Hip geometric parameters are associated with radiographic and clinical hip osteoarthritis: Findings from a cross-sectional study in UK Biobank.

OBJECTIVE: To examine the extent to which geometric parameters derived from dual-energy x-ray absorptiometry (DXA) scans in the UK Biobank study are related to hip osteoarthritis (HOA) independently of sex, age and body size. DESIGN: Femoral neck width (FNW), diameter of the femoral head (DFH) and hip axis length (HAL) were derived automatically from left hip DXA scans in UK Biobank using outline points placed around the hip by a machine-learning program. Correlations were calculated between geometric parameters, age, height, and weight. Logistic regression was used to examine the relationship of geometric parameters with radiographic HOA, hospital diagnosed HOA (HESOA), and Cox proportional hazards model to evaluate the relationship with total hip replacement (THR). Analyses were adjusted for sex, age, height, weight, and geometric parameters. RESULTS: The study consisted of 40,312 participants. In age and sex-adjusted analyses, FNW, HAL and DFH were related to increased risk of radiographic HOA. In a model adjusted for age, sex, height, weight and other geometric parameters, both FNW and HAL retained independent relationships with radiographic HOA [FNW: odds ratios 2.38 (2.18-2.59), HAL: 1.25 (1.15-1.36)], while DFH was now protective [0.55 (0.50-0.61)]. Only FNW was independently related to HESOA [2.20 (1.80-2.68)] and THR [hazard ratios 2.51 (1.89-3.32)]. CONCLUSION: Greater FNW and HAL were independently related to an increased risk of radiographic HOA, whereas greater DFH appeared to be protective. Greater FNW was independently associated with HESOA and THR. These results suggest that DXA-derived geometric parameters, particularly FNW, could help determine HOA and THR risk.

High bone mass and cam morphology are independently related to hip osteoarthritis: findings from the High Bone Mass cohort.

BACKGROUND: High bone mass (HBM, BMD Z-score ≥ + 3.2) and cam morphology (bulging of lateral femoral head) are associated with greater odds of prevalent radiographic hip osteoarthritis (rHOA). As cam morphology is itself a manifestation of increased bone deposition around the femoral head, it is conceivable that cam morphology may mediate the relationship between HBM and rHOA. We therefore aimed to determine if individuals with HBM have increased odds of prevalent cam morphology. In addition, we investigated whether the relationship between cam and prevalent and incident osteoarthritis was preserved in a HBM population. METHODS: In the HBM study, a UK based cohort of adults with unexplained HBM and their relatives and spouses (controls), we determined the presence of cam morphology using semi-automatic methods of alpha angle derivation from pelvic radiographs. Associations between HBM status and presence of cam morphology, and between cam morphology and presence of rHOA (or its subphenotypes: osteophytes, joint space narrowing, cysts, and subchondral sclerosis) were determined using multivariable logistic regression, adjusting for age, sex, height, weight, and adolescent physical activity levels. The association between cam at baseline and incidence of rHOA after an average of 8 years was determined. Generalised estimating equations accounted for individual-level clustering. RESULTS: The study included 352 individuals, of whom 235 (66.7%) were female and 234 (66.5%) had HBM. Included individuals contributed 694 hips, of which 143 had a cam deformity (20.6%). There was no evidence of an association between HBM and cam morphology (OR = 0.97 [95% CI: 0.63-1.51], p = 0.90) but a strong relationship was observed between cam morphology and rHOA (OR = 3.96 [2.63-5.98], p = 5.46 × 10-11) and rHOA subphenotypes joint space narrowing (OR = 3.70 [2.48-5.54], p = 1.76 × 10-10), subchondral sclerosis (OR = 3.28 [1.60-6.60], p = 9.57 × 10-4) and osteophytes (OR = 3.01 [1.87-4.87], p = 6.37 × 10-6). Cam morphology was not associated with incident osteoarthritis (OR = 0.76 [0.16-3.49], p = 0.72). CONCLUSIONS: The relationship between cam morphology and rHOA seen in other studies is preserved in a HBM population. This study suggests that the risk of OA conferred by high BMD and by cam morphology are mediated via distinct pathways.

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank.

OBJECTIVES: To examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed. DESIGN: Participants from UKB with a left hip dual-energy X-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain. RESULTS: 6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41-4.25)], JSN [1.53 (1.24-1.88)], and acetabular [1.87 (1.48-2.36)], superior [1.94 (1.45-2.57)] and inferior [4.75 (3.44-6.57)] femoral osteophytes, and hip pain [1.48 (1.05-2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain. CONCLUSIONS: Cam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution.

Statistical shape modeling of the hip and the association with hip osteoarthritis: a systematic review.

OBJECTIVE: To summarize available evidence on the association between hip shape as quantified by statistical shape modeling (SSM) and the incidence or progression of hip osteoarthritis. DESIGN: We conducted a systematic search of five electronic databases, based on a registered protocol (available: PROSPERO CRD42020145411). Articles presenting original data on the longitudinal relationship between radiographic hip shape (quantified by SSM) and hip OA were eligible. Quantitative meta-analysis was precluded because of the use of different SSM models across studies. We used the Newcastle-Ottawa Scale (NOS) for risk of bias assessment. RESULTS: Nine studies (6,483 hips analyzed with SSM) were included in this review. The SSM models used to describe hip shape ranged from 16 points on the femoral head to 85 points on the proximal femur and hemipelvis. Multiple hip shape features and combinations thereof were associated with incident or progressive hip OA. Shape variants that seemed to be consistently associated with hip OA across studies were acetabular dysplasia, cam morphology, and deviations in acetabular version (either excessive anteversion or retroversion). CONCLUSIONS: Various radiographic, SSM-defined hip shape features are associated with hip OA. Some hip shape features only seem to increase the risk for hip OA when combined together. The heterogeneity of the used SSM models across studies precludes the estimation of pooled effect sizes. Further studies using the same SSM model and definition of hip OA are needed to allow for the comparison of outcomes across studies, and to validate the found associations.

An automated workflow based on hip shape improves personalized risk prediction for hip osteoarthritis in the CHECK study.

OBJECTIVE: To design an automated workflow for hip radiographs focused on joint shape and tests its prognostic value for future hip osteoarthritis. DESIGN: We used baseline and 8-year follow-up data from 1,002 participants of the CHECK-study. The primary outcome was definite radiographic hip osteoarthritis (rHOA) (Kellgren-Lawrence grade ≥2 or joint replacement) at 8-year follow-up. We designed a method to automatically segment the hip joint from radiographs. Subsequently, we applied machine learning algorithms (elastic net with automated parameter optimization) to provide the Shape-Score, a single value describing the risk for future rHOA based solely on joint shape. We built and internally validated prediction models using baseline demographics, physical examination, and radiologists scores and tested the added prognostic value of the Shape-Score using Area-Under-the-Curve (AUC). Missing data was imputed by multiple imputation by chained equations. Only hips with pain in the corresponding leg were included. RESULTS: 84% were female, mean age was 56 (±5.1) years, mean BMI 26.3 (±4.2). Of 1,044 hips with pain at baseline and complete follow-up, 143 showed radiographic osteoarthritis and 42 were replaced. 91.5% of the hips had follow-up data available. The Shape-Score was a significant predictor of rHOA (odds ratio per decimal increase 5.21, 95%-CI (3.74-7.24)). The prediction model using demographics, physical examination, and radiologists scores demonstrated an AUC of 0.795, 95%-CI (0.757-0.834). After addition of the Shape-Score the AUC rose to 0.864, 95%-CI (0.833-0.895). CONCLUSIONS: Our Shape-Score, automatically derived from radiographs using a novel machine learning workflow, may strongly improve risk prediction in hip osteoarthritis.

Adipose-tissue-derived therapeutic cells in their natural environment as an autologous cell therapy strategy: the microtissue-stromal vascular fraction.

The prerequisite for a successful clinical use of autologous adipose-tissue-derived cells is the highest possible regenerative potential of the applied cell population, the stromal vascular fraction (SVF). Current isolation methods depend on high enzyme concentration, lysis buffer, long incubation steps and mechanical stress, resulting in single cell dissociation. The aim of the study was to limit cell manipulation and obtain a derivative comprising therapeutic cells (microtissue-SVF) without dissociation from their natural extracellular matrix, by employing a gentle good manufacturing practice (GMP)-grade isolation. The microtissue-SVF yielded larger numbers of viable cells as compared to the improved standard-SVF, both with low enzyme concentration and minimal dead cell content. It comprised stromal tissue compounds (collagen, glycosaminoglycans, fibroblasts), capillaries and vessel structures (CD31+, smooth muscle actin+). A broad range of cell types was identified by surface-marker characterisation, including mesenchymal, haematopoietic, pericytic, blood and lymphatic vascular and epithelial cells. Subpopulations such as supra-adventitial adipose-derived stromal/stem cells and endothelial progenitor cells were significantly more abundant in the microtissue-SVF, corroborated by significantly higher potency for angiogenic tube-like structure formation in vitro. The microtissue-SVF showed the characteristic phenotype and tri-lineage mesenchymal differentiation potential in vitro and an immunomodulatory and pro-angiogenic secretome. In vivo implantation of the microtissue-SVF combined with fat demonstrated successful graft integration in nude mice. The present study demonstrated a fast and gentle isolation by minor manipulation of liposuction material, achieving a therapeutically relevant cell population with high vascularisation potential and immunomodulatory properties still embedded in a fraction of its original matrix.

Development of a fully automatic shape model matching (FASMM) system to derive statistical shape models from radiographs: application to the accurate capture and global representation of proximal femur shape.

OBJECTIVE: To evaluate the accuracy and sensitivity of a fully automatic shape model matching (FASMM) system to derive statistical shape models (SSMs) of the proximal femur from non-standardised anteroposterior (AP) pelvic radiographs. DESIGN: AP pelvic radiographs obtained with informed consent and appropriate ethical approval were available for 1105 subjects with unilateral hip osteoarthritis (OA) who had been recruited previously for The arcOGEN Study. The FASMM system was applied to capture the shape of the unaffected (i.e., without signs of radiographic OA) proximal femur from these radiographs. The accuracy and sensitivity of the FASMM system in calculating geometric measurements of the proximal femur and in shape representation were evaluated relative to validated manual methods. RESULTS: De novo application of the FASMM system had a mean point-to-curve error of less than 0.9 mm in 99% of images (n = 266). Geometric measurements generated by the FASMM system were as accurate as those obtained manually. The analysis of the SSMs generated by the FASMM system for male and female subject groups identified more significant differences (in five of 17 SSM modes after Bonferroni adjustment) in their global proximal femur shape than those obtained from the analysis of conventional geometric measurements. Multivariate gender-classification accuracy was higher when using SSM mode values (76.3%) than when using conventional hip geometric measurements (71.8%). CONCLUSIONS: The FASMM system rapidly and accurately generates a global SSM of the proximal femur from radiographs of varying quality and resolution. This system will facilitate complex morphometric analysis of global shape variation across large datasets. The FASMM system could be adapted to generate SSMs from the radiographs of other skeletal structures such as the hand, knee or pelvis.

Automated Radiographic Measurements of Knee Osteoarthritis.

OBJECTIVE: Herewith, we report the development of Orthopedic Digital Image Analysis (ODIA) software that is developed to obtain quantitative measurements of knee osteoarthritis (OA) radiographs automatically. Manual segmentation and measurement of OA parameters currently hamper large-cohort analyses, and therefore, automated and reproducible methods are a valuable addition in OA research. This study aims to test the automated ODIA measurements and compare them with available manual Knee Imaging Digital Analysis (KIDA) measurements as comparison. DESIGN: This study included data from the CHECK (Cohort Hip and Cohort Knee) initiative, a prospective multicentre cohort study in the Netherlands with 1,002 participants. Knee radiographs obtained at baseline of the CHECK cohort were included and mean medial/lateral joint space width (JSW), minimal JSW, joint line convergence angle (JLCA), eminence heights, and subchondral bone intensities were compared between ODIA and KIDA. RESULTS: Of the potential 2,004 radiographs, 1,743 were included for analyses. Poor intraclass correlation coefficients (ICCs) were reported for the JLCA (0.422) and minimal JSW (0.299). The mean medial and lateral JSW, eminence height, and subchondral bone intensities reported a moderate to good ICC (0.7 or higher). Discrepancies in JLCA and minimal JSW between the 2 methods were mostly a problem in the lateral tibia plateau. CONCLUSIONS: The current ODIA tool provides important measurements of OA parameters in an automated manner from standard radiographs of the knee. Given the automated and computerized methodology that has very high reproducibility, ODIA is suitable for large epidemiological cohorts with various follow-up time points to investigate structural progression, such as CHECK or the Osteoarthritis Initiative (OAI).

A fully automatic system to assess foot collapse on lateral weight-bearing foot radiographs: A pilot study.

BACKGROUND: Foot collapse is primarily diagnosed and monitored using lateral weight-bearing foot x-ray images. There are several well-validated measurements which aid assessment. However, these are subject to inter- and intra-user variability. OBJECTIVE: To develop and validate a software system for the fully automatic assessment of radiographic changes associated with foot collapse; automatically generating measurements for calcaneal tilt, cuboid height and Meary's angle. METHODS: This retrospective study was approved by the Health Research Authority (IRAS 244852). The system was developed using lateral weight-bearing foot x-ray images, and evaluated against manual measurements from five clinical experts. The system has two main components: (i) a Random Forest-based point-finder to outline the bones of interest; and (ii) a geometry-calculator to generate the measurements based on the point positions from the point-finder. The performance of the point-finder was assessed using the point-to-point error (i.e. the mean absolute distance between each found point and the equivalent ground truth point, averaged over all points per image). For assessing the performance of the geometry-calculator, linear mixed models were fitted to estimate clinical inter-observer agreement and to compare the performance of the software system to that of the clinical experts. RESULTS: A total of 200 images were collected from 79 subjects (mean age: 56.4 years ±12.9 SD, 30/49 females/males). There was good agreement among all clinical experts with intraclass correlation estimates between 0.78 and 0.86. The point-finder achieved a median point-to-point error of 2.2 mm. There was no significant difference between the clinical and automatically generated measurements using the point-finder points, suggesting that the fully automatically obtained measurements are in agreement with the manually obtained measurements. CONCLUSIONS: The proposed system can be used to support and automate radiographic image assessment for diagnosing and managing foot collapse, saving clinician time, and improving patient outcomes.

The association between statistical shape modeling-defined hip morphology and features of early hip osteoarthritis in young adult football players: Data from the femoroacetabular impingement and hip osteoarthritis cohort (FORCe) study.

Objective: To explore the relationship between radiographic hip shape and features of early hip osteoarthritis (OA) on magnetic resonance imaging (MRI) in young male and female football players without radiographic hip OA. Design: We used baseline data from a cohort of symptomatic and asymptomatic football players aged 18-50 years. Hip shape was assessed on anteroposterior radiographs with statistical shape modeling (SSM) for men and women separately. Cartilage defects and labral tears were graded using the Scoring Hip Osteoarthritis with MRI (SHOMRI) system. We used logistic regression with generalized estimating equations to estimate associations between each hip shape variant, called shape modes, and cartilage defects or labral tears. Results: We included 229 participants (446 hips, 77.4% male). For each sex, 15 shape modes were analyzed. In men, three shape modes were associated with cartilage defects: adjusted odds ratios (aOR) 0.75 (95%CI 0.58-0.97) per standard deviation (SD) for mode 1; 1.34 (95%CI 1.05-1.69) per SD for mode 12; and 0.61 (95%CI 0.48-0.78) per SD for mode 15; and one also with labral tears: aOR 1.30 (95%CI 1.01-1.69) per SD for mode 12. These modes generally represented variations in the femoral neck and subtypes of cam morphology, with and without pincer morphology. For women, there was no evidence for associations with the outcomes. Conclusions: Several hip shape variants were associated with cartilage defects on MRI in young male football players. Specifically, one subtype of cam morphology was associated with both cartilage defects and labral tears. Hip shape was not associated with early OA features in women.

Different from the Beginning: WM Maturity of Female and Male Extremely Preterm Neonates-A Quantitative MRI Study.

BACKGROUND AND PURPOSE: Former preterm born males are at higher risk for neurodevelopmental disabilities compared with female infants born at the same gestational age. This retrospective study investigated sex-related differences in the maturity of early myelinating brain regions in infants born <28 weeks' gestational age using diffusion tensor- and relaxometry-based MR imaging. MATERIALS AND METHODS: Quantitative MR imaging sequence acquisitions were analyzed in a sample of 35 extremely preterm neonates imaged at term-equivalent ages. Quantitative MR imaging metrics (fractional anisotropy; ADC [10-3mm2/s]; and T1-/T2-relaxation times [ms]) of the medulla oblongata, pontine tegmentum, midbrain, and the right/left posterior limbs of the internal capsule were determined on diffusion tensor- and multidynamic, multiecho sequence-based imaging data. ANCOVA and a paired t test were used to compare female and male infants and to detect hemispheric developmental asymmetries. RESULTS: Seventeen female (mean gestational age at birth: 26 + 0 [SD, 1 + 4] weeks+days) and 18 male (mean gestational age at birth: 26 + 1 [SD, 1 + 3] weeks+days) infants were enrolled in this study. Significant differences were observed in the T2-relaxation time (P = .014) of the pontine tegmentum, T1-relaxation time (P = .011)/T2-relaxation time (P = .024) of the midbrain, and T1-relaxation time (P = .032) of the left posterior limb of the internal capsule. In both sexes, fractional anisotropy (P [♀] < .001/P [♂] < .001) and ADC (P [♀] = .017/P [♂] = .028) differed significantly between the right and left posterior limbs of the internal capsule. CONCLUSIONS: The combined use of various quantitative MR imaging metrics detects sex-related and interhemispheric differences of WM maturity. The brainstem and the left posterior limb of the internal capsule of male preterm neonates are more immature compared with those of female infants at term-equivalent ages. Sex differences in WM maturation need further attention for the personalization of neonatal brain imaging.

Complementary and alternative medicine and musculoskeletal pain in the first year of adjuvant aromatase inhibitor treatment in early breast cancer patients.

BACKGROUND: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment. PATIENTS AND METHODS: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points. RESULTS: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use. CONCLUSIONS: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients.

Photobiomodulation of freshly isolated human adipose tissue-derived stromal vascular fraction cells by pulsed light-emitting diodes for direct clinical application.

A highly interesting source for adult stem cells is adipose tissue, from which the stromal vascular fraction (SVF)-a heterogeneous cell population including the adipose-derived stromal/stem cells-can be obtained. To enhance the regenerative potential of freshly isolated SVF cells, low-level light therapy (LLLT) was used. The effects of pulsed blue (475 nm), green (516 nm), and red (635 nm) light from light-emitting diodes applied on freshly isolated SVF were analysed regarding cell phenotype, cell number, viability, adenosine triphosphate content, cytotoxicity, and proliferation but also osteogenic, adipogenic, and proangiogenic differentiation potential. The colony-forming unit fibroblast assay revealed a significantly increased colony size after LLLT with red light compared with untreated cells, whereas the frequency of colony-forming cells was not affected. LLLT with green and red light resulted in a stronger capacity to form vascular tubes by SVF when cultured within 3D fibrin matrices compared with untreated cells, which was corroborated by increased number and length of the single tubes and a significantly higher concentration of vascular endothelial growth factor. Our study showed beneficial effects after LLLT on the vascularization potential and proliferation capacity of SVF cells. Therefore, LLLT using pulsed light-emitting diode light might represent a new approach for activation of freshly isolated SVF cells for direct clinical application.

Results of the regional intercomparison exercise for the determination of operational quantity HP(10) in Latin America.

Several intercomparison exercises were organised by the International Atomic Energy Agency (IAEA) on the determination of operational quantities at the regional or interregional basis. In the Latin American region an intercomparison for the determination of the operational quantity Hp(10) was completed mid-2004, as a follow-up to previous exercises carried out during the 1990s. Eighteen individual external monitoring services from nineteen Member States participated in the first phase. The second phase grouped 15 services that had participated in the first phase. Dosemeter irradiations in photon beams were done by four Secondary Standard Dosimetry Laboratories (SSDLs) of the region. The preparation of this exercises involved an audit by the IAEA SSDL, where reference irradiations were provided to all participants for verification of their systems. During the first phase (2002-2003) only 9 out of 18 services met the performance requirements for such monitoring services. Necessary corrective actions and procedure verification were implemented. During the second phase (2004) 11 out of 15 services fulfilled the performance criteria. This intercomparison shows that there has been improvement in the second phase and most participants demonstrated a satisfactory performance of the quantity tested.

[Fiberless miniature chandelier LED endoilluminator for pars plana vitrectomy]. / Faserloser Miniatur-Chandelier-LED-Endoilluminator für die Pars-plana-Vitrektomie.

BACKGROUND: Currently available chandelier endoilluminators for pars plana vitrectomy consist of conventional optical fibers coupled to a light source. The light probes of these fibers now provide wide emittance angles but it is still often not possible to illuminate the whole intraocular space via just one incision. Therefore, several light probes or additional handheld endoilluminators have to be used simultaneously or the lights have to be repositioned during surgery. OBJECTIVE: The presented prototype of a fiberless chandelier light-emitting diode (LED) endoilluminator aims at illuminating the whole intraocular space with just one incision while reducing the risk of harming the retina. MATERIAL AND METHODS: The light source is a white LED with a conical tip that allows stable fixation within an incision. The physical properties of these LEDs were determined and used for calculating the relevant irradiance to assess the risk of causing harm to the eye. The illumination of the intraocular space was investigated using porcine eyes. RESULTS: The illumination of porcine eyes with the modified LEDs was bright and homogeneous. Measurements and subsequent calculations proved that the expected thermal load and photochemical hazard were very low for human eyes. CONCLUSION: The hitherto existing experimental results on porcine eyes and the theoretical considerations on human eyes were found to be positive; therefore, it is expected that this new fiberless chandelier LED endoilluminator will prove to be advantageous for human patients. It promises a reduced number of incisions with a simplified handling and need to add handheld light sources only if minimal intensity oblique illumination is helpful together with the chandelier illumination. This contributes to a significant reduction of phototoxicity risks and additionally there is a chance for a cost reduction because expensive xenon or mercury lamps are no longer necessary. These expectations have to be verified by further studies on human eyes.

Impact of Histopathological Factors, Patient History and Therapeutic Variables on Recurrence-free Survival after Ductal Carcinoma in Situ: 8-Year Follow-up and Questionnaire Survey.

Introduction: Ductal carcinoma in situ (DCIS) is a premalignant lesion of the glandular component of the breast and a precursor lesion of invasive breast cancer. In recent decades the incidence of DCIS has risen continuously, mainly because of more extensive screening and more advanced diagnostic procedures. There is an increasing need for evidence-based treatment guidelines which will protect patients as far as possible from recurrence or invasive cancer but also from overtreatment. This retrospective single-center clinical trial analyzed recurrence-free survival times, rates of invasive and non-invasive events, and the impact of patient history, histopathological variables and therapeutic factors on recurrence-free survival times. Material and Methods: A total of 200 patients who underwent surgery between 2000 and 2007 for pure DCIS were included in the study. As part of follow-up a questionnaire was sent to patients and their respective gynecologists. Results: In the follow-up period, 12.5 % (n = 25) of the 200 patients had recurrence (invasive or non-invasive event). Menopausal status, tumor grade and tumor size were significantly associated with recurrence. Low-grade DCIS was significantly more often hormone receptor-positive than high-grade DCIS. Patients who had postoperative radiotherapy significantly more often also received endocrine drug treatment. There was a significant association between younger patient age and drug treatment. The study found that in the investigated cohort, premenopausal women had a significantly shorter recurrence-free time compared to postmenopausal women. Conclusion: This paper summarizes the current literature on DCIS. There is a need for more prospective clinical trials to improve the prognosis of premenopausal women with large and hormone receptor-positive DCIS.

Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex.

Goal-directed actions are guided by expected outcomes of those actions. Humans with bilateral damage to ventromedial prefrontal cortex, or the amygdala, are deficient in their ability to use information about positive and negative outcomes to guide their choice behavior. Similarly, rats and monkeys with orbital prefrontal or amygdala damage have been found to be impaired in their responses to changing values of outcomes. In the present study, we tested whether direct, functional interaction between the amygdala and the orbital prefrontal cortex is necessary for guiding behavior based on expected outcomes. Unlike control monkeys, rhesus monkeys with surgical disconnection of these two structures, achieved by crossed unilateral lesions of the amygdala in one hemisphere and orbital prefrontal cortex in the other, combined with forebrain commissurotomy, were unable to adjust their choice behavior after a change in the outcome (here, a reduction in the value of a particular reinforcer). The lesions did not affect motivation to work for a food reinforcer, or food preferences, per se. Hence, the amygdala and orbital prefrontal cortex act as part of an integrated neural system guiding decision-making and adaptive response selection.

Interim Analysis of a Phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), the first taxane to be used routinely in clinical practice, has aroused considerable interest for its high single-agent activity in breast cancer and its novel mechanism of action. The 4' epimer of doxorubicin, epirubicin is an agent with high activity against breast cancer but a lower rate of toxic side effects, especially cardiotoxic events, than its parent compound. Although the paclitaxel/doxorubicin combination has yielded response rates between 63% and 94% in phase I/II studies, some severe cardiotoxic events were reported. The rationale for our study was to evaluate the paclitaxel/epirubicin combination, focusing mainly on cardiotoxicity. In all, 57 patients with metastatic breast cancer entered the study, 28% of whom had primary metastatic breast cancer with large tumors at the primary site. Half of the patients had received adjuvant chemotherapy. Study medication consisted of 60 mg/m2 epirubicin given intravenously over 1 hour, followed by paclitaxel 175 mg/m2 administered as a 3-hour intravenous infusion after premedication with steroids, antihistamines, and H2 antagonists. The main toxicity was neutropenia (World Health Organization toxicity index grade 3/4, 72%). Other hematologic side effects were rare and no febrile neutropenia was reported. Peripheral neuropathy, arthralgia, and myalgia were mild (only World Health Organization grade 1 and 2). All patients had alopecia. The paclitaxel dose was escalated to 200 mg/m2 in eight patients, four of whom received a further escalation to 225 mg/m2. Severe neutropenia necessitated dose reductions in eight patients. No cardiac adverse events were reported. Of 41 patients evaluable for response, seven had complete remissions and 21 had partial remissions (68%). An additional 12 patients (29%) had stable disease. The combination of paclitaxel 175 mg/m2 and epirubicin 60 mg/m2 can be administered safely to patients with metastatic breast cancer. Although response was not the primary end point of this trial, the response data are nonetheless encouraging and suggest that further evaluation of the role of this combination in the first-line treatment of metastatic breast cancer is warranted.

Preliminary results of a phase II study of epirubicin and paclitaxel as first-line treatment in patients with metastatic breast cancer.

Preliminary results of this ongoing phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) plus epirubicin administered as first-line treatment to women with metastatic breast cancer indicate encouraging response rates and no severe toxicity. Among the 57 patients admitted to this study, 52% had received prior adjuvant chemotherapy (85% with cyclophosphamide/methotrexate/5-fluorouracil), 46% had received radiotherapy, and 30% had received both forms of therapy; 63% of patients were postmenopausal, mainly with poorly differentiated tumors, and 80% presented with > or = 2 metastatic sites. Epirubicin 60 mg/m2 was administered intravenously as a 1-hour infusion followed by paclitaxel 175 mg/m2 infused over 3 hours. Standard premedication was given. Granulocyte colony-stimulating factor support was not used. Neutropenia was evident in 72% of cycles but was not severe. Instances of anemia and thrombocytopenia were rare. Alopecia was universal. All nonhematologic toxicity observed was mild or moderate (peripheral neuropathy, myalgia, nausea, vomiting World Health Organization toxicity grade < 2). At this time, 41 patients are currently evaluable for response, complete and partial remission are evident in seven and 21 patients, respectively. The overall response rate so far is 68%. An additional 12 patients show evidence of stable disease, and one has shown disease progression. Paclitaxel is considered a promising new drug in the adjuvant treatment of patients with metastatic breast cancer. Combining it with epirubicin allows safe administration with no evidence of severe cardiotoxicity. The incidence of adverse cardiac events was much lower than that observed with combinations of paclitaxel and doxorubicin.