG-43 formalism. Conclusions: Use of model-based dose calculation algorithms for brachytherapy taking the three-dimensional treatment geometry into account increases the dosimetric accuracy in planning and follow up of treatments. The comprehensive description and derivations provided gives a rigid background for further clinical, educational and research applications. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to reduce hepatic fat content in patients with primary nonalcoholic fatty liver disease (NAFLD); however, its effect in patients with human immunodeficiency virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD and lipodystrophy (ARRIVE) trial was a double-blind, randomized, investigator-initiated, placebo-controlled trial to test the efficacy of 12 weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty patients with HIV-associated NAFLD, defined by magnetic resonance imaging (MRI)-proton density fat fraction (PDFF) amp;gt;= 5%, were randomized to receive either aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized regions of interest. Secondary endpoints included changes in liver stiffness using magnetic resonance elastography (MRE) and vibration-controlled transient elastography (VCTE), and exploratory endpoints included changes in total-body fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI, and cardiac MRI. The mean (+/- standard deviation) of age and body mass index were 48.2 +/- 10.3 years and 30.7 +/- 4.6 kg/m(2), respectively. There was no difference in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%, P = 0.26). There was no difference in the relative decline in mean MRI-PDFF between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were no differences in MRE-derived and VCTE-derived liver stiffness and whole-body (fat and muscle) composition analysis by MRI or DXA. Compared to baseline, end-of-treatment aminotransferases were lower in the aramchol group but not in the placebo arm. There were no significant adverse events. Conclusion: Aramchol, over a 12-week period, did not reduce hepatic fat or change body fat and muscle composition by using MRI-based assessment in patients with HIV-associated NAFLD (clinicaltrials.gov ID:NCT02684591).

Background & aims: Long-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.

Methods: We conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.

Results: MALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2-8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).

Conclusions: This study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.

Impact and implications: Several implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.

Background and purpose: To investigate the dose-response relation between the dose to the vagina and the patient-reported symptom absence of vaginal elasticity and how time to follow-up influences this relation. Material and methods: The study included 78 long-term gynecological cancer survivors treated between 1991 and 2003 with external beam radiation therapy. Of those, 24 experienced absence of vaginal elasticity. A normal tissue complication model is introduced that takes into account the influence of time to follow-up on the dose-response relation and the patients age. The best estimates of the dose-response parameters were calculated using Probit, Probit-Relative Seriality (RS) and Probit-time models. Log likelihood (LL) values and the Akaike Information Criterion (AIC) were used to evaluate the model fit. Results: The dose-response parameters for absence of vaginal elasticity according to the Probit and Probit-time models with the 68% Confidence Intervals (CI) were: LL = 39.8, D-50 = 49.7 (47.2-52.4) Gy, gamma(50) =1.40 (1.12-1.70) and LL = 37.4, D-50 = 46.9 (43.5-50.9) Gy, gamma(50) = 1.81 (1.17-2.51) respectively. Conclusions: The proposed model, which describes the influence of time to follow-up on the dose response relation, fits our data best. Our data indicate that the steepness of the dose-response curve of the dose to the vagina and the symptom absence of vaginal elasticity increases with time to follow-up, while D-50 decreases. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Introduction

Dual antiplatelet therapy (DAPT), including potent P2Y12 inhibition after ST-elevation myocardial infarction (STEMI) is recommended in clinical guidelines. However, bleeding complications are common, and associated with worse outcomes. The aim of this study was to assess incidence of bleeding events with a clopidogrel-based compared to a ticagrelor-based DAPT strategy, in a real world population. Secondary aims were to assess ischemic complications and mortality.

Methods and Results

We identified 330 consecutive STEMI patients with a clopidogrel-based and 330 with a ticagrelor-based DAPT strategy. Patientś medical records were searched for bleeding and ischemic complications, over 6 months follow-up.

The two groups were well balanced in baseline characteristics, age (69 years inboth groups), sex (31% vs 32% females), history of diabetes (19% vs 21%), hypertension (43% in both) and MI (17% vs 15%). There was no difference in CRUSADE bleeding score (28 vs 29). After discharge, there were more than twice as many bleeding events with a ticagrelor-based compared with a clopidogrel-based strategy (13.3% vs. 6.5%, p = 0.005). Bleeding events included significantly more severe bleeding complications (TIMI major/minor [5.8 vs 1.0, p = 0.001]) during the ticagrelor-based period. There was no significant difference in the composite of death, MI or stroke (7.8% vs 7.1%, p = 0.76).

Conclusions

In this observational study, a ticagrelor-based DAPT strategy was associated with significantly more bleeding complications, without any significant change in death, MI or stroke. Larger studies are needed to determine whether bleeding complications off-sets benefits with a more potent DAPT strategy in older and more comorbid real-life patients.

Objectives It remains uncertain which embolization material is best for portal vein embolization (PVE). We investigated the various materials for effectiveness in inducing future liver remnant (FLR) hypertrophy, technical and growth success rates, and complication and resection rates. Methods A systematic review from 1998 to 2019 on embolization materials for PVE was performed on Pubmed, Embase, and Cochrane. FLR growth between the two most commonly used materials was compared in a random effects meta-analysis. In a separate analysis using local data (n = 52), n-butyl cyanoacrylate (NBCA) was compared with microparticles regarding costs, radiation dose, and procedure time. Results In total, 2896 patients, 61.0 +/- 4.0 years of age and 65% male, from 51 papers were included in the analysis. In 61% of the patients, either NBCA or microparticles were used for embolization. The remaining were treated with ethanol, gelfoam, or sclerosing agents. The FLR growth with NBCA was 49.1% +/- 29.7 compared to 42.2% +/- 40 with microparticles (p = 0.037). The growth success rate with NBCA vs microparticles was 95.3% vs 90.7% respectively (p &lt; 0.001). There were no differences in major complications between NBCA and microparticles. In the local analysis, NBCA (n = 41) entailed shorter procedure time and reduced fluoroscopy time (p &lt; 0.001), lower radiation exposure (p &lt; 0.01), and lower material costs (p &lt; 0.0001) than microparticles (n = 11). Conclusion PVE with NBCA seems to be the best choice when combining growth of the FLR, procedure time, radiation exposure, and costs.

The choriocapillaris is an exceptionally high density, two-dimensional, sheet-like capillary network, characterized by the highest exchange rate of nutrients for waste products per area in the organism. These unique morphological and physiological features are critical for supporting the extreme metabolic requirements of the outer retina needed for vision. The developmental mechanisms and processes responsible for generating this unique vascular network remain, however, poorly understood. Here we take advantage of the zebrafish as a model organism for gaining novel insights into the cellular dynamics and molecular signaling mechanisms involved in the development of the choriocapillaris. We show for the first time that zebrafish have a choriocapillaris highly similar to that in mammals, and that it is initially formed by a novel process of synchronized vasculogenesis occurring simultaneously across the entire outer retina. This initial vascular network expands by un-inhibited sprouting angiogenesis whereby all endothelial cells adopt tip-cell characteristics, a process which is sustained throughout embryonic and early post-natal development, even after the choriocapillaris becomes perfused. Ubiquitous sprouting was maintained by continuous VEGF-VEGFR2 signaling in endothelial cells delaying maturation until immediately before stages where vision becomes important for survival, leading to the unparalleled high density and lobular structure of this vasculature. Sprouting was throughout development limited to two dimensions by Bruchs membrane and the sclera at the anterior and posterior surfaces respectively. These novel cellular and molecular mechanisms underlying choriocapillaris development were recapitulated in mice. In conclusion, our findings reveal novel mechanisms underlying the development of the choriocapillaris during zebrafish and mouse development. These results may explain the uniquely high density and sheet-like organization of this vasculature.

n/a

BACKGROUND: We studied patients treated with radical cystectomy for locally advanced bladder cancer to compare the results of both preoperative positron emission tomography/computed tomography (PET/CT) and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes.

METHODS: Patients who had bladder cancer and were candidates for cystectomy underwent preoperative PET/CT using 18-fluorodeoxyglucose (FDG) and conventional CT. The results regarding lymph node involvement were independently evaluated by two experienced radiologists and were subsequently compared with histopathology results, the latter of which were reassessed by an experienced uropathologist (HO).

RESULTS: There were 54 evaluable patients (mean age 68 years, 47 [85 %] males and 7 [15 %] females) with pT and pN status as follows: < pT2-14 (26 %), pT2-10 (18 %), and > pT2-30 (56 %); pN0 37 (69 %) and pN+ 17 (31 %). PET/CT showed positive lymph nodes in 12 patients (22 %), and 7 of those cases were confirmed by histopathology; the corresponding results for conventional CT were 11 (20 %) and 7 patients (13 %), respectively. PET/CT had 41 % sensitivity, 86 % specificity, 58 % PPV, and 76 % NPV, whereas the corresponding figures for conventional CT were 41 %, 89 %, 64 %, and 77 %. Additional analyses of the right and left side of the body or in specified anatomical regions gave similar results.

CONCLUSIONS: In this study, PET/CT and conventional CT had similar low sensitivity in detecting and localizing regional lymph node metastasis in bladder cancer.