Stereotactic Radiosurgery for Women Older than 65 with Breast Cancer Brain Metastases.

BACKGROUND: Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution. METHODS: An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses. RESULTS: A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, p = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, p = 0.074) and HER2 positive (42% vs. 29%, p = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, p = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, p = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, p = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, p = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, p = 0.048), KPS ≤ 80 (HR = 2.24, p < 0.001), HER2 positive disease (HR = 0.46, p < 0.001), isolated CNS metastatic disease (HR = 0.29, p < 0.001), number of brain metastases treated with RT (HR = 1.06, p = 0.028), and fractionated SRS (HR = 0.53, p = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, p < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, p = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated. CONCLUSIONS: Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.

Adjuvant chemotherapy after curative D2 gastrectomy in Latin American patients with gastric cancer.

Background: Gastric cancer (GC) is the fourth most common cause of cancer deaths around the world and the first cause of cancer deaths in Peru; however, there are no prospective trials for adjuvant chemotherapy in GC after curative gastrectomy in this country. The objective of this study was to evaluate the effectiveness of adjuvant chemotherapy in stage II-III gastric cancer patients who underwent D2 gastrectomy. Methods: We included patients with stage II-III gastric cancer who underwent radical gastrectomy and D2 dissection between 2014 and 2016 at our institution. Patients received 3-week cycles of capecitabine (1,000 mg/m2 twice daily on days 1-14) plus oxaliplatin (130 mg/m2 on day 1) for 6 months. Survival curves were estimated with the Kaplan-Meier method, and the Cox proportional hazards model was used to identify prognostic factors for survival. Results: In total, 173 patients were included: 100 (57.8%) patients received adjuvant chemotherapy and surgery (AChS) and 73 (42.2%) surgery alone (SA). Three-year disease-free survival (DFS) was higher in the AChS groups (69%) than in the SA group (52.6%) (p = 0.034). Regarding overall survival (OS), 31 patients (31%) died in the AChS group compared with 34 (46.6%) in the SA group (p = 0.027). In the multivariate analysis, adjuvant chemotherapy was an independent prognostic factor for DFS (HR = 0.60; 95% CI = 0.37-0.97; p = 0.036) and OS (HR = 0.58; 95% CI = 0.36-0.95; p = 0.029). ACh showed consistent benefit in DFS and OS for patients with albumin >3.5 g/dL, lymphovascular and perineural invasion, pT4, pN2-3, pathologic stage (PS) IIIA and IIIB and lymph node ratio (LNR) > 13.1. Conclusion: These data suggest that adjuvant capecitabine and oxaliplatin reduce the recurrence and mortality in patients with stage II-III gastric cancer who underwent D2 gastrectomy. PS IIIA and IIIB and LNR > 13.1 benefited more from receiving adjuvant chemotherapy and poorly cohesive gastric carcinoma did not significantly reduce the rates of survival.

Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency.

OBJECTIVE: To analyze whether telomere length, X-chromosome inactivation (XCI), and androgen receptor (AR) GAG polymorphism are related to idiopathic premature ovarian insufficiency (POI). DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): A total of 121 women, including 46 nonsyndromic POI and 75 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age, weight, height, body mass index (BMI), systolic and diastolic arterial pressure, E2, androstenedione, T, and C-reactive protein were assessed. Telomere length was estimated by quantitative real-time polymerase chain reaction, XCI was measured using the Human Androgen Receptor and X-linked retinitis pigmentosa 2 (RP2) methylation assays. AR and FMR1 polymorphism was assessed by quantitative fluorescent polymerase chain reaction and sequencing. RESULT(S): Premature ovarian insufficiency women had a higher mean age, weighed less, and exhibited lower C-reactive protein, E2, and androstenedione levels. The AR polymorphism did not differ between the groups. Four patients had premutation (55-200 CGG repeats), and none displayed a full mutation in the FMR1 gene. However, patients with POI showed shorter telomere length and higher frequency of skewed XCI. Extreme skewing (≥90%) was observed in 15% of women with POI, and shorter telomeres correlated with XCI skewing in both groups. CONCLUSION(S): Skewed XCI and shortened telomere length were associated with idiopathic POI, despite no alterations in the AR and FMR1 genes. Additionally, there is a tendency for women with short telomeres to exhibit skewed XCI.

Multi-centre evaluation of accuracy and reproducibility of planar and SPECT image quantification: An IAEA phantom study.

Accurate quantitation of activity provides the basis for internal dosimetry of targeted radionuclide therapies. This study investigated quantitative imaging capabilities at sites with a variety of experience and equipment and assessed levels of errors in activity quantitation in Single-Photon Emission Computed Tomography (SPECT) and planar imaging. Participants from 9 countries took part in a comparison in which planar, SPECT and SPECT with X ray computed tomography (SPECT-CT) imaging were used to quantify activities of four epoxy-filled cylinders containing 133Ba, which was chosen as a surrogate for 131I. The sources, with nominal volumes of 2, 4, 6 and 23mL, were calibrated for 133Ba activity by the National Institute of Standards and Technology, but the activity was initially unknown to the participants. Imaging was performed in a cylindrical phantom filled with water. Two trials were carried out in which the participants first estimated the activities using their local standard protocols, and then repeated the measurements using a standardized acquisition and analysis protocol. Finally, processing of the imaging data from the second trial was repeated by a single centre using a fixed protocol. In the first trial, the activities were underestimated by about 15% with planar imaging. SPECT with Chang's first order attenuation correction (Chang-AC) and SPECT-CT overestimated the activity by about 10%. The second trial showed moderate improvements in accuracy and variability. Planar imaging was subject to methodological errors, e.g., in the use of a transmission scan for attenuation correction. The use of Chang-AC was subject to variability from the definition of phantom contours. The project demonstrated the need for training and standardized protocols to achieve good levels of quantitative accuracy and precision in a multicentre setting. Absolute quantification of simple objects with no background was possible with the strictest protocol to about 6% with planar imaging and SPECT (with Chang-AC) and within 2% for SPECT-CT.

Three-Step Model for Polarized Sorting of KIF17 into Dendrites.

Kinesin and dynein motors drive bidirectional cargo transport along microtubules and have a critical role in polarized cargo trafficking in neurons [1, 2]. The kinesin-2 family protein KIF17 is a dendrite-specific motor protein and has been shown to interact with several dendritic cargoes [3-7]. However, the mechanism underlying the dendritic targeting of KIF17 remains poorly understood [8-11]. Using live-cell imaging combined with inducible trafficking assays to directly probe KIF17 motor activity in living neurons, we found that the polarized sorting of KIF17 to dendrites is regulated in multiple steps. First, cargo binding of KIF17 relieves autoinhibition and initiates microtubule-based cargo transport. Second, KIF17 does not autonomously target dendrites, but enters the axon where the actin cytoskeleton at the axon initial segment (AIS) prevents KIF17 vesicles from moving further into the axon. Third, dynein-based motor activity is able to redirect KIF17-coupled cargoes into dendrites. We propose a three-step model for polarized targeting of KIF17, in which the collective function of multiple motor teams is required for proper dendritic sorting.

Dynein Regulator NDEL1 Controls Polarized Cargo Transport at the Axon Initial Segment.

The development and homeostasis of neurons relies heavily on the selective targeting of vesicles into axon and dendrites. Microtubule-based motor proteins play an important role in polarized transport; however, the sorting mechanism to exclude dendritic cargo from the axon is unclear. We show that the dynein regulator NDEL1 controls somatodendritic cargo transport at the axon initial segment (AIS). NDEL1 localizes to the AIS via an interaction with the scaffold protein Ankyrin-G. Depletion of NDEL1 or its binding partner LIS1 results in both cell-wide and local defects, including the non-polarized trafficking of dendritic cargo through the AIS. We propose a model in which LIS1 is a critical mediator of local NDEL1-based dynein activation at the AIS. By localizing to the AIS, NDEL1 facilitates the reversal of somatodendritic cargos in the proximal axon.

TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays.

Axon formation, the initial step in establishing neuronal polarity, critically depends on local microtubule reorganization and is characterized by the formation of parallel microtubule bundles. How uniform microtubule polarity is achieved during axonal development remains an outstanding question. Here, we show that the tripartite motif containing (TRIM) protein TRIM46 plays an instructive role in the initial polarization of neuronal cells. TRIM46 is specifically localized to the newly specified axon and, at later stages, partly overlaps with the axon initial segment (AIS). TRIM46 specifically forms closely spaced parallel microtubule bundles oriented with their plus-end out. Without TRIM46, all neurites have a dendrite-like mixed microtubule organization resulting in Tau missorting and altered cargo trafficking. By forming uniform microtubule bundles in the axon, TRIM46 is required for neuronal polarity and axon specification in vitro and in vivo. Thus, TRIM46 defines a unique axonal cytoskeletal compartment for regulating microtubule organization during neuronal development.

Visualization and quantification of nascent RAD51 filament formation at single-monomer resolution.

During recombinational repair of double-stranded DNA breaks, RAD51 recombinase assembles as a nucleoprotein filament around single-stranded DNA to form a catalytically proficient structure able to promote homology recognition and strand exchange. Mediators and accessory factors guide the action and control the dynamics of RAD51 filaments. Elucidation of these control mechanisms necessitates development of approaches to quantitatively probe transient aspects of RAD51 filament dynamics. Here, we combine fluorescence microscopy, optical tweezers, and microfluidics to visualize the assembly of RAD51 filaments on bare single-stranded DNA and quantify the process with single-monomer sensitivity. We show that filaments are seeded from RAD51 nuclei that are heterogeneous in size. This heterogeneity appears to arise from the energetic balance between RAD51 self-assembly in solution and the size-dependent interaction time of the nuclei with DNA. We show that nucleation intrinsically is substrate selective, strongly favoring filament formation on bare single-stranded DNA. Furthermore, we devised a single-molecule fluorescence recovery after photobleaching assay to independently observe filament nucleation and growth, permitting direct measurement of their contributions to filament formation. Our findings yield a comprehensive, quantitative understanding of RAD51 filament formation on bare single-stranded DNA that will serve as a basis to elucidate how mediators help RAD51 filament assembly and accessory factors control filament dynamics.

Microtubule-based transport - basic mechanisms, traffic rules and role in neurological pathogenesis.

Microtubule-based transport is essential for neuronal function because of the large distances that must be traveled by various building blocks and cellular materials. Recent studies in various model systems have unraveled several regulatory mechanisms and traffic rules that control the specificity, directionality and delivery of neuronal cargos. Local microtubule cues, opposing motor activity and cargo-adaptors that regulate motor activity control microtubule-based transport in neurons. Impairment of intracellular transport is detrimental to neurons and has emerged as a common factor in several neurological disorders. Genetic approaches have revealed strong links between intracellular transport processes and the pathogenesis of neurological diseases in both the central and peripheral nervous system. This Commentary highlights recent advances in these areas and discusses the transport defects that are associated with the development of neurological diseases.

Microtubule plus-end tracking proteins SLAIN1/2 and ch-TOG promote axonal development.

Development, polarization, structural integrity, and plasticity of neuronal cells critically depend on the microtubule network and its dynamic properties. SLAIN1 and SLAIN2 are microtubule plus-end tracking proteins that have been recently identified as regulators of microtubule dynamics. SLAINs are targeted to microtubule tips through an interaction with the core components of microtubule plus-end tracking protein network, End Binding family members. SLAINs promote persistent microtubule growth by recruiting the microtubule polymerase ch-TOG to microtubule plus-ends. Here, we show that SLAIN1/2 and ch-TOG-proteins are highly enriched in brain and are expressed throughout mouse brain development. Disruption of the SLAIN-ch-TOG complex in cultured primary rat hippocampal neurons by RNA interference-mediated knockdown and a dominant-negative approach perturbs microtubule growth by increasing catastrophe frequency and inhibits axon extension during neuronal development. Our study shows that proper control of microtubule dynamics is important for axon elongation in developing neurons.

Evaluation of the roughness of composite resins submitted to different surface treatments.

The aim of this study was to evaluate the surface roughness of restorative composite resins after polishing with aluminum oxide discs and applying an adhesive layer The following composite resins were used: Filtek Z250 (hybrid, 3MESPE, A2) and Filtek Supreme XT (nanofilled, 3M ESPE, A2E). Thirty specimens of each composite were made using a condensation silicone mold (5.0 x 2.0 mm) into which the composites were inserted and submitted to light pressure. After polymerization using the halogen light source Curing Light 2500 (3M) for 40 seconds, the specimens were assigned to the following groups: G1-Z250/CO- control, did not receive any treatment; G2-Z250/SL--the specimens underwent finishing and polishing with Sof-Lex discs; G3-Z250/ADE, application of an adhesive layer on the top of the specimen and light curing for 20 seconds. Groups G4, G5 and G6 followed the same treatment sequence, but using Filtek Supreme XT The specimens were stored in deionized water at 37 degrees C for 24 h. Three readings of surface roughness were made for each specimen. The results were submitted to variance analysis by Two-Way ANOVA Test and Tukey HSD Test. The mean values obtained were: G3 (0.2325 +/- 0.1484 microm) and G6 (0.2266 +/- 0.0463 microm), which were higher than the other groups and did not differ statistically from each other. Groups G1 (0.1023 +/- 0.0464 microm), G4 (0.1083 +/- 0.0241 microm), G5 (0.1160 +/- 0.0252 microm) and G2 (0.1360 +/- 0.0131 microm) had the lowest average roughness and did not differ statistically among each other. It was concluded that the Sof-Lex discs performed better for the surface treatment of the composites resins tested, producing similar values of surface roughness for both composites. Covering with dentin adhesive increased the surface roughness in both composites.

Evaluation of the roughness of composite resins submitted to different surface treatments / Evaluación de la rugosidad de resinas compuestas después de diferentes tratamientos de superficie

El propósito del presente estudio fue evaluar la rugosidad superficial de resinas compuestas después de ser pulidas con discos de óxido de aluminio y de aplicar una capa de adhesivo. Se utilizó resina Filtek Z250 y Filtek Supreme XT. Se fabricaron treinta especímenes de cada resina utilizando una matriz de silicona (5,0 x 2,0 mm). Después de su polimerización por 40 segundos, se formaron los siguientes grupos: G1-Z250/CO û control, que no recibió ningún tratamiento; G2-Z250/SL û los especímenes fueronacabados y pulidos con discos Sof-Lex; G3-Z250/ADE û se aplicó una capa de adhesivo en la parte superficial de los especímenes polimerizada por 20 segundos. Los grupos G4, G5 y G6 siguieron el mismo patrón, utilizando resina Filtek Supreme XT. Tres lecturasde rugosidad superficial fueron hechas en cada especímen. Se evaluaron mediante la pruebas de ANOVA Two-Way y Tukey HDS (p = 0,05), obteniendo los siguientes valores: G3 (0.2325 ± 0.1484 μm) y G6 (0.2266 ± 0.0463 μm) obtuvieron valores superiores a los otros grupos sin diferencia estadística. G1 (0.1023 ± 0.0464 μm), G4 (0.1083 ± 0.0241 μm), G5 (0.1160 ± 0.0252 μm) y G2(0.1360 ± 0.0131 μm) obtuvieron los menores valores de rugosidadsuperficial sin diferencia estadística. Se concluyó que los discos Sof-Lex presentaron un mejor desempeño para el tratamiento superficial de las resinas compuestas, siendo capaces de producirvalores similares de rugosidad de la superficie de ambos compuestos.La aplicación de una capa hidrofóbica de monómeros en las resinas produjo una elevada rugosidad superficial.(AU)

Evaluation of the roughness of composite resins submitted to different surface treatments / Evaluación de la rugosidad de resinas compuestas después de diferentes tratamientos de superficie

El propósito del presente estudio fue evaluar la rugosidad superficial de resinas compuestas después de ser pulidas con discos de óxido de aluminio y de aplicar una capa de adhesivo. Se utilizó resina Filtek Z250 y Filtek Supreme XT. Se fabricaron treinta especímenes de cada resina utilizando una matriz de silicona (5,0 x 2,0 mm). Después de su polimerización por 40 segundos, se formaron los siguientes grupos: G1-Z250/CO – control, que no recibió ningún tratamiento; G2-Z250/SL – los especímenes fueronacabados y pulidos con discos Sof-Lex; G3-Z250/ADE – se aplicó una capa de adhesivo en la parte superficial de los especímenes polimerizada por 20 segundos. Los grupos G4, G5 y G6 siguieron el mismo patrón, utilizando resina Filtek Supreme XT. Tres lecturasde rugosidad superficial fueron hechas en cada especímen. Se evaluaron mediante la pruebas de ANOVA Two-Way y Tukey HDS (p = 0,05), obteniendo los siguientes valores: G3 (0.2325 ± 0.1484 μm) y G6 (0.2266 ± 0.0463 μm) obtuvieron valores superiores a los otros grupos sin diferencia estadística. G1 (0.1023 ± 0.0464 μm), G4 (0.1083 ± 0.0241 μm), G5 (0.1160 ± 0.0252 μm) y G2(0.1360 ± 0.0131 μm) obtuvieron los menores valores de rugosidadsuperficial sin diferencia estadística. Se concluyó que los discos Sof-Lex presentaron un mejor desempeño para el tratamiento superficial de las resinas compuestas, siendo capaces de producirvalores similares de rugosidad de la superficie de ambos compuestos.La aplicación de una capa hidrofóbica de monómeros en las resinas produjo una elevada rugosidad superficial.

Depressed mood symptoms during the menopausal transition: observations from the Seattle Midlife Women's Health Study.

AIM: To describe patterns of depressed mood during the menopausal transition (MT) and to investigate relationships between patterns of depressed mood and MT stages. METHODS: Women during MT and early postmenopause rated depressed mood from 0 to 4 in a 3-day diary. Variables were percentage days with zero ratings, days with ratings of 3 or 4, and slope of ratings over time. Cluster analysis was used. RESULTS: Six distinct clusters were identified for 164 women. The three largest clusters (n = 134) had depressed mood ratings of zero (93% of days, 73%, 50%, respectively). Ratings of 3 or 4 were infrequent for these three clusters (0%, 3%, 9%, respectively). The three smallest clusters (n = 30) had zero ratings for 32% of days, 14% and 8%, respectively. The fourth cluster had 16% rated 3 or 4 with a positive slope. The fifth and sixth clusters had 23% and 6% of days at 3 or 4 with a negative slope. MT stage was not related to depressed mood ratings. Most women did not have depressed mood during the MT. Of those who did, some experienced improvement. IMPLICATIONS: The majority of women for the majority of the time experienced MT without a high severity of depressed mood while a small group of women had mood worsening over time and others improved. Depressed mood that occurs during the MT should not be attributed automatically to menstrual cycle changes or normative changes. Instead, features of a woman's life that contribute to depression should also be considered.

CardioKnowledge: a knowledge management environment.

Knowledge management supports decision-making by capturing and analyzing key performance indicators, providing visibility into the effectiveness of the business model, and by concentrating collaborative work and employee knowledge reviews on critical business problems. CardioKnowledge is a knowledge management environment based on the business and process requirements of a health care organization in Cardiology. CardioKnowledge supports organizational processes in order to facilitate the communication and exchange of knowledge among the cardiologists, medical students and other employees.

Three stages of the menopausal transition from the Seattle Midlife Women's Health Study: toward a more precise definition.

OBJECTIVES: As more interest centers on the years surrounding menopause, the inconsistent use of nonspecific terminology to define these years becomes a problem. Our objective was to describe the development of specific criteria that define stages within the menopausal transition and to apply these criteria to classify midlife women into a stage of transition. DESIGN: A total of 184 midlife women from the Seattle Midlife Women's Health Study taking no hormones and for whom data were available about initial menstrual cycle changes were studied. Questionnaires about menstrual cycle changes and menstrual calendars were mailed yearly. Intra-individual analyses for type and chronology of menstrual cycle changes during midlife for change in flow amount or duration, cycle length change, cycle irregularity, or skipped periods were conducted. RESULTS: Changes in flow or cycle length most frequently preceded irregularity without skipped periods, which preceded skipped periods. Initial changes began in the early 30s and most frequently between ages 40 and 44. Only 14% had irregularity as the initial change. Three stages of the menopausal transition were identified: early (flow and/or cycle length changes), middle (irregularity without skipping), and late (skipped periods). Age did not differentiate the three stages. CONCLUSIONS: These findings provide evidence for a progression of menstrual cycle events through the menopausal transition, which form the basis for three stages of the transition: early, middle, and late transition. Studies about the entire transition need to include women younger than 45. Both menstrual calendars and questionnaire data are needed to identify these three stages, and precise definitions of irregularity and skipped period are necessary.