Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits.

Preoperative evaluation of oral hygiene may predict the overall survival of patients with esophageal cancer.

BACKGROUND: Previously, the association between tooth loss and prognosis after esophagectomy was reported; however, the presence of periodontal disease has not been assessed. This study investigated the association between the degree of oral hygiene, as evaluated by tooth loss and periodontal disease, and the prognosis of patients with esophageal cancer. METHODS: A total of 163 esophageal cancer patients who underwent surgery with perioperative oral care and examination were enrolled. We assessed the periodontal pocket depth for the presence of periodontal disease and established a periodontal pocket index, defined as the sum of the periodontal pocket depth of the remaining tooth divided by the total count of the remaining teeth. Patients were divided into three groups: Group A (tooth loss < 13 and periodontal pocket index < 3.67); Group B (tooth loss < 13 and periodontal pocket index ≥ 3.67); and Group C (tooth loss ≥ 13). Overall survival and cancer-specific survival were analyzed, and a multivariate analysis was performed. RESULTS: There was a significant difference in the 5-year overall survival rates between the groups (A:B:C = 74.8%:62.8%:50.5%; p = 0.0098), but not in the 5-year cancer-specific survival rates (A:B:C = 80.2%:64.2%:62.2%; p = 0.0849). In multivariate analysis, oral hygiene (tooth loss < 13 and periodontal pocket index ≥ 3.67 + tooth loss ≥ 13; p = 0.041) was a significant independent poor prognostic factor for overall survival. CONCLUSIONS: Oral evaluation, focusing on tooth loss and periodontal disease, is meaningful in predicting the long-term prognosis of postoperative esophageal cancer patients.

Predictive factors for dental inflammation with exacerbation during cancer therapy with FDG-PET/CT imaging.

PURPOSE: Oral adverse events, such as dental inflammation with exacerbation, are stressful and lead to poor nutrition in patients undergoing cancer therapy. Thus, the prediction of risk factors for dental inflammation with exacerbation is important before cancer therapy is initiated. We hypothesized that, during cancer therapy (DIECT), fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging could be useful to predict dental inflammation with exacerbation. METHODS: We enrolled 124 patients who underwent FDG-PET/CT for diagnostic staging before cancer treatment. We then assessed DIECT outcomes after basic perioperative oral treatment. Moreover, we evaluated clinical parameters, therapeutic strategies, periodontal examination (probing depth (PD) and bleeding on probing (BOP)), dental imaging, and FDG-PET/CT imaging results of patients with and without DIECT. Furthermore, PET/CT images were assessed as per the FDG accumulation of the dental lesion (PAD) grading system. RESULTS: Univariate analysis demonstrated significant differences in age, periodontal examination (PD and BOP), and PAD grade between patients with and without DIECT. Furthermore, multivariate logistic regression analysis identified independent predictive factors for a positive periodontal examination (PD) (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.8-19.7; P = 0.004) and PAD grade (OR 11.6, 95% CI 3.2-41.2; P = 0.0002). In patients with cancer, PAD grade using FDG-PET/CT imaging was an independent and informative risk factor for DIECT. CONCLUSION: Our results suggested that, for patients with DIECT, periodontal examination and PAD grade were independent predictive factors. Hence, regardless of the presence or absence of any lesion on dental imaging, PAD grade might be an additional tool, in addition to periodontal examination that potentially improves oral care management.

Evaluation of bone marrow invasion on the machine learning of 18 F-FDG PET texture analysis in lower gingival squamous cell carcinoma.

OBJECTIVES: Lower gingival squamous cell carcinoma (LGSCC) has the potential to invade the alveolar bone. Traditionally, the diagnosis of LGSCC relied on morphological imaging, but inconsistencies between these assessments and surgical findings have been observed. This study aimed to assess the correlation between LGSCC bone marrow invasion and PET texture features and to enhance diagnostic accuracy by using machine learning. METHODS: A retrospective analysis of 159 LGSCC patients with pretreatment 18 F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) examination from 2009 to 2017 was performed. We extracted radiomic features from the PET images, focusing on pathologic bone marrow invasion detection. Extracted features underwent the least absolute shrinkage and selection operator algorithm-based selection and were then used for machine learning via the XGBoost package to distinguish bone marrow invasion presence. Receiver operating characteristic curve analysis was performed. RESULTS: From the 159 patients, 88 qualified for further analysis (59 men; average age, 69.2 years), and pathologic bone marrow invasion was identified in 69 (78%) of these patients. Three significant radiological features were identified: Gray level co-occurrence matrix_Correlation, INTENSITY-BASED_IntensityInterquartileRange, and MORPHOLOGICAL_SurfaceToVolumeRatio. An XGBoost machine-learning model, using PET radiomic features to detect bone marrow invasion, yielded an area under the curve value of 0.83. CONCLUSION: Our findings highlighted the potential of 18 F-FDG PET radiomic features, combined with machine learning, as a promising avenue for improving LGSCC diagnosis and treatment. Using 18 F-FDG PET texture features may provide a robust and accurate method for determining the presence or absence of bone marrow invasion in LGSCC patients.

Diagnostic usefulness of ¹8F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma.

PURPOSE: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of (18)F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of (18)F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. METHODS: The study group comprised 68 OSCC patients who underwent both (18)F-FAMT and (18)F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. RESULTS: The sensitivity of primary tumour detection by (18)F-FAMT and (18)F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of (18)F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for (18)F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of (18)F-FAMT were significantly higher than those of (18)F-FDG. The uptake of (18)F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. CONCLUSION: (18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation.

The interface stiffness and topographic feature dictate interfacial invasiveness of cancer spheroids.

During cancer metastasis, tumor cells likely navigate, in a collective manner, discrete tissue spaces comprising inherently heterogeneous extracellular matrix microstructures where interfaces may be frequently encountered. Studies have shown that cell migration modes can be determined by adaptation to mechanical/topographic cues from interfacial microenvironments. However, less attention has been paid to exploring the impact of interfacial mechnochemical attributes on invasive and metastatic behaviors of tumor aggregates. Here, we excogitated a collagen matrix-solid substrate interface platform to investigate the afore-stated interesting issue. Our data revealed that stiffer interfaces stimulated spheroid outgrowth by motivating detachment of single cells and boosting their motility and velocity. However, stronger interfacial adhesive strength between matrix and substrate led to the opposite outcomes. Besides, this interfacial parameter also affected the morphological switch between migration modes of the detached cells and their directionality. Mechanistically, myosin II-mediated cell contraction, compared to matrix metalloproteinases-driven collagen degradation, was shown to play a more crucial role in the invasive outgrowth of tumor spheroids in interfacial microenvironments. Thus, our findings highlight the importance of heterogeneous interfaces in addressing and combating cancer metastasis.

A deep learning-based pipeline for analyzing the influences of interfacial mechanochemical microenvironments on spheroid invasion using differential interference contrast microscopic images.

Metastasis is the leading cause of cancer-related deaths. During this process, cancer cells are likely to navigate discrete tissue-tissue interfaces, enabling them to infiltrate and spread throughout the body. Three-dimensional (3D) spheroid modeling is receiving more attention due to its strengths in studying the invasive behavior of metastatic cancer cells. While microscopy is a conventional approach for investigating 3D invasion, post-invasion image analysis, which is a time-consuming process, remains a significant challenge for researchers. In this study, we presented an image processing pipeline that utilized a deep learning (DL) solution, with an encoder-decoder architecture, to assess and characterize the invasion dynamics of tumor spheroids. The developed models, equipped with feature extraction and measurement capabilities, could be successfully utilized for the automated segmentation of the invasive protrusions as well as the core region of spheroids situated within interfacial microenvironments with distinct mechanochemical factors. Our findings suggest that a combination of the spheroid culture and DL-based image analysis enable identification of time-lapse migratory patterns for tumor spheroids above matrix-substrate interfaces, thus paving the foundation for delineating the mechanism of local invasion during cancer metastasis.

Predictive factors for refractory stage I and II anti-resorptive agent-related osteonecrosis of the jaw.

OBJECTIVES: We aimed to predict the possibility of patients with stage I and II anti-resorptive agent-related osteonecrosis of the jaw (ARONJ) developing resistance to our treatment protocol by evaluating their clinical and imaging factors. MATERIALS AND METHODS: We enrolled 58 patients with ARONJ who underwent imaging modality. As objective variables, we considered the healing, stage-down, and stable stages as successful outcomes, and the stage-up stage as resistant-to-treatment. As explanatory variables, we investigated the clinical and imaging factors. Furthermore, we examined stage-down as an improvement outcome to compare with the stable and stage-up stages, which were considered as no-improvement outcomes. We conducted unpaired between-group comparisons on all explanatory variables using χ2 tests for independence. RESULTS: Among 58 patients, the treatment was successful in 53 (91.4%); however, the disease was resistant in five (8.6%). Among the clinical factors, the resistant patients had a longer duration of administration of bone-modifying agents (BMAs) (cut-off: 1251 days, p = 0.032, odds ratio = 11.2, 95% confidence interval 1.115-122.518). In addition, the target disease that was being treated bone metastasis of malignant tumor was the only significant refractory factor (p = 0.024, OR: 3.667 95% CI 1.159-11.603) CONCLUSIONS: A combination of metabolic and morphological imaging modalities may be useful for oral surgeons to evaluate the disease activity and predict course of refractory ARONJ.

Determination of diagnostic and predictive parameters for vertical mandibular invasion in patients with lower gingival squamous cell carcinoma: A retrospective study.

Vertical mandibular invasion of lower gingival squamous cell carcinoma (LGSCC) determines the method of resection, which significantly affects the patient's quality of life. Therefore, in mandibular invasion by LGSCC, it is extremely important to monitor progression, specifically whether invasion is limited to the cortical bone or has progressed to the bone marrow. This retrospective study aimed to identify the diagnostic and predictive parameters for mandibular invasion, particularly vertical invasion, to enable appropriate selection of the method of mandibular resection. Of the patients who underwent surgery for LGSCC between 2009 and 2017, 64 were eligible for participation in the study based on tissue microarrays (TMA) from surgical specimens. This study analyzed morphological features using computed tomography (CT), and metabolic characteristics using maximum standardized uptake value (SUVmax), peak value of SUV (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Moreover, immunohistochemical analysis of proteins, including parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), E-cadherin, and programmed cell death-1 ligand 1 (PD-L1), was performed. Statistical analysis was performed using univariate logistic regression analysis with the forward selection method. The present study showed that MTV (≥2.9 cm3) was an independent diagnostic and predictive factor for positivity of mandibular invasion. Additionally, TLG (≥53.9 bw/cm3) was an independent diagnostic and predictive factor for progression to bone marrow invasion. This study demonstrated that in addition to morphological imaging by CT, the volume-based parameters of MTV and TLG on fluorine-18 fluorodeoxyglucose positron emission tomography were important for predicting pathological mandibular invasion in patients with LGSCC. A more accurate preoperative diagnosis of vertical mandibular invasion would enable the selection of appropriate surgical procedure for mandibular resection.

Thermomechanical Properties and Fracture Toughness Improvement of Thermosetting Vinyl Ester Using Liquid Metal and Graphene Nanoplatelets.

In this study, a eutectic gallium-indium (EGaIn) alloy and graphene nanoplatelets (GnPs) were employed as reinforcements for a comonomer vinyl ester (cVE) resin at different weight fractions up to 2% via a direct polymerization process. First, the effect of EGaIn on the curing kinetics of cVE was evaluated. The thermal and mechanical properties, and the fracture toughness of two types of cVE composites consisting of EGaIn and GnPs were then studied. The results showed that sub-micron sized EGaIn (≤1 wt.%) could promote the curing reaction of cVE without changing the curing mechanism. However, with further increases in EGaIn loading between 1 and 2 wt.%, the curing reaction rate tends to decrease. Both EGaIn and GnPs showed a significant enhancement in strengthening and toughening the cVE matrix with the presence of filler loading up to 1 wt.%. EGaIn was more effective than GnPs in promoting the flexural and impact strength. An increase of up to 50% and 32% were recorded for these mechanical properties, when EGaln was used, as compared to 46%, and 18% for GnPs, respectively. In contrast, the GnPs/cVE composites exhibited a greater improvement in the fracture toughness and fracture energy by up to 50% and 56% in comparison with those of the EGaIn/cVE ones by up to 32% and 39%, respectively. Furthermore, the stiffness of both the EgaIn/cVE and GnPs/cVE composites showed a significant improvement with an increase of up to 1.76 and 1.83 times in the normalized storage modulus, respectively, while the glass transition temperature (Tg) values remained relatively constant. This work highlights the potential of EGaIn being employed as a filler in creating high-performance thermoset composites, which facilitates its widening applications in many structural and engineering fields, where both higher toughness and stiffness are required.

FOXM1 expression mediates growth suppression during terminal differentiation of HO-1 human metastatic melanoma cells.

Induction of terminal differentiation represents a potentially less toxic cancer therapy. Treatment of HO-1 human metastatic melanoma cells with IFN-ß plus mezerein (MEZ) promotes terminal differentiation with an irreversible loss of growth potential. During this process, the transcription factor FOXM1 is down-regulated potentially inhibiting transactivation of target genes including those involved in G(2)/M progression and cell proliferation. We investigated the mechanism of FOXM1 down-regulation and its physiological role in terminal differentiation. Genetic and pharmacological studies revealed that FOXM1 down-regulation was primarily caused by MEZ activation of PKCα and co-treatment with IFN-ß plus MEZ augmented the effect of PKCα. Promoter analysis with a mutated E-box on the FOXM1 promoter, and in vitro and in vivo binding assays confirm a direct role of c-Myc on FOXM1 expression. Reduction of c-Myc and overexpression of Mad1 by IFN-ß plus MEZ treatment should cause potent and persistent reduction of FOXM1 expression during terminal differentiation. Overexpression of FOXM1 restored expression of cell cycle-associated genes and increased the proportion of cells in the S phase. Our experiments support a model for terminal differentiation in which FOXM1 down-regulation via activation of PKCα followed by suppression of c-Myc expression, are causal events in promoting growth inhibition during terminal differentiation.

Image screening for maxillo-mandibular actinomycosis with CT, 18F-FDG-PET/CT, and 18F-α-methyl tyrosine PET/CT.

OBJECTIVES: Clinical features and imaging findings of maxillo-mandibular actinomycosis are similar to those of intraosseous carcinoma. The purpose of this study is to clarify the characteristics of the imaging findings for screening of maxillo-mandibular actinomycosis using CT and PET. METHODS: Reports on maxillo-mandibular actinomycosis published between 1997 and 2016 were searched in PubMed using "actinomycosis," "maxilla," and "mandibular" as keywords. Ten cases suspected to have malignant tumors on diagnostic imaging findings were selected. In addition, three patients who visited Gunma University Hospital were also included. The 13 total cases were subjected to a pooled analysis of diagnostic screening of maxillo-mandibular actinomycosis using CT, 18F-FDG-PET/CT (FDG-PET/CT) and 18F-α-methyl tyrosine PET/CT (FAMT-PET/CT). Additionally, cases of intraosseous carcinoma were analyzed as comparative controls to investigate the difference between maxillo-mandibular actinomycosis and intraosseous carcinoma on CT imaging. RESULTS: CT images of the 13 cases with maxillo-mandibular actinomycosis were investigated; spotty-type bone resorption was observed in 66.7% (8/12). Moreover, FDG-PET/CT showed abnormal accumulation, but FAMT-PET/CT showed no apparent abnormal accumulation. CONCLUSIONS: Clinical and imaging findings of maxillo-mandibular actinomycosis are similar to those of intraosseous carcinoma. Differential diagnostic screening can confirm spotty-type bone resorption in cortical bone with CT and specific accumulation in malignant tumors with FAMT-PET/CT. This screening facilitates the rapid implementation of therapeutic interventions.

Multi-omics Analysis of Ferroptosis Regulation Patterns and Characterization of Tumor Microenvironment in Patients with Oral Squamous Cell Carcinoma.

Ferroptosis is a newly recognized mechanism of regulated cell death. It was reported to be highly associated with immune therapy and chemotherapy. However, its mechanism of regulation in the tumor microenvironment (TME) and influence on oral squamous cell carcinoma (OSCC) therapy are unknown. We identified a ferroptosis-specific gene-expression signature, an FPscore, developed by a principal component analysis (PCA) algorithm to evaluate the ferroptosis regulation patterns of individual tumor. Multi-omics analysis of ferroptosis regulation patterns was conducted. Three distinct ferroptosis regulation subtypes, which linked to outcomes and the clinical relevance of each patient, were established. A high FPscore of patients with OSCC was associated with a favorable prognosis, a ferroptosis-related immune-activation phenotype, potential sensitivities to the chemotherapy and immunotherapy. Importantly, a high FPscore correlated with a low gene copy number burden and high immune checkpoint expressions. We validated the prognostic value of the FPscore using independent immunotherapy and pan-cancer cohorts. Comprehensive evaluation of individual tumors with distinct ferroptosis regulation patterns provides new mechanistic insights, which may be clinically relevant for the application of combination therapies in OSCC.

Texture analysis of [18F]-fluorodeoxyglucose-positron emission tomography/computed tomography for predicting the treatment response of postoperative recurrent or metastatic oral squamous cell carcinoma treated with cetuximab.

OBJECTIVE: To assess the value of the texture analysis of fluorine-18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in predicting the treatment response of postoperative recurrent or metastatic oral squamous cell carcinoma (POR/M-OSCC) treated with cetuximab. METHODS: A total of 14 patients undergoing 18F-FDG-PET/CT with POR/M-OSCC were divided into the responder and non-responder groups according to cetuximab response by Response Evaluation Criteria in Solid Tumors (RECIST). The regions of interest (ROI) were set at the POR/M-OSCC lesions with the highest uptake of 18F-FDG, and the volumetric and texture features were analyzed. The features with correlation coefficient of 0.6 or more were further evaluated using the logistic regression analysis to create a model. RESULTS: The SHAPEVolume(vx), SHAPEVolume(mL), metabolic tumor volume (MTV), and gray-level run-length matrix run-length nonuniformity (GLRLMRLNU) were significantly different between the responder (n = 6) and non-responder (n = 8) groups (p = 0.044, 0.042, 0.047, and 0.012, respectively). The model's area under the curve (AUC) was found to be 0.83, 0.83, 0.79, and 0.92, respectively. The heatmap with PET feature dendrogram showed four distinct clusters including them in patient's responder and non-responder groups. CONCLUSIONS: Higher MTV, GLRLMRLNU, SHAPEVolume(vx), and SHAPEVolume(mL) in 18F-FDG-PET images may have the prediction values for treatment response with POR/M-OSCC treated with cetuximab.

Resistance to Preoperative Oral Care Is Associated With Postoperative Pneumonia After Oesophageal Cancer Surgery.

BACKGROUND/AIM: Postoperative pneumonia is a serious complication of major oesophageal surgery. We aimed to clarify the association between the degree of improvement in oral hygiene by perioperative oral care and postoperative pneumonia in oesophageal cancer patients. PATIENTS AND METHODS: Oesophageal cancer patients (n=129) who underwent esophagectomy received perioperative oral care. Their oral hygiene was evaluated using the Oral Assessment Guide (OAG). The relationship between perioperative OAG scores and postoperative complications was analysed. RESULTS: The average OAG scores before starting oral care, pre-operation, and post-operation were 11.0±1.7, 9.1±1.5, and 11.2±3.0, respectively (p<0.001). An increase in preoperative OAG scores was independently associated with postoperative pneumonia on multivariate analysis (p=0.027). CONCLUSION: Preoperative oral care improves oral hygiene in patients undergoing oesophageal cancer surgery. No improvement in oral hygiene despite preoperative oral care was an independent predictor of postoperative pneumonia.

Environmental sampling for SARS-CoV-2 at a reference laboratory and provincial hospital in central Viet Nam, 2020.

OBJECTIVE: To determine whether environmental surface contamination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred at a provincial hospital in Viet Nam that admitted patients with novel coronavirus disease 2019 (COVID-19) and at the regional reference laboratory responsible for confirmatory testing for SARS-CoV-2 in 2020. METHODS: Environmental samples were collected from patient and staff areas at the hospital and various operational and staff areas at the laboratory. Specimens from frequently touched surfaces in all rooms were collected using a moistened swab rubbed over a 25 cm2 area for each surface. The swabs were immediately transported to the laboratory for testing by real-time reverse transcription polymerase chain reaction (RT-PCR). Throat specimens were collected from staff at both locations and were also tested for SARS-CoV-2 using real-time RT-PCR. RESULTS: During the sampling period, the laboratory tested 6607 respiratory specimens for SARS-CoV-2 from patients within the region, and the hospital admitted 9 COVID-19 cases. Regular cleaning was conducted at both sites in accordance with infection prevention and control (IPC) practices. All 750 environmental samples (300 laboratory and 450 hospital) and 30 staff specimens were negative for SARS-CoV-2. DISCUSSION: IPC measures at the facilities may have contributed to the negative results from the environmental samples. Other possible explanations include sampling late in a patient's hospital stay when virus load was lower, having insufficient contact time with a surface or using insufficiently moist collection swabs. Further environmental sampling studies of SARS-CoV-2 should consider including testing for the environmental presence of viruses within laboratory settings, targeting the collection of samples to early in the course of a patient's illness and including sampling of confirmed positive control surfaces, while maintaining appropriate biosafety measures.

18F-FDG and 18F-FAMT PET-derived metabolic parameters predict outcome of oral squamous cell carcinoma.

OBJECTIVES: L-3-[18F]-Fluoro-α-methyl tyrosine (FAMT), an amino acid positron emission tomography (PET) tracer, complements [18F]-fluorodeoxyglucose (FDG) in the diagnosis of malignancies. We compared the predictive ability of FAMT PET versus FDG PET regarding metastatic oral squamous cell carcinoma (OSCC) outcomes for distant metastasis, including lymph node metastasis, and identified the relevant metabolic parameters for each. METHODS: We enrolled 160 patients with OSCC who underwent PET/computed tomography using FDG and FAMT before treatment. Outcomes were assessed using clinicopathological characteristics such as the standardized uptake value (SUVmax, SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis or total lesion retention. Univariate and multivariate Cox proportional hazards models were used to identify the independent predictors of disease-free survival (DFS) and overall survival (OS) during an average follow-up time of 1401.7 and 1646.0 days, respectively. Areas under the receiver operating characteristic curves were analyzed for the accuracy and predictive value of imaging parameters. RESULTS: Clinical parameters (excluding age) and PET metabolic parameters were significantly associated with OS. Multivariate analysis showed that an infiltrative growth pattern [p = 0.034, hazard ratio (HR) = 2.30], and the FDG-measured SUVpeak (p = 0.045, HR = 2.45) were independent risk factors for DFS and that lymph node metastasis (p = 0.03, HR = 2.57) and the FAMT-measured MTV (p = 0.004, HR = 3.65) were independent risk factors for OS. CONCLUSIONS: In patients with OSCC, FDG PET predicted DFS, whereas FAMT predicted OS. The two PET tracers, combined with clinical parameters, provide complementary, outcome-related diagnostic information in OSCC.

Correlation between 18F-1-amino-3-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) uptake and expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter 1 (LAT1) in primary prostate cancer.

PURPOSE: To evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of 18F-1-amino-3-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) which is approved for the detection of recurrent PCa. METHODS: Twenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of 18F-fluciclovine and the uptake in PCa was expressed as SUVmax at six sequential 4-min time frames and as tracer distribution volume (VT) using Logan plots over 0-24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/VT, and Gleason grade group (GGG) were assessed using Spearman's rank correlation coefficient (ρ). RESULTS: Forty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of 18F-fluciclovine and higher LAT1 staining intensity (p < 0.05). The uptake of 18F-fluciclovine correlated significantly with LAT1 expression (ρ = 0.39, p = 0.01, for SUVmax at 2 min and ρ = 0.39, p = 0.01 for VT). No correlation between ASCT2 expression and 18F-fluciclovine uptake or GGG was found. CONCLUSIONS: Our findings suggest that LAT1 is moderately associated with the transport of 18F-fluciclovine in local PCa not exposed to hormonal therapy. Both high and low Gleason grade tumors express ASCT2 while LAT1 expression is less conspicuous and may be absent in some low-grade tumors. Our observations may be of importance when using 18F-fluciclovine imaging in the planning of focal therapies for PCa.

Activatable fluorescence detection of epidermal growth factor receptor positive mediastinal lymph nodes in murine lung cancer model.

It is important to detect mediastinal lymph node metastases in patients with lung cancer to improve outcomes, and it is possible that activatable fluorescence imaging with indocyanine green (ICG) can help visualize metastatic lymph nodes. Therefore, we investigated the feasibility of applying this method to mediastinal lymph node metastases in an epidermal growth factor receptor (EGFR)-positive squamous cell carcinoma of the lung. Tumors were formed by injecting H226 (EGFR-positive) and H520 (EGFR-negative) cell lines directly in the lung parenchyma of five mice each. When computed tomography revealed tumors exceeding 8 mm at their longest or atelectasis that occupied more than half of lateral lung fields, a panitumumab (Pan)-ICG conjugate was injected in the tail vein (50 µg/100 µL). The mice were then sacrificed 48 hours after injection and their chests were opened for fluorescent imaging acquisition. Lymph node metastases with the five highest fluorescent signal intensities per mouse were chosen for statistical analysis of the average signal ratios against the liver. Regarding the quenching capacity, the Pan-ICG conjugate had almost no fluorescence in phosphate-buffered saline, but there was an approximate 61.8-fold increase in vitro after treatment with 1% sodium dodecyl sulfate. Both the fluorescent microscopy and the flow cytometry showed specific binding between the conjugate and H226, but almost no specific binding with H520. The EGFR-positive mediastinal lymph node metastases showed significantly higher average fluorescence signal ratios than the EGFR-negative ones (n = 25 per group) 48 hours after conjugate administration (70.1% ± 4.5% vs. 13.3% ± 1.8%; p < 0.05). Thus, activatable fluorescence imaging using the Pan-ICG conjugate detected EGFR-positive mediastinal lymph node metastases with high specificity.

New advances on glial activation in health and disease.

In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults including astrocyte activation, astrogliosis and other morphological changes, and innate and adaptive immune responses.