The prognostic role of 18F-FDG PET/CT-based response evaluation in children with stage 4 neuroblastoma.

OBJECTIVES: To evaluate the association between metabolic response on 18F-FDG PET/CT and long-term survival in children with neuroblastoma (NB). METHODS: A total of 39 consecutive children with newly diagnosed stage 4 NB undergoing both 18F-FDG PET/CT imaging at baseline and after chemotherapy were retrospectively analyzed. The associations between metabolic parameters, including SUVmax of the lesion with the most intense 18F-FDG uptake at baseline (SUVb), after chemotherapy (SUVe), and the percentage change between SUVb and SUVe, and long-term survival were evaluated. RESULTS: With a median follow-up of 56 months, 22 patients who had achieved complete resolution on PET (no residual 18F-FDG uptake higher than the surrounding backgrounds) after chemotherapy had superior 5-year overall survival (OS) (73.6% vs. 39.0%, p = 0.044). SUVb > 6.9 indicated significantly poorer 5-year event-free survival (EFS) (12.5% vs. 59.3%, p = 0.005), as did SUVe > 1.2 (18.8% vs. 41.7%, p = 0.041). Children with SUVe > 1.2 had shorter 5-year OS (33.9% vs. 75.0%, p = 0.018). Multivariate analysis identified SUVe > 1.2 as an independent predictor for both EFS [hazard ratio (HR), 3.479, 95% CI, 1.381-8.761, p = 0.008] and OS (HR, 6.948, 95% CI, 1.663-29.025, p = 0.008), while SUVb > 6.9 was a predictor for EFS (HR, 2.889, 95% CI, 1.064-7.842, p = 0.037). Among 11 children with both SUVb > 6.9 and SUVe > 1.2, all experienced disease progression or relapse within 2 years since diagnosis. CONCLUSION: 18F-FDG PET/CT could be of useful to evaluate treatment response in children with stage 4 NB. CLINICAL RELEVANCE STATEMENT: 18F-FDG PET/CT after chemotherapy exhibits prognostic significance in neuroblastoma and holds potential as an alternative imaging modality for response evaluation, especially in cases with metaiodobenzylguanidine-nonavid or persistent avid disease. KEY POINTS: The prognostic value of chemotherapy response on 18F-FDG PET/CT in advanced neuroblastoma is unknown. Higher 18F-FDG uptake after chemotherapy was associated with worse long-term event-free survival and overall survival. 18F-FDG PET/CT after chemotherapy holds prognostic significance in children with stage 4 neuroblastoma.

Relationships of serum MMP-7 and clinical characteristics in choledochal cyst children.

BACKGROUND: Matrix metalloproteinase-7 (MMP-7) is associated with biliary injury. This study aimed to evaluate the relationships of serum MMP-7 with clinical characteristics in choledochal cysts (CDC) children. METHODS: Between June 2020 and July 2022, we conducted a prospective study of CDCs who underwent one-stage definitive operation at our center. Serum MMP-7 was measured using an enzyme-linked immunosorbent assay. We evaluated the relationships between serum MMP-7 and age, laboratory tests, imaging examinations, liver fibrosis, MMP-7 expression, and perforation. RESULTS: A total of 328 CDCs were enrolled in the study, with a median serum MMP-7 of 7.67 ng/mL. Higher serum MMP-7 was correlated with younger age at diagnosis (p < 0.001), larger cyst sizes (p < 0.001), higher liver fibrosis stages (p < 0.001), and higher incidence of perforation (p < 0.01). Liver MMP-7 was mainly expressed in intrahepatic and extrahepatic biliary epithelial cells. The area under the receiver operating characteristic curve (AUROC) was 0.630 (p < 0.001) for serum MMP-7 in predicting perforation. When serum MMP-7 was combined with γ-glutamyl transferase (GGT), the AUROC increased to 0.706 (p < 0.001). CONCLUSIONS: Serum MMP-7 was associated with biliary obstruction in CDCs. Patients with high serum MMP-7 were more likely to have severe liver damage and biliary injury, with higher incidences of liver fibrosis and perforation.

Development and validation of non-invasive models in predicting advanced fibrosis of choledochal cyst.

PURPOSE: Patients with choledochal cyst (CDC) develop liver fibrosis, especially advanced fibrosis without prompt surgery. This study validated the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) and Fibrosis-4 index (FIB-4) and constructed a model for predicting advanced fibrosis in pediatric CDCs. METHODS: Between January 2020 and March 2022, 330 CDCs (advanced fibrosis: 34, Ludwig staging 3-4; non-advanced fibrosis: 296, Ludwig staging 0-2) were reviewed. APRI and FIB-4 were validated. The area under the receiver operating characteristic (AUROC) curve was used to assess discrimination. Relevant variables were analyzed by backward stepwise logistic regression. Enhanced bootstrap method was used for internal verification with 1000 samples. RESULTS: The AUROCs of APRI and FIB-4 were 0.761 (0.673-0.850) and 0.561 (0.455-0.667). AST to prealbumin ratio (APAR), was constructed with an AUROC of 0.776 (0.693-0.860). The AUROCs of APAR + APRI and APAR + FIB-4 were 0.791 (0.713-0.869) and 0.782 (0.699-0.865). No significant differences were noted in the AUROCs of the indices or their combinations. APAR and APRI could be used together to reduce missed diagnosis rate. The risk of advanced fibrosis varied from different APAR and APRI scores. CONCLUSION: Both APAR and APRI were indispensable to identify CDC patients at high risk of advanced fibrosis.

Correlation of ectopic distal location of papilla of Vater and clinical characteristics in pediatric choledochal cysts.

PURPOSE: Ectopic distal location of papilla of Vater (EDLPV) is an obvious pathological feature of choledochal cyst (CDC). This study aimed to investigate the correlation between EDLPV and clinical characteristics of CDCs. METHODS: Three groups were studied: Group 1 (G1), papilla in the middle third of second part of duodenum (n = 38); Group 2 (G2), papilla from the distal third of second part to the beginning of third part of duodenum (n = 168); Group 3 (G3), papilla from the middle of third part to fourth part of duodenum (n = 121). Relative variables among three groups were compared. RESULTS: Compared with G1 and G2, G3 patients had the largest cysts (relative diameter: 1.18 vs. 1.60 vs. 2.62, p < 0.001), the youngest age (20.52 vs. 19.47 vs. -3.40 months, p < 0.001), the highest rate of prenatal diagnosis (26.32% vs. 36.31% vs. 62.81%, p < 0.001), the lowest occurrence of protein plugs in common channel (44.74% vs. 38.69% vs. 16.53%, p < 0.001), and the most elevated total bilirubin level (7.35 vs. 9.95 vs. 28.70 µmol/L, p < 0.001). Prenatally diagnosed G3 patients had heavier liver fibrosis than G2 (13.16% vs. 1.67%, p = 0.015). CONCLUSION: The more distal papilla location, the more severe clinical characteristics of CDCs, suggesting a crucial role in its pathogenesis.

Usefulness of brain FDG PET/CT imaging in pediatric patients with suspected autoimmune encephalitis from a prospective study.

PURPOSE: Early diagnosis and treatment are of paramount importance for pediatric patients with autoimmune encephalitis (AE). The aim is to evaluate the usefulness of FDG PET/CT in pediatric patients with suspected AE from a prospective study. METHODS: The prospective study was conducted over a period of 23.5 months from May 14, 2019, to April 30, 2021. All patients (< 18-year-old) were hospitalized at the department of pediatric neurology and met the criteria of clinical suspected AE. The children underwent the tests of blood samplings, CSF, EEG, MRI, and 18F-FDG PET/CT. The criteria for FDG PET/CT diagnosis of AE were large lobar hypometabolism with or without focal hypermetabolism found on PET/CT. The clinical final diagnosis of AE includes seropositive and seronegative AE based on the diagnostic criteria. RESULTS: One hundred four pediatric inpatients (57 boys, 47 girls) were included, of which 58 children were diagnosed with AE (seropositive, 16; seronegative, 42), 45 children were diagnosed with non-AE, and one boy remained indeterminate diagnosis. Large lobar hypometabolism was found in 61 children, of which 54 (88.5%) children were finally diagnosed with AE. The sensitivity, specificity, and accuracy of FDG PET/CT for diagnosis of AE were 93.1%, 84.4%, and 89.3%, respectively, with a positive predictive value of 88.5% and a negative predictive value of 90.5%. The most common involved with hypometabolism was the parietal lobe, followed by occipital and frontal lobes, finally the temporal lobe on PET/CT in children with AE. CONCLUSION: Brain FDG PET/CT imaging has high specificity, sensitivity, and accuracy for diagnosis of AE in clinical suspected AE children. CLINICAL TRIALS: gov. NCT02969213. Registered 17 October 2016.

One- versus two-stage single-incision laparoscopic cyst excision and hepaticojejunostomy in patients with completely perforated choledochal cysts and good medical conditions.

BACKGROUND: The aim of the current study was to evaluate the efficacy of one- and two-stage single-incision laparoscopic hepaticojejunostomy (SILH) for perforated CDCs with good medical conditions. METHODS: Between June 2015 and December 2020, 57 patients were reviewed: Group 1: patients who underwent one-stage SILH (n = 16); Group 2: patients who underwent two-stage SILH (n = 41). The demographic characteristics, operational details, postoperative outcomes and postoperative complications were evaluated. RESULTS: The mean follow-up durations of group 1 and 2 were 39.3 and 38.6 months, respectively. One patient (6.3%) in group 1, and 4 patients (9.8%) in group 2 were converted to laparotomy (p = 0.67). No statistical significance was found in operative time, blood transfusion, time to resume full diet, duration of drainage after definitive surgery and postoperative hospital stays between the two groups. Four patients in group 2 developed bile leakage, which was higher than that in group 1 (9.8% vs 0, p = 0.20). None suffered incidental injury, bleeding, anastomotic stenosis, cholangitis, cholelithiasis, pancreatic leakage, pancreatitis, Roux-loop obstruction, adhesive intestinal obstruction or wound infection. Liver function normalized within 1 year postoperatively in both groups. CONCLUSIONS: In experienced hands, one-stage single-incision laparoscopic hepaticojejunostomy is safe and effective for patients with complete perforations and good medical conditions.

Recombinant human thyrotropin (rhTSH)-aided radioiodine treatment for non-toxic multinodular goitre.

BACKGROUND: Multinodular goitre is common in women. Treatments for non-toxic multinodular goitre include surgery, levothyroxine suppressive therapy, and radioiodine. Radioiodine therapy is the only non-surgical alternative for non-toxic multinodular goitre. However, a high amount of radioiodine is needed to enable the thyroid nodules to adequately take up the radioiodine, because the multinodular goitre takes up a low amount of iodine. Recombinant human thyrotropin (rhTSH) has been used to increase radioiodine uptake and reduce thyroid volume of the multinodular goitre. Whether the improved reduction of the goitre resulting from rhTSH-stimulated radioiodine therapy is beneficial to the person remains controversial. OBJECTIVES: To assess the effects of recombinant human thyrotropin-aided radioiodine treatment for non-toxic multinodular goitre. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Scopus as well as ICTRP Search Portal and ClinicalTrials.gov. The date of the last search of all databases was 18 December 2020. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) comparing the effects of rhTSH-aided radioiodine treatment compared with radioiodine alone for non-toxic multinodular goitre, with at least 12 months of follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Screening for inclusion, data extraction, and risk of bias assessment were carried out by one review author and checked by a second. Our main outcomes were health-related quality of life (QoL), hypothyroidism, adverse events, thyroid volume, all-cause mortality, and costs. We used a random-effects model to perform meta-analyses, and calculated risk ratios (RRs) for dichotomous outcomes, and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs. A total of 197 participants were allocated to rhTSh-aided radioiodine therapy, and 124 participants were allocated to radioiodine. A single dose of radioiodine was administered 24 hours after the intramuscular injection of a single dose of rhTSH. The duration of follow-up ranged between 12 and 36 months. Low-certainty evidence from one study, with 85 participants, showed uncertain effects for QoL for either intervention. RhTSH-aided radioiodine increased hypothyroidism compared with radioiodine alone (64/197 participants (32.5%) in the rhTSH-aided radioiodine group versus 15/124 participants (12.1%) in the radioiodine alone group; RR 2.53, 95% CI 1.52 to 4.20; 6 studies, 321 participants; moderate-certainty evidence in favour of radioiodine alone). A total of 118/197 participants (59.9%) in the rhTSH-aided radioiodine group compared with 60/124 participants (48.4%) in the radioiodine alone group experienced adverse events (random-effects RR 1.24, 95% CI 0.94 to 1.63; 6 studies, 321 participants; fixed-effect RR 1.23, 95% CI 1.02 to 1.49 in favour of radioiodine only; low-certainty evidence). RhTSH-aided radioiodine reduced thyroid volume with a MD of 11.9% (95% CI 4.4 to 19.4; 6 studies, 268 participants; moderate-certainty evidence). One study with 28 participants reported one death in the radioiodine alone group (very-low certainty evidence). No study reported on costs. AUTHORS' CONCLUSIONS: RhTSH-aided radioiodine treatment for non-toxic multinodular goitre, compared to radioiodine alone, probably increased the risk of hypothyroidism but probably led to a greater reduction in thyroid volume. Data on QoL and costs were sparse or missing.

Germline and somatic mtDNA mutation spectrum of rheumatoid arthritis patients in the Taizhou area, China.

OBJECTIVE: Reactive oxygen species are believed to be involved in the onset of RA, and the association between nuclear-encoded mitochondrial respiratory chain-related variants and RA has recently been revealed. However, little is known about the landscape of mitochondrial DNA (mtDNA) variants in RA. METHODS: Next-generation sequencing was conducted to profile mtDNA germline and somatic variants in 124 RA patients and 123 age- and sex-matched healthy controls in the Taizhou area, China. Fisher's exact test, SKAT and SKAT-O were used for gene-burden tests to investigate RA-related variants of mitochondrial genes. Predictive tools were applied to evaluate the pathogenicity of mtDNA variants, and mtDNA haplogroups were assigned according to mtDNA mutations recorded in PhyloTree database. The frequency distribution of mtDNA haplogroups between the groups was compared using χ2 analysis. RESULTS: We identified 467 RA-unique and 341 healthy control-unique mtDNA variants, with 443 common variants. Only MT-ATP6 with a significant burden of variants was identified by Fisher's exact test, SKAT and SKAT-O, even after Bonferroni adjustment, and the enrichment variants in MT-ATP6 was mainly driven by m.8830C>A, m.8833G>C and m.8843T>A variants. Besides, four frequently low-heteroplasmic variants including the three variants above and m.14135T>G of MT-ND5 were detected in RA only; except for m.8830C>A, they are considered potential pathogenicity based on functional predictions. χ2 analysis before Bonferroni adjustment revealed haplogroup F1/F1a to be negatively associated with RA (P < 0.05). CONCLUSION: These results profiled the landscape of germline and somatic mtDNA variants in RA and supported the effects of mitochondrial genes on RA.

Fast growing angiosarcoma of the right atrium after radiofrequency catheter ablation: a missed diagnosis or misdiagnosis case report.

BACKGROUND: Primary angiosarcomas of the right atrium are extremely rare, often resulted in missed diagnosis or misdiagnosis with routine examination tools. These malignant cardiac tumors are highly aggressive with generally poor prognosis. Surgical excision is the mainstay of treatment as it is essentially not responsive to current regimens of chemoradiotherapy. CASE PRESENTATION: Herein, we describe a patient who initially presented with paroxysmal atrial fibrillation and was subsequently treated with radiofrequency catheter ablation (RFCA). Prior to RFCA, an initial transesophageal echocardiography revealed a local thickening of the intratrial septum. Three months later, she was hospitalized with progressive dyspnea and massive pericardial effusion. A large immobile, non-pedunculated mass, occupying almost half of the right atrium was detected by transthoracic and transesophageal echocardiogram. Multimodality cardiac imaging was useful in further characterizing this mass, which was ultimately diagnosed as an angiosarcoma based upon biopsy results. The growth rate was extremely rapid following RFCA, and patient underwent surgical excision. After discharge, the angiosarcoma recurred and patient survived for 7 months from the first episode of tamponade. CONCLUSIONS: Primary cardiac angiosarcoma of the right atrium can easily be mistaken for structural anomalies in its early stages, losing the opportunity for initiating earlier treatments to improve potential patient outcomes. The correct diagnosis of this rare case relied on the comprehensive utilization of multimodal imaging techniques including biopsy.

Metabolic tumor burden on baseline 18F-FDG PET/CT improves risk stratification in pediatric patients with mature B-cell lymphoma.

PURPOSE: In order to better identify patients most at risk of treatment failure and disease progression in pediatric mature B-cell non-Hodgkin lymphoma (B-NHL), the prognostic role of metabolic tumor burden measured on baseline 18F-FDG PET/CT scan, including total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), was investigated. METHODS: Pretreatment 18F-FDG PET/CT scans from 46 consecutive pediatric patients (median age 7 years; range 2-18 years) with newly diagnosed B-NHL were retrospectively analyzed. Clinicopathological parameters and imaging characteristics, including TMTV, TLG, and bone marrow (BM) involvement detected by PET/CT were compared to predict progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up time was 31 months. Areas under the curve of TMTV and TLG to predict events were 0.820 and 0.816, respectively. The 2-year PFS and OS were 29% and 43% in 7 patients with high TLG (> 5797 g) vs. 93% and 96% in those with low TLG (P < 0.001). High TMTV (> 524 cm3) was present in ten patients and predicted a significantly inferior outcome (PFS: 50% vs. 92%, P = 0.001; OS: 60% vs. 96%, P = 0.002). In multivariate analysis, TMTV and TLG outperformed other clinicopathological factors, including serum lactate dehydrogenase and BM involvement on biopsy, and remained the most robust predictors of survival. Furthermore, TLG sub-stratified patients with distinct outcomes efficiently within high- or intermediate-risk groups, with the negative predictive value of 100% and 92% and the positive predictive value of 100% and 50% for high-risk and intermediate-risk patients, respectively. On the other hand, BM involvement identified only by PET demonstrated an inferior prognostic value in comparison with BM biopsy. CONCLUSIONS: Baseline TMTV and TLG are both strong independent prognostic factors for pediatric B-NHL and provide a potential approach to aid in risk sub-stratification, especially in patients with high-risk disease.

[Preparation and quality standard of standard decoction of Scrophulariae Radix pieces].

The standard decoction of Chinese herbal decoction pieces is a standard reference substance to measure whether different dosage forms of Chinese medicine are basically consistent with those of clinical decoction,and provides new ideas and methods for effectively solving the problems of uneven quality in Chinese medicine dispensing granules. In this study,a systematic method for evaluating the quality of Scrophulariae Radix decoction was established from the perspective of " standard decoction",providing reference for the quality control of the Scrophulariae Radix dispensing granules. 15 batches of Scrophulariae Radix decoction pieces from different origins were collected,and 15 batches of standard decoctions were prepared according to the standardized process with water as solvent.Harpagide and harpagoside were used as quantitative detection indicators to determine the content,calculate the transfer rates and determine the extraction rate. The high performance liquid chromatography( HPLC) was used to establish a standard decoction fingerprint analysis method. The results showed that the transfer rates of harpagide and harpagoside in 15 batches of Scrophulariae Radix pieces standard decoction were( 70. 84±13. 39) % and( 48. 56±6. 40) % respectively; the extraction rate was( 57. 47±5. 89) %. Nine peaks were identified in the HPLC fingerprint,and the similarity was higher than 0. 97 between the fingerprints of 15 batches of standard decoction and the control fingerprint. In this study,the preparation process of standard decoction of Scrophulariae Radix pieces conformed to the traditional decoction preparation method. The sources of the samples were representative,and the established fingerprint method was stable and feasible,which can provide reference for the preparation and quality control of Scrophulariae Radix dispensing granules.

Prognostic value of metabolic indices and bone marrow uptake pattern on preoperative 18F-FDG PET/CT in pediatric patients with neuroblastoma.

PURPOSE: To evaluate the prognostic value of metabolic parameters and bone marrow uptake (BMU) patterns on pretherapeutic 18-F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in pediatric patients with neuroblastoma (NB). PATIENTS AND METHODS: Forty-seven pediatric patients with newly diagnosed neuroblastoma who underwent 18F-FDG PET/CT were retrospectively reviewed. Clinicopathological factors and metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and bone marrow uptake patterns on PET/CT were compared to predict recurrence-free survival (RFS) and overall survival (OS) by univariate and multivariate analysis. RESULTS: During the follow-up period, 27 (57.4%) patients experienced recurrence. MTV (P = 0.001), TLG (P = 0.004) and BMU patterns (P = 0.025) remained significant predictive factors for tumor recurrence, along with tumor size, histology, stage, lactate dehydrogenase (LDH) and other distant metastasis (except bone metastasis). Univariate analysis showed that histology, stage, tumor size (>37.25 cm), other distant metastasis, MTV (>88.10cm3) and TLG (>1045.2 g) and BMU patterns correlated with both RFS and OS (P < 0.05). On multivariate analysis, TLG remained the only independent prognostic factor for RFS (P = 0.016) and OS (P = 0.012), and BMU patterns and MTV were statistically significant for OS (P = 0.024 and P = 0.038, respectively). CONCLUSION: Pretherapeutic 18F-FDG PET/CT can provide reliable prognostic information for neuroblastoma pediatric patients, and patients with high MTV, TLG and focal bone marrow (unifocal and multifocal) uptake on PET/CT may have inferior outcomes during subsequent treatment.

PET/CT predicts bone marrow involvement in paediatric non-Hodgkin lymphoma and may preclude the need for bone marrow biopsy in selected patients.

OBJECTIVES: To investigate the role of 18F-FDG PET/CT to detect bone marrow (BM) involvement in paediatric non-Hodgkin lymphoma (NHL). METHODS: Pretreatment PET/CT scans from 93 consecutive paediatric patients with NHL were retrospectively reviewed. Patterns of BM FDG uptake and standardized uptake value of the fifth lumbar vertebra (SUVBM) were compared with bone marrow biopsy (BMB) for diagnosis of BM involvement. RESULTS: Of 93 patients, 41 were judged to have BM involvement. Thirty-nine were identified by PET/CT, versus 23 by BMB. Sensitivity and specificity were 95 % and 98 % for PET/CT and 56 % and 100 % for BMB, respectively. None of the patients with BM FDG uptake lower than liver had positive BMB. In 45 patients presenting homogeneously increased BM uptake, positive BMB was achieved in 93 % (14/15) of patients with FDG uptake expanding to the distal portion of extremities, compared to 7 % (2/30) of those without. A multifocal pattern was observed in 25 patients and 18 had negative BMB. SUVBM differentiated BM involvement from benign BM activation with an area under the curve of 0.885 (p < 0.001). CONCLUSIONS: PET/CT had a high level of accuracy for detecting BM involvement in paediatric NHL. BMB might be omitted in selected patients. KEY POINTS: • PET/CT allows for accurate detection of bone marrow involvement. • Patterns of bone marrow FDG uptake are highly correlated with marrow disease. • Bone marrow biopsy could be omitted in selected paediatric patients.

Size-dependent superparamagnetic iron oxide nanoparticles dictate interleukin-1ß release from mouse bone marrow-derived macrophages.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely investigated for their biomedical applications in magnetic resonance imaging, targeting therapy, cell labeling, etc. It has been well documented that macrophages produce interleukin (IL)-1ß via several signaling pathways, such as inflammasome activation in response to particles including silica, asbestos and urea crystals with lipopolysaccharide priming. However, the size and dose effects of SPIONs on macrophages and the mechanisms remain unclear. In this study, we explored the cytotoxicity and mechanisms of the synthesized SPIONs with different size distributions of 30, 80 and 120 nm, and compared their potential capability in inducing IL-1ß release in mouse bone marrow-derived macrophages (BMMs). We found that SPIONs induced IL-1ß release in a size- and dose-dependent manner, in which the smallest SPIONs triggered the highest IL-1ß in BMMs. When cellular uptake of SPIONs was inhibited by the actin polymerization inhibitor, cytochalasin D, SPION-induced IL-1ß release was suppressed in BMMs. Preventing lysosome damage with bafilomycin A1 or CA-074-Me also counteracted SPION-induced IL-1ß release. Moreover, SPION-activated IL-1ß release was also attenuated by reactive oxygen species scavengers, diphenylene iodonium or N-acetylcysteine. Our results elucidated the effects of size and dose on the cytotoxicity and mechanisms of IL-1ß release of SPIONs on macrophages, which facilitate the theoretical and experimental application of SPIONs in biotechnology and biomedicine in the future.

Complete Metabolic Response on Interim 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography to Predict Long-Term Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy.

BACKGROUND: This study aims to investigate the prognostic role of complete metabolic response (CMR) on interim 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in patients with breast cancer (BC) receiving neoadjuvant chemotherapy (NAC) according to tumor subtypes and PET timing. PATIENTS AND METHODS: Eighty-six consecutive patients with stage II/III BC who received PET/CT during or following NAC were included. Time-dependent receiver operating characteristic analysis and Kaplan-Meier analysis were used to determine correlation between metabolic parameters and survival outcomes. RESULTS: The median follow-up duration was 71 months. Maximum standardized uptake value (SUVmax) on an interim PET/CT independently correlated with survival by multivariate analysis (overall survival [OS]: hazard ratio: 1.139, 95% confidence interval: 1.058-1.226, p = .001). By taking PET timing into account, best association of SUVmax with survival was obtained on PET after two to three cycles of NAC (area under the curve [AUC]: 0.941 at 1 year after initiation of NAC) and PET after four to five (AUC: 0.871 at 4 years), while PET after six to eight cycles of NAC had less prognostic value. CMR was obtained in 62% of patients (23/37) with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) BC, in 48% (12/25) triple-negative BC (TNBC), and in 75% (18/24) HER2-positive (HER2+) tumors. Patients with CMR on an early-mid PET had 5-year OS rates of 92% for ER+/HER2- tumors and 80% for TNBC, respectively. Among HER2+ subtype, 89% patients (16/18) with CMR had no relapse. CONCLUSION: CMR indicated a significantly better outcome in BC and may serve as a favorable imaging prognosticator. The Oncologist 2017;22:526-534 IMPLICATIONS FOR PRACTICE: This study shows a significantly better outcome for breast cancer (BC) patients who achieved complete metabolic response (CMR) on 18F-fluorodeoxyglucose emission tomography/computed tomography (PET/CT) during neoadjuvant chemotherapy, especially for hormone receptor-positive tumors and triple negative BC. Moreover, PET/CT performed during an early- or mid-course neoadjuvant therapy is more predictive for long-term survival outcome than a late PET/CT. These findings support that CMR may serve as a favorable imaging prognosticator for BC and has potential for application to daily clinical practice.

18F-FDG PET/CT is useful in initial staging, restaging for pediatric rhabdomyosarcoma.

BACKGROUND: This study aimed to evaluate 18F-fluordeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) as an adjunct to CT and/or magnetic resonance imaging (MRI) in the staging and follow-up of pediatric rhabdomyosarcoma (RMS). METHODS: A total of 28 consecutive pediatric RMS (20 males, 8 females; mean age: 4.8 years, 10 embryonal, 18 alveolar), in whom FDG PET/CT was performed at staging (13 patients), to evaluate the therapeutic effects and to follow-up (15 patients), were retrospectively included. FDG PET/CT was compared with MRI or CT performed with a less than a 10-day interval for initial staging in 13 patients. Histological data and follow-up (mean, 18 months) were considered as the standard of reference for result interpretation. RESULTS: At staging, FDG PET/CT and CT/MRI were equally effective in the detection of the primary RMS (accuracy, 100%). FDG PET/CT revealed metastases in lymph nodes, prostate, intestinal wall, chest wall and the peritoneum in 5 patients missed by CT or MRI, and found 41positive lymph node territories in 6 patients, 8 lung metastases in 3 patients and 40 lesions located in other anatomical regions (muscle, brain, etc.) in 4 patients versus 16, 6, and 29 for CT or MRI. In 4 patients (31%), modifications were made and comprised 1 local therapy change and 3 changes of systemic treatment as well. Follow-up time ranged from 3 to 48 months, with a median follow-up time of 18 months in 15 patients for evaluation of therapeutic effects. Alveolar RMS (ARMS) had significantly high SUVmax, and more metastases was found in ARMS. CONCLUSIONS: 18F-FDG PET/CT may be useful in staging and restaging pediatric RMS, especially for assessing secondary lesions with potential therapeutic strategy alteration. The significant high SUVmax of ARMS and more metastases may indicate worse prognosis which needs further study. This study confirms that 18F-FDG PET/CT is also valuable in therapeutic assessment and follow-up.

Radioiodine therapy versus antithyroid medications for Graves' disease.

BACKGROUND: Graves' disease is the most common cause of hyperthyroidism. Both antithyroid medications and radioiodine are commonly used treatments but their frequency of use varies between regions and countries. Despite the commonness of the diagnosis, any possible differences between the two treatments with respect to long-term outcomes remain unknown. OBJECTIVES: To assess the effects of radioiodine therapy versus antithyroid medications for Graves' disease. SEARCH METHODS: We performed a systematic literature search in the Cochrane Library, MEDLINE and EMBASE and the trials registers ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was September 2015 for all databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effects of radioiodine therapy versus antithyroid medications for Graves' disease with at least two years follow-up. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts for relevance. One author carried out screening for inclusion, data extraction and 'Risk of bias' assessment and a second author checked this. We presented data not suitable for meta-analysis as descriptive data. We analysed the overall quality of evidence utilising the GRADE instrument. MAIN RESULTS: We included two RCTs involving 425 adult participants with Graves' disease in this review. Altogether 204 participants were randomised to radioiodine therapy and 221 to methimazole therapy. A single dose of radioiodine was administered. The duration of methimazole medication was 18 months. The period of follow-up was at least two years, depending on the outcome measured. For most outcome measures risk of bias was low; for the outcomes health-related quality of life as well as development and worsening of Graves' ophthalmopathy risks of performance bias and detection bias were high in at least one of the two RCTs.Health-related quality of life appeared to be similar in the radioiodine and methimazole treatment groups, however no quantitative data were reported (425 participants; 2 trials; low quality evidence). The development and worsening of Graves' ophthalmopathy was observed in 76 of 202 radioiodine-treated participants (38%) and in 40 of 215 methimazole-treated participants (19%): risk ratio (RR) 1.94 (95% confidence interval (CI) 1.40 to 2.70); 417 participants; 2 trials; low quality evidence. A total of 35% to 56% of radioiodine-treated participants and 42% of participants treated with methimazole were smokers, which is associated with the risk of worsening or development of Graves' ophthalmopathy. Euthyroidism was not achieved by any participant being treated with radioiodine compared with 64/68 (94%) of participants after methimazole treatment (112 participants; 1 trial). In this trial thyroxine therapy was not introduced early in both treatment arms to avoid hypothyroidism. Recurrence of hyperthyroidism (relapse) in favour of radioiodine treatment showed a RR of 0.20 (95% CI 0.01 to 2.66); P value = 0.22; 417 participants; 2 trials; very low quality evidence. Heterogeneity was high (I² = 91%) and the RRs were 0.61 or 0.06 with non-overlapping CIs. Adverse events other than development of worsening of Graves' ophthalmopathy for radioiodine therapy were hypothyroidism (39 of 41 participants (95%) compared with 0% of participants receiving methimazole, however thyroxine treatment to avoid hypothyroidism was not introduced early in the radioiodine group - 104 participants; 1 trial; very low quality evidence) and drug-related adverse events for methimazole treatment (23 of 215 participants (11%) reported adverse effects likely related to methimazole therapy - 215 participants; 2 trials; very low quality evidence). The outcome measures all-cause mortality and bone mineral density were not reported in the included trials. One trial (174 participants) reported socioeconomic effects: costs based on the official hospital reimbursement system in Sweden for patients without relapse and methimazole treatment were USD 1126/1164 (young/older methimazole group) and for radioiodine treatment USD 1862. Costs for patients with relapse and methimazole treatment were USD 2284/1972 (young/older methimazole group) and for radioiodine treatment USD 2760. AUTHORS' CONCLUSIONS: The only antithyroid drug investigated in the two included trials was methimazole, which might limit the applicability of our findings with regard to other compounds such as propylthiouracil. Results from two RCTs suggest that radioiodine treatment is associated with an increased risk of Graves' ophthalmopathy. Our findings suggest some benefit from radioiodine treatment for recurrence of hyperthyroidism (relapse) but there is uncertainty about the magnitude of the effect size.

Risk stratification in patients with advanced-stage breast cancer by pretreatment [(18) F]FDG PET/CT.

BACKGROUND: The objective of the current study was to investigate the prognostic value of pretreatment [(18) F] fluorodeoxyglucose position emission tomography/computed tomography ([(18) F]FDG PET/CT) in patients with advanced-stage breast cancer. METHODS: Pretreatment PET/CT scans from 240 consecutive patients with American Joint Committee on Cancer stage III or stage IV BC were analyzed retrospectively. Clinicopathological factors and metabolic parameters of the primary tumor including maximum standardized uptake value (SUVmax ), metabolic tumor volume, and total lesion glycolysis (TLG) with a range of thresholds were compared to predict progression-free survival (PFS) and overall survival (OS) using a time-dependent receiver operating characteristic curve and Cox proportional hazards regression analyses. RESULTS: SUVmax with a cutoff value of 6.0, TLG30% with a cutoff value of 158 g, and phenotype associated with PFS and OS were analyzed using multivariate analysis. The mean TLG30% of primary tumors for patients with stage III and stage IV disease was 405 g and 750 g (P = .010), respectively. Patients with triple-negative breast cancer or a TLG30% >158 g or with both were categorized as being at high risk, and those with non-triple-negative breast cancer and a primary tumor with a TLG30% ≤158 g were defined as low risk. The 5-year PFS rates for stage III disease among patients with low-risk versus high-risk BC were 85% and 67.5%, respectively. For patients with stage IV disease, the 5-year PFS rates were 45% and 9%, respectively, for patients with low-risk versus high-risk disease. Patients with stage III and high-risk BC had OS rates that were similar to those for patients with stage IV and low-risk BC (P = .552). CONCLUSIONS: The TLG30% from pretreatment PET/CT was found to independently correlate with survival outcomes and appears to be able to effectively stratify both patients with stage III and those with stage IV BC.

A novel COL4A5 splicing mutation causes alport syndrome in a Chinese family.

BACKGROUND: Alport syndrome (AS) is characterised by haematuria, proteinuria, a gradual decline in kidney function, hearing loss, and eye abnormalities. The disease is caused by mutations in COL4An (n = 3, 4, 5) that encodes 3-5 chains of type IV collagen in the glomerular basement membrane. AS has three genetic models: X-linked, autosomal recessive, and autosomal dominant. The most common type of AS is X-linked AS, which is caused by COL4A5. METHODS: We enrolled children with renal insufficiency and a family history of kidney disorders. The proband was identified using whole-exome sequencing. Sanger sequencing was performed to verify the mutation site. Minigene technology was used to analyse the influence of mutant genes on pre-mRNA shearing, and the Iterative Threading ASSEmbly Refinement (I-TASSER) server was used to analyse the protein structure changes. RESULTS: The proband, together with her mother and younger brother, displayed microscopic haematuria and proteinuria, Pathological examination revealed mesangial hyperplasia and sclerosis. A novel mutation (NM_000495.5 c.4298-8G > A) in the intron of the COL4A5 gene in the proband was discovered, which was also present in the proband's mother, brother, and grandmother. In vitro minigene expression experiments verified that the c.4298-8G > A mutation caused abnormal splicing, leading to the retention of six base pairs at the end of intron 46. The I-TASSER software predicted that the mutation affected the hydrogen-bonding structure of COL4A5 and the electrostatic potential on the surface of the protein molecules. CONCLUSIONS: Based on the patient's clinical history and genetic traits, we conclude that the mutation at the splicing site c.4298-8G > A of the COL4A5 gene is highly probable to be the underlying cause within this particular family. This discovery expands the genetic spectrum and deepens our understanding of the molecular mechanisms underlying AS.