bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduction of inter-observer differences in the delineation of the target in spinal metastases SBRT using an automatic contouring dedicated system
Authors: Giaj-Levra Niccolò , Figlia Vanessa , Cuccia Francesco , Mazzola Rosario , Nicosia Luca , Ricchetti Francesco , Rigo Michele , Attinà Giorgio , Vitale Claudio , Sicignano Gianluisa , De Simone Antonio , Naccarato Stefania , Ruggieri Ruggero , Alongi Filippo 
Published: October 2021

Abstract
Background
Approximately one third of cancer patients will develop spinal metastases, that can be associated with back pain, neurological symptoms and deterioration in performance status. Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) have been offered in clinical practice mainly for the management of oligometastatic and oligoprogressive patients, allowing the prescription of high total dose delivered in one or few sessions to small target volumes, minimizing the dose exposure of normal tissues. Due to the high delivered doses and the proximity of critical organs at risk (OAR) such as the spinal cord, the correct definition of the treatment volume becomes even more important in SBRT treatment, thus making it necessary to standardize the method of target definition and contouring, through the adoption of specific guidelines and specific automatic contouring tools. An automatic target contouring system for spine SBRT is useful to reduce inter-observer differences in target definition. In this study, an automatic contouring tool was evaluated.

Methods
Simulation CT scans and MRI data of 20 patients with spinal metastases were evaluated. To evaluate the advantage of the automatic target contouring tool (Elements SmartBrush Spine), which uses the identification of different densities within the target vertebra, we evaluated the agreement of the contours of 20 spinal target (2 cervical, 9 dorsal and 9 lumbar column), outlined by three independent observers using the automatic tool compared to the contours obtained manually, and measured by DICE similarity coefficient.

Results
The agreement of GTV contours outlined by independent operators was superior with the use of the automatic contour tool compared to manually outlined contours (mean DICE coefficient 0.75 vs 0.57, p = 0.048).

Conclusions
The dedicated contouring tool allows greater precision and reduction of inter-observer differences in the delineation of the target in SBRT spines. Thus, the evaluated system could be useful in the setting of spinal SBRT to reduce uncertainties of contouring increasing the level of precision on target delivered doses.
Pulmonary nodular lymphoid hyperplasia in a 53-year-old man with malignant sign: a case report
Authors: Yang Zhen , Wei Lianshuang , Li Xu , Liu Xin 
Published: October 2021

Abstract
Background
Pulmonary nodular lymphoid hyperplasia (PNLH) is a rare benign illness. Due to atypical clinical and radiographic presentations, diagnosis largely depends on postoperative pathological examination. Thus, preoperative misdiagnosis is often occurred.

Case presentation
We present a case of asymptomatic PNLH that was seen as ground-glass opacity (GGO) on computed tomography (CT). After 3-year observation, the diagnosis tends to adenocarcinoma owing to increasing density of the node and vessel convergence sign, which were signs of malignancy. Video-assisted segmentectomy (S10) was carried out. Histopathologic examination of postoperative specimen showed follicular lymphoid hyperplasia with interfollicular lymphoplasmacytosis, consistent with PNLH. The follow-up chest CT images showed no recurrence or metastasis.

Conclusion
Although it is a benign disease, PNLH can exhibit malignant signs in the imaging examinations, which could lead to misdiagnosis. This reminds us of the uncertainty between imaging findings and diagnosis. The diagnosis depends on postoperative pathological examination. Volume doubling time is a potential parameter to differentiate PNLH from lung cancer.
Hepatic dysfunction in patients who received acute DeBakey type I aortic dissection repair surgery: incidence, risk factors, and long-term outcomes
Authors: Wang Zhigang , Ge Min , Chen Cheng , Lu Lichong , Zhang Lifang , Wang Dongjin 
Published: October 2021

Abstract
Background
Hepatic dysfunction (HD) increases the morbidity and mortality rates after cardiac surgery. However, few studies have investigated the association between HD and acute DeBakey type I aortic dissection (ADIAD) surgery. This retrospective study aimed to identify risk factors for developing HD in patients who received acute type I aortic dissection repair and its consequences.

Methods
A total of 830 consecutive patients who received ADIAD surgery from January 2014 to December 2019 at our center were screened for this study. The End-Stage Liver Disease (MELD) score more than 14 was applied to identify postoperative HD. Logistic regression model was applied to identify risk factors for postoperative HD, Kaplan–Meier survival analysis and Cox proportional hazards regression assay were conducted to analyze the association between HD and postoperative long-term survival.

Results
Among 634 patients who eventually enrolled in this study, 401 (63.2%) experienced postoperative HD with a 30-Day mortality of 15.5%. Preoperative plasma fibrinogen level (PFL) [odds ratio (OR): 0.581, 95% confidence interval (CI): 0.362–0.933, P = 0.025], serum creatinine (sCr) on admission (OR: 1.050, 95% CI 1.022–1.079, P < 0.001), cardiopulmonary bypass (CPB) time (OR: 1.017, 95% CI 1.010–1.033, P = 0.039), and postoperative mechanical ventilation (MV) duration (OR: 1.019, 95% CI 1.003–1.035, P = 0.020) were identified as independent risk factors for developing postoperative HD by multivariate analyses. In addition, the Kaplan–Meier analysis indicated that the long-term survival rate was significantly different between patients with or without postoperative HD. However, the hazard ratios of long-term survival for these two groups were not significantly different.

Conclusions
HD was a common complication after ADIAD surgery and associated with an increasing 30-Day mortality rate. Decreased PFL, elevated sCr, prolonged CPB duration, and longer postoperative MV time were independent risk factors for postoperative HD.
Integrated Chinese and western medicine interventions for atopic dermatitis: a systematic review and meta-analysis
Authors: Sum Chi Him , Ching Jessica , Zhang Hongwei , Loo Steven , Lo Cho Wing , Lai Mei Kwan , Cheong Pui Kuan , Yu Chau Leung , Lin Zhi-xiu 
Published: October 2021

Abstract
Background
Atopic dermatitis (AD) is a chronic relapsing skin disease characterized by recurring episodes of itchiness with skin erythema and surface damages. Chinese medicine (CM) is widely used for the management of AD in China not only by its own, but also used in combination with conventional therapy (integrated Chinese-Western medicine, ICWM). Although many clinical trials on the effectiveness of ICWM on AD have been conducted, however, up to date, no sound evidence has been established on the clinical effectiveness and safety of ICWM for AD.

Objectives
To systematically review the currently available clinical evidence on the clinical effectiveness and safety of ICWM for AD.

Methods
Randomised and quasi-randomised controlled trials, which investigated ICWM interventions with at least one control group using the same conventional interventions, no treatment or placebo treatment, were included. Four English (CENTRAL, MEDLINE, EMBASE, AMED) and three Chinese (CNKI, CBM, WanFang Med) databases were searched. Risk of bias was assessed according to the Cochrane’s tool. Meta-analysis was performed to pool the data.

Results
From 1473 entries, 55 studies were included, involving 5953 participants aged between 35 days and 67 years old. Duration of treatment ranged from 1 to 24 weeks. Only 2 studies were judged to have low risk of bias, 3 studies had unclear risk of bias, and the other 50 studies were with high risk of bias. ICWM was found to be superior over WM alone in improving clinical severity of AD (measured by EASI, SCORAD), health-related quality of life (measured by CDLQI, DLQI), long term control of AD (recurrence rate), patients/investigator global score (clinical effectiveness rate), and serum IgE level. Adverse events associated with ICWM were found to be comparable with WM alone.

Conclusion
ICWM seems to produce superior treatment response than WM alone in managing AD without increased risk of adverse events. However, the current available evidence remains too weak to make a conclusive decision.
Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases
Authors: Ardissone Anna , Bruno Claudio , Diodato Daria , Donati Alice , Ghezzi Daniele , Lamantea Eleonora , Lamperti Costanza , Mancuso Michelangelo , Martinelli Diego , Primiano Guido , Procopio Elena , Rubegni Anna , Santorelli Filippo , Schiaffino Maria Cristina , Servidei Serenella , Tubili Flavia , Bertini Enrico , Moroni Isabella 
Published: October 2021

Abstract
Background
Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.

Results
Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.

Conclusion
We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.
Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF©
Authors: Taylor Fiona , Akin Cem , Lamoureux Roger E. , Padilla Brad , Green Tanya , Boral Anthony L. , Mazar Iyar , Mar Brenton , Shields Alan L. , Siebenhaar Frank 
Published: October 2021

AbstractBackgroundAdvanced systemic mastocytosis (AdvSM), indolent systemic mastocytosis (ISM), and smoldering systemic mastocytosis (SSM) are rare diseases characterized by neoplastic mast cell infiltration of more than one organ. A content-valid patient-reported outcome (PRO) questionnaire that assesses relevant signs and symptoms that are important and understandable to individuals with a condition is critical for assessing new treatment benefit as well as supporting product labeling claims. Notably, no such PRO questionnaire has been developed in accordance with regulatory and scientific guidelines for use in AdvSM, ISM, and SSM patient populations. To fill that gap, this study documents the development and content validity of instruments evaluating signs and symptoms of systemic mastocytosis.MethodsA review of peer-reviewed literature, advice meetings with clinical therapeutic area experts, patient concept elicitation interviews, concept selection and questionnaire construction meetings, and patient cognitive debriefing interviews were conducted, and regulatory feedback was incorporated.ResultsFor AdvSM, 26 sign- and symptom-level concepts were identified in literature, 39 by clinicians, and 33 by patients. For ISM/SSM, 38 sign- and symptom-level concepts were identified in the literature, 39 by clinicians, and 57 by patients. Two patient-reported instruments, the Advanced Systemic Mastocytosis Symptom Assessment Form (AdvSM-SAF) and Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF)(©Blueprint Medicines Corporation), were developed based on consolidated findings. Cognitive debriefing interviews with AdvSM and ISM patients showed the AdvSM-SAF and ISM-SAF were understood and interpreted as intended by the majority of patients.ConclusionThe AdvSM-SAF and ISM-SAF are content-valid tools measuring symptoms from AdvSM and ISM patients’ perspective.
Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias
Authors: Fattizzo Bruno , Giannotta Juri Alessandro , Cecchi Nicola , Barcellini Wilma 
Published: October 2021

AbstractCongenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
Nintedanib in idiopathic and secondary pleuroparenchymal fibroelastosis
Authors: Nasser Mouhamad , Si-Mohamed Salim , Turquier Ségolène , Traclet Julie , Ahmad Kaïs , Philit François , Bonniaud Philippe , Chalabreysse Lara , Thivolet-Béjui Françoise , Cottin Vincent 
Published: October 2021

Abstract
Background
Pleuroparenchymal fibroelastosis (PPFE) has a variable disease course with dismal prognosis in the majority of patients with no validated drug therapy. This study is to evaluate the effect of nintedanib in patients with idiopathic and secondary PPFE. Patients admitted to a tertiary care center (2010–2019) were included into this retrospective analysis if they had a multidisciplinary diagnosis of PPFE, had been followed-up for 3 months or more, and had lung function tests and chest CTs available for review. Changes in pulmonary function tests were assessed using non-parametric tests and linear mixed effect model. Lung volumes were measured with lobar segmentation using chest CT.

Results
Out of 21 patients with PPFE, nine had received nintedanib, six had received another treatment and another six patients were monitored without drug therapy. Annual FVC (% of predicted) relative decline was − 13.6 ± 13.4%/year before nintedanib and − 1.6 ± 6.02%/year during nintedanib treatment (p = 0.014), whereas no significant change in FVC% relative decline was found in patients receiving another treatment (− 13.25 ± 34 before vs − 16.61 ± 36.2%/year during treatment; p = 0.343). Using linear mixed effect model, the slope in FVC was − 0.97%/month (95% CI: − 1.42; − 0.52) before treatment and − 0.50%/month (95% CI: − 0.88; 0.13) on nintedanib, with a difference between groups of + 0.47%/month (95% CI: 0.16; 0.78), p = 0.004. The decline in the upper lung volumes measured by CT was − 233 mL/year ± 387 mL/year before nintedanib and − 149 mL/year ± 173 mL/year on nintedanib (p = 0.327). Nintedanib tolerability was unremarkable.

Conclusion
In patients with PPFE, nintedanib treatment might be associated with slower decline in lung function, paving the way for prospective, controlled studies.
Executive functions and quality of life in children with neurofibromatosis type 1
Authors: Roy Arnaud , Roulin Jean-Luc , Gras-Le Guen Christèle , Corbat Marie-Laure , Barbarot Sébastien 
Published: October 2021

AbstractBackgroundTo examine the impact of executive function disorders on health-related quality of life (QoL) in children with neurofibromatosis type 1 (NF1), we conducted a prospective single-center study among 40 children with NF1 aged 8–12 years (mean = 9.7,SD = 1.4) and their parents, comparing them with 56 healthy control children matched for age, sex, parental education level, and handedness. We collected children’s self-reports and parents’ proxy reports of QoL with the Kidscreen-52 questionnaire, and measured executive functions by combining seven performance-based tests and a daily life questionnaire completed by parents and teachers.ResultsSeveral QoL domains were significantly impaired in the children with NF1, compared with healthy controls, mainly according to their parents’ reports (3 out of 9 scales; Cohen’sd: 0.57–0.76), with particularly low scores in the social support and peers and school environment domains. Executive function difficulties (Cohen’sd: 0.64–1.72) significantly predicted the impairment of QoL domains as perceived by the children or their parents, regardless of the indirect indicators of learning disabilities.ConclusionsBoth performance-based executive function scores and behavioral ratings of executive functions in daily life by parents and teachers were associated with low QoL levels in the children with NF1. The school environment and social integration appear to be particularly affected and should therefore be targeted in the management of the disease.
Postsynaptic structure formation of human iPS cell-derived neurons takes longer than presynaptic formation during neural differentiation in vitro
Authors: Togo Kazuyuki , Fukusumi Hayato , Shofuda Tomoko , Ohnishi Hiroshi , Yamazaki Hiroyuki , Hayashi Mariko Kato , Kawasaki Nana , Takei Nobuyuki , Nakazawa Takanobu , Saito Yumiko , Baba Kousuke , Hashimoto Hitoshi , Sekino Yuko , Shirao Tomoaki , Mochizuki Hideki , Kanemura Yonehiro 
Published: October 2021

AbstractThe generation of mature synaptic structures using neurons differentiated from human-induced pluripotent stem cells (hiPSC-neurons) is expected to be applied to physiological studies of synapses in human cells and to pathological studies of diseases that cause abnormal synaptic function. Although it has been reported that synapses themselves change from an immature to a mature state as neurons mature, there are few reports that clearly show when and how human stem cell-derived neurons change to mature synaptic structures. This study was designed to elucidate the synapse formation process of hiPSC-neurons. We propagated hiPSC-derived neural progenitor cells (hiPSC-NPCs) that expressed localized markers of the ventral hindbrain as neurospheres by dual SMAD inhibition and then differentiated them into hiPSC-neurons in vitro. After 49 days of in vitro differentiation, hiPSC-neurons significantly expressed pre- and postsynaptic markers at both the transcript and protein levels. However, the expression of postsynaptic markers was lower than in normal human or normal rat brain tissues, and immunostaining analysis showed that it was relatively modest and was lower than that of presynaptic markers and that its localization in synaptic structures was insufficient. Neurophysiological analysis using a microelectrode array also revealed that no synaptic activity was generated on hiPSC-neurons at 49 days of differentiation. Analysis of subtype markers by immunostaining revealed that most hiPSC-neurons expressed vesicular glutamate transporter 2 (VGLUT2). The presence or absence of NGF, which is required for the survival of cholinergic neurons, had no effect on their cell fractionation. These results suggest that during the synaptogenesis of hiPSC-neurons, the formation of presynaptic structures is not the only requirement for the formation of postsynaptic structures and that the mRNA expression of postsynaptic markers does not correlate with the formation of their mature structures. Technically, we also confirmed a certain level of robustness and reproducibility of our neuronal differentiation method in a multicenter setting, which will be helpful for future research. Synapse formation with mature postsynaptic structures will remain an interesting issue for stem cell-derived neurons, and the present method can be used to obtain early and stable quality neuronal cultures from hiPSC-NPCs.
A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma
Authors: Mei Heng , Li Chenggong , Jiang Huiwen , Zhao Xinying , Huang Zhiping , Jin Dan , Guo Tao , Kou Haiming , Liu Lin , Tang Lu , Yin Ping , Wang Zhihui , Ai Lisha , Ke Sha , Xia Yimeng , Deng Jun , Chen Lei , Cai Li , Sun Chunyan , Xia Linghui , Hua Gaoquan , Hu Yu 
Published: October 2021

Abstract
Background
BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations.

Methods
We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial.

Results
BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months.

Conclusion
Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM.
Trial registration: Chictr.org.cn ChiCTR1800018143.