RESUMEN
The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation of output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine in vivo live reporters exist. Here, we introduce a reporter line in which the AIS is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well as whole-cell patch-clamp recordings in vitro, ex vivo, and in vivo, we confirm that the subcellular scaffold of the AIS and electrophysiological parameters of labeled cells remain unchanged. We further uncover rapid AIS remodeling following increased network activity in this model system, as well as highly reproducible in vivo labeling of AIS over weeks. This novel reporter line allows longitudinal studies of AIS modulation and plasticity in vivo in real-time and thus provides a unique approach to study subcellular plasticity in a broad range of applications.
RESUMEN
BACKGROUND AND PURPOSE: Long acquisition times limit the feasibility of established non-contrast-enhanced MRA (non-CE-MRA) techniques. The purpose of this study was to evaluate a highly accelerated flow-independent sequence (Relaxation-Enhanced Angiography without Contrast and Triggering [REACT]) for imaging of the extracranial arteries in acute ischemic stroke (AIS). MATERIALS AND METHODS: Compressed SENSE (CS) accelerated (factor 7) 3D isotropic REACT (fixed scan time: 01:22 min, reconstructed voxel size 0.625 × 0.625 × 0.75 mm3) and CE-MRA (CS factor 6, scan time: 1:08 min, reconstructed voxel size 0.5 mm3) were acquired in 76 AIS patients (69.4 ± 14.3 years, 33 females) at 3 Tesla. Two radiologists assessed scans for the presence of internal carotid artery (ICA) stenosis and stated their diagnostic confidence using a 5-point scale (5 = excellent). Vessel quality of cervical arteries as well as the impact of artifacts and image noise were scored on 5-point scales (5 = excellent/none). Apparent signal- and contrast-to-noise ratios (aSNR/aCNR) were measured for the common carotid artery (CCA) and ICA (C1-segment). RESULTS: REACT provided a sensitivity of 88.5% and specificity of 100% for clinically relevant (≥50%) ICA stenosis with substantial concordance to CE-MRA regarding stenosis grading (Cohen's kappa 0.778) and similar diagnostic confidence (REACT: mean 4.5 ± 0.4 vs. CE-MRA: 4.5 ± 0.6; P = 0.674). Presence of artifacts (3.6 ± 0.5 vs. 3.5 ± 0.7; P = 0.985) and vessel quality (all segments: 3.6 ± 0.7 vs. 3.8 ± 0.7; P = 0.004) were comparable between both techniques with REACT showing higher scores at the CCA (4.3 ± 0.6 vs. 3.8 ± 0.9; P < 0.001) and CE-MRA at V2- (3.3 ± 0.5 vs. 3.9 ± 0.8; P < 0.001) and V3-segments (3.3 ± 0.5 vs. 4.0 ± 0.8; P < 0.001). For all vessels, REACT showed a lower impact of image noise (3.8 ± 0.6 vs. 3.6 ± 0.7; P = 0.024) while yielding higher aSNR (52.5 ± 15.1 vs. 37.9 ± 12.5; P < 0.001) and aCNR (49.4 ± 15.0 vs. 34.7 ± 12.3; P < 0.001) for all vessels combined. CONCLUSIONS: In patients with acute ischemic stroke, highly accelerated REACT provides an accurate detection of ICA stenosis with vessel quality and scan time comparable to CE-MRA.
Asunto(s)
Accidente Cerebrovascular Isquémico , Angiografía por Resonancia Magnética , Humanos , Femenino , Masculino , Angiografía por Resonancia Magnética/métodos , Anciano , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Persona de Mediana Edad , Cuello/diagnóstico por imagen , Cuello/irrigación sanguínea , Medios de Contraste , Anciano de 80 o más Años , Relación Señal-Ruido , Procesamiento de Imagen Asistido por Computador/métodos , Artefactos , Imagenología Tridimensional/métodos , Reproducibilidad de los Resultados , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodosRESUMEN
Rare-earth and actinide complexes are critical for a wealth of clean-energy applications. Three-dimensional (3D) structural generation and prediction for these organometallic systems remains a challenge, limiting opportunities for computational chemical discovery. Here, we introduce Architector, a high-throughput in-silico synthesis code for s-, p-, d-, and f-block mononuclear organometallic complexes capable of capturing nearly the full diversity of the known experimental chemical space. Beyond known chemical space, Architector performs in-silico design of new complexes including any chemically accessible metal-ligand combinations. Architector leverages metal-center symmetry, interatomic force fields, and tight binding methods to build many possible 3D conformers from minimal 2D inputs including metal oxidation and spin state. Over a set of more than 6,000 x-ray diffraction (XRD)-determined complexes spanning the periodic table, we demonstrate quantitative agreement between Architector-predicted and experimentally observed structures. Further, we demonstrate out-of-the box conformer generation and energetic rankings of non-minimum energy conformers produced from Architector, which are critical for exploring potential energy surfaces and training force fields. Overall, Architector represents a transformative step towards cross-periodic table computational design of metal complex chemistry.
RESUMEN
Real-world data on the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) are still limited. The NEPTUN study evaluated effectiveness and safety of first-line nab-paclitaxel (Abraxane) plus carboplatin (nab-P/C) in patients with advanced NSCLC in routine clinical practice in Germany. Patients included in our study were aged ≥18 years, diagnosed with locally advanced or metastatic NSCLC and with decision for first-line nab-P/C in routine clinical practice. Primary objective was 6-month progression-free survival rate (PFS6), secondary objectives included overall survival (OS), overall response rate (ORR) and safety. From 2016 to 2019, 408 patients from 75 sites were enrolled. PFS6 was 39.5% (95% CI: 34.2-44.8), median PFS was 5.1 months (95% CI: 4.6-5.6), ORR was 42.9% (95% CI: 37.7-48.2). Median OS was 10.5 months (95% CI: 9.2-11.6). In subgroup analyses, median OS for squamous vs non-squamous histology was 11.5 months (95% CI: 9.2-13.8) vs 9.8 months (95% CI: 8.1-11.3) and for patients aged ≥70 vs <70 years median OS was 12.4 months (95% CI: 9.8-15.1) vs 9.6 months (95% CI: 7.7-11.1). Adverse events (AEs) related to nab-paclitaxel were reported in 247 (66.4%) patients, while carboplatin-related AEs were documented in 224 (60.2%) patients. Most frequently related AEs were leukopenia (22.3%) for nab-paclitaxel and anemia (20.2%) for carboplatin. Nab-P/C-related deaths were reported in 2 (0.5%) patients (sepsis and neutropenic sepsis). No new or unexpected safety signals emerged. These results support the effectiveness and safety of first-line nab-P/C in patients with advanced NSCLC reported in the pivotal trial and highlight the clinical value of this regimen in the real-world setting.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adolescente , Adulto , Carcinoma de Pulmón de Células no Pequeñas/patología , Carboplatino/efectos adversos , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Paclitaxel/efectos adversosRESUMEN
PURPOSE: To describe (non)adherence with denosumab among patients with solid tumors and bone metastases. METHODS: This retrospective, observational study pooled data from two completed prospective, multicenter cohort studies (X-TREME; Study 240) in adult patients with bone metastases from primary breast, prostate, lung, kidney, or other solid cancer types and administered denosumab 120 mg in routine clinical practice in Germany and Central and Eastern Europe. The studies were conducted between May 2012 and May 2017; pooled analysis was completed in August 2021. Medication adherence was described according to a three-component consensus taxonomy: initiation (first-ever administration ≤ 90 days from bone metastasis diagnosis), implementation (actual vs prescribed dosing; optimal implementation = regular/consistent dosing), and persistence (≤ 60-day gap between administrations at 3, 6, 9, and 12 months). Descriptive analyses were conducted for each cancer type. RESULTS: The analysis included 1748 patients with solid tumors and bone metastases. Adherence with denosumab was generally high across the initiation, implementation, and persistence phases. Most patients experienced timely initiation (from 64.4% [kidney cancer] to 81.2% [breast cancer]) and optimal implementation (from 62.4% [lung cancer] to 72.5% [breast cancer]). The proportion of patients who were persistent with treatment at 6 months ranged from 41.4% (lung cancer) to 77.8% (prostate cancer). CONCLUSIONS: This study revealed variations by cancer type in the initiation, implementation, and persistence of denosumab in patients with solid tumors and bone metastases in routine clinical practice. Further cancer-specific studies are warranted to examine the determinants of (non)adherence with denosumab, and potential ways to improve medication adherence.
Asunto(s)
Conservadores de la Densidad Ósea , Neoplasias Óseas , Neoplasias de la Mama , Neoplasias Pulmonares , Adulto , Masculino , Humanos , Denosumab/uso terapéutico , Estudios Retrospectivos , Conservadores de la Densidad Ósea/uso terapéutico , Estudios Prospectivos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Cumplimiento de la Medicación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The central lymphatic system consists of the thoracic duct, cisterna chyli and the retroperitoneal lymphatics through which lymph and chyle flows. Disorders of the central lymphatic system can for instance lead to leakage (chylothorax), accumulation of fluid (lymphedema) and retrograde flow (protein losing enteropathy). Abnormalities in the central lymphatic system were overlooked for years, followed by lack of diagnostic and therapeutic options. This has changed, as the technique of intranodal contrast injection in inguinal lymph nodes brought renewed interest in the central lymphatic system. In this article, the importance of intranodal contrast injection in diagnosis and treatment of disorders of the central lymphatic system will be presented through 3 clinical cases.
Asunto(s)
Quilotórax , Vasos Linfáticos , Linfedema , Quilotórax/diagnóstico , Quilotórax/etiología , Quilotórax/terapia , Humanos , Sistema Linfático/patología , Vasos Linfáticos/diagnóstico por imagen , Vasos Linfáticos/patología , Conducto Torácico/patologíaRESUMEN
A comprehensive lymphatic system is indispensable for a well-functioning body; it is integral to the immune system and is also interrelated with the digestive system and fluid homeostasis. The main difficulty in examining the lymphatic system is its fine-meshed structure. This remains a challenge, leaving patients with uninterpreted symptoms and a dearth of potential therapies. We review the history of the lymphatic system up to the present with the aim of improving current knowledge. Several findings described throughout history have made fundamental contributions to elucidating the lymphatic system. The first contributions were made by the ancient Egyptians and the ancient Greeks. Vesalius obtained new insights by dissecting corpses. Thereafter, Ruysch (1638-1731) gained an understanding of lymphatic flow. In 1784, Mascagni published his illustration of the whole lymphatic network. The introduction of radiological lymphography revolutionized knowledge of the lymphatic system. Pedal lymphangiography was first described by Monteiro (1931) and Kinmonth (1952). Lymphoscintigraphy (nuclear medicine), magnetic resonance imaging, and near-infrared fluorescence lymphography further improved visualization of the lymphatic system. The innovative dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) transformed understanding of the central lymphatic system, enabling central lymphatic flow disorders in patients to be diagnosed and even allowing for therapeutic planning. From the perspective of the history of lymph visualization, DCMRL has ample potential for identifying specific causes of debilitating symptoms in patients with central lymphatic system abnormalities and even allows for therapeutic planning.
Asunto(s)
Enfermedades Linfáticas , Vasos Linfáticos , Medios de Contraste , Humanos , Sistema Linfático/diagnóstico por imagen , Vasos Linfáticos/diagnóstico por imagen , Linfografía/métodos , Imagen por Resonancia Magnética/métodosRESUMEN
BACKGROUND: Platinum-based chemotherapy remains a first-line standard of care for approximately 30% of patients with non-small cell lung cancer (NSCLC) not harboring a druggable alteration. Favorable efficacy and safety of the nab-paclitaxel/carboplatin (nab-P/C) combination was shown in the pivotal phase 3 trial. However, information on effectiveness of nab-P/C in a real-world setting in Germany is missing. The NEPTUN study prospectively investigated the effectiveness and safety of nab-P/C in patients with advanced NSCLC in a real-world setting. METHODS: Patients with advanced or metastatic NSCLC received first-line nab-P/C according to clinical routine. The primary endpoint was 6-month progression-free survival rate (PFS6). Other endpoints included further effectiveness parameters, safety and quality of life. Data were analyzed descriptively. RESULTS: 408 patients were enrolled. PFS6 was 40.8% (95% confidence interval [CI], 35.3-46.2); median PFS was 5.2 months (95% CI, 4.5-5.7). overall response rate was 41.5% (95% CI, 36.3-46.8). Median overall survival (OS) was 10.5 months (95% CI, 9.2-11.6). Subgroup analyses revealed median OS for squamous versus non-squamous histology (11.8 months [95% CI, 9.2-13.8] vs. 9.6 months [95% CI, 7.7-11.2]) and age ≥70 versus <70 years (11.7 months [95% CI, 9.4-14.3] vs. 9.6 months [95% CI, 7.5-11.2]). Most common treatment-emergent adverse events (TEAEs) were anemia (26.5%), leukopenia (25.7%), and thrombocytopenia (16.6%). Mostly reported grade 3/4 TEAEs were leukopenia (10.2%), anemia (8.6%), and pneumonia (5.1%). nab-paclitaxel-related deaths as reported by the investigator occurred in 0.8% of patients. CONCLUSION: These real-world data support the effectiveness and safety of nab-P/C as first-line treatment for patients with advanced NSCLC independent of tumor histology. The results are comparable with the pivotal phase 3 trial. No new safety signals emerged.
Asunto(s)
Albúminas/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/farmacología , Carboplatino/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Paclitaxel/farmacología , Estudios ProspectivosRESUMEN
BACKGROUND: Small-animal single-photon emission computed tomography (SPECT) systems with multi-pinhole collimation and large stationary detectors have advantages compared to systems with moving small detectors. These systems benefit from less labour-intensive maintenance and quality control as fewer prone parts are moving, higher accuracy for focused scans and maintaining high resolution with increased sensitivity due to focused pinholes on the field of view. This study aims to investigate the performance of a novel ultra-high-resolution scanner with two-detector configuration (U-SPECT5-E) and to compare its image quality to a conventional micro-SPECT system with three stationary detectors (U-SPECT+). METHODS: The new U-SPECT5-E with two stationary detectors was used for acquiring data with 99mTc-filled point source, hot-rod and uniformity phantoms to analyse sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR). Three dedicated multi-pinhole mouse collimators with 75 pinholes each and 0.25-, 0.60- and 1.00-mm pinholes for extra ultra-high resolution (XUHR-M), general-purpose (GP-M) and ultra-high sensitivity (UHS-M) imaging were examined. For CNR analysis, four different activity ranges representing low- and high-count settings were investigated for all three collimators. The experiments for the performance assessment were repeated with the same GP-M collimator in the three-detector U-SPECT+ for comparison. RESULTS: Peak sensitivity was 237 cps/MBq (XUHR-M), 847 cps/MBq (GP-M), 2054 cps/MBq (UHS-M) for U-SPECT5-E and 1710 cps/MBq (GP-M) for U-SPECT+. In the visually analysed sections of the reconstructed mini Derenzo phantoms, rods as small as 0.35 mm (XUHR-M), 0.50 mm (GP-M) for the two-detector as well as the three-detector SPECT and 0.75 mm (UHS-M) were resolved. Uniformity for maximum resolution recorded 40.7% (XUHR-M), 29.1% (GP-M, U-SPECT5-E), 16.3% (GP-M, U-SPECT+) and 23.0% (UHS-M), respectively. UHS-M reached highest CNR values for low-count images; for rods smaller than 0.45 mm, acceptable CNR was only achieved by XUHR-M. GP-M was superior for imaging rods sized from 0.60 to 1.50 mm for intermediate activity concentrations. U-SPECT5-E and U-SPECT+ both provided comparable CNR. CONCLUSIONS: While uniformity and sensitivity are negatively affected by the absence of a third detector, the investigated U-SPECT5-E system with two stationary detectors delivers excellent spatial resolution and CNR comparable to the performance of an established three-detector-setup.
RESUMEN
We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available 99mTc-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with 99mTc-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with ~ 100 MBq [99mTc]Tc-MIBI or ~ 150 MBq [99mTc]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1 = "very poor" to 5 = "very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time.
Asunto(s)
Tomografía Computarizada de Emisión de Fotón Único/instrumentación , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Huesos/diagnóstico por imagen , Diseño de Equipo/instrumentación , Diseño de Equipo/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/instrumentación , Procesamiento de Imagen Asistido por Computador/métodos , Ratones , Fantasmas de Imagen , Ratas , Tecnecio/administración & dosificación , Tecnecio Tc 99m Sestamibi/administración & dosificaciónRESUMEN
Rodent neocortical neurons undergo prominent postnatal development and maturation. The process is associated with structural and functional maturation of the axon initial segment (AIS), the site of action potential initiation. In this regard, cell size and optimal AIS length are interconnected. In sensory cortices, developmental onset of sensory input and consequent changes in network activity cause phasic AIS plasticity that can also control functional output. In non-sensory cortices, network input driving phasic events should be less prominent. We, therefore, explored the relationship between postnatal functional maturation and AIS maturation in principal neurons of the primary motor cortex layer V (M1LV), a non-sensory area of the rat brain. We hypothesized that a rather continuous process of AIS maturation and elongation would reflect cell growth, accompanied by progressive refinement of functional output properties. We found that, in the first two postnatal weeks, cell growth prompted substantial decline of neuronal input resistance, such that older neurons needed larger input current to reach rheobase and fire action potentials. In the same period, we observed the most prominent AIS elongation and significant maturation of functional output properties. Alternating phases of AIS plasticity did not occur, and changes in functional output properties were largely justified by AIS elongation. From the third postnatal week up to five months of age, cell growth, AIS elongation, and functional output maturation were marginal. Thus, AIS maturation in M1LV is a continuous process that attunes the functional output of pyramidal neurons and associates with early postnatal development to counterbalance increasing electrical leakage due to cell growth.
Asunto(s)
Segmento Inicial del Axón/fisiología , Crecimiento/fisiología , Corteza Motora/crecimiento & desarrollo , Corteza Motora/fisiología , Neuronas Motoras/fisiología , Potenciales de Acción/fisiología , Factores de Edad , Animales , Diferenciación Celular , Células Cultivadas , Modelos Neurológicos , Corteza Motora/citología , Neurogénesis/fisiología , Plasticidad Neuronal , RatasRESUMEN
The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.
RESUMEN
The aim of this study is to analyse the connection between relationship stability and attractive alternatives, which is stressed in micro-level theories on union dissolution. The stability of relationships can be influenced by the availability of alternative partners, whereby the probability that a person will meet these alternatives is determined by the distribution of individuals with specific characteristics in the contextual setting the person is embedded in. Research on this macro-micro connection is sparse in Europe. The availability of alternatives on the contextual level is operationalised through varying sex ratios between and within German districts. The estimation of the union dissolution risk as a function of individual and contextual predictors is based on a discrete-time multilevel event-history analysis using pairfam data and data from official statistics. The main hypothesis, which asserts that there is a positive connection between unbalanced sex ratios and union dissolution, is not supported. This result calls into question the robustness of previous findings.
RESUMEN
PURPOSE: Overactivation of TGF-ß signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-ß receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies. PATIENTS AND METHODS: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off. RESULTS: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%). CONCLUSIONS: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.
Asunto(s)
Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
A key component allowing a neuron to function properly within its dynamic environment is the axon initial segment (AIS), the site of action potential generation. In visual cortex, AIS of pyramidal neurons undergo periods of activity-dependent structural plasticity during development. However, it remains unknown how AIS morphology is organized during development for downstream cells in the visual pathway (retinal ganglion cells; RGCs) and whether AIS retain the ability to dynamically adjust to changes in network state. Here, we investigated the maturation of AIS in RGCs during mouse retinal development, and tested putative activity-dependent mechanisms by applying visual deprivation with a focus on the AIS-specific cisternal organelle (CO), a presumed Ca2+-store. Whole-mount retinae from wildtype and Thy1-GFP transgenic mice were processed for multi-channel immunofluorescence using antibodies against AIS scaffolding proteins ankyrin-G, ßIV-spectrin and the CO marker synaptopodin (synpo). Confocal microscopy in combination with morphometrical analysis of AIS length and position as well as synpo cluster size was performed. Data indicated that a subset of RGC AIS contains synpo clusters and that these show significant dynamic regulation in size during development as well as after visual deprivation. Using super resolution microscopy, we addressed the subcellular localization of synpo in RGC axons. Similar to cortical neurons, RGCs show a periodic distribution of AIS scaffolding proteins. A previously reported scaffold-deficient nanodomain correlating with synpo localization is not evident in all RGC AIS. In summary, our work demonstrates a dynamic regulation of both the AIS and synpo in RGCs during retinal development and after visual deprivation, providing first evidence that the AIS and CO in RGCs can undergo structural plasticity in response to changes in network activity.
RESUMEN
The aim was to assess the performance of prostate 3T MRI for pelvic lymph node (LN) staging in prostate cancer (PCa), in comparison to 68Gallium-prostate specific membrane antigen PET-CT (68Ga-PSMA PET-CT) as reference standard for LN detection. 130 patients with PCa underwent non-contrast-enhanced multiparametric prostate 3T MRI and 68Ga-PSMA-PET-CT within 180 days at our institution. Overall, 187 LN metastases (n = 43 patients) detected by 68Ga-PSMA-PET-CT were characterized by calculating maximum standardized uptake value (SUVmax), area, diameter and anatomical location including iliac, obturator, presacral and inguinal region. MRI achieved an overall sensitivity, specificity, positive and negative predictive value of 81.6% (CI 71.1-88.9%), 98.6% (CI 97.6-99.2%), 73.5% (CI 52.1-87.6%) and 99.5% (CI 98.8-99.8%), respectively. On a region-based analysis, detection rates differed non-significantly (ps > 0.12) in the anatomical regions. On a size-dependent analysis, detection of LN > 10 mm did not differ significantly (ps > 0.09) from LN ≤ 10 mm. In comparison to single T1 sequence evaluation, additional use of the T2 weighted sequences did not improve the overall performance significantly (p > 0.05). 3T prostate MRI represented an accurate tool for the detection of LN compared to 68Ga-PSMA-PET-CT. Especially for LN metastases smaller than 10 mm, MRI was less accurate compared to 68Ga-PSMA-PET-CT.
Asunto(s)
Imagen por Resonancia Magnética/normas , Neoplasias Pélvicas/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Neoplasias de la Próstata/diagnóstico por imagen , Anciano , Isótopos de Galio , Radioisótopos de Galio , Humanos , Metástasis Linfática , Imagen por Resonancia Magnética/métodos , Masculino , Glicoproteínas de Membrana , Estadificación de Neoplasias , Compuestos Organometálicos , Neoplasias Pélvicas/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Valor Predictivo de las Pruebas , Neoplasias de la Próstata/patología , RadiofármacosRESUMEN
BACKGROUND: The purpose of this study was to evaluate the imaging properties of hepatic metastases in 68Ga-PSMA positron emission tomography (PET) in patients with prostate cancer (PC). METHODS: 68Ga-PSMA-PET/CT scans of PC patients available in our database were evaluated retrospectively for liver metastases. Metastases were identified using 68Ga-PSMA-PET, CT, MRI and follow-up scans. Different parameters including, maximum standardized uptake values (SUVmax) of the healthy liver and liver metastases were assessed by two- and three-dimensional regions of interest (2D/3D ROI). RESULTS: One hundred three liver metastases in 18 of 739 PC patients were identified. In total, 80 PSMA-positive (77.7%) and 23 PSMA-negative (22.3%) metastases were identified. The mean SUVmax of PSMA-positive liver metastases was significantly higher than that of the normal liver tissue in both 2D and 3D ROI (p ≤ 0.05). The mean SUVmax of PSMA-positive metastases was 9.84 ± 4.94 in 2D ROI and 10.27 ± 5.28 in 3D ROI; the mean SUVmax of PSMA-negative metastases was 3.25 ± 1.81 in 2D ROI and 3.40 ± 1.78 in 3D ROI, and significantly lower than that of the normal liver tissue (p ≤ 0.05). A significant (p ≤ 0.05) correlation between SUVmax in PSMA-positive liver metastases and both size (ρSpearman = 0.57) of metastases and PSA serum level (ρSpearman = 0.60) was found. CONCLUSIONS: In 68Ga-PSMA-PET, the majority of liver metastases highly overexpress PSMA and is therefore directly detectable. For the analysis of PET images, it has to be taken into account that also a significant portion of metastases can only be detected indirectly, as these metastases are PSMA-negative.
Asunto(s)
Neoplasias Hepáticas/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Anciano , Ácido Edético/análogos & derivados , Isótopos de Galio , Radioisótopos de Galio , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Oligopéptidos , Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Neoplasias de la Próstata/patología , RadiofármacosRESUMEN
BACKGROUND: International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10-41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy. METHODS: We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18-95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15-30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022. FINDINGS: Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0-60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6-63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI -8·6%; pnon-inferiority=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526). INTERPRETATION: Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms. FUNDING: The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.