Pericardial effusion in oncological patients: current knowledge and principles of management.

BACKGROUND: This article provides an up-to-date overview of pericardial effusion in oncological practice and a guidance on its management. Furthermore, it addresses the question of when malignancy should be suspected in case of newly diagnosed pericardial effusion. MAIN BODY: Cancer-related pericardial effusion is commonly the result of localization of lung and breast cancer, melanoma, or lymphoma to the pericardium via direct invasion, lymphatic dissemination, or hematogenous spread. Several cancer therapies may also cause pericardial effusion, most often during or shortly after administration. Pericardial effusion following radiation therapy may instead develop after years. Other diseases, such as infections, and, rarely, primary tumors of the pericardium complete the spectrum of the possible etiologies of pericardial effusion in oncological patients. The diagnosis of cancer-related pericardial effusion is usually incidental, but cancer accounts for approximately one third of all cardiac tamponades. Drainage, which is mainly attained by pericardiocentesis, is needed when cancer or cancer treatment-related pericardial effusion leads to hemodynamic impairment. Placement of a pericardial catheter for 2-5 days is advised after pericardial fluid removal. In contrast, even a large pericardial effusion should be conservatively managed when the patient is stable, although the best frequency and timing of monitoring by echocardiography in this context are yet to be established. Pericardial effusion secondary to immune checkpoint inhibitors typically responds to corticosteroid therapy. Pericardiocentesis may also be considered to confirm the presence of neoplastic cells in the pericardial fluid, but the yield of cytological examination is low. In case of newly found pericardial effusion in individuals without active cancer and/or recent cancer treatment, a history of malignancy, unremitting or recurrent course, large effusion or presentation with cardiac tamponade, incomplete response to empirical therapy with nonsteroidal anti-inflammatory, and hemorrhagic fluid at pericardiocentesis suggest a neoplastic etiology.

Development of a performance rubric for transanal endoscopic rectal purse-string sutures.

BACKGROUND: Placing a transanal endoscopic rectal purse-string suture (taEPS) is the crucial first component of transanal total mesorectal excision (taTME). However, no structured training is available to improve the procedure-specific skills for taEPS. The aim of this study was to create a performance rubric to improve taEPS skills and provide preliminary evidence for its validity. METHODS: A performance rubric was created based on technical considerations for taEPS, identified by consulting with taTME surgical and performance assessment experts. Ten independent, blinded raters assessed 10 videotaped taEPS procedures of consecutive taTME cases, at National Cancer Center Hospital East (NCCHE), Chiba, Japan, in January 2018-March 2019 using the rubric and the Global Operative Assessment of Laparoscopic Skills (GOALS). Internal consistency and inter-rater reliabilities were calculated. Videotaped taEPS procedures were timed and assessed by the rubric. Correlation between rubric scores and suturing times were analyzed. RESULTS: The rubric consists of four items: loading the needle (LN), atraumatic needle passage (AP), planned suture path (PS), and overall performance (OA). Videotaped performances were graded on a 3-point Likert scale; scores were calculated as sums of the points. Cronbach's α for internal consistency was 0.713. Inter-rater reliabilities were LN: 0.73, AP: 0.76, PS: 0.71, and OA: 0.70. Rubric and GOALS scores were strongly correlated (r = 0.964, p < 0.001). In 112 consecutive taEPS performances, rubric scores were strongly correlated with suturing time (r = - 0.69, p < 0.001). Surgeons' experience with taTME was associated with rubric scores and suturing time. CONCLUSIONS: This study provides preliminary validation for the taEPS skill performance rubric. The rubric's structured training may facilitate skill acquisition by providing trainees with critical clinical considerations.

Superomedial pedicle skin-reducing mastectomy in ptotic and large-sized breasts with two-stage reconstruction through transaxillary video-assisted technique: An effective surgical and anesthetic approach.

Introduction: Skin-reducing mastectomy has been applied to several surgical techniques in which subcutaneous mastectomy is associated with various types of skin reduction, with preservation of a lower dermal flap to reinforce the inferior lateral seat of an implant. The aim of the study is to present a case series of patients with pendulous/ptotic and/or large-sized breasts treated for breast cancer at the Breast Surgery Unit of Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy, with the superomedial pedicle skin-reducing mastectomy technique, two-stage reconstruction, and transaxillary video-assisted technique, when a postoperative radiotherapy was indicated. We verified its effectiveness by discussing its results, especially in patients who are candidates for postmastectomy radiotherapy. Materials and methods: A single-center retrospective study was performed between January 2020 and March 2021 on a prospectively filled database of conservative mastectomies. Of the 64 patients who underwent nipple/skin-sparing mastectomies in the mentioned period, 17 (mean age 46 years, range 30-62 years) were treated with superomedial pedicle skin-reducing mastectomy, with two-stage breast reconstruction through transaxillary video-assisted replacement expander with definitive prosthesis and contralateral symmetrization, selected for postmastectomy radiotherapy. Results: We had only three minor complications. No flap necrosis, no infections, no breast seromas, and no reconstructive failures were observed. During follow-up of the patients treated with video-assisted reconstruction, there were no cases of infection, hematoma, implant rupture, or suture dehiscence in the reconstructed breast. Discussion: Skin-reducing mastectomy with superomedial pedicle is a safe and reliable procedure to treat breast cancer in selected patients, i.e., those with pendulous/ptotic and or large-sized breasts. Particularly, in patients who undergo postmastectomy radiotherapy, the two-stage reconstruction with video-assisted transaxillary endoscopic approach can find its main indication, using incisions positioned far from the mammary region, offering numerous advantages.

A randomized, controlled trial of once-weekly teriparatide injection versus alendronate in patients at high risk of osteoporotic fracture: primary results of the Japanese Osteoporosis Intervention Trial-05.

In this randomized, controlled trial, treatment with once-weekly subcutaneous injection of teriparatide for 72 weeks was found to be associated with a significant reduction in the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. INTRODUCTION: To determine whether the anti-fracture efficacy of teriparatide is superior to that of alendronate, a prospective, randomized, open-label, blinded-endpoint trial was performed. METHODS: Japanese women aged at least 75 years were eligible for the study if they had primary osteoporosis and were at high risk of fracture. Patients were randomly assigned in a 1:1 ratio to receive sequential therapy (once-weekly subcutaneous injection of teriparatide 56.5 µg for 72 weeks followed by alendronate for 48 weeks) or monotherapy with alendronate for 120 weeks. The primary endpoint was the incidence of morphometric vertebral fractures at 72 weeks (at the end of teriparatide treatment). RESULTS: Between October 2014 and December 2017, 1011 patients (505 in the teriparatide group and 506 in the alendronate group) were enrolled. Of these, 778 patients (351 and 427, respectively) were included in the primary analysis. The incidence of morphometric vertebral fractures was significantly lower in the teriparatide group (56 per 419.9 person-years, annual incidence rate 0.1334) than in the alendronate group (96 per 553.6 person-years, annual incidence rate 0.1734), with a rate ratio of 0.78 (95% confidence interval 0.61 to 0.99, P = 0.04). In both groups, adverse events were most frequently reported in the following system organ classes: infections and infestations, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. CONCLUSION: Once-weekly subcutaneous injection of teriparatide significantly reduced the incidence of morphometric vertebral fractures compared with alendronate in women with primary osteoporosis who were at high risk of fracture. TRIAL REGISTRATION: jRCTs031180235 and UMIN000015573, March 12, 2019.

Mechanical regulation of bone homeostasis through p130Cas-mediated alleviation of NF-κB activity.

Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions. Here, we demonstrate that Cas is distributed in the nucleus and supports mechanical loading-mediated bone homeostasis by alleviating NF-κB activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-κB activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-κB-mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-κB activity. Collectively, fluid shear stress-dependent Cas-mediated alleviation of NF-κB activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-κB together with systemic distribution of interstitial fluid, the Cas-NF-κB interplay may also underpin regulatory mechanisms in other tissues and organs.

Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer.

BACKGROUND: Accumulating evidence suggests that radiotherapy success has an immune-associated component. The immunogenomic profiles associated with responses to chemoradiotherapy (CRT) were assessed in patients with locally advanced rectal cancer in this study. METHODS: CD8+ tumour-infiltrating lymphocyte (TIL) and stromal lymphocyte densities were assessed by immunohistochemistry using pretreatment biopsies from patients with advanced rectal cancer who had preoperative CRT. Whole-exome sequencing and gene expression microarray analysis were conducted to investigate the genomic properties associated with the response to CRT and CD8+ TIL density. Response to CRT was determined based on Dworak tumour regression grade (TRG); tumours with complete (TRG 4) or near-complete (TRG 3) regression were grouped as good responders, and those with TRG 1 as non-responders. RESULTS: Immunohistochemical examinations (275 patients) showed that pre-CRT CD8+ TIL density was associated with better response to CRT and improved recurrence-free survival, whereas pre-CRT stromal CD8+ cell density was not associated with either response to CRT or recurrence-free survival. Whole-exome sequencing (74 patients) showed that the numbers of single-nucleotide variations (SNVs) and neoantigens predicted from SNVs were higher in good responders than in non-responders, and these correlated positively with CD8+ TIL density (rS = 0·315 and rS = 0·334 respectively). Gene expression microarray (90 patients) showed that CD8A expression correlated positively with the expression of programmed cell death 1 (PDCD1) (rS = 0·264) and lymphocyte-activation gene 3 (LAG3) (rS = 0·507). CONCLUSION: Pre-CRT neoantigen-specific CD8+ T cell priming may be a key event in CRT responses where immune checkpoint molecules could be useful targets to enhance tumour regression.

ANTECEDENTES: Las evidencias existentes sugieren que el éxito de la radioterapia tiene un componente asociado con el sistema inmunitario. En este estudio se evaluaron los perfiles inmunogenómicos asociados con la respuesta a la quimiorradioterapia (chemoradiotherapy, CRT) en pacientes con cáncer de recto localmente avanzado. MÉTODOS: Las densidades de los linfocitos infiltrantes de tumor CD8+ (tumour-infiltrating lymphocyte, TIL) y de los linfocitos del estroma se evaluaron por inmunohistoquímicas en las biopsias antes del tratamiento de pacientes con cáncer de recto localmente avanzado que recibieron CRT preoperatoria. Se realizó secuenciación de todo el exoma, así como microarrays de expresión génica, para investigar las propiedades genómicas asociadas con la respuesta a la CRT y a la densidad de los TIL CD8+. La respuesta a la CRT se determinó según el grado de regresión del tumor de Dworak (tumour regression grade, TRG), agrupándose como buenos respondedores los casos de regresión tumoral completa (TRG4) o casi completa (TRG3) y como no respondedores, los casos de grado TRG1. RESULTADOS: Los exámenes inmunohistoquímicos (n = 275) mostraron que la densidad pre-CRT de TIL CD8+ se asoció con una mejor respuesta a la CRT y una mejor supervivencia libre de recidiva, aunque la densidad de células CD8+ del estroma previa a la CRT no se asoció con la respuesta a la CRT ni con la supervivencia libre de recidiva. La secuenciación de todo el exoma (n = 74) mostró que el número de variaciones de nucleótidos únicos (single nucleotide variations, SNVs) y los neoantígenos predichos a partir de los SNVs fueron mayores en los que respondieron bien que en los que no respondieron, y éstos se correlacionaron positivamente con la densidad de los TIL CD8+ (Spearman r = 0,315 y r = 0,334 respectivamente). Los microarrays de expresión génica (n = 90) mostraron que la expresión CD8A se correlacionó positivamente con la expresión del ligando de muerte programada-1 (r = 0,264) y con el antígeno linfocitario del gen 3 (r = 0,507). CONCLUSIÓN: La activación de células T CD8+ específicas para neoantígenos previa a la CRT puede ser un evento clave en la respuesta a la misma donde las moléculas del punto de control inmunitario podrían ser dianas útiles para intensificar la regresión del tumor.

Beyond the physician's perspective: A review of patient-reported outcomes in dermatologic surgery and cosmetic dermatology.

Patient-reported outcome measures (PROMs) are utilized in health care to quantify the patient's perspective of a health condition or treatment on outcomes, such as health-related quality of life (HRQoL) and patient satisfaction. In dermatology, this is particularly relevant because the patient's perspective is critical in evaluating the outcome of cosmetic procedures as well as skin cancer treatment. We review seven validated PROMs that have been reported in the dermatologic surgery and cosmetic dermatology literature. For patients undergoing cosmetic procedures, the use of PROMs provides additional valuable outcome data beyond physician assessment. For patients with skin cancer, women experience a unique and often greater impact on HRQoL during treatment, which has been captured through PROMs. The recent development of multi-module instruments, such as the FACE-Q and FACE-Q Skin Cancer, have facilitated comprehensive assessments of treatment that impact multiple domains of HRQoL. The use of PROMs allows for dermatologists to reliably capture important disease- and treatment-related concerns, thus improving the patient experience.

Preliminary Study on Prevalence and Associated Factors with Sarcopenia in a Geriatric Hospitalized Rehabilitation Setting.

The reported prevalence of sarcopenia has shown a wide range, crucially based on the diagnostic criteria and setting. This cross-sectional study evaluated the prevalence of sarcopenia and sought to identify factors associated with sarcopenia on admission in a specialized geriatric rehabilitation setting based on the newly developed the Asian Working Group for Sarcopenia algorithm. Among 87 participants (mean age, 76.05 ± 7.57 years), 35 (40.2%) were classified as showing sarcopenia on admission. Prevalence was high, particularly among participants ≥80 years old, with tendencies toward lower body mass index, smoking habit, lower cognitive function, and greater functional impairment compared with the non-sarcopenic group. Identification of sarcopenia in elderly patients before rehabilitation and consideration of risk factors may prove helpful in achieving rehabilitation outcomes.

Chiral Surface Twists and Skyrmion Stability in Nanolayers of Cubic Helimagnets.

Theoretical analysis and Lorentz transmission electron microscopy (LTEM) investigations in an FeGe wedge demonstrate that chiral twists arising near the surfaces of noncentrosymmetric ferromagnets [Meynell et al., Phys. Rev. B 90, 014406 (2014)] provide a stabilization mechanism for magnetic Skyrmion lattices and helicoids in cubic helimagnet nanolayers. The magnetic phase diagram obtained for freestanding cubic helimagnet nanolayers shows that magnetization processes differ fundamentally from those in bulk cubic helimagnets and are characterized by the first-order transitions between modulated phases. LTEM investigations exhibit a series of hysteretic transformation processes among the modulated phases, which results in the formation of the multidomain patterns.

Multi-site study of diffusion metric variability: effects of site, vendor, field strength, and echo time on regions-of-interest and histogram-bin analyses.

It is now common for magnetic-resonance-imaging (MRI) based multi-site trials to include diffusion-weighted imaging (DWI) as part of the protocol. It is also common for these sites to possess MR scanners of different manufacturers, different software and hardware, and different software licenses. These differences mean that scanners may not be able to acquire data with the same number of gradient amplitude values and number of available gradient directions. Variability can also occur in achievable b-values and minimum echo times. The challenge of a multi-site study then, is to create a common protocol by understanding and then minimizing the effects of scanner variability and identifying reliable and accurate diffusion metrics. This study describes the effect of site, scanner vendor, field strength, and TE on two diffusion metrics: the first moment of the diffusion tensor field (mean diffusivity, MD), and the fractional anisotropy (FA) using two common analyses (region-of-interest and mean-bin value of whole brain histograms). The goal of the study was to identify sources of variability in diffusion-sensitized imaging and their influence on commonly reported metrics. The results demonstrate that the site, vendor, field strength, and echo time all contribute to variability in FA and MD, though to different extent. We conclude that characterization of the variability of DTI metrics due to site, vendor, field strength, and echo time is a worthwhile step in the construction of multi-center trials.

Multi-site Study of Diffusion Metric Variability: Characterizing the Effects of Site, Vendor, Field Strength, and Echo Time using the Histogram Distance.

MRI-based multi-site trials now routinely include some form of diffusion-weighted imaging (DWI) in their protocol. These studies can include data originating from scanners built by different vendors, each with their own set of unique protocol restrictions, including restrictions on the number of available gradient directions, whether an externally-generated list of gradient directions can be used, and restrictions on the echo time (TE). One challenge of multi-site studies is to create a common imaging protocol that will result in a reliable and accurate set of diffusion metrics. The present study describes the effect of site, scanner vendor, field strength, and TE on two common metrics: the first moment of the diffusion tensor field (mean diffusivity, MD), and the fractional anisotropy (FA). We have shown in earlier work that ROI metrics and the mean of MD and FA histograms are not sufficiently sensitive for use in site characterization. Here we use the distance between whole brain histograms of FA and MD to investigate within- and between-site effects. We concluded that the variability of DTI metrics due to site, vendor, field strength, and echo time could influence the results in multi-center trials and that histogram distance is sensitive metrics for each of these variables.

Human induced pluripotent stem cell-derived fiber-shaped cardiac tissue on a chip.

We propose a method for the production of a fiber-shaped three-dimensional (3D) cellular construct of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for the quantification of the contractile force. By culturing the cardiomyocytes in a patterned hydrogel structure with fixed edges, we succeeded in fabricating hiPS-CM fibers with aligned cardiomyocytes. The fiber generated contractile force along the fiber direction due to the hiPS-CM alignment, and we were able to measure its contractile force accurately. Furthermore, to demonstrate the drug reactivity of hiPS-CM fibers, the changes in the contractile frequency and force following treatment with isoproterenol and propranolol were observed. We believe that hiPS-CM fibers will be a useful tool for pharmacokinetic analyses during drug development.

Effects of Cold Stimulation on Mitochondrial Activity and VEGF Expression in vitro.

We aimed to clarify the effects of cold stimulation at various temperatures on mitochondrial activity and vascular endothelial growth factor (VEGF) expression in vitro. Human fibroblast, human mesenchymal stem cell, and rat skeletal muscle myoblast cell lines were used. For each cell type, cells were divided into 4 groups and stimulated in various cold temperatures (0, 4, 17 and 25°C) 3 times for 15 min each by placement on crushed ice or floating on cold water set at each temperature. Control cells were subjected to warm water at 37°C. Factors related to mitochondrial activity, mitochondrial DNA copy numbers, and VEGF expression were analyzed 24 h after the last cold stimulation. In all cell types, significant increases of factors related to mitochondrial activity and mitochondrial DNA copy numbers were seen in the 4°C and 17°C-stimulated cells compared with control cells. In rat skeletal muscle cells stimulated at 4°C, VEGF expression significantly increased compared to the control cells. Our data suggest that cold stimulation at certain temperatures promotes mitochondrial activity, biogenesis and VEGF expression.

Lectin-like oxidized low density lipoprotein receptor 1-deficient mice show resistance to instability-induced osteoarthritis.

OBJECTIVES: The lectin-like oxidized low density lipoprotein (ox-LDL) receptor 1 (LOX-1)/ox-LDL system, which contributes to the pathogenesis of atherosclerosis, may be involved in the development of osteoarthritis (OA). However, the mechanisms by which the LOX-1/ox-LDL system contributes to OA development in vivo are unclear. In this study, we investigated the direct involvement of LOX-1/ox-LDL in OA development by using LOX-1-knockout (LOX-1(-)/(-)) mice in a joint instability-induced model of OA. METHOD: OA development was evaluated with histological scoring at 4 and 8 weeks after surgery to induce knee destabilization in LOX-1(+)/(+) and LOX-1(-)/(-) mice. Immunohistological analysis was used to evaluate the expression of LOX-1, ox-LDL, Runt-related transcription factor 2 (Runx2), and type X collagen (COL X) in articular chondrocytes and osteophyte-forming cells. In addition, double immunofluorescence staining was performed to determine the relationships between LOX-1 and Runx2 or COL X expression. RESULTS: In the model of knee destabilization, symptoms were significantly suppressed in LOX-1(-)/(-) mice. LOX-1, ox-LDL, Runx2, and COL X were overexpressed in articular chondrocytes and osteophyte-forming cells in LOX-1(+)/(+) mice and were significantly downregulated in articular chondrocytes and osteophyte-forming cells in LOX-1(-)/(-) mice compared with those in LOX-1(+)/(+) mice. Double immunostaining indicated that LOX-1 localization coincided with Runx2 and COL X expression. CONCLUSIONS: These data indicate that the LOX-1/ox-LDL system plays a pivotal role in the pathogenesis of instability-induced OA through endochondral ossification. LOX-1-positive chondrocytes and osteophyte-forming cells may be possible targets to prevent disease progression in OA.

Cerebral Reorganization after Hemispherectomy: A DTI Study.

BACKGROUND AND PURPOSE: Hemispherectomy is a neurosurgical procedure to treat children with intractable seizures. Postsurgical improvement of cognitive and behavioral functions is observed in children after hemispherectomy suggesting plastic reorganization of the brain. Our aim was to characterize changes in DTI scalars in WM tracts of the remaining hemisphere in children after hemispherectomy, assess the associations between WM DTI scalars and age at the operation and time since the operation, and evaluate the changes in GM fractional anisotropy values in patients compared with controls. MATERIALS AND METHODS: Patients with congenital or acquired neurologic diseases who required hemispherectomy and had high-quality postsurgical DTI data available were included in this study. Atlas- and voxel-based analyses of DTI raw data of the remaining hemisphere were performed. Fractional anisotropy and mean, axial, and radial diffusivity values were calculated for WM and GM regions. A linear regression model was used for correlation between DTI scalars and age at and time since the operation. RESULTS: Nineteen patients after hemispherectomy and 21 controls were included. In patients, a decrease in fractional anisotropy and axial diffusivity values and an increase in mean diffusivity and radial diffusivity values of WM regions were observed compared with controls (P < .05, corrected for multiple comparisons). In patients with acquired pathologies, time since the operation had a significant positive correlation with white matter fractional anisotropy values. In all patients, an increase in cortical GM fractional anisotropy values was found compared with controls (P < .05). CONCLUSIONS: Changes in DTI metrics likely reflect Wallerian and/or transneuronal degeneration of the WM tracts within the remaining hemisphere. In patients with acquired pathologies, postsurgical fractional anisotropy values correlated positively with elapsed time since the operation, suggesting a higher ability to recover compared with patients with congenital pathologies leading to hemispherectomy.

Wavelength-selective light-triggered strand exchange reaction.

We prepared an oligodeoxynucleotide (ODN) bearing two 4-hydroxy-2-mercaptobenzimidazole nucleobase analogues (SB(NV) and SB(NB)) modified with different photolabile groups. This ODN enabled a light-triggered strand exchange reaction in a wavelength-selective manner.

Predicting future uncertainty constraints on global warming projections.

Projections of global mean temperature changes (ΔT) in the future are associated with intrinsic uncertainties. Much climate policy discourse has been guided by "current knowledge" of the ΔTs uncertainty, ignoring the likely future reductions of the uncertainty, because a mechanism for predicting these reductions is lacking. By using simulations of Global Climate Models from the Coupled Model Intercomparison Project Phase 5 ensemble as pseudo past and future observations, we estimate how fast and in what way the uncertainties of ΔT can decline when the current observation network of surface air temperature is maintained. At least in the world of pseudo observations under the Representative Concentration Pathways (RCPs), we can drastically reduce more than 50% of the ΔTs uncertainty in the 2040 s by 2029, and more than 60% of the ΔTs uncertainty in the 2090 s by 2049. Under the highest forcing scenario of RCPs, we can predict the true timing of passing the 2 °C (3 °C) warming threshold 20 (30) years in advance with errors less than 10 years. These results demonstrate potential for sequential decision-making strategies to take advantage of future progress in understanding of anthropogenic climate change.