Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol.

This paper presents the work performed to transition a lab-scale synthesis (1 g) to a large-scale (400 g) synthesis of the 3-5-diamino-1H-Pyrazole Disperazol, a new pharmaceutical for treatment of antibiotic-resistant Pseudomonas aeruginosa biofilm infections. The potentially hazardous diazotisation step in the lab-scale synthesis was transformed to a safe and easy-to-handle flow chemistry step. Additionally, the paper presents an OSHA-recommended safety assessment of active compound E, as performed by Fauske and Associates, LLC, Burr Ridge, IL, USA.

Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019.

BACKGROUND: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019. MATERIAL AND METHODS: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. RESULTS: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each). CONCLUSION: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer.

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer.Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus.Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk.Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

Deep learning-based classification of organs at risk and delineation guideline in pelvic cancer radiation therapy.

Deep learning (DL) models for radiation therapy (RT) image segmentation require accurately annotated training data. Multiple organ delineation guidelines exist; however, information on the used guideline is not provided with the delineation. Extraction of training data with coherent guidelines can therefore be challenging. We present a supervised classification method for pelvis structure delineations where bowel cavity, femoral heads, bladder, and rectum data, with two guidelines, were classified. The impact on DL-based segmentation quality using mixed guideline training data was also demonstrated. Bowel cavity was manually delineated on CT images for anal cancer patients (n = 170) according to guidelines Devisetty and RTOG. The DL segmentation quality from using training data with coherent or mixed guidelines was investigated. A supervised 3D squeeze-and-excite SENet-154 model was trained to classify two bowel cavity delineation guidelines. In addition, a pelvis CT dataset with manual delineations from prostate cancer patients (n = 1854) was used where data with an alternative guideline for femoral heads, rectum, and bladder were generated using commercial software. The model was evaluated on internal (n = 200) and external test data (n = 99). By using mixed, compared to coherent, delineation guideline training data mean DICE score decreased 3% units, mean Hausdorff distance (95%) increased 5 mm and mean surface distance (MSD) increased 1 mm. The classification of bowel cavity test data achieved 99.8% unweighted classification accuracy, 99.9% macro average precision, 97.2% macro average recall, and 98.5% macro average F1. Corresponding metrics for the pelvis internal test data were all 99% or above and for the external pelvis test data they were 96.3%, 96.6%, 93.3%, and 94.6%. Impaired segmentation performance was observed for training data with mixed guidelines. The DL delineation classification models achieved excellent results on internal and external test data. This can facilitate automated guideline-specific data extraction while avoiding the need for consistent and correct structure labels.

Reduced fracture incidence in patients having surgery for primary hyperparathyroidism.

OBJECTIVE: The indication of surgery in primary hyperparathyroidism has been controversial, as many patients experience mild disease. The primary aim was to evaluate fracture incidence in a contemporary population-based cohort of patients having surgery for primary hyperparathyroidism. The secondary aim was to investigate whether preoperative serum calcium, adenoma weight or multiglandular disease influence fracture incidence. DESIGN: A retrospective cohort study with population controls. Primary outcomes, defined by discharge diagnoses and prescriptions, were any fracture and fragility fracture, secondary outcomes were multiple fractures anytime and osteoporosis. Subjects were followed 10 years pre- and up to 10 years postoperatively (or 31 December 2015). Multiple events per subject were allowed. Fracture incidence rate ratios (IRRs) for patients pre- and postoperatively were tabulated and evaluated with mixed-effects Poisson regression. Secondary outcomes were evaluated using conditional logistic regression. PATIENTS: A Swedish nationwide cohort of patients having surgery for primary hyperparathyroidism (n = 5009) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery between 2003 and 2013 was matched with population controls (n = 14,983). Data were cross-linked with Statistics Sweden and the National Board of Health and Welfare. MEASUREMENTS: Preoperative serum calcium and adenoma weight at pathological examination. RESULTS: Patients had an increased incidence rate of any fracture preoperatively, IRR 1.27 (95% confidence interval: 1.11-1.46), highest in the last year before surgery. Fracture incidence was not increased postoperatively. Serum calcium, adenoma weight and multiglandular disease were not associated with fracture incidence. CONCLUSIONS: Fracture incidence is higher in patients with primary hyperparathyroidism but is normalized after surgery.

Anal cancer in Sweden 2015-2019. Implementation of guidelines, structural changes, national registry and early results.

BACKGROUND: Squamous cell cancer of the anus is an uncommon malignancy, usually caused by human papilloma virus (HPV). Chemoradiotherapy (CRT) is the recommended treatment in localized disease with cure rates of 60-80%. Local failures should be considered for salvage surgery. With the purpose of improving and equalizing the anal cancer care in Sweden, a number of actions were taken between 2015 and 2017. The aim of this study was to describe the implementation of guidelines and organizational changes and to present early results from the first 5 years of the Swedish anal cancer registry (SACR). METHODS: The following were implemented: (1) the first national care program with treatment guidelines, (2) standardized care process, (3) centralization of CRT to four centers and salvage surgery to two centers, (4) weekly national multidisciplinary team meetings where all new cases are discussed, (5) the Swedish anal cancer registry (SACR) was started in 2015. RESULTS: The SACR included 912 patients with a diagnosis of anal cancer from 2015 to 2019, reaching a national coverage of 95%. We could show that guidelines issued in 2017 regarding staging procedures and radiotherapy dose modifications were rapidly implemented. At baseline 52% of patients had lymph node metastases and 9% had distant metastases. Out of all patients in the SACR 89% were treated with curative intent, most of them with CRT, after which 92% achieved a local complete remission and the estimated overall 3-year survival was 85%. CONCLUSIONS: This is the first report from the SACR, demonstrating rapid nation-wide implementation of guidelines and apparently good treatment outcome in patients with anal cancer in Sweden. The SACR will hopefully be a valuable source for future research.

Region-of-interest analysis approaches in neuroimaging studies of body ownership: An activation likelihood estimation meta-analysis.

How do we feel that we own our body? By manipulating the integration of multisensory signals and creating the illusory experience of owning external body parts and entire bodies, researchers have investigated the neurofunctional correlates of body ownership. Recent attempts to synthesize the neuroimaging literature of body ownership through meta-analysis have shown partly inconsistent results. A large proportion of functional magnetic resonance imaging (fMRI) findings on body ownership include analyses based on regions of interest (ROIs). This approach can produce inflated findings when results are synthesized in meta-analyses. We conducted a systematic search of the fMRI literature of ownership of body parts and entire bodies. Three activation likelihood estimation (ALE) meta-analyses were conducted, testing the impact of including ROI-based findings. When both whole-brain and ROI-based results were included, frontal and posterior parietal multisensory areas were associated with body ownership. When only ROI-based results were included, larger areas of the frontal and posterior parietal cortices and the middle occipital gyrus were associated with body ownership. A whole-brain meta-analysis, excluding ROI-based results, found no significant convergence of activation across the brain. These findings highlight the difficulty of quantitatively synthesizing a neuroimaging field where a large part of the literature is based on findings from ROI-based analyses. We discuss these findings in the light of current practices within this field of research and highlight current problems of meta-analytic approaches of body ownership. We recommend the sharing of unthresholded data as a means to facilitate future meta-analyses of the neuroimaging literature of body ownership.

Induction of Native c-di-GMP Phosphodiesterases Leads to Dispersal of Pseudomonas aeruginosa Biofilms.

A decade of research has shown that the molecule c-di-GMP functions as a central second messenger in many bacteria. A high level of c-di-GMP is associated with biofilm formation, whereas a low level of c-di-GMP is associated with a planktonic single-cell bacterial lifestyle. c-di-GMP is formed by diguanylate cyclases and is degraded by specific phosphodiesterases. We previously presented evidence that the ectopic expression of the Escherichia coli phosphodiesterase YhjH in Pseudomonas aeruginosa results in biofilm dispersal. More recently, however, evidence has been presented that the induction of native c-di-GMP phosphodiesterases does not lead to a dispersal of P. aeruginosa biofilms. The latter result may discourage attempts to use c-di-GMP signaling as a target for the development of antibiofilm drugs. However, here, we demonstrate that the induction of the P. aeruginosa c-di-GMP phosphodiesterases PA2133 and BifA indeed results in the dispersal of P. aeruginosa biofilms in both a microtiter tray biofilm assay and a flow cell biofilm system.

Genetic testing in women with early-onset breast cancer: a Traceback pilot study.

PURPOSE: In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. METHODS: Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. RESULTS: Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. CONCLUSION: The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.

Patterns of pathologic lymph nodes in anal cancer: a PET-CT-based analysis with implications for radiotherapy treatment volumes.

BACKGROUND: This study investigates the patterns of PET-positive lymph nodes (LNs) in anal cancer. The aim was to provide information that could inform future anal cancer radiotherapy contouring guidelines. METHODS: The baseline [18F]-FDG PET-CTs of 190 consecutive anal cancer patients were retrospectively assessed. LNs with a Deauville score (DS) of ≥3 were defined as PET-positive. Each PET-positive LN was allocated to a LN region and a LN sub-region; they were then mapped on a standard anatomy reference CT. The association between primary tumor localization and PET-positive LNs in different regions were analyzed. RESULTS: PET-positive LNs (n = 412) were identified in 103 of 190 patients (54%). Compared to anal canal tumors with extension into the rectum, anal canal tumors with perianal extension more often had inguinal (P < 0.001) and less often perirectal (P < 0.001) and internal iliac (P < 0.001) PET-positive LNs. Forty-two patients had PET-positive LNs confined to a solitary region, corresponding to first echelon nodes. The most common solitary LN region was inguinal (25 of 42; 60%) followed by perirectal (26%), internal iliac (10%), and external iliac (2%). No PET-positive LNs were identified in the ischiorectal fossa or in the inguinal area located posterolateral to deep vessels. Skip metastases above the bottom of the sacroiliac joint were quite rare. Most external iliac PET-positive LNs were located posterior to the external iliac vein; only one was located in the lateral external iliac sub-region. CONCLUSIONS: The results support some specific modifications to the elective clinical target volume (CTV) in anal cancer. These changes would lead to reduced volumes of normal tissue being irradiated, which could contribute to a reduction in radiation side-effects.

Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status.

BACKGROUND: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers. METHODS: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. RESULTS: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07-3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26-4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11-3.59, P = 0.02). CONCLUSIONS: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.

Oxidative stress response plays a role in antibiotic tolerance of Streptococcus mutans biofilms.

Knowledge about biofilm-associated antibiotic tolerance mechanisms is warranted in order to develop effective treatments against biofilm infections. We performed a screen of a Streptococcus mutans transposon mutant library for mutants with reduced biofilm-associated antimicrobial tolerance, and found that the spxA1 gene plays a role in tolerance towards gentamicin and other antibiotics such as vancomycin and linezolid. SpxA1 is a regulator of genes involved in the oxidative stress response in S. mutans. The oxidative stress response genes gor and ahpC were found to be up-regulated upon antibiotic treatment of S. mutans wild-type biofilms, but not spxA1 mutant biofilms. The gor gene product catalyses the formation of glutathione which functions as an important antioxidant during oxidative stress, and accordingly biofilm-associated antibiotic tolerance of the spxA1 mutant could be restored by exogenous addition of glutathione. Our results indicate that the oxidative stress response plays a role in biofilm-associated antibiotic tolerance of S. mutans, and add to the on-going debate on the role of reactive oxygen species in antibiotic mediated killing of bacteria.

High patient satisfaction with a simplified BRCA1/2 testing procedure: long-term results of a prospective study.

PURPOSE: In the BRCAsearch study, unselected breast cancer patients were prospectively offered germline BRCA1/2 mutation testing through a simplified testing procedure. The purpose of the present study was to evaluate satisfaction with the BRCAsearch testing procedure and, furthermore, to report on uptake rates of prophylactic surgeries among mutation carriers. METHODS: Pre-test information was provided by a standardized invitation letter instead of in-person genetic counseling. The patients were offered contact with a genetic counselor for telephone genetic counseling if they felt a need for that. Mutation carriers were telephoned and given a time for a face-to-face post-test genetic counseling appointment. Non-carriers were informed about the test result through a letter. One year after the test results were delivered, a study-specific questionnaire was mailed to the study participants who had consented to testing. The response rate was 83.1% (448 of 539). RESULTS: A great majority (96.0%) of the responders were content with the method used for providing information within the study, and 98.7% were content with having pursued genetic testing. 11.1% answered that they would have liked to receive more oral information. In an adjusted logistic regression model, patients with somatic comorbidity (OR 2.56; P = 0.02) and patients born outside of Sweden (OR 3.54; P = 0.01) were more likely, and patients with occupations requiring at least 3 years of university or college education (OR 0.37; P = 0.06) were less likely to wanting to receive more oral information. All 11 mutation carriers attended post-test genetic counseling. At a median follow-up of 2 years, the uptake of prophylactic salpingo-oophorectomy was 100%, and the uptake of prophylactic mastectomy was 55%. CONCLUSIONS: Satisfaction with a simplified BRCA1/2 testing procedure was very high. Written pre-test information has now replaced in-person pre-test counseling for breast cancer patients in our health care region.

Written pretest information and germline BRCA1/2 pathogenic variant testing in unselected breast cancer patients: predictors of testing uptake.

PURPOSE: This study aimed to evaluate predictors of testing uptake among unselected breast cancer patients who were offered germline BRCA1/2 testing in a prospective study. METHODS: Pretest information was provided by a standardized invitation letter instead of in-person counseling. Data was abstracted from medical records. Using multivariate logistic regressions, predictors of testing uptake were analyzed. RESULTS: The overall uptake of testing was 67% (539 of 805 patients). Low uptake rates were found for patients aged ≥80 years (33%), and patients born outside of Europe (37%). In adjusted analysis, age ≥80 years (odds ratio [OR] 0.10; P = 0.002), psychiatric disorders (OR 0.46; P = 0.006), occupation requiring at least 3 years of university or college education (OR 2.03; P = 0.003), and breast cancer or ovarian cancer in first-degree or second-degree relatives (OR 1.66; P = 0.02) were independently associated with uptake of BRCA1/2 testing. Somatic comorbidity in patients aged <70 years was associated with lower testing uptake. CONCLUSION: Testing uptake varies across different subgroups according to patient-related factors that are readily available in the medical records. Knowledge about these factors enables health care professionals to identify patients who are less likely to pursue genetic testing.

BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer.

PURPOSE: To evaluate a simplified method of pre-test information and germline BRCA1/2 mutation testing. METHODS: In a prospective, single-arm study, comprehensive BRCA1/2 testing was offered to unselected patients with newly diagnosed breast cancer at three hospitals in south Sweden (BRCAsearch, ClinicalTrials.gov Identifier: NCT02557776). Pre-test information was provided by a standardized invitation letter, but the patients could contact a genetic counselor for telephone genetic counseling if they felt a need for that. Noncarriers were informed about the test result through a letter. Mutation carriers were contacted and offered an appointment for in-person post-test genetic counseling. RESULTS: During the period Feb 2, 2015-Aug 26, 2016, eight hundred and eighteen patients were invited to participate in the study. Through Jan 31, 2017, five hundred and forty-two (66.2%) of them consented to analysis of BRCA1 and BRCA2. Eleven pathogenic mutations were found (BRCA1, n = 2; BRCA2, n = 9), corresponding to a mutation prevalence of 2.0%. Six out of 11 fulfilled the Swedish BRCA testing criteria, and 9 out of 11 fulfilled the NCCN testing criteria. None of the BRCA-associated tumors were of the luminal A-like subtype. Very few patients contacted us for telephone genetic counseling or practical questions, suggesting that a majority felt that the written pre-test information was sufficient for them to make a decision on testing. CONCLUSIONS: Streamlining the process of pre-test information, genetic testing, and delivery of test results was feasible and was associated with an uptake of genetic testing in 2/3 of the breast cancer patients.

Vertebral fractures and their association with health-related quality of life, back pain and physical function in older women.

Studies investigating prevalent vertebral fracture (VF) diagnosed using densitometry-based VF assessment (VFA) and associations with physical function, assessed by performance-based measures, are lacking. In this population-based study of 1027 older women, we found that prevalent VF, identified by VFA, was associated with inferior physical health, back pain and inferior physical function. PURPOSE: Several studies have investigated the associations between health-related quality of life (HRQL) and back pain with prevalent VF, detected by spine radiographs, but just a few have been population-based and have used vertebral fracture assessment (VFA) for diagnosing VF. The aims of this study were to investigate associations between prevalent VF, detected by VFA, with HRQL, back pain and physical function, and investigate if also mild VFs were associated with these clinical parameters. METHODS: One thousand twenty-seven women aged 75-80 years participated in this population-based cross-sectional study. VF was identified by VFA using dual-energy X-ray absorptiometry. HRQL was assessed by SF-12, back pain during the past 12 months using a questionnaire, and physical function was tested with one leg standing (OLS), Timed Up and Go (TUG), walking speed, 30-s chair stand test and maximum grip strength. RESULTS: Physical health (Physical Component Summary, PCS), derived from SF-12, was worse (43.5 ± 11.3 vs. 46.2 ± 10.5, p < 0.001) and back pain more frequent in women with any VF than in women without (69.0 vs. 59.9%, p = 0.008). PCS and physical function (OLS, 30-s chair stand test), were significantly worse for mild VF compared to no VF (43.8 ± 10.9 vs. 46.2 ± 10.5, p < 0.001, 12.7 ± 9.9 vs. 15.3 ± 10.4 s, p = 0.038, 10.7 ± 3.2 vs. 11.4 ± 3.4 times, p = 0.021, respectively). In multivariable adjusted linear regression models, VF prevalence was associated with PCS (ß = - 0.079, p = 0.007), TUG (ß = 0.067, p = 0.021), walking speed (ß = - 0.071, p = 0.009) and 30-s chair stand test (ß = - 0.075, p = 0.012). CONCLUSIONS: In conclusion, prevalent VF, diagnosed by VFA, was associated with inferior physical health, back pain and inferior physical function, indicating VFA is useful for diagnosing clinically relevant vertebral fractures. Also, mild VF was associated with inferior physical health and inferior physical function.

Axial loading during MRI influences T2-mapping values of lumbar discs: a feasibility study on patients with low back pain.

PURPOSE: To investigate whether axial loading of the spine during MRI (alMRI) instantaneously induces changes in biochemical disc features as reflected by altered quantitative T2 values in patients with chronic low back pain (LBP). METHODS: T2 mapping was performed on 11 LBP patients (54 lumbar discs) during the conventional unloaded MRI and subsequent alMRI. Each disc was divided into five volumetric regions of interests (ROIs), anterior annulus fibrosus (AF) (ROI 1), the interface anterior AF-nucleus pulposus (NP) (ROI 2), NP (ROI 3), the interface NP-posterior AF (ROI 4), and the posterior AF (ROI 5). The mean T2 values for each ROI were compared between MRI and alMRI and correlated with degeneration grade (Pfirrmann), disc angle, and disc level. RESULTS: With alMRI, T2 values increased significantly in the whole disc as well as in various parts of the disc with an increase in ROI 1-3 and a decrease in ROI 5. The changes in T2 values correlated to degeneration grade, changes in disc angle, and lumbar level. CONCLUSION: alMRI instantaneously induces T2-value changes in lumbar discs and is, thus, a feasible method to reveal dynamic, biochemical disc features in patients with chronic LBP.

Added value of interpreter experience in occult and suspect hip fractures: a retrospective analysis of 254 patients.

The influence of experience in categorizing suspect and occult fractures on radiography compared to MRI and clinical outcome has not been studied. The aim of this study is to evaluate the importance of experience in diagnosing normal or suspect hip radiographs compared to MRI. Primarily reported normal or suspect radiography in 254 patients with low-energy hip trauma and subsequent MRI was re-evaluated by two experienced reviewers. Primary readings and review were compared. The prevalence of fractures among normal and suspect radiographic studies was assessed. Clinical outcome was used as reference. At review of radiography, 44 fractures (17 %) were found. Significantly more fractures were found among suspect cases than among normal cases. At MRI, all 44 fractures were confirmed, and further 64 fractures were detected (25 %). MRI detected all fractures with no missed fractures revealed at follow-up. There were a significantly higher proportion of fractures at MRI among the suspect radiographic diagnoses for both the primary report and at review than among occult cases. The more experienced reviewers classified radiography examinations with higher accuracy than primary reporting general radiologists. There was almost complete agreement on MRI diagnoses.

Long-term prognosis of early-onset breast cancer in a population-based cohort with a known BRCA1/2 mutation status.

All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2-7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9-18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy.