Work ability 8 years after breast cancer: exploring the role of social support in a nation-wide survey.

INTRODUCTION: As the 5-year survival rate after breast cancer in Norway is 92%, the population of breast cancer survivors (BCSs) is increasing. Knowledge of work ability in this population is scarce. In a population-based cohort of BCSs, we explored work ability 8 years after diagnosis and the association between work ability and social support, and cancer-related variables including late effects and lifestyle factors. METHODS: In 2019, all Norwegian women < 59 years when diagnosed with stage I-III breast cancer in 2011 or 2012, were identified by the Cancer Registry of Norway and invited to participate in a survey on work life experiences. Work ability was assessed using the Work Ability Index (scale 0-10). Factors associated with excellent work ability (score ≥ 9) were identified using univariate and multivariate logistic regression analyses, and adjusted for socioeconomic-, health- and cancer-related variables. RESULTS: Of the 1951 eligible BCSs, 1007 (52.8%) responded. After excluding survivors with relapse (n = 1), missing information on work ability score (n = 49), or work status (n = 31), the final sample comprised 926 BCSs within working age at survey (< 67 years). Mean age at survey was 56 years and 8 years (SD 0.7) had passed since diagnosis. Work ability had been reduced from 8.9 (SD 2.3) at diagnosis to 6.3 (SD 3.1). One in three BCSs reported poor work ability (WAS ≤ 5), and seven out of ten reported that their physical work ability had been reduced due to cancer. Social support from colleagues during cancer therapy was associated with excellent work ability, which was not observed for social support provided by supervisors or the general practitioner. Cognitive impairment and fatigue were inversely associated with work ability. None of the cancer-related variables, including treatment, were associated with work ability 8 years after diagnosis. CONCLUSION: In this population-based sample, one in three BCSs reported poor work ability 8 years after diagnosis. Collegial social support during cancer therapy appears to be a protective factor for sustained work ability, whilst survivors struggling with fatigue and cognitive impairments may represent a particularly vulnerable group for reduced work ability.

Long-term quality of life among breast cancer survivors eligible for screening at diagnosis: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to explore the long-term quality of life (QoL) among breast cancer survivors eligible for mammographic screening at diagnosis and compare that to QoL among women with no history of breast cancer. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of randomised controlled trials and observational studies published between January 2000 and July 2019 was performed. Eight studies were included in the review. Six studies with QoL measurement scales (0-100) were included in the meta-analysis. We used fixed and random effects models to obtain Cohen's d with 95% confidence interval (CI). Heterogeneity among studies was evaluated by the I2 statistics. RESULTS: Information about 6145 breast cancer survivors diagnosed between 1995 and 2012 and followed for >1-10 years was analysed. Four studies used SF-36/RAND-36, three studies used EORTC QLQ-C30, one study used FACT-G and one study used FACT-B. The mean score of QoL for breast cancer survivors varied from 63.0 (RAND SF-36, 0-100) to 110.5 (FACT-B, 0-123). Two studies showed better, three studies showed similar and two studies showed poorer mean scores for breast cancer survivors compared with women with no history of breast cancer. The meta-analysis showed no significant differences in QoL for breast cancer survivors compared with women with no history of breast cancer (Cohen's d = -0.07, 95% confidence interval [CI] -0.14 to 0.00 and I2 = 83.7% for the fixed effect model; Cohen's d = -0.00, 95% CI -0.18 to 0.17 and I2 = 82.4% for the random effects model). CONCLUSION: QoL did not differ between breast cancer survivors eligible for mammographic screening at diagnosis and followed for >1-10 years and women with no history of breast cancer.

ALICE: a randomized placebo-controlled phase II study evaluating atezolizumab combined with immunogenic chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CI) represents an important novel development in cancer treatment. Metastatic triple-negative breast cancer (mTNBC) is incurable, with a median survival of only ~ 13 months. We have initiated the randomized placebo-controlled phase IIb study ALICE, evaluating PD-L1 blockade combined with immunogenic chemotherapy in mTNBC patients (n = 75). Intriguingly, the host immune response is strongly predictive for the effect of chemotherapy in mTNBC. In the ALICE trial, we release the brake on the immune response by use of atezolizumab, an inhibitory antibody against PD-L1. We utilize anthracyclines, shown to trigger the immune system, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ALICE is a randomized, double-blind, placebo-controlled exploratory phase II study evaluating the safety and efficacy of atezolizumab when combined with immunogenic chemotherapy in subjects with mTNBC. The trial will enroll 75 evaluable subjects, randomized 2:3 into two arms (A:B). The patients receive identical chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (50 mg per day, first 2 weeks in each 4 week cycle). Patients in arm A receive placebo, while patients in arm B receive atezolizumab. The primary objectives are assessment of toxicity and progression-free survival. The secondary objectives include overall survival, tumor response rate, clinical benefit rate, patient reported outcomes, biomarkers and assessment of tumor-immune evolution during therapy. DISCUSSION: The question of how CI should be combined with chemotherapy, is a key challenge facing the field. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with PD-L1 blockade, and if low-dose cyclophosphamide counters tumor tolerance. However, the data from patients is as yet very limited, and the clinical evaluation of these hypotheses is among the key objectives in the ALICE trial. The study includes extensive biobanking and translational sub-projects, also addressing other clinically important questions. These analyses may uncover mechanisms of drug efficacy or tumor resistance, and identify biomarkers allowing personalized therapy. If the trial suggests acceptable safety of the ALICE therapy and provide a signal of clinical efficacy, further studies are warranted. Trial registration NCT03164993, May 24th 2017; https://clinicaltrials.gov/ct2/show/record/NCT03164993.

ICON: a randomized phase IIb study evaluating immunogenic chemotherapy combined with ipilimumab and nivolumab in patients with metastatic hormone receptor positive breast cancer.

BACKGROUND: Immunotherapy with checkpoint inhibitors (CPI) targeting PD-1 or CTLA-4 has emerged as an important treatment modality for several cancer forms. In hormone receptor positive breast cancer (HR + BC), this therapeutic approach is largely unexplored. We have started a clinical trial, ICON (CA209-9FN), evaluating CPI combined with selected chemotherapy in patients with metastatic HR + BC. The tumor lymphocyte infiltration is predictive for the effect of chemotherapy in BC. In ICON, we use anthracycline, which are considered as "immunogenic" chemotherapy, and low-dose cyclophosphamide, which has been reported to counter immunosuppressive cells. METHODS: ICON is a randomized exploratory phase IIb study evaluating the safety and efficacy of combining nivolumab (nivo; anti-PD-1) and ipilimumab (ipi; anti-CTLA-4) with chemotherapy in subjects with metastatic HR + BC. Primary objectives are aassessment of toxicity and progression-free survival. The trial will enrol 75 evaluable subjects, randomized 2:3 into two arms (A:B). Patients in Arm A receive only chemotherapy, i.e. pegylated liposomal doxorubicin (PLD 20 mg/m2 intravenously every 2nd week) + cyclophosphamide (cyclo; 50 mg per day, first 2 weeks in each 4 week cycle). Patients in Arm B receive PLD + cyclo + ipilimumab (1 mg intravenously every 6th week) + nivolumab (240 mg intravenously every 2nd week). Patients in arm A will be offered ipi + nivo after disease progression. DISCUSSION: ICON is among the first clinical trials combining chemotherapy with PD-1 and CTLA-4 blockade, and the first in BC. There is a strong preclinical rationale for exploring if anthracyclines, which are considered to induce immunogenic cell death, synergize with CPI, and for combining PD-1 and CTLA-4 blockade, as these checkpoints are important in different phases of the immune response. If the ICON trial suggests acceptable safety and provide a signal of clinical efficacy, further studies are warranted. The cross-over patients from Arm A receiving ipilimumab/nivolumab without concomitant chemotherapy represent the first BC cohort receiving this therapy. The ICON trial includes a series of translational sub-projects addressing clinically important knowledge gaps. These studies may uncover biomarkers or mechanisms of efficacy and resistance, thereby informing the development of novel combinatory regimes and of personalised biomarker-based therapy. Trial registration NCT03409198, Jan 24th 2018; https://clinicaltrials.gov/ct2/show/record/NCT03409198.

Evolution and risk factors of anal incontinence during the first 6 years after first delivery: a prospective cohort study.

OBJECTIVE: To explore changes in prevalence of anal incontinence (AI) from late first pregnancy to 6 years postpartum, and to evaluate possible risk factors for changes in AI during the 6-year period. DESIGN: Prospective longitudinal cohort study. SETTING: Two Norwegian health regions. POPULATION OR SAMPLE: Women with first deliveries between May 2009 and December 2010. METHODS: Participants reported AI in late pregnancy, 6 months, 1 and 6 years after first delivery using postal or digital questionnaires. AI prevalence was calculated, and mixed effects Poisson regression analyses with robust variance were applied. MAIN OUTCOME MEASURES: AI from late pregnancy to 6 years postpartum. RESULTS: Among 1571 participants, 65% had normal vaginal first deliveries, 20% had vaginal deliveries complicated by instrumental intervention and/or obstetric anal sphincter injury (IVD ± OASIS). Nearly 1 in 10 women reported persistent incontinence during the 6 years. The overall AI prevalence was reduced from late pregnancy to 1 year postpartum for all modes of delivery. At 6 years postpartum, women with IVD ± OASIS had a higher AI prevalence (23%; 95% CI 16-30%) compared with women with caesarean section (8%; 95% CI 2-13%) or normal vaginal delivery (12%; 95% CI 9-16%). Moreover, women who were <23 years, ≥34 years, unemployed during first pregnancy, who had active bowel disease (PR: 2.4; 95% CI 2.0-2.7), or bowel evacuation problems during the 6-year period had higher AI prevalence. CONCLUSIONS: Mode of first delivery modified AI prevalence during the 6-year period, whereas age, bowel disease and bowel evacuation problems were associated with higher prevalence of AI from late first pregnancy to 6 years postpartum. TWEETABLE ABSTRACT: Complicated vaginal delivery, age and bowel emptying problems increase the risk of long-term anal incontinence.

Correction of excessive intraarticular varus deformities in total knee arthroplasty is associated with deteriorated postoperative ankle function.

PURPOSE: The aim of this study was to demonstrate, whether the degree of limb alignment correction in varus knee osteoarthritis correlated with an increase in ankle symptoms and to define a cut-off value concerning the degree of correction above which to expect ankle problems. METHODS: Ninety-nine consecutive patients with preoperative intraarticular varus knee deformities who underwent total knee arthroplasty were retrospectively analyzed. Patients were examined clinically (Knee Society Score, Forgotten Joint Score, Foot Function Index, Range of Motion of the knee and ankle joint, pain scales) as well as radiologically. The mean follow-up time was 57 months. RESULTS: The degree of operative limb alignment correction strongly correlated with the Foot Function Index (R = 0.91, p < 0.05). Given this, higher degrees of knee malalignment corrections were associated with worse postoperative outcomes in the knee and ankle joint-despite postoperative improved joint line orientations. Subsequently, a cut-off value for arthritic varus deformities (14.5°) could be calculated, above which the prevalence of ankle symptoms increased manifold [OR = 15.6 (3.2-77.2 95% CI p < 0.05)]. Furthermore, ROM restrictions in the subtalar joint were associated with a worse outcome in the ankle joint. CONCLUSIONS: When correcting excessive intraarticular varus knee osteoarthritis, surgeons have to be aware of possible postoperative ankle symptoms and should consider ankle deformities or decreased subtalar ROM before operative procedures. LEVEL OF EVIDENCE: III.

An in vitro model of lissencephaly: expanding the role of DCX during neurogenesis.

Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.

Cartilage Imaging: Techniques and Developments.

Cartilage degeneration is one of the most common chronic age-related joint disorders leading to pain and reduced joint motion. The increasing prevalence of osteoarthritis requires accurate cartilage imaging, both clinically and in research. Detailed cartilage imaging is also necessary for traumatic cartilage lesions and for pre- and postoperative assessment of cartilage repair procedures. Although still widely used, conventional radiography bears significant limitations because it assesses cartilage indirectly by joint space width. Magnetic resonance imaging (MRI) enables direct visualization of cartilage damage along with other concomitantly affected joint tissues. Several semiquantitative grading systems and volumetric analysis methods exist to assess cartilage damage and cartilage repair on MRI. Quantification of hyaline and fibrocartilage biochemical composition is possible with novel MRI methods such as T2- and T1ρ-mapping, delayed gadolinium-enhanced MRI of cartilage, glycosaminoglycan chemical exchange saturation transfer, and sodium imaging, along with quantitative computed tomography arthrography. These techniques provide promising quantitative imaging biomarkers that can detect early cartilage changes before morphological alterations occur.

Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study.

OBJECTIVE: We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study. METHODS: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one-year follow-up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed-effects models. RESULTS: sTNF-R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL-1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow-up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF-R1 and IL-1Ra. There were no significant associations between change in symptoms and inflammatory markers. CONCLUSION: Persistently increased sTNF-R1 and IL-1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress-related mechanisms associated with acute episodes.

The protective effect of humic-rich substances on atypical Aeromonas salmonicida subsp. salmonicida infection in common carp (Cyprinus carpio L.).

When challenged with atypical Aeromonas salmonicida subsp. salmonicida, exposure of the common carp (Cyprinus carpio L.) to different humic-rich compounds resulted in a significant reduction in infection rates. Specifically, in fish exposed to (i) humic-rich water and sludge from a recirculating system, (ii) a synthetic humic acid, and (iii) a Leonardite-derived humic-rich extract, infection rates were reduced to 14.9%, 17.0% and 18.8%, respectively, as compared to a 46.8% infection rate in the control treatment. An additional set of experiments was performed to examine the effect of humic-rich components on the growth of the bacterial pathogen. Liquid culture medium supplemented with either humic-rich water from the recirculating system, the synthetic humic acid or the Leonardite humic-rich extract resulted in a growth reduction of 41.1%, 45.2% and 61.6%, respectively, as compared to the growth of the Aeromonas strain in medium devoid of humic substances. Finally, in a third set of experiments it was found that while the innate immune system of the carps was not affected by their exposure to humic-rich substances, their acquired immune system was affected. Fish, immunized against bovine serum albumin, displayed elevated antibody titres as compared to immunized carps which were not exposed to the various sources of humic substances.

Ethnic differences in postpartum weight retention: a Norwegian cohort study.

OBJECTIVE: To explore ethnic differences in weight retention 14 weeks postpartum. DESIGN: Population-based cohort study. SETTING: The STORK Groruddalen Study. POPULATION: A multi-ethnic cohort of healthy pregnant women attending primary antenatal care at three public Child Health Clinics, in Oslo, Norway (n = 642). METHODS: An explanatory linear regression was performed to model the relationship between ethnicity and postpartum weight retention. Forward selection of 12 explanatory factors was used to adjust for potential confounding factors, based on univariate analysis and adjusted R(2) . MAIN OUTCOME MEASURE: Postpartum weight retention. RESULTS: Unadjusted mean postpartum weight retention was 2.3 (4.9) kg for women from Western Europe and varied from 3.7 (3.5) to 6.3 (4.7) kg among the five ethnic minority groups. The proportion of women in the highest quintile (postpartum weight retention >8.5-24.4 kg) significantly differed by ethnicity (P < 0.01 for the proportion of women from South Asia, the Middle East and Africa compared with Western Europeans). Women from all ethnic minority groups had a higher relative increase in weight from pre-pregnancy to postpartum (P < 0.01) compared with Western Europeans. After adjustments for significant exposures, women from the Middle East retained 2.0 kg (95% CI: 1.0-3.0), South Asia 2.8 kg (91.9-3.6), and Africa 4.4 kg (3.1-5.8) more than Western Europeans (P < 0.01). CONCLUSIONS: Significantly more women with an ethnic origin from South Asia, the Middle East and Africa had high postpartum weight retention compared with Western European women.

Reduced CD5(+) CD24(hi) CD38(hi) and interleukin-10(+) regulatory B cells in active anti-neutrophil cytoplasmic autoantibody-associated vasculitis permit increased circulating autoantibodies.

Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is B cell-dependent, although how particular B cell subsets modulate immunopathogenesis remains unknown. Although their phenotype remains controversial, regulatory B cells (Bregs ), play a role in immunological tolerance via interleukin (IL)-10. Putative CD19(+) CD24(hi) CD38(hi) and CD19(+) CD24(hi) CD27(+) Bregs were evaluated in addition to their CD5(+) subsets in 69 patients with ANCA-associated vasculitis (AAV). B cell IL-10 was verified by flow cytometry following culture with CD40 ligand and cytosine-phosphate-guanosine (CpG) DNA. Patients with active disease had decreased levels of CD5(+) CD24(hi) CD38(hi) B cells and IL-10(+) B cells compared to patients in remission and healthy controls (HCs). As IL-10(+) and CD5(+) CD24(hi) CD38(hi) B cells normalized in remission within an individual, ANCA titres decreased. The CD5(+) subset of CD24(hi) CD38(hi) B cells decreases in active disease and rebounds during remission similarly to IL-10-producing B cells. Moreover, CD5(+) B cells are enriched in the ability to produce IL-10 compared to CD5(neg) B cells. Together these results suggest that CD5 may identify functional IL-10-producing Bregs . The malfunction of Bregs during active disease due to reduced IL-10 expression may thus permit ANCA production.

T2* mapping and delayed gadolinium-enhanced magnetic resonance imaging in cartilage (dGEMRIC) of humeral articular cartilage--a histologically controlled study.

BACKGROUND: Cartilage biochemical imaging modalities that include the magnetic resonance imaging (MRI) techniques of T2* mapping (sensitive to water content and collagen fiber network) and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC, sensitive to the glycosaminoglycan content) can be effective instruments for early diagnosis and reliable follow-up of cartilage damage. The purpose of this study was to provide T2* mapping and dGEMRIC values in various histologic grades of cartilage degeneration in humeral articular cartilage. METHODS: A histologically controlled in vitro study was conducted that included human humeral head cartilage specimens with various histologic grades of cartilage degeneration. High-resolution, 3-dimensional (3D) T2* mapping and dGEMRIC were performed that enabled the correlation of MRI and histology data. Cartilage degeneration was graded according to the Mankin score, which evaluates surface morphology, cellularity, toluidine blue staining, and tidemark integrity. SPSS software was used for statistical analyses. RESULTS: Both MRI mapping values decreased significantly (P < .001) with increasing cartilage degeneration. Spearman rank analysis revealed a significant correlation (correlation coefficients ranging from -0.315 to 0.784; P < .001) between the various histologic parameters and the T2* and T1Gd mapping values. CONCLUSION: This study demonstrates the feasibility of 3D T2* and dGEMRIC to identify various histologic grades of cartilage damage of humeral articular cartilage. With regard to the advantages of these mapping techniques with high image resolution and the ability to accomplish a 3D biochemically sensitive imaging, we consider that these imaging techniques can make a positive contribution to the currently evolving science and practice of cartilage biochemical imaging.

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.

Spectrum of T2* values in knee joint cartilage at 3 T: a cross-sectional analysis in asymptomatic young adult volunteers.

OBJECTIVE: To establish baseline T2* values in healthy knee joint cartilage at 3 T. MATERIALS AND METHODS: Thirty-four volunteers (mean age: 24.6 ± 2.7 years) with no history or clinical findings indicative of any knee joint disease were enrolled. The protocol included a double-echo steady-state (DESS) sequence for morphological cartilage evaluation and a gradient-echo multi-echo sequence for T2* assessment. Bulk and zonal T2* values were assessed in eight regions: posterior lateral femoral condyle; central lateral femoral condyle; trochlea; patella; lateral tibial plateau; posterior medial femoral condyle; central medial femoral condyle; and medial tibial plateau. Statistical evaluation comprised a two-tailed t test and a one-way analysis of variance to identify zonal and regional differences. RESULTS: T2* mapping revealed higher T2* values in the superficial zone in all regions (P values ≤ 0.001) except for the posterior medial femur condyle (P = 0.087), and substantial regional differences demonstrating superior values in trochlear cartilage, intermediate values in patellar and central femoral condylar cartilage, and low T2* values in posterior femoral condylar cartilage and tibial plateau cartilage. CONCLUSION: Substantial regional differences in T2* measures should be taken into consideration when conducting T2* mapping of knee joint cartilage.

Impact of Prosigna test on adjuvant treatment decision in lymph node-negative early breast cancer-a prospective national multicentre study (EMIT-1).

BACKGROUND: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions. PATIENTS AND METHODS: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed. RESULTS: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94). CONCLUSION: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals.

Kidney transplant: functional assessment with diffusion-tensor MR imaging at 3T.

PURPOSE: To evaluate the feasibility of diffusion-tensor (DT) imaging at 3 T for functional assessment of transplanted kidneys. MATERIALS AND METHODS: This study was approved by the local ethics committee; written informed consent was obtained. Between August 2009 and October 2010, 40 renal transplant recipients were prospectively included in this study and examined with a clinical 3-T magnetic resonance (MR) imager. An echo-planar DT imaging sequence was performed in coronal orientation by using five b values (0, 200, 400, 600, 800 sec/mm(2)) and 20 diffusion directions. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined for the cortex and medulla of the transplanted kidney. Relationships between FA, ADC, and allograft function, determined by the estimated glomerular filtration rate (eGFR), were assessed by using Pearson correlation coefficient. ADC and FA were compared between patients with good or moderate allograft function (group A; eGFR > 30 mL/min/1.73 m(2)) and patients with impaired function (group B; eGFR ≤ 30 mL/min/1.73 m(2)) by using a student t test. P < .05 indicated a statistically significant difference. RESULTS: Mean FA of the renal medulla and cortex was significantly higher in group A (0.39 ± 0.06 and 0.17 ± 0.4) compared with group B (0.27 ± 0.05 and 0.14 ± 0.03) (P < .001 and P = .009, respectively). Mean ADCs of renal cortex and medulla were significantly higher in group A than in group B (P = .007 and P = .01, respectively). In group B, mean medullary FA was significantly lower in patients whose renal function did not recover (0.22 ± 0.02) compared with those with stable allograft function at 6 months (0.29 ± 0.05, P < .001). There was significant correlation between eGFR and medullary FA (r = 0.65, P < .001), cortical ADC (r = 0.43, P = .003), and medullary ADC (r = 0.35, P = .01). CONCLUSION: DT imaging is a promising noninvasive technique for functional assessment of renal allografts. FA values in the renal medulla exhibit a good correlation with renal function.

T2* mapping and delayed gadolinium-enhanced magnetic resonance imaging in cartilage (dGEMRIC) of glenohumeral cartilage in asymptomatic volunteers at 3 T.

OBJECTIVES: To establish baseline T2* and T1Gd values of glenohumeral cartilage at 3 T. METHODS: Forty asymptomatic volunteers (mean age: 24.8 ± 2.2 years) without shoulder abnormalities were included. The MRI protocol comprised a double-echo steady-state (DESS) sequence for morphological cartilage evaluation, a gradient-echo multiecho sequence for T2* assessment, and a gradient-echo dual-flip-angle sequence for T1Gd mapping. Statistical assessment involved a one-way analysis of variance (ANOVA) to identify the differences between various regions of the glenohumeral joint and intraclass correlation (ICC) analysis comparing repetitive T2* and T1Gd measures to assess intra- and interobserver reliability. RESULTS: Both techniques revealed significant differences between superior and inferior glenohumeral cartilage demonstrating higher T2* (26.2 ms vs. 23.2 ms, P value < 0.001) and T1Gd (750.1 ms vs. 720.2 ms, P value = 0.014) values in the superior regions. No trend was observed in the anterior-posterior measurement (P value range: 0.279-1.000). High intra- and interobserver agreement (ICC value range: 0.895-0.983) was noted for both T2* and T1Gd mapping. CONCLUSIONS: T2* and T1Gd mapping are reliable in the assessment of glenohumeral cartilage. The values from this study can be used for comparison to identify cartilage degeneration in patients suffering from shoulder joint abnormalities. KEY POINTS: • T2* mapping and dGEMRIC are sensitive to collagen degeneration and proteoglycan depletion. • This study aimed to establish baseline T2*/dGEMRIC values of glenohumeral cartilage. • Both techniques revealed significant differences between superior and inferior glenohumeral cartilage. • High intra-/interreader agreement was noted for both T2* mapping and dGEMRIC. • These baseline normal values should be useful when identifying potential degeneration.

Pathways to renal biopsy and diagnosis among patients with ANCA small-vessel vasculitis.

OBJECTIVES: Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA-SVV) is an autoimmune systemic process increasingly recogniSed since the advent of antibody testing for the disease. Prompt diagnosis and institution of immunosuppressive therapy has been shown to improve patient outcome. The goal of this study was to better understand how patients navigate the health care system from symptom presentation to biopsy diagnosis, and to study the effects of prompt versus delayed diagnosis. METHODS: Disease symptoms and number of physicians seen prior to renal biopsy were assessed for 127 ANCA-SVV patients. Direct, delayed, and quest pathways to diagnosis and treatment of vasculitis were defined for both patients and providers. Kruskal-Wallis and Fisher exact tests were used to evaluate continual measures and compare categorical variables across pathways. RESULTS: Among patients who sought direct care, physician delay in referral to a nephrologist was common (49/127, 71%, p=0.0023). Patients who delayed seeking care also experienced a delayed diagnosis 57% of the time (p=0.0023). Patients presenting with prodromal flu or upper respiratory involvement were more likely to have a delay/quest patient pathway (56% and 55%, respectively) than a direct patient pathway (44%, p=0.033 and 45%, p=0.019, respectively). There was a trend for patients with more severe loss of renal function to have a more direct referral to a nephrologist. CONCLUSIONS: Delay in diagnosis of ANCA SVV may be due to lack of or non-specific symptoms, especially in patients who present with non-renal manifestations of disease. Better algorithms are needed to identify extra-renal manifestations, expedite diagnosis and improve patient outcomes.

Magnetic resonance imaging and histology of ovine hip joint cartilage in two age populations: a sheep model with assumed healthy cartilage.

OBJECTIVE: To compare morphologically normal appearing cartilage in two age groups with delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and correlate magnetic resonance imaging (MRI) findings with histology. MATERIALS AND METHODS: Twenty femoral head specimens collected from ten lambs (group I) and ten young adult sheep (group II) underwent dGEMRIC and histological assessment. A region of 2 cm(2) with morphologically normal-appearing cartilage was marked with a surgical suture for subsequent matching of MRI and histological sections. The MRI protocol included a three-dimensional (3D) double-echo steady-state sequence for morphological cartilage assessment, a B1 pre-scan with various flip angles for B1 field heterogeneity correction, and 3D volumetric interpolated breathhold examination for T1(Gd) mapping (dGEMRIC). Histological analysis was performed according to the Mankin scoring system. RESULTS: A total of 303 regions of interest (ROI; 101 MRI reformats matching 101 histological sections) was assessed. Twenty-six ROIs were excluded owing to morphologically apparent cartilage damage or insufficient MR image quality. Therefore, 277 ROIs were analyzed. Histological analyses revealed distinct degenerative changes in various cartilage samples of group II (young adult sheep). Corresponding T1(Gd) values were significantly lower in the group of sheep (mean T1(Gd) = 540.4 ms) compared with the group of lambs (mean T1(Gd) = 623.6 ms; p < 0.001). CONCLUSIONS: Although morphologically normal, distinct cartilage degeneration may be present in young adult sheep cartilage. dGEMRIC can reveal these changes and may be a tool for the assessment of early cartilage degeneration.