Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85-99 years had 20-times lower odds of chemotherapy use than those aged 65-74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI -15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85-99 years had slightly shorter median time to first chemotherapy compared with those aged 65-74 years, consistently between jurisdictions (-3·7 days, 95% PI -7·6 to 0·1). INTERPRETATION: Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Use of radiotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There is little evidence on variation in radiotherapy use in different countries, although it is a key treatment modality for some patients with cancer. Here we aimed to examine such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), nine Canadian provinces (Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in radiotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data, or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 902 312 patients with a new diagnosis of one of the studied cancers, 115 357 (12·8%) did not meet inclusion criteria, and 786,955 were included in the analysis. There was large interjurisdictional variation in radiotherapy use, with wide 95% PIs: 17·8 to 82·4 (pooled estimate 50·2%) for oesophageal cancer, 35·5 to 55·2 (45·2%) for rectal cancer, 28·6 to 54·0 (40·6%) for lung cancer, and 4·6 to 53·6 (19·0%) for stomach cancer. For patients with stage 2-3 rectal cancer, interjurisdictional variation was greater than that for all patients with rectal cancer (95% PI 37·0 to 84·6; pooled estimate 64·2%). Radiotherapy use was infrequent but variable in patients with pancreatic (95% PI 1·7 to 16·5%), liver (1·8 to 11·2%), colon (1·6 to 5·0%), and ovarian (0·8 to 7·6%) cancer. Patients aged 85-99 years had three-times lower odds of radiotherapy use than those aged 65-74 years, with substantial interjurisdictional variation in this age difference (odds ratio [OR] 0·38; 95% PI 0·20-0·73). Women had slightly lower odds of radiotherapy use than men (OR 0·88, 95% PI 0·77-1·01). There was large variation in median time to first radiotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation (eg, oesophageal 95% PI 11·3 days to 112·8 days; pooled estimate 62·0 days; rectal 95% PI 34·7 days to 77·3 days; pooled estimate 56·0 days). Older patients had shorter median time to radiotherapy with appreciable interjurisdictional variation (-9·5 days in patients aged 85-99 years vs 65-74 years, 95% PI -26·4 to 7·4). INTERPRETATION: Large interjurisdictional variation in both use and time to radiotherapy initiation were observed, alongside large and variable age differences. To guide efforts to improve patient outcomes, underlying reasons for these differences need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

PGD: Shared gene linking polycystic ovary syndrome and endometrial cancer, influencing proliferation and migration through glycometabolism.

The relationship among polycystic ovary syndrome (PCOS), endometrial cancer (EC), and glycometabolism remains unclear. We explored shared genes between PCOS and EC, using bioinformatics to unveil their pathogenic connection and influence on EC prognosis. Gene Expression Omnibus datasets GSE226146 (PCOS) and GSE196033 (EC) were used. A protein-protein interaction (PPI) network was constructed to identify the central genes. Candidate markers were screened using dataset GSE54250. Differences in marker expression were confirmed in mouse PCOS and human EC tissues using RT-PCR and immunohistochemistry. The effect of PGD on EC proliferation and migration was explored using Ki-67 and Transwell assays. PGD's impact on the glycometabolic pathway within carbon metabolism was assessed by quantifying glucose content and lactic acid production. R software identified 31 common genes in GSE226146 and GSE196033. Gene Ontology functional classification revealed enrichment in the "purine nucleoside triphosphate metabolism process," with key Kyoto Encyclopedia of Genes and Genomes pathways related to "carbon metabolism." The PPI network identified 15 hub genes. HK2, NDUFS8, PHGDH, PGD, and SMAD3 were confirmed as candidate markers. The RT-PCR analysis validated distinct HK2 and PGD expression patterns in mouse PCOS ovarian tissue and human EC tissue, as well as in normal and EC cells. Transfection experiments with Ishikawa cells further confirmed PGD's influence on cell proliferation and migration. Suppression of PGD expression impeded glycometabolism within the carbon metabolism of EC cells, suggesting PGD as a significant PCOS risk factor impacting EC proliferation and migration through modulation of single carbon metabolism. These findings highlight PGD's pivotal role in EC onset and prognosis.

Rapid Fabrication of Large-Grain Opal Films and Photonic Crystal Hydrogel Sensors by a Filter Paper-Enhanced Evaporation Chip.

Developing a rapid fabrication method for crack-free opal films is a significant challenge with broad applications. We developed a microfluidic platform known as the "filter paper-enhanced evaporation microfluidic chip" (FPEE-chip) for the fabrication of photonic crystal and inverse opal hydrogel (IOPH) films. The chip featured a thin channel formed by bonding double-sided adhesive poly(ethylene terephthalate) with a polymethyl methacrylate cover and a glass substrate. This channel was then filled with nanosphere colloids. The water was guided to evaporate rapidly at the surface of the filter paper, allowing the nanospheres to self-assemble and accumulate within the channel under capillary forces. Experimental results confirmed that the self-assembly method based on the FPEE-chip was a rapid platform for producing high-quality opal, with centimeter-sized opal films achievable in less than an hour. Furthermore, the filter paper altered the stress release mechanism of the opal films during drying, resulting in fewer cracks. This platform was proven capable of producing large-grain, crack-free opal films of up to 30 mm2 in size. We also fabricated crack-free IOPH pH sensors that exhibited color and size responsiveness to pH changes. The coefficient of variation of the gray color distribution for crack-free IOPH ranged from 0.03 to 0.07, which was lower than that of cracked IOPH (ranging from 0.07 to 0.14). Additionally, the grayscale peak value in 1 mm2 of the crack-free IOPH was more than twice that of the cracked IOPH at the same pH. The FPEE-chip demonstrated potential as a candidate for developing vision sensors.

The molecular signature and prognosis of glioma with preoperative intratumoral hemorrhage: a retrospective cohort analysis.

BACKGROUND: Intratumoral hemorrhage, though less common, could be the first clinical manifestation of glioma and is detectable via MRI; however, its exact impacts on patient outcomes remain unclear and controversial. The 2021 WHO CNS 5 classification emphasised genetic and molecular features, initiating the necessity to establish the correlation between hemorrhage and molecular alterations. This study aims to determine the prevalence of intratumoral hemorrhage in glioma subtypes and identify associated molecular and clinical characteristics to improve patient management. METHODS: Integrated clinical data and imaging studies of patients who underwent surgery at the Department of Neurosurgery at Peking Union Medical College Hospital from January 2011 to January 2022 with pathological confirmation of glioma were retrospectively reviewed. Patients were divided into hemorrhage and non-hemorrhage groups based on preoperative magnetic resonance imaging. A comparison and survival analysis were conducted with the two groups. In terms of subgroup analysis, we classified patients into astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant, 1p/19q-codeleted; glioblastoma, IDH-wildtype; pediatric-type gliomas; or circumscribed glioma using integrated histological and molecular characteristics, according to WHO CNS 5 classifications. RESULTS: 457 patients were enrolled in the analysis, including 67 (14.7%) patients with intratumoral hemorrhage. The hemorrhage group was significantly older and had worse preoperative Karnofsky performance scores. The hemorrhage group had a higher occurrence of neurological impairment and a higher Ki-67 index. Molecular analysis indicated that CDKN2B, KMT5B, and PIK3CA alteration occurred more in the hemorrhage group (CDKN2B, 84.4% vs. 62.2%, p = 0.029; KMT5B, 25.0% vs. 8.9%, p = 0.029; and PIK3CA, 81.3% vs. 58.5%, p = 0.029). Survival analysis showed significantly worse prognoses for the hemorrhage group (hemorrhage 18.4 months vs. non-hemorrhage 39.1 months, p = 0.01). In subgroup analysis, the multivariate analysis showed that intra-tumoral hemorrhage is an independent risk factor only in glioblastoma, IDH-wildtype (162 cases of 457 overall, HR = 1.72, p = 0.026), but not in other types of gliomas. The molecular alteration of CDK6 (hemorrhage group p = 0.004, non-hemorrhage group p < 0.001), EGFR (hemorrhage group p = 0.003, non-hemorrhage group p = 0.001), and FGFR2 (hemorrhage group p = 0.007, non-hemorrhage group p = 0.001) was associated with shorter overall survival time in both hemorrhage and non-hemorrhage groups. CONCLUSIONS: Glioma patients with preoperative intratumoral hemorrhage had unfavorable prognoses compared to their nonhemorrhage counterparts. CDKN2B, KMT5B, and PIK3CA alterations were associated with an increased occurrence of intratumoral hemorrhage, which might be future targets for further investigation of intratumoral hemorrhage.

Correlation Between Impaired Sensitivity to Thyroid Hormones and Serum Uric Acid in Female Patients With Obesity and After Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: An alterable risk factor for hyperuricemia is obesity. Additionally, obese people may have a moderate form of acquired resistance to thyroid hormones. Thyrotropin, thyroid hormones, and obesity all interact subtly. However, the connection between thyroid hormone sensitivity and hyperuricemia in obese patients both before and after laparoscopic sleeve gastrectomy (LSG) has not yet been clarified. The objective of our study was to investigate the connection between impaired thyroid hormone sensitivity and elevated uric acid (UA) levels before and after LSG. METHODS: In total, 1054 euthyroid patients with obesity (481 males, 573 females), 248 (143 female patients) of whom underwent subsequent LSG, were enrolled in this retrospective study. Anthropometric measurements and thyroid hormone and UA levels were taken before and 3 months after LSG. RESULTS: Female patients with obesity with impaired sensitivity to thyroid hormones had higher UA levels (P for trend <.01). The odds ratio of the fourth vs first quartile of thyroid feedback quantile index, thyrotropin index, and thyrotropin-thyroxine resistance index were 4.285 (confidence interval: 1.360-13.507), 3.700 (confidence interval: 1.276-10.729), and 2.839 (confidence interval: 1.014-7.948), respectively, with robust relationships with female hyperuricemia (all P < .05). However, there was only a positive correlation between the decline in UA levels and thyroid feedback quantile index, thyrotropin, and thyrotropin-thyroxine resistance index in female patients following LSG. CONCLUSION: Female hyperuricemia is correlated with higher thyroid hormone resistance index scores. Resistance to thyroid hormones was greatly improved by LSG. The decrease in UA levels after surgery is correlated with the improvement of thyroid hormone resistance after LSG.

In silico analysis of NAC gene family in the mangrove plant Avicennia marina provides clues for adaptation to intertidal habitats.

NAC (NAM, ATAF1/2, CUC2) transcription factors (TFs) constitute a plant-specific gene family. It is reported that NAC TFs play important roles in plant growth and developmental processes and in response to biotic/abiotic stresses. Nevertheless, little information is known about the functional and evolutionary characteristics of NAC TFs in mangrove plants, a group of species adapting coastal intertidal habitats. Thus, we conducted a comprehensive investigation for NAC TFs in Avicennia marina, one pioneer species of mangrove plants. We totally identified 142 NAC TFs from the genome of A. marina. Combined with NAC proteins having been functionally characterized in other organisms, we built a phylogenetic tree to infer the function of NAC TFs in A. marina. Gene structure and motif sequence analyses suggest the sequence conservation and transcription regulatory regions-mediated functional diversity. Whole-genome duplication serves as the driver force to the evolution of NAC gene family. Moreover, two pairs of NAC genes were identified as positively selected genes of which AmNAC010/040 may be imposed on less constraint toward neofunctionalization. Quite a few stress/hormone-related responsive elements were found in promoter regions indicating potential response to various external factors. Transcriptome data revealed some NAC TFs were involved in pneumatophore and leaf salt gland development and response to salt, flooding and Cd stresses. Gene co-expression analysis found a few NAC TFs participates in the special biological processes concerned with adaptation to intertidal environment. In summary, this study provides detailed functional and evolutionary information about NAC gene family in mangrove plant A. marina and new perspective for adaptation to intertidal habitats.

Combined metabolome and transcriptome analysis reveals a critical role of lignin biosynthesis and lignification in stem-like pneumatophore development of the mangrove Avicennia marina.

MAIN CONCLUSION: Transcriptional and metabolic regulation of lignin biosynthesis and lignification plays crucial roles in Avicennia marina pneumatophore development, facilitating its adaptation to coastal habitats. Avicennia marina is a pioneer mangrove species in coastal wetland. To cope with the periodic intertidal flooding and hypoxia environment, this species has developed a complex and extensive root system, with its most unique feature being a pneumatophore with a distinct above- and below-ground morphology and vascular structure. However, the characteristics of pneumatophore lignification remain unknown. Studies comparing the anatomy among above-ground pneumatophore, below-ground pneumatophore, and feeding root have suggested that vascular structure development in the pneumatophore is more like the development of a stem than of a root. Metabolome and transcriptome analysis illustrated that the accumulation of syringyl (S) and guaiacyl (G) units in the pneumatophore plays a critical role in lignification of the stem-like structure. Fourteen differentially accumulated metabolites (DAMs) and 10 differentially expressed genes involved in the lignin biosynthesis pathway were targeted. To identify genes significantly associated with lignification, we analyzed the correlation between 14 genes and 8 metabolites and further built a co-expression network between 10 transcription factors (TFs), including 5 for each of MYB and NAC, and 23 enzyme-coding genes involved in lignin biosynthesis. 4-Coumarate-CoA ligase, shikimate/quinate hydroxycinnamoyl transferase, cinnamyl alcohol dehydrogenase, caffeic acid 3-O-methyltransferase, phenylalanine ammonia-lyase, and peroxidase were identified to be strongly correlated with these TFs. Finally, we examined 9 key candidate genes through quantitative real-time PCR to validate the reliability of transcriptome data. Together, our metabolome and transcriptome findings reveal that lignin biosynthesis and lignification regulate pneumatophore development in the mangrove species A. marina and facilitate its adaptation to coastal habitats.

Hydrogen sulfide upregulates the alternative respiratory pathway in mangrove plant Avicennia marina to attenuate waterlogging-induced oxidative stress and mitochondrial damage in a calcium-dependent manner.

Hydrogen sulfide (H2 S) is considered to mediate plant growth and development. However, whether H2 S regulates the adaptation of mangrove plant to intertidal flooding habitats is not well understood. In this study, sodium hydrosulfide (NaHS) was used as an H2 S donor to investigate the effect of H2 S on the responses of mangrove plant Avicennia marina to waterlogging. The results showed that 24-h waterlogging increased reactive oxygen species (ROS) and cell death in roots. Excessive mitochondrial ROS accumulation is highly oxidative and leads to mitochondrial structural and functional damage. However, the application of NaHS counteracted the oxidative damage caused by waterlogging. The mitochondrial ROS production was reduced by H2 S through increasing the expressions of the alternative oxidase genes and increasing the proportion of alternative respiratory pathway in the total mitochondrial respiration. Secondly, H2 S enhanced the capacity of the antioxidant system. Meanwhile, H2 S induced Ca2+ influx and activated the expression of intracellular Ca2+ -sensing-related genes. In addition, the alleviating effect of H2 S on waterlogging can be reversed by Ca2+ chelator and Ca2+ channel blockers. In conclusion, this study provides the first evidence to explain the role of H2 S in waterlogging adaptation in mangrove plants from the mitochondrial aspect.

The clinical and metabolic characteristics of children and adolescents with hypothalamic dysfunction: A single-centre study from China.

OBJECTIVE: Hypothalamic dysfunction is characterized by complex aetiologies, multiple forms of onset and various clinical symptoms. This study aims to explore the clinical and metabolic characteristics of hypothalamic dysfunction in Chinese children and adolescents. DESIGN: This study is a single-centre, retrospective study that covers patients from 1989 to 2019. PATIENTS: We included 40 children and adolescents with hypothalamic dysfunction from our medical centre in Beijing, China. RESULTS: Intracranial tumour (37.5%) was the most common aetiology of children and adolescents with hypothalamic dysfunction, especially germ cell tumours, hypopituitarism (82.5%), weight gain (72.5%) and central diabetes insipidus (70.0%) were the most common symptoms in these patients. Furthermore, serum alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase, uric acid, total cholesterol, triglycerides and low-density lipoprotein cholesterol was significantly higher in hypothalamic dysfunction patients than sex- and age-matched controls and sex, age and body mass index (BMI)-matched controls (all p < 0.05). However, albumin and high-density lipoprotein cholesterol were lower (p< 0.05). Moreover, 95% (38/40) of the patients had metabolic diseases. In addition, the incidence of dyslipidaemia and hyperuricemia in children and adolescents with hypothalamic dysfunction was significantly higher than both sex- and age-matched controls and sex-, age- and BMI-matched controls (both p < 0.05) as well. CONCLUSIONS: Intracranial tumour was the most common aetiology in children and adolescents with hypothalamic dysfunction. In addition, these patients presented a worse metabolic profile on average than healthy patients.

Multidelay MR Arterial Spin Labeling Perfusion Map for the Prediction of Cerebral Hyperperfusion After Carotid Endarterectomy.

BACKGROUND: Multidelay arterial spin labeling (ASL) generates time-resolved perfusion maps, which may provide sufficient and accurate hemodynamic information in carotid stenosis. PURPOSE: To use imaging markers derived from multidelay ASL magnetic resonance imaging (MRI) and to determine the optimal strategy for predicting cerebral hyperperfusion after carotid endarterectomy (CEA). STUDY TYPE: Prospective observational cohort. SUBJECTS: A total of 79 patients who underwent CEA for carotid stenosis. FIELD STRENGTH/SEQUENCE: A 3.0 T/pseudo-continuous ASL with three postlabeling delays of 1.0, 1.57, and 2.46 seconds using fast-spin echo readout. ASSESSMENT: Cerebral perfusion pressure, antegrade, and collateral flow were scored on a four-grade ordinal scale based on preoperative multidelay ASL perfusion maps. Simultaneously, quantitative hemodynamic parameters including cerebral blood flow (CBF), arterial transit time (ATT), relative CBF (rCBF) and relative ATT (rATT; ipsilateral/contralateral values) were calculated. On the CBF ratio map obtained through dividing postoperative by preoperative CBF map, regions of interest were placed covering ipsilateral middle cerebral artery territory. Three neuroradiologists conducted this procedure. Cerebral hyperperfusion was defined as a CBF ratio >2. STATISTICAL TESTS: Weighted κ values, independent sample t test, chi-square test, Mann-Whitney U-test, multivariable logistic regression analysis, receiver-operating characteristic curve analysis, and Delong test. Significance level was P < 0.05. RESULTS: Cerebral hyperperfusion was observed in 15 (19%) patients. Higher blood pressure (odd ratio [OR] = 1.08) and carotid near-occlusion (NO; OR = 7.31) were clinical risk factors for postoperative hyperperfusion. Poor ASL perfusion score (OR = 37.33), decreased CBF (OR = 0.74), prolonged ATT (OR = 1.02), lower rCBF (OR = 0.91), and higher rATT (OR = 1.12) were independent imaging predictors of hyperperfusion. ASL perfusion score exhibited the highest specificity (95.3%), while CBF exhibited the highest sensitivity (93.3%) for the prediction of hyperperfusion. When combined with ASL perfusion score, CBF and ATT, the predictive ability was significantly higher than using blood pressure and NO alone (AUC: 0.98 vs. 0.78). DATA CONCLUSIONS: Multidelay ASL can accurately predict cerebral hyperperfusion after CEA with high sensitivity and specificity. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

Three-Dimensional Fast Spin Echo Pituitary MRI in Treatment-Naïve Cushing's Disease: Reduced Impact of Reader Experience and Increased Diagnostic Accuracy.

BACKGROUND: In patients with Cushing's disease, the preoperative identification of pituitary adenomas is crucial to treatment. However, increasing diagnostic accuracy remains an unresolved issue. PURPOSE: To evaluate the diagnostic accuracy and the impact of readers' experience regarding high-resolution contrast-enhanced magnetic resonance imaging (hrMRI) for identifying pituitary adenomas in comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI). STUDY TYPE: Retrospective. POPULATION: Sixty-five patients (median age, 39 years; interquartile range [IQR], 28-53 years; 60% females) with treatment-naïve Cushing's disease. FIELD STRENGTH/SEQUENCE: 3-T, seven fast spin echo sequences. ASSESSMENT: The diagnostic accuracies of identifying pituitary adenomas on cMRI, dMRI, combined cMRI and dMRI (cdMRI), and hrMRI were independently evaluated by six readers with three experience levels (high: >20 years, modest: 10-20 years, low: <10 years; two readers for each experience level). Readers were asked to localize the lesion, and measure its diameter on the sequence where identified. The reference standard was postoperative histopathology. The impact of readers' experience and interobserver agreement were assessed. Image quality was assessed using a 5-point Likert scale, including overall image quality, sharpness, and structural conspicuity. STATISTICAL TESTS: McNemar's test, Cochran's test, Wilcoxon signed-rank test, Mann-Whitney U test, and κ statistics for interobserver agreement. A P-value <0.05 was considered statistically significant. RESULTS: For identifying pituitary adenomas (median diameter, 5 mm; IQR, 4-5 mm), hrMRI had significantly higher sensitivity (87.7%-93.8%) than cMRI, dMRI, and cdMRI (52.3%-75.4%) for readers with different experience levels. The interobserver agreement was moderate (κ = 0.461-0.523). The sensitivity for hrMRI was comparable between readers with different experience levels (P = 0.371). All image quality scores on hrMRI were significantly higher than cMRI and dMRI (5.0 vs. 4.0). DATA CONCLUSION: For identifying pituitary adenomas in patients with treatment-naïve Cushing's disease, hrMRI may show high diagnostic accuracy and seems not to be affected by readers' experience. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Diagnosis and Management of Idiopathic Hypothalamic Dysfunction: A Case Series and Systematic Review.

INTRODUCTION: Idiopathic hypothalamic dysfunction (IHD) is a rare syndrome with heterogeneous clinical symptoms. This study aimed to systematically review the clinical features and potential treatment of IHD based on our case series and literature. METHODS: We analysed six recently diagnosed cases of IHD in Peking Union Medical College Hospital and conducted a systematic review of IHD case studies published before August 25, 2021, using the PubMed/Medline database. All 12 articles that met the definition of IHD and provided individual clinical data were reviewed. RESULTS: Of the 19 cases reviewed (13 from the literature and 6 from our centre), the median age at onset was 6 years. Obesity/weight gain (n = 14, 73.7%) and electrolyte abnormalities (n = 14, 73.7%) were the most common hypothalamic physiological dysfunction, followed by autonomic dysregulation (n = 13, 68.4%) and adipsia (n = 13, 68.4%). The most common initial symptom of young patients was obesity/weight gain, whereas the initial symptoms of the three adult patients were hypothalamic amenorrhoea, delayed sexual development, and polydipsia. 11 (57.9%) patients had obesity, and three of our patients were diagnosed with metabolic syndrome in late adolescence or early adulthood. Three of our cases diagnosed with growth hormone deficiency received growth hormone therapy, which exerted positive effects on growth promotion and weight stabilization. CONCLUSION: Although obesity/weight gain was the most common symptom of IHD, uncommon initial symptoms such as electrolyte abnormalities and sexual disorders also require attention, especially in patients with late childhood- or adult-onset IHD. Consistent monitoring of metabolic profiles is recommended. Positive effects of growth hormone replacement therapy on growth and weight were observed, but more extensive cohort studies are required to confirm its efficacy and safety.

High-resolution contrast-enhanced MRI with three-dimensional fast spin echo improved the diagnostic performance for identifying pituitary microadenomas in Cushing's syndrome.

OBJECTIVES: To assess the diagnostic performance of high-resolution contrast-enhanced MRI (hrMRI) with three-dimensional (3D) fast spin echo (FSE) sequence by comparison with conventional contrast-enhanced MRI (cMRI) and dynamic contrast-enhanced MRI (dMRI) with 2D FSE sequence for identifying pituitary microadenomas. METHODS: This single-institutional retrospective study included 69 consecutive patients with Cushing's syndrome who underwent preoperative pituitary MRI, including cMRI, dMRI, and hrMRI, between January 2016 to December 2020. Reference standards were established by using all available imaging, clinical, surgical, and pathological resources. The diagnostic performance of cMRI, dMRI, and hrMRI for identifying pituitary microadenomas was independently evaluated by two experienced neuroradiologists. The area under the receiver operating characteristics curves (AUCs) were compared between protocols for each reader by using the DeLong test to assess the diagnostic performance for identifying pituitary microadenomas. The inter-observer agreement was assessed by using the κ analysis. RESULTS: The diagnostic performance of hrMRI (AUC, 0.95-0.97) was higher than cMRI (AUC, 0.74-0.75; p ≤ .002) and dMRI (AUC, 0.59-0.68; p ≤ .001) for identifying pituitary microadenomas. The sensitivity and specificity of hrMRI were 90-93% and 100%, respectively. There were 78% (18/23) to 82% (14/17) of the patients, who were misdiagnosed on cMRI and dMRI and correctly diagnosed on hrMRI. The inter-observer agreement for identifying pituitary microadenomas was moderate on cMRI (κ = 0.50), moderate on dMRI (κ = 0.57), and almost perfect on hrMRI (κ = 0.91), respectively. CONCLUSIONS: The hrMRI showed higher diagnostic performance than cMRI and dMRI for identifying pituitary microadenomas in patients with Cushing's syndrome. KEY POINTS: • The diagnostic performance of hrMRI was higher than cMRI and dMRI for identifying pituitary microadenomas in Cushing's syndrome. • About 80% of patients, who were misdiagnosed on cMRI and dMRI, were correctly diagnosed on hrMRI. • The inter-observer agreement for identifying pituitary microadenomas was almost perfect on hrMRI.

Treatment of coracoid process fractures combined with acromioclavicular joint dislocation using clavicular hook plate.

BACKGROUND: The injury mechanism of acromioclavicular (AC) dislocation combined with coracoid process (CP) fracture is not clear, and there is no consensus on its treatment. This study was performed to evaluate the diagnosis of CP fractures combined with AC dislocation and the effectiveness of operative treatment using a clavicular hook plate. METHODS: Eighteen patients with CP fractures combined with AC dislocation were treated with a clavicular hook plate from May 2012 to June 2021. The patients comprised 10 male and 8 female patients with an average age of 38 years (range, 16-54 years). The injury was caused by falling in 15 patients, traffic accidents in 2 patients, and falling from a height in 1 patient. The Eyres type of CP fracture was type II in 1 patient, type III in 11 patients, type IV in 3 patients, and type V in 3 patients. The Ogawa type of CP fracture was type I in 17 patients and type II in 1 patient. The Rockwood type of AC dislocation was type V in 1 patient, variation type III in 15 patients, and variation type V in 2 patients. The interval from injury to the operation was 3 days (range, 1-7 days). Postoperative complications and CP fracture healing were recorded. Functional assessment at the last follow-up was performed by an independent reviewer using the Constant score and visual analog scale score. RESULTS: All 18 patients were followed up for a mean period of 49 months (range, 12-123 months). Nine patients had acromion osteolysis and 3 patients had CP fracture nonunion (Eyres type II, III, and V in 1 patient each); however, no patients developed shoulder pain, incision infection, limitation of shoulder movement, clinical symptoms of subcoracoid impingement, or AC dislocation relapse. At the last follow-up, the mean Constant score was 99 (range, 94-100). CONCLUSIONS: The possibility of CP fracture should be considered in patients with AC dislocation to avoid a missed diagnosis. Fixation with a clavicular hook plate is a feasible treatment for CP fracture combined with AC dislocation and provides a satisfactory outcome. CP fracture healing may be related to the fracture morphology.

Quantifying Information of Dynamical Biochemical Reaction Networks.

A large number of complex biochemical reaction networks are included in the gene expression, cell development, and cell differentiation of in vivo cells, among other processes. Biochemical reaction-underlying processes are the ones transmitting information from cellular internal or external signaling. However, how this information is measured remains an open question. In this paper, we apply the method of information length, based on the combination of Fisher information and information geometry, to study linear and nonlinear biochemical reaction chains, respectively. Through a lot of random simulations, we find that the amount of information does not always increase with the length of the linear reaction chain; instead, the amount of information varies significantly when this length is not very large. When the length of the linear reaction chain reaches a certain value, the amount of information hardly changes. For nonlinear reaction chains, the amount of information changes not only with the length of this chain, but also with reaction coefficients and rates, and this amount also increases with the length of the nonlinear reaction chain. Our results will help to understand the role of the biochemical reaction networks in cells.

Novel pathogenic variants in CUBN uncouple proteinuria from renal function.

BACKGROUND: Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin. METHODS: Exome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants' expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice. RESULTS: In this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and α1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane. CONCLUSIONS: Here, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy.

Feasibility of evaluating the histologic and genetic subtypes of WHO grade II-IV gliomas by diffusion-weighted imaging.

BACKGROUND: To explore the feasibility of diffusion-weighted imaging (DWI) metrics to predict the histologic subtypes and genetic status of gliomas (e.g., IDH, MGMT, and TERT) noninvasively. METHODS: One hundred and eleven patients with pathologically confirmed WHO grade II-IV gliomas were recruited retrospectively. Apparent diffusion coefficient (ADC) values were measured in solid parts of gliomas on co-registered T2-weighted images and were compared with each other in terms of WHO grading and genotypes using t-tests. Receiver operating characteristic analysis was performed to assess the diagnostic performances of ADC. Subsequently, multiple linear regression was used to find independent variables, which can directly affect ADC values. RESULTS: The values of overall mean ADC (omADC) and normalized ADC (nADC) of high grade gliomas and IDH wildtype gliomas were lower than low grade gliomas and IDH mutated gliomas (P < 0.05). nADC values showed better diagnostic performance than omADC in identifying tumor grade (AUC: 0.787 vs. 0.750) and IDH status (AUC: 0.836 vs. 0.777). ADC values had limited abilities in distinguishing TERT status (AUC = 0.607 for nADC and 0.617 for omADC) and MGMT status (AUC = 0.651 for nADC). Only tumor grade and IDH status were tightly associated with ADC values. CONCLUSION: DWI metrics can predict glioma grading and IDH mutation noninvasively, but have limited use in detecting TERT mutation and MGMT methylation.

Arterial transit artifacts on arterial spin labeling MRI can predict cerebral hyperperfusion after carotid endarterectomy: an initial study.

OBJECTIVES: To investigate whether preoperative arterial spin labeling (ASL) MRI can predict cerebral hyperperfusion after carotid endarterectomy (CEA) in patients with carotid stenosis. METHODS: Consecutive patients with carotid stenosis who underwent CEA between May 2015 and July 2021 were included. For each patient, a cerebral blood flow ratio (rCBF) map was obtained by dividing postoperative CBF with preoperative CBF images from two pseudo-continuous ASL scans. Hyperperfusion regions with rCBF > 2 were extracted and weighted with rCBF to calculate the hyperperfusion index. According to the distribution of the hyperperfusion index, patients were divided into hyperperfusion and non-hyperperfusion groups. Preoperative ASL images were scored based on the presence of arterial transit artifacts (ATAs) in 10 regions of interest corresponding to the Alberta Stroke Programme Early Computed Tomography Score methodology. The degree of stenosis and primary and secondary collaterals were evaluated to correlate with the ASL score. Logistic regression and receiver operating characteristic curve analyses were performed to assess the predictive ability of the ASL score for cerebral hyperperfusion. RESULTS: Of 86 patients included, cerebral hyperperfusion was present in 17 (19.8%) patients. Carotid near occlusion, opening of posterior communicating arteries with incomplete anterior semicircle, and leptomeningeal collaterals were associated with lower ASL scores (p < 0.05). The preoperative ASL score was an independent predictor of cerebral hyperperfusion (OR = 0.48 [95% CI [0.33-0.71]], p < 0.001) with the optimal cutoff value of 25 points (AUC = 0.98, 94.1% sensitivity, 88.4% specificity). CONCLUSIONS: Based on the presence of ATAs, ASL can non-invasively predict cerebral hyperperfusion after CEA in patients with carotid stenosis. KEY POINTS: • Carotid near occlusion, opening of posterior communicating arteries with incomplete anterior semicircle, and leptomeningeal collaterals were associated with lower ASL scores. • The ASL score performed better than the degree of stenosis, type of CoW, and leptomeningeal collaterals, as well as the combination of the three factors for the prediction of cerebral hyperperfusion. • For patients with carotid stenosis, preoperative ASL can non-invasively identify patients at high risk of cerebral hyperperfusion after carotid endarterectomy without complex post-processing steps.

Sellar germinoma mimicking IgG4-related hypophysitis: a case report.

BACKGROUND: The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar germinoma is usually infiltrated by lymphocytes or plasma cells, and may be confused with hypophysitis. CASE PRESENTATION: A 36-year-old man with diabetes insipidus, elevated serum IgG4 level (336 mg/dl), and sellar mass was suspected to have IgG4-related hypophysitis, and no other lesion of IgG4-related disease was detected. After treated by prednisone and mycophenolate mofetil, the serum IgG4 decreased to 214 mg/dl. However, after withdrawal of the drugs, the IgG4 level increased to 308 mg/dl. Endocrine assessments revealed panhypopituitarism, and the sellar mass enlarged. Transsphenoidal sellar exploration and biopsy was conducted. Pathological examination showed that the lesion was germinoma with lymphocytes and plasma cells infiltration, and IgG4-staining was positive (70/HPF, IgG4/IgG ratio = 10%). The patient was then treated by cisplatin and etoposide. After four cycles of chemotherapy, the serum IgG4 was 201 mg/dl, and the sellar mass was invisible. CONCLUSION: Sellar germinoma can mimic the clinical characteristics of IgG4-related hypophysitis. Poor response to glucocorticoids can be used as an exclusion criterion in the clinical diagnosis of IgG4-related hypophysitis.