This phase III randomized study compared concurrent cisplatin–radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 ...patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m2 weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval CI = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio HR = 0.71 95% CI = 0.5 to 1.0). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 95% CI = 0.59 to 1.4), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 95% CI = 0.3 to 0.88), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.
•Inadvertent radiation to the brain is common during definitive radiotherapy for NPC.•Post-IMRT neurocognitive impairment is prevalent and profound among NPC survivors.•Verbal memory, processing ...speed, executive function, and motor dexterity are predominantly impaired.•Radiation doses to the whole brain, temporal lobe, and hippocampus may be associated with neurocognitive impairment.
Neurocognitive impairment from inadvertent brain irradiation is common following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aimed to determine the prevalence, pattern, and radiation dose-toxicity relationship of this late complication.
We undertook a cross-sectional study of 190 post-IMRT NPC survivors. Neurocognitive function was screened using the Montreal Cognitive Assessment-Hong Kong (HK-MoCA). Detailed assessments of eight distinct neurocognitive domains were conducted: intellectual capacity (WAIS-IV), attention span (Digit Span and Visual Spatial Span), visual memory (Visual Reproduction Span), verbal memory (Auditory Verbal Learning Test), processing speed (Color Trail Test), executive function (Stroop Test), motor dexterity (Grooved Pegboard Test) and language ability (Verbal Fluency Test). The mean percentiles and Z-scores were compared with normative population data. Associations between radiation dose and brain substructures were explored using multivariable logistic regression.
The median post-IMRT interval was 7.0 years. The prevalence of impaired HK-MoCA was 25.3 % (48/190). Among the participants, 151 (79.4 %) exhibited impairments in at least one neurocognitive domain. The predominantly impaired domains included verbal memory (short-term: mean Z-score, −0.56, p < 0.001; long-term: mean Z-score, −0.70, p < 0.001), processing speed (basic: mean Z-score, −1.04, p < 0.001; advanced: mean Z-score, −0.38, p < 0.001), executive function (mean Z-score, −1.90, p < 0.001), and motor dexterity (dominant hand: mean Z-score, −0.97, p < 0.001). Radiation dose to the whole brain, hippocampus, and temporal lobe was associated with impairments in executive function, verbal memory, processing speed, and motor dexterity.
Neurocognitive impairment is prevalent and profound in post-IMRT NPC survivors. Cognitive assessment and rehabilitation should be considered part of survivorship care.
Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 ...deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.
Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight ...European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph).
We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (
IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and
CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model.
The tumour necrosis factor (
TNF) −308G→A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0·005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1·29 95% CI 1·10–1·51 for GA and 1·65 1·16–2·34 for AA, p for trend <0·0001), but not for follicular lymphoma. The interleukin 10
(IL10) −3575T→A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0·02), again particularly for diffuse large B-cell lymphoma (p for trend=0·006). For individuals homozygous for the
TNF −308A allele and carrying at least one
IL10 −3575A allele, risk of diffuse large B-cell lymphoma doubled (2·13 1·37–3·32, p=0·00083).
Common polymorphisms in
TNF and
IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.
Abstract Occurrence and localization of receptor components of the glial cell line-derived neurotrophic factor (GDNF) family ligands, the Ret receptor tyrosine kinase and the GDNF family receptor ...(GFR) alpha-1 to -3, were examined by immunohistochemistry in the normal human brainstem at fetal, neonatal, and adult age. Immunoreactive elements were detectable at all examined ages with uneven distribution and consistent pattern for each receptor. As a rule, the GFRalpha-1 and GFRalpha-2 antisera produced the most abundant and diffuse tissue labelling. Immunoreactive perikarya were observed within sensory and motor nuclei of cranial nerves, dorsal column nuclei, olivary nuclear complex, reticular formation, pontine nuclei, locus caeruleus, raphe nuclei, substantia nigra, and quadrigeminal plate. Nerve fibers occurred within gracile and cuneate fasciculi, trigeminal spinal tract and nucleus, facial, trigeminal, vestibular and oculomotor nerves, solitary tract, medial longitudinal fasciculus, medial lemniscus, and inferior and superior cerebellar peduncles. Occasionally, glial cells were stained. Age changes were appreciable in the distribution pattern of each receptor. On the whole, in the grey matter, labelled perikarya were more frequently observed in pre- and perinatal than in adult specimens; on the other hand, in discrete regions, nerve fibers and terminals were abundant and showed a plexiform arrangement only in adult tissue; finally, distinct fiber systems in the white matter were immunolabelled only at pre- and perinatal ages. The results obtained suggest the involvement of Ret and GFRalpha receptors signalling in processes subserving both the organization of discrete brainstem neuronal systems during development and their functional activity and maintenance in adult life.
We studied the role of colour Doppler energy (CDE) (or power Doppler) imaging in the differentiation between endometriomas and other adnexal masses in premenopausal non-pregnant women. A total of 170 ...consecutive patients with persistent adnexal masses was submitted to B-mode transvaginal ultrasonography associated with CDE imaging evaluation. Plasma concentrations of CA125 were measured before surgery. Using CDE imaging evaluation of vessel distribution, the occurrence of one of the following findings was considered to indicate the likely presence of endometrioma: (i) a round-shaped homogeneous hypoechoic 'tissue' of low-level echoes without papillary proliferations associated with 'poor' vascularization; (ii) a round-shaped homogeneous hypoechoic 'tissue' of low-level echoes with an echogenic portion in which no flow was detected. The overall agreement between the test result and the actual outcome was calculated using the k index. The CDE imaging evaluation was more accurate in the diagnosis of endometriomas compared with B-mode ultrasonography alone (k = 0.88 and 0.80 respectively). According to the logistic regression equation obtained, the probability of the presence of endometrioma varied between a minimum of 1.4% for patients with no risk factors to a maximum of 95.6% for patients with two risk factors (CDE result and value of CA125 >25 IU/ml).
Highlights ► LTBP-2 was significantly down-regulated in NPC cell lines and biopsies. ► LTBP-2 silencing is associated with promoter hypermethylation. ► LTBP-2 suppresses malignancy by impairing in ...vitro & in vivo cell growth properties. ► LTBP-2 pleiotropically inhibits angiogenesis, VEGF secretion and migration. ► LTBP-2 confers tumor cell dormancy in microenvironment favorable for metastasis.
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•Fatty liver disease is a growing cause of cirrhosis and liver cancer globally.•Disease burden is expected to increase with the epidemics of obesity and diabetes.•Modeling shows slow ...growth in total cases and greater increase in advanced cases.•Mortality and advanced liver disease will more than double during 2016–2030.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.
A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.
If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.
NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
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