Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by ...the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker.
Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor
status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2).
Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with
amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2
nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (
) or 12-18 months (
, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively.
A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.
Aim
Gastroparesis is a common non‐motor system symptom of Parkinson's disease (PD). However, the mechanism responsible for the gastric motor abnormality is not clear. We previously reported on the ...impaired gastric motility in 6‐hydroxydopamine (6‐OHDA) rats, which were treated with a bilateral microinjection of 6‐OHDA in the substantia nigra (SN). We hypothesize that the enhanced dopamine system and reduced acetylcholine (Ach) in gastric tissues might contribute to the delayed gastric emptying observed in PD.
Methods
A strain gauge force transducer, digital X‐ray imaging system, Western blot, immunofluorescence and Radio Immunoassay were used in this study.
Results
Dopaminergic neurones in the SN were greatly reduced following the bilateral microinjection of 6‐OHDA. 6‐OHDA rats exhibited impaired gastric motility and delayed gastric emptying, accompanied by increased dopamine content and the overexpression of D2 receptors in the stomach. The administration of the D2 receptor antagonist domperidone relieved gastric dysmotility in 6‐OHDA rats, but the D1 receptor antagonist SCH23390 failed to do so. Subdiaphragmatic vagotomy prevented the increase in the gastric dopamine content and D2 receptor expression and improved gastric dysmotility in 6‐OHDA rats.
Conclusion
Dopaminergic deficiency in the SN results in impaired gastric motility, possibly as a result of the enhanced activity of dopamine system and reduced Ach in gastric tissue. The vagus nerve plays an important role in peripheral gastric motility disorder.
With first-principles density functional theory calculations, we demonstrate that quantum capacitance of graphene-based electrodes can be improved by the N-doping, vacancy defects, and adsorbed ...transition-metal atoms. The enhancement of the quantum capacitance can be contributed to the formation of localized states near Dirac point and/or shift of Fermi level induced by the defects and doping. In addition, the quantum capacitance is found to increase monotonically following the increase of defect concentrations. It is also found that the localized states near Fermi level results in the spin-polarization effect.
A model is developed to study the stress generation in a spherical particle subjected to lithium insertion. The model accounts for both the plastic deformation and the coexistence of lithium-poor and ...lithium-rich phases with a sharp and curved phase boundary. Such two-phase and inelastic deformation characteristics often arise during lithiation of crystalline particles with high capacity. A flexible sigmoid function is used to create the lithium profile with a step-like change in lithium concentration, mimicking a sharp phase boundary that separates a pristine core and a lithiated shell in the particle. The mechanics results, obtained by an analytic formulation and finite difference calculations, show the development of tensile hoop stress in the surface layer of the lithiated shell. This hoop tension provides the driving force of surface cracking, as observed by in situ transmission electron microscopy. The two-phase lithiation model is further compared with the single-phase one, which assumes a gradual and smooth variation in radial lithium distributions, and thus predicts only hoop compression in the surface layer of the particle. Furthermore, the effect of dilatational vs. unidirectional lithiation strains in the two-phase model is studied, thereby underscoring the critical role of anisotropy of lithiation strain in controlling stress generation in high-capacity electrodes for lithium ion batteries.
On the basis of the existing performance evaluation criteria analysis and four assumptions, a performance evaluation plot has been proposed in this paper. This plot takes the ratios of heat transfer ...enhancement and friction factor increase as its two coordinates. The quadrant of the coordinate where both (
Nu
e/
Nu
0), (
f
e/
f
0) are greater than 1.0 can be divided into four regions. In Region 1 heat transfer is actually deteriorated based on identical pumping power, in Region 2 heat transfer is enhanced based on identical pumping power but deteriorated based on identical pressure drop, in Region 3 heat transfer is enhanced based on identical pressure drop but the increase in friction factor is larger than the enhancement of heat transfer at identical flow rate, and in Region 4 heat transfer enhancement ratio is larger than friction factor increase ratio based on identical flow rate. For some techniques which lead to the reduction of both heat transfer rate and friction factor, the proposed plot is still applicable. Different enhanced techniques for the same reference one can be easily and clearly compared for their effectiveness when enhancement study is based on energy-saving. Five practical examples are provided to show the functions of the plot.
In 2006, Children's Oncology Group (COG) reclassified subgroups of toddlers diagnosed with neuroblastoma from high-risk to intermediate-risk, when the age cutoff for high-risk assignment was raised ...from 365 days (12 months) to 547 days (18 months). The primary aim of this retrospective study was to determine if excellent outcome was maintained after assigned reduction of therapy.
Children <3 years old at diagnosis, enrolled on a COG biology study from 1990 to 2018, were eligible (n = 9,189). Assigned therapy was reduced for two cohorts of interest on the basis of the age cutoff change: 365-546 days old with International Neuroblastoma Staging System (INSS) stage 4,
not amplified (
), favorable International Neuroblastoma Pathology Classification (INPC), hyperdiploid tumors (12-18mo/Stage4/FavBiology), and 365-546 days old with INSS stage 3,
and unfavorable INPC tumors (12-18mo/Stage3/
/Unfav). Log-rank tests compared event-free survival (EFS) and overall survival (OS) curves.
For 12-18mo/Stage4/FavBiology, 5-year EFS/OS (± SE) before (≤2006; n = 40) versus after (>2006; n = 55) assigned reduction in therapy was similar: 89% ± 5.1%/89% ± 5.1% versus 87% ± 4.6%/94% ± 3.2% (
= .7;
= .4, respectively). For 12-18mo/Stage3/
/Unfav, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/
/Unfav classified as high-risk ≤2006 had an EFS/OS of 91% ± 4.4%/91% ± 4.5% versus 38% ± 1.3%/43% ± 1.3% for all other high-risk patients <3 years old (
< .0001;
< .0001, respectively). The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3/
/Unfav classified as intermediate-risk >2006 had an EFS/OS of 88% ± 4.3%/95% ± 2.9% versus 88% ± 0.9%/95% ± 0.6% for all other intermediate-risk patients <3 years old (
= .87;
= .85, respectively).
Excellent outcome was maintained among subsets of toddlers with neuroblastoma assigned to reduced treatment after reclassification of risk group from high to intermediate on the basis of new age cutoffs. Importantly, as documented in prior trials, intermediate-risk therapy is not associated with the degree of acute toxicity and late effects commonly observed with high-risk regimens.
The combination of irinotecan, temozolomide, dintuximab, and granulocyte-macrophage colony-stimulating factor (I/T/DIN/GM-CSF) demonstrated activity in patients with relapsed/refractory neuroblastoma ...in the randomized Children's Oncology Group ANBL1221 trial. To more accurately assess response rate and toxicity, an expanded cohort was nonrandomly assigned to I/T/DIN/GM-CSF.
Patients were eligible at first relapse or first designation of refractory disease. Oral T and intravenous (IV) irinotecan were administered on days 1 to 5 of 21-day cycles. DIN was administered IV (days 2-5), and GM-CSF was administered subcutaneously (days 6-12). The primary end point was objective response, analyzed on an intent-to-treat basis per the International Neuroblastoma Response Criteria.
Seventeen eligible patients were randomly assigned to I/T/DIN/GM-CSF (February 2013 to March 2015); 36 additional patients were nonrandomly assigned to I/T/DIN/GM-CSF (August 2016 to May 2017). Objective (complete or partial) responses were observed in nine (52.9%) of 17 randomly assigned patients (95% CI, 29.2% to 76.7%) and 13 (36.1%) of 36 expansion patients (95% CI, 20.4% to 51.8%). Objective responses were seen in 22 (41.5%) of 53 patients overall (95% CI, 28.2% to 54.8%); stable disease was also observed in 22 of 53. One-year progression-free and overall survival for all patients receiving I/T/DIN/GM-CSF were 67.9% ± 6.4% (95% CI, 55.4% to 80.5%) and 84.9% ± 4.9% (95% CI, 75.3% to 94.6%), respectively. Two patients did not receive protocol therapy and were evaluable for response but not toxicity. Common grade ≥ 3 toxicities were fever/infection (18 35.3% of 51), neutropenia (17 33.3% of 51), pain (15 29.4% of 51), and diarrhea (10 19.6% of 51). One patient met protocol-defined criteria for unacceptable toxicity (grade 4 hypoxia). Higher DIN trough levels were associated with response.
I/T/DIN/GM-CSF has significant antitumor activity in patients with relapsed/refractory neuroblastoma. Study of chemoimmunotherapy in the frontline setting is indicated, as is further evaluation of predictive biomarkers.
Background
Hepatic vein tumour thrombus (HVTT) is a major determinant of survival outcomes for patients with hepatocellular carcinoma (HCC). An Eastern Hepatobiliary Surgery Hospital (EHBH)‐HVTT ...model was established to predict the prognosis of patients with HCC and HVTT after liver resection, in order to identify optimal candidates for liver resection.
Methods
Patients with HCC and HVTT from 15 hospitals in China were included. The EHBH‐HVTT model with contour plot was developed using a non‐linear model in the training cohort, and subsequently validated in internal and external cohorts.
Results
Of 850 patients who met the inclusion criteria, there were 292 patients who had liver resection and 198 who did not in the training cohort, and 124 and 236 in the internal and external validation cohorts respectively. Contour plots for the EHBH‐HVTT model were established to predict overall survival (OS) rates of patients visually, based on tumour diameter, number of tumours and portal vein tumour thrombus. This differentiated patients into low‐ and high‐risk groups with distinct long‐term prognoses in the liver resection cohort (median OS 34·7 versus 12·0 months; P < 0·001), internal validation cohort (32·8 versus 10·4 months; P = 0·002) and external validation cohort (15·2 versus 6·5 months; P = 0·006). On subgroup analysis, the model showed the same efficacy in differentiating patients with HVTT in peripheral and major hepatic veins, the inferior vena cava, or in patients with coexisting portal vein tumour thrombus.
Conclusion
The EHBH‐HVTT model was accurate in predicting prognosis in patients with HCC and HVTT after liver resection. It identified optimal candidates for liver resection among patients with HCC and HVTT, including tumour thrombus in the inferior vena cava, or coexisting portal vein tumour thrombus.
Antecedentes
La trombosis tumoral de la vena hepática (hepatic vein tumour thrombus, HVTT) es un determinante importante de los resultados de supervivencia en pacientes con carcinoma hepatocelular (hepatocellular carcinoma, HCC). Se desarrolló el modelo llamado Eastern Hepatobiliary Surgery Hospital (EHBH)‐HVTT para predecir el pronóstico de los pacientes con HCC y HVTT después de la resección hepática (liver resection, LR), con el fin de identificar los candidatos óptimos para LR entre estos pacientes.
Métodos
Se incluyeron pacientes con HCC y HVTT de 15 hospitales en China. El modelo EHBH‐HVTT con gráfico de contorno se desarrolló utilizando un modelo no lineal en la cohorte de entrenamiento, siendo posteriormente validado en cohortes internas y externas.
Resultados
De 850 pacientes que cumplieron con los criterios de inclusión, hubo 292 pacientes en el grupo LR y 198 pacientes en el grupo no LR en la cohorte de entrenamiento, y 124 y 236 en las cohortes de validación interna y externa. Los gráficos de contorno del modelo EHBH‐HVTT se establecieron para predecir visualmente las tasas de supervivencia global (overall survival, OS) de los pacientes, en función del diámetro del tumor, número de tumores y del trombo tumoral de la vena porta (portal vein tumour thrombus, PVTT). Esto diferenciaba a los pacientes en los grupos de alto y bajo riesgo, con distinto pronóstico a largo plazo en las 3 cohortes (34,7 versus 12,0 meses, 32,8 versus 10,4 meses y 15,2 versus 6,5 meses, P < 0,001). En el análisis de subgrupos, el modelo mostró la misma eficacia en la diferenciación de pacientes con HVTT, con trombo tumoral en la vena cava inferior (inferior vena cava tumour thrombus, IVCTT) o en pacientes con PVTT coexistente.
Conclusión
El modelo EHBH‐HVTT fue preciso para la predicción del pronóstico en pacientes con HCC y HVTT después de la LR. Identificó candidatos óptimos para LR en pacientes con HCC y HVTT, incluyendo IVCTT o PVTT coexistente.
The Eastern Hepatobiliary Surgery Hospital–hepatic vein tumour thrombus (EHBH‐HVTT) model was accurate in predicting prognosis in patients with hepatocellular carcinoma (HCC) and HVTT after liver resection. It identified optimal candidates for liver resection among patients with HCC and HVTT, including inferior vena cava tumour thrombus, or coexisting portal vein tumour thrombus (PVTT).
predicts prognosis
Almonertinib, a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective to EGFR T790M-mutant non-small cell lung cancer (NSCLC). However, there is ...no available information on the form and molecular mechanism of Almonertinib-induced death in NSCLC cells. Herein, CCK-8 and colony formation assays, flow cytometry, electron microscopy, and western blots assay showed that Almonertinib inhibited NSCLC cells growth and proliferation by inducing apoptosis and autophagy which can be inhibited by a broad spectrum of caspase inhibitor Z-VAD-fmk or autophagy inhibitor chloroquine. Importantly, Almonertinib-induced autophagy was cytoprotective in NSCLC cells, and the blockade of autophagy improved cell apoptosis. In addition, Almonertinib increased reactive oxygen species (ROS) generation and clearance of ROS through pretreatment with N-acetyl-L-cysteine (NAC) inhibited the decrease of cell viability, apoptosis and increase of LC3-II induced by Almonertinib. The results of Western blot showed that both EGFR activity and downstream signaling pathways were inhibited by Almonertinib. Taken together, these findings indicated that Almonertinib induced apoptosis and autophagy by promoting ROS production in NSCLC cells.
Aim
The intestinal barrier is made up of epithelial cells and intercellular junctional complexes to regulate epithelial ion transport and permeability. Dopamine (DA) is able to promote duodenal ...epithelial ion transport through D1‐like receptors, which includes subtypes of D1 (D1R) and D5 (D5R), but whether D1‐like receptors influence the duodenal permeability is unclear.
Methods
FITC–dextran permeability, short‐circuit current (ISC), Western blot, immunohistochemistry and ELISA were used in human D5R transgenic mice and hyperendogenous enteric DA (HEnD) rats in this study.
Results
Dopamine induced a downward deflection in ISC and an increase in FITC–dextran permeability of control rat duodenum, which were inhibited by the D1‐like receptor antagonist, SCH‐23390. However, DA decreased duodenal transepithelial resistance (TER), an effect also reversed by SCH‐23390. A strong immunofluorescence signal for D5R, but not D1R, was observed in the duodenum of control rat. In human D5R knock‐in transgenic mice, duodenal mucosa displayed an increased basal ISC with high FITC–dextran permeability and decreased TER with a lowered expression of tight junction proteins, suggesting attenuated duodenal barrier function in these transgenic mice. D5R knock‐down transgenic mice manifested a decreased basal ISC with lowered FITC–dextran permeability. Moreover, an increased FITC–dextran permeability combined with decreased TER and tight junction protein expression in duodenal mucosa were also observed in HEnD rats.
Conclusion
This study demonstrates, for the first time, that DA enhances duodenal permeability of control rat via D5R, which provides new experimental and theoretical evidence for the influence of DA on duodenal epithelial barrier function.
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