Focal incidental colorectal fluorodeoxyglucose uptake: Should it be spotlighted?

Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) has emerged as a cornerstone in cancer evaluation imaging, with a well-established history spanning several years. This imaging modality, encompassing the examination of the body from the base of the skull to the upper thighs, comprehensively covers the chest and abdominopelvic regions in a singular scan, allowing for a holistic assessment of nearly the entire body, including areas of marginal interest. The inherent advantage of this expansive scan range lies in its potential to unveil unexpected incidental abnormal hypermetabolic areas. The identification of incidental focal FDG uptake within colorectal regions during PET/CT scans is not an uncommon occurrence, albeit fraught with challenges associated with non-specific FDG uptake. The presence of benign colorectal lesions or physiological uptake poses a particular obstacle, as these may manifest with FDG uptake levels that mimic malignancy. Consequently, physicians are confronted with a diagnostic dilemma when encountering abnormal FDG uptake in unexpected colorectal areas. Existing studies have presented divergent results concerning these uptakes. Standardized uptake value and its derivatives have served as pivotal metrics in quantifying FDG uptake in PET images. In this article, we aim to succinctly explore the distinctive characteristics of FDG, delve into imaging findings, and elucidate the clinical significance of incidental focal colorectal uptake. This discussion aims to contribute valuable insights into the nuanced interpretation of such findings, fostering a comprehensive understanding.

Unexpected focal fluorodeoxyglucose uptake in main organs; pass through or pass by?

Since the inception of fluorine-18 fluorodeoxyglucose (F-18 FDG), positron emission tomography/computed tomography (PET/CT) utilizing F-18 FDG has become widely accepted as a valuable imaging modality in the field of oncology, with global prevalence in clinical practice. Given that a single Torso PET/CT scan encompasses the anatomical region from the skull base to the upper thigh, the detection of incidental abnormal focal hypermetabolism in areas of limited clinical interest is both feasible and not uncommon. Numerous investigations have been undertaken to delineate the distinctive features of these findings, yet the outcomes have proven inconclusive. The incongruent results of these studies present a challenge for physicians, leaving them uncertain about the appropriate course of action. This article provides a succinct overview of the characteristics of fluorodeoxyglucose, followed by a comprehensive discussion of the imaging findings and clinical significance associated with incidental focal abnormal F-18 FDG activity in several representative organs. In conclusion, while the prevalence of unrecognized malignancy varies across organs, malignancies account for a substantial proportion, ranging from approximately one-third to over half, of incidental focal uptake. In light of these rates, physicians are urged to exercise vigilance in not disregarding unexpected uptake, facilitating more assured clinical decisions, and advocating for further active evaluation.

Evaluation of Three Imaging Methods to Quantify Key Events in Pelvic Bone Metastasis.

BACKGROUND: The purpose of this study is to compare turbo spin echo diffusion-weighted images in radial trajectory (BLADE DWI) with multi-shot echoplanar imaging (RESOLVE DWI) for imaging the metastatic lesion in the pelvic bone to find a correlation between ADC values and standardized uptake values (SUVs) of FDG uptake in PET/CT. The study also seeks to compare the values of metastatic lesions with those of benign bone lesions, specifically red marrow hyperplasia. METHODS: The retrospective IRB-approved study included patients with bone metastasis and red marrow hyperplasia in the pelvic bone who underwent 3.0 T MRI with BLADE/RESOLVE DWI sequences and F-18 FDG PET/CT within one month. BVC (best value comparator) was used in determining the nature of bone lesions. Apparent diffusion coefficient (ADC) and standardized uptake value (SUV) were measured by a radiologist and a nuclear medicine physician. MRI image quality was graded with a Likert scale regarding the visualization of the sacroiliac joint, sacral neural foramen, hamstring tendon at ischial tuberosity, and tumor border. Signal-to-noise ratio (SNR) and imaging time were compared between the two DWIs. Mean, peak, and maximum SUVs between metastatic and benign red marrow lesions were compared. SUVs and ADC values were compared. AUROC analyses and cut-off values were obtained for each parameter. Mann-Whitney U, Spearman's rho, and Kolmogorov-Smirnov tests were applied using SPSS. RESULTS: The final study group included 58 bone lesions (19 patients (male: female = 6:13, age 52.5 ± 9.6, forty-four (75.9%) bone metastasis, fourteen (24.1%) benign red marrow hyperplasia). ADCs from BLADE and RESOLVE were significantly higher in bone metastasis than red marrow hyperplasia. BLADE showed higher ADC values, higher anatomical scores, and higher SNR than RESOLVE DWI (p < 0.05). Imaging times were longer for BLADE than RESOLVE (6 min 3 s vs. 3 min 47 s, p < 0.05). There was a poor correlation between ADC values and SUVs (correlation coefficient from 0.04 to 0.31). The AUROC values of BLADE and RESOLVE MRI ranged from 0.892~0.995. Those of PET ranged from 0.877~0.895. The cut-off ADC values between the bone metastasis and red marrow hyperplasia were 355.0, 686.5, 531.0 for BLADE min, max, and average, respectively, and 112.5, 737.0, 273.0 for RESOLVE min, max, and average, respectively. The cut-off SUV values were 1.84, 5.01, and 3.81 for mean, peak, and max values, respectively (p < 0.05). CONCLUSIONS: Compared with RESOLVE DWI, BLADE DWI showed improved image quality of pelvic bone MRI in the aspect of anatomical depiction and SNR, higher ADC values, albeit longer imaging time. BLADE and RESOLVE could differentiate bone metastasis and red marrow hyperplasia with quantifiable cut-off values. Further study is necessary to evaluate the discrepancy between the quantifiers between PET and MRI.

Additional Role of Midbrain F-18 FP-CIT Uptake on PET in Evaluation of Essential Tremor and Parkinsonism.

BACKGROUND: Parkinsonism is a term used for the collection of clinical features that cause movement disorders similar to those in Parkinson's disease. Accurate differentiation of these disorders is critical for the treatment and prognosis of any disease. Fluorine-18 N-(3-fluoropropyl)-2ß- carboxymethoxy-3ß-(4-iodophenyl) nortropane (F-18 FP-CIT) has been used in the evaluation of parkinsonism by its uptake in the dopamine active transporter (DAT) of the striatum. Its uptake in other areas of the brain, such as serotonin transporter (SERT) in the midbrain or thalamus, is also recognised. OBJECTIVE: To investigate whether midbrain SERT uptake of F-18 FP-CIT on positron emission tomography (PET) could be applied to the differentiation of parkinsonism in combination with striatal DAT uptake. METHODS: This retrospective study included clinically diagnosed three essential tremors (ET), 53 parkinsonism patients (21 idiopathic Parkinson's disease (IPD), 6 multiple system atrophy - cerebellar type (MSA-C), 7 multiple system atrophy - parkinsonian type (MSA-P), 8 vascular parkinsonism (VP), and 11 drug-induced parkinsonism (DIP)), and 16 healthy controls. The patient group consisted of 29 men and 27 women (age mean ± SD years, 69.9 ± 8.5 and 69.2 ± 8.9, respectively), and the healthy controls consisted of 8 men and 8 women (age mean ± SD years, 64.5 ± 8.2 and 64.3 ± 7.6, respectively). Mean standardized uptake values (SUVs) and activity volumes were measured from the visualized FP-CIT uptake of the midbrain (substantia nigra and dorsal raphe nucleus) as well as the striatum (caudate nucleus and putamen). The mean SUVs of the occipital region were measured as the background activity. The semiquantitative binding ratio (BR) was calculated using the following formula: BR = (SUVmean of the region of interest - SUVmean of background)/SUVmean of the background. SUV, volume, and BR in each type of parkinsonism were compared with those in healthy controls using both nonparametric and parametric methods. The correlation between the visual score of the qualitative analysis and the BR was examined. RESULTS: Except for the dorsal raphe nucleus in VP, the midbrain BRs in all parkinsonism showed a statistically significant decrease compared to those in healthy controls. Both midbrain and striatal BRs were significantly decreased only in patients with IPD or MSA-P; a greater decrease of substantia nigra BR was identified in MSA-P than in IPD (p < 0.05). The striatal BRs in MSA-C, VP, and DIP showed no significant difference from those in healthy controls. Finally, four patterns of uptake were identified: 1) decreased striatal and midbrain uptake for IPD and MSA-P, 2) normal striatal uptake and decreased midbrain uptake (both substantia nigra and dorsal raphe nucleus) for MSA-C and DIP, 3) normal striatal uptake and decreased substantia nigra uptake (without decreased dorsal raphe nucleus uptake) for VP, and 4) normal striatal and midbrain uptake for ET. CONCLUSION: The possible differential diagnoses were split into two groups when only striatal uptake was considered but they were divided into four groups after adding midbrain uptake. Although additional midbrain F-18 FP-CIT uptake still could not make a final definitive diagnosis, it could provide another piece of information and specific diagnostic guidelines for the differentiation of parkinsonism.

Significance of incidental focal fluorine-18 fluorodeoxyglucose uptake in colon/rectum, thyroid, and prostate: With a brief literature review.

BACKGROUND: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT), a functional imaging method, is usually performed on the entire torso, and regions of unexpected suspicious focal hypermetabolism are not infrequently observed. Among the regions, colon, thyroid, and prostate were found to be the common organs in a recent umbrella review. Some studies reported that a high rate of malignancy was shown in incidentally identified focal hypermetabolic regions and suggested that further examinations should not be ignored. AIM: To investigate the malignancy rate of incidental focal FDG uptake, useful PET parameters and their cutoffs in discrimination between malignant and benign lesions. METHODS: Retrospectively, the final reports of 16510 F-18 FDG PET/CT scans performed at our hospital between January 2016 and March 2022 were reviewed to identify incidentally observed FDG uptake in the colon/rectum, thyroid, and prostate. The scans of patients with current or prior malignancies at each corresponding location, without the final reports of histopathology or colonoscopy (for colon and rectum) for the corresponding hypermetabolic regions, or with diffuse (not focal) hypermetabolism were excluded. Finally, 88 regions of focal colorectal hypermetabolism in 85 patients (48 men and 37 women with mean age 67.0 ± 13.4 years and 63.4 ± 15.8 years, respectively), 48 focal thyroid uptakes in 48 patients (12 men and 36 women with mean age 62.2 ± 13.1 years and 60.8 ± 12.4 years, respectively), and 39 focal prostate uptakes in 39 patients (mean age 71.8 ± 7.5 years) were eligible for this study. For those unexpected focal hypermetabolic regions, rates of malignancy were calculated, PET parameters, such as standardized uptake value (SUV), capable of distinguishing between malignant and benign lesions were investigated, and the cutoffs of those PET parameters were determined by plotting receiver operating characteristic curves. RESULTS: In the colon and rectum, 29.5% (26/88) were malignant and 33.0% (29/88) were premalignant lesions. Both SUVmax and SUVpeak differentiated malignant/premalignant from benign lesions, however, no parameters could distinguish malignant from premalignant lesions. Higher area under the curve was shown with SUVmax (0.752, 95%CI: 0.649-0.856, P < 0.001) and the cutoff was 7.6. In the thyroid, 60.4% (29/48) were malignant. The majority were well-differentiated thyroid cancers (89.7%, 26/29). The results of BRAF mutation tests were available for 20 of the 26 well-differentiated thyroid cancers and all 20 had the mutation. Solely SUVmax differentiated malignant from benign lesions and the cutoff was 6.9. In the prostate, 56.4% (22/39) were malignant. Only SUVmax differentiated malignant from benign lesions and the cutoff was 3.8. Overall, among the 175 focal hypermetabolic regions, 60.6% (106/175) were proven to be malignant and premalignant (in colon and rectum) lesions. CONCLUSION: Approximately 60% of the incidentally observed focal F-18 FDG uptake in the colon/rectum, thyroid, and prostate were found to be malignant. Of the several PET parameters, SUVmax was superior to others in distinguishing between malignant/premalignant and benign lesions. Based on these findings, incidental focal hypermetabolism should not be ignored and lead physicians to conduct further investigations with greater confidence.

Assessment of incidental focal colorectal uptake by analysis of fluorine-18 fluorodeoxyglucose positron emission tomography parameters.

BACKGROUND: Colon and rectal cancers are among the top five cancers worldwide in terms of their incidence and mortality rates. As the treatment options for cure include surgery even in specific advanced-stage cases, the early detection of lesions is important for applying active treatment methods. Fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) is an established imaging study for many types of cancers; however, physiologic uptake in the gastrointestinal tract is a frequent finding and may interfere with lesion identification. Nevertheless, as unexpectedly observed focal colorectal F-18 FDG uptake may harbor malignant lesions, further examination must not be avoided. AIM: To assess the clinical implications of unexpected focal colorectal F-18 FDG uptake by analyzing FDG PET parameters. METHODS: A total of 15143 F-18 FDG PET/CT scans performed at our hospital between January 2016 and September 2021 were retrospectively reviewed to identify incidentally observed focal colorectal FDG uptake. Finally, 83 regions showing focal colorectal FDG uptake with final histopathological reports from 80 patients (45 men and 35 women with mean ages of 66.9 ± 10.7 years and 63.7 ± 15.3 years, respectively) were eligible for inclusion in the present study. Each focal hypermetabolic colorectal region was classified as malignant, premalignant, or benign according to the histopathological report. PET parameters such as maximum and peak standardized uptake value (SUVmax and SUVpeak), metabolic tumor volume (MTV), mean SUV of the metabolic tumor volume (mSUVmtv), and total lesion glycolysis (TLG) were measured or calculated for the corresponding hypermetabolic regions. Parametric and non-parametric statistical comparisons of these parameters were performed among the three groups. Receiver operating characteristic curves were plotted to identify cut-off values. RESULTS: The detection rate of incidental focal colorectal uptake was 0.53% (80/15,143). Of the 83 regions with unexpected focal colorectal hypermetabolism, 28.9% (24/83) were malignant, 32.5% (27/83) were premalignant, and 38.6% (32/83) were benign. Overall, 61.4% of the regions had malignant or premalignant lesions. SUVmax, SUVpeak, and mSUVmtv differentiated malignant and/or premalignant lesions from benign lesions with statistical significance (P < 0.05). mSUVmtv3.5 differentiated malignant from benign lesions, with the largest area under the curve (AUC) of 0.792 and a cut-off of 4.9. SUVmax showed the largest AUC of 0.758 with a cut-off value of 7.5 for distinguishing between premalignant and benign lesions. Overall, SUVmax with a cut-off value of 7.6 (AUC: 0.770, 95% confidence interval (CI): 0.668-0.872; sensitivity, 0.686; specificity, 0.688) was a superior parameter for distinguishing between malignant/premalignant and benign lesions or physiologic uptake. No parameters differentiated malignant from premalignant lesions. Moderate or weak positive correlations were observed between the long diameter of the malignant lesions and PET parameters such as SUVpeak and some mSUVmtv. CONCLUSION: Approximately two-thirds (61.4%) of incidental focal hypermetabolic colorectal regions were malignant/premalignant lesions, for which SUVmax was an independent diagnostic parameter. Unexpected suspicious focal colorectal FDG uptake should not be avoided and consideration for further evaluation is strongly recommended not to miss the two-thirds.

Severity Evaluation of Regional Cerebrovascular Reactivity in Acute Stroke Patients Using SPECT.

BACKGROUND: Cerebrovascular Reactivity (CVR), as measured using perfusion Single Photon Emission Computed Tomography (SPECT), is an important indicator for the treatment and prognosis of cerebrovascular disease, but there are a few studies on acute stroke or small vascular disease using SPECT. OBJECTIVE: This study evaluated the regional severity with quantitatively determined CVR in patients with acute stroke. METHODS: Fifty-eight patients who took brain SPECT images were selected to localize quantitative CVR values. The severity of the disease (Grade 1 to 4) was determined through image-based clinical assessment in the absence and presence of a CVR map, and their results were compared. RESULTS: In 1st diagnosis without the map, the mean CVR values of Grades 2 and 3 were -6.07 % and -9.12 %, respectively (P=0.034), while they were -4.78 % and -12.34 % in 2nd diagnosis with the map, respectively (P<0.001), suggesting that the CVR difference with the map was much more pronounced than without the map. Furthermore, in the ROC analysis, the diagnostic sensitivity between Grades 2 and 3 in the 2nd diagnosis (AUC=0.899, P<0.001) was substantially greater than the 1st diagnosis (AUC=0.646, P=0.048). CONCLUSION: This study demonstrated that the quantitative CVR maps could reinforce the clinical evaluation of cerebral severity by showing that they can provide statistically significant results between severity and CVR. Furthermore, this study was the first to evaluate the effectiveness of quantitative CVR by examining the difference in the presence or absence of CVR in patients with acute stroke.

Characterization of focal hypermetabolic thyroid incidentaloma: An analysis with F-18 fluorodeoxyglucose positron emission tomography/computed tomography parameters.

BACKGROUND: Incidentally found thyroid tumor (thyroid incidentaloma, TI) on F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is reported in 2.5%-5% of patients being investigated for non-thyroid purposes. Up to 50% of these cases have been diagnosed to be malignant by cytological/histological results. Ultrasonography (US) and fine-needle aspiration cytology are recommended for thyroid nodules with high FDG uptake (hypermetabolism) that are 1 cm or greater in size. It is important to accurately determine whether a suspicious hypermetabolic TI is malignant or benign. AIM: To distinguish malignant hypermetabolic TIs from benign disease by analyzing F-18 FDG PET-CT parameters and to identify a cut-off value. METHODS: Totally, 12761 images of patients who underwent F-18 FDG PET-CT for non-thyroid purposes at our hospital between January 2016 and December 2020 were retrospectively reviewed, and 339 patients [185 men (mean age: 68 ± 11.2) and 154 women (mean age: 63 ± 15.0)] were found to have abnormal, either focal or diffuse, thyroid FDG uptake. After a thorough review of their medical records, US, and cytological/histological reports, 46 eligible patients with focal hypermetabolic TI were included in this study. The TIs were categorized as malignant and benign according to the cytological/histological reports, and four PET parameters [standardized uptake value (SUV)max, SUVpeak, SUVmean, and metabolic tumor volume (MTV)] were measured on FDG PET-CT. Total lesion glycolysis (TLG) was calculated by multiplying the SUVmean by MTV. Both parametric and non-parametric methods were used to compare the five parameters between malignant and benign lesions. Receiver operating characteristic (ROC) curve analysis was performed to identify a cut-off value. RESULTS: Each of the 46 patients [12 men (26.1%; mean age: 62 ± 13.1 years) and 34 women (73.9%; mean age: 60 ± 12.0 years)] with focal hypermetabolic TIs had one focal hypermetabolic TI. Among them, 26 (56.5%) were malignant and 20 (43.5%) were benign. SUVmax, SUVpeak, SUVmean, and TLG were all higher in malignant lesions than benign ones, but the difference was statistically significant (P = 0.012) only for SUVmax. There was a positive linear correlation (r = 0.339) between SUVmax and the diagnosis of malignancy. ROC curve analysis for SUVmax revealed an area under the curve of 0.702 (P < 0.05, 95% confidence interval: 0.550-0.855) and SUVmax cut-off of 8.5 with a sensitivity of 0.615 and a specificity of 0.789. CONCLUSION: More than half of focal hypermetabolic TIs on F-18 FDG PET-CT were revealed as malignant lesions, and SUVmax was the best parameter for discriminating between malignant and benign disease. Unexpected focal hypermetabolic TIs with the SUVmax above the cut-off value of 8.5 may have a greater than 70% chance of malignancy; therefore, further active assessment is required.

Inhibition of poly (ADP-Ribose) polymerase: A promising strategy targeting pancreatic cancer with BRCAness phenotype.

The use of chemotherapeutic regimens for the treatment of pancreatic cancer is still limited because pancreatic cancer is usually diagnosed at an advanced stage as a refractory disease in which symptoms are difficult to recognize in the early stages. Furthermore, at advanced stages, there are important challenges to achieve clinical benefit and symptom resolution, even with the use of an expanded spectrum of anticancer drugs. Recently, a point of reduced susceptibility to conventional chemotherapies by breast cancer susceptibility gene (BRCA) mutations led to a new perspective for overcoming the resistance of pancreatic cancer within the framework of increased genome instability. Poly (ADP-Ribose) polymerase (PARP) -1 is an enzyme that can regulate intrinsic functions, such as response to DNA damage. Therefore, in an environment where germline mutations in BRCAs (BRCAness) inhibit homologous recombination in DNA damage, resulting in a lack of DNA damage response, a key role of PARP-1 for the adaptation of the genome instability could be further emphasized. Here, we summarized the key functional role of PARP-1 in genomic instability of pancreatic cancer with the BRCAness phenotype and listed clinical applications and outcomes of PARP-1 inhibitors to highlight the importance of targeting PARP-1 activity.

Negligible Effect of Quercetin in the Pharmacokinetics of Sulfasalazine in Rats and Beagles: Metabolic Inactivation of the Interaction Potential of Quercetin with BCRP.

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow cytometry. The induction of BCRP was investigated in LS174T cells using quantitative PCR. The expression of rat BCRP in rat small intestine, liver, and kidney was also measured after multiple administrations of quercetin in rats (50, 100, and 250 mg/kg, seven days). The in vivo pharmacokinetic changes of sulfasalazine following single or multiple administration of quercetin in rats and beagles were investigated. Although the induction effect of quercetin on BCRP was observed in vitro, the in vivo expression of rat BCRP was not changed by multiple quercetin administrations. Oral administration of quercetin did not affect the plasma concentration or pharmacokinetic parameters of sulfasalazine, regardless of dose and dosing period in either rats or beagles. In addition, the inhibitory effect of quercetin metabolites on BCRP/mBcrp1 was not observed. These results suggest that the in vivo drug interaction caused by quercetin via BCRP was negligible, and it may be related to the metabolic inactivation of quercetin for the inhibition of BCRP.

Sarcopenia's Prognostic Impact on Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

BACKGROUND: Although sarcopenia has been reported to predict survival in cancer patients, its impact on patients who received immune checkpoint inhibitors (ICIs) has not been thoroughly investigated. This systematic review aimed to assess the long-term oncologic impact of sarcopenia on patients who received ICIs. METHODS: A systematic review of studies indexed in the PubMed, Embase, and Cochrane databases, up to April 1, 2021, was conducted. Studies that reported hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) based on sarcopenia in patients treated with ICIs were included. The inverse variance method was used with a random-effects model for data analysis. RESULTS: A total of 1284 patients from 14 studies were included. Among the patients who received ICIs, patients with sarcopenia had a significant increase in overall mortality compared to patients without sarcopenia in univariate analyses (HR = 1.66, 95% CI = 1.20-2.29, p = 0.002) and in adjusted HRs (HR = 1.55, 95% CI = 1.15-2.10, p = 0.004). The same results were obtained for PFS by both univariate analysis (HR = 1.75, 95% CI = 1.37-2.23, p < 0.001) and adjusted HRs (HR = 1.63, 95% CI 1.28-2.09, p < 0.001). CONCLUSIONS: Sarcopenia appears to be an effective biomarker for predicting long-term oncologic outcomes in patients receiving ICI therapy and hence plays an important role when making treatment decisions. However, the fundamental role of this association with survival should be further investigated in large cohorts and clinical trials.

Long-term survival of patients with anaplastic thyroid cancer after multimodal treatment.

BACKGROUND: Anaplastic thyroid cancer (ATC) is among the most aggressive human malignancies, with a mean survival time of 6 months regardless of the treatment. METHODS: This retrospective study used the single-centre database system of the Gangnam Severance Hospital. The management and outcome data of 23 patients with a definitive histological diagnosis of ATC were reviewed. RESULTS: The 23 long-term survivors were 11 men and 12 women, with a mean age of 58 years. Nine patients had distant metastases at the time of diagnosis. Surgical debulking or complete resection of the tumour was performed for 19 patients, and chemotherapy was administered to 15 patients, radiotherapy to 18 patients, and tyrosine kinase inhibitors to 6 patients. In total, 14 patients were treated with a combination of surgery and radiotherapy with or without chemotherapy. Only 5 patients were treated with surgery alone. Overall, 15 patients underwent R0 resection, 2 underwent R1 resection, and 2 underwent R2 resection. The median survival was 1,090 days, the median follow-up was 646 days, and the 2- and 3-year survival rates were 59.7% and 35.8%, respectively. A total of 10 patients died: 7 with local disease and 3 with distant metastasis. CONCLUSIONS: Although ATC is typically an incurable disease, patients with ATC who underwent multimodality treatments including resection, chemotherapy, radiotherapy, and thyrosine kinase inhibitors would survive more than 1 year.

ß-Caryophyllene in the Essential Oil from Chrysanthemum Boreale Induces G1 Phase Cell Cycle Arrest in Human Lung Cancer Cells.

Chrysanthemum boreale is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from C. boreale (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography-mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, ß-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. ß- Caryophyllene induced G1 cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21CIP1/WAF1 and p27KIP1. These results indicate that ß-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.

Initial diagnostic workup of parkinsonism: Dopamine transporter positron emission tomography versus susceptibility map-weighted imaging at 3T.

BACKGROUND AND PURPOSE: Evaluation of dorsal nigral hyperintensity on MRI can help detect nigrostriatal degeneration. We aimed to compare the diagnostic performance between susceptibility map-weighted imaging (SMWI) and N-3-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) as an initial diagnostic tool of parkinsonism. MATERIALS AND METHODS: This local ethics committee-approved retrospective study enrolled 223 patients with parkinsonism and 15 healthy subjects (mean age, 69.7 years; 135 females) who underwent both SMWI at 3T and 18F-FP-CIT PET. The diagnostic performances of the two tests for nigrostriatal degeneration were compared by evaluating whether the 90% confidence interval (CI) of the difference between the two tests was within the equivalence margin by using the DTComPair package of R. The concordance rate was tested by Cohen's kappa. RESULTS: The diagnostic sensitivities of SMWI and 18F-FP-CIT PET were 94.5% and 100% per SN and 100% and 100% per participant, respectively; their specificities were 95.3% and 86.7% per SN and 94.4% and 84.0% per participant, respectively. While the diagnostic sensitivity was comparable between the two tests for each SN and participant, the lower 90% CI of the differences in the specificity were -0.086 per SN and -0.104 per participant, indicating a higher diagnostic specificity of SMWI than that of 18F-FP-CIT PET. When excluding 20 participants with basal ganglia lesions, the two tests exhibited similar diagnostic performance and had excellent agreement (k = 0.899 per SN; k = 0.945 per participant). CONCLUSION: For patients with parkinsonism, SMWI and 18F-FP-CIT PET exhibit similar diagnostic performance.

Silicon Dioxide Nanoparticles Enhance Endotoxin-Induced Lung Injury in Mice.

Silicon dioxide nanoparticles (SiONPs), which are metal oxide nanoparticles, have been used in a wide variety of applications. In this study, acute pulmonary responses were examined after the intranasal instillation of SiONPs in mice primed with or without lipopolysaccharide (LPS, intranasal, 5 µg/mouse). The exposure to SiONPs increased the inflammatory cell counts and proinflammatory cytokines in the bronchoalveolar lavage fluid. SiONPs induced airway inflammation with increases in the phosphorylation of mitogen-activated protein kinases (MAPKs). The ratios of the inflammatory responses induced by the SiONPs were increased in the acute pulmonary disease model primed by LPS. Taken together, SiONPs exhibited toxicity to the respiratory system, which was associated with MAPK phosphorylation. In addition, the exposure to SiONPs exacerbated any existing inflammatory pulmonary diseases. These data showed the additive, as well as synergistic, interaction effects of SiONPs and LPS. We conclude that the exposure to SiONPs causes potential toxicity in humans, especially those with respiratory diseases.

Investigation into Enhancing Capecitabine Efficacy in Colorectal Cancer by Inhibiting Focal Adhesion Kinase Signaling.

BACKGROUND/AIM: Capecitabine is a pro-drug of 5-fluorouracil (5-FU), and is an orally available chemotherapeutic used to treat colorectal cancer (CRC). Recently, research has focused on improving its efficacy at lower doses in order to minimize its well-known toxicities. In this study, we investigated the possibility of improving the antitumor effect of capecitabine against CRC by destabilizing focal adhesion kinase (FAK) signaling. MATERIALS AND METHODS: Optimal dosages for capecitabine and lactate calcium salt (LCS) were determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide MTT assay. The viability of CRC cells was investigated by MTT and clonogenic assays after single or combination treatment with capecitabine and LCS. Western blot analyses were used to determine changes in the expression of components of the FAK and AKT signaling cascade, and this information was used to elucidate the underlying mechanism. A xenograft model was established to evaluate the antitumor efficacy of the combination treatment, as well as its necrotic effect and organ toxicity. RESULTS: The addition of LCS to capecitabine treatment led to an increase in the proteolysis of the FAK signaling cascade components, including SRC proto-oncogene, non-receptor tyrosine kinase; AKT serine/threonine kinase 1; and nuclear factor-kappa B, resulting in a decrease in the viability and clonogenic ability of CRC cells. In vivo antitumor efficacy, including tumor necrosis, was significantly increased with the combination treatment relative to both single treatments, and no organ toxicity was found in any experimental group. CONCLUSION: The addition of LCS increased the anticancer efficacy of capecitabine at a lower dose than is currently used in human patients.

Ethanol Extract of Potentilla supina Linne Suppresses LPS-induced Inflammatory Responses through NF-κB and AP-1 Inactivation in Macrophages and in Endotoxic mice.

In this study, we investigated the antiinflammatory effects of ethanol extracts of Potentilla. supina Linne (EPS) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and septic mice. EPS suppressed LPS-induced nitric oxide, prostaglandin E2 , TNF-α, interleukin-6 and interleukin-1ß at production and mRNA levels in LPS-induced RAW 264.7 macrophages. Consistent with these observations, EPS attenuated the expressions of inducible nitric oxide synthase and cyclooxygenase-2 by downregulation of their promoter activities. Molecularly, EPS reduced the LPS-induced transcriptional activity and DNA-binding activity of nuclear factor-κB (NF-κB), and this was associated with a decrease of translocation and phosphorylation of p65 NF-κB by inhibiting the inhibitory κB-α degradation and IKK-α/ß phosphorylation. Furthermore, EPS inhibited the LPS-induced activation of activator protein-1 by reducing the expression of c-Fos and c-Jun in nuclear. EPS also suppressed the phosphorylation of mitogen-activated protein kinase, such as p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In an LPS-induced endotoxemia mouse model, pretreatment with EPS reduced the mRNA levels of inducible nitric oxide synthase, cyclooxygenase-2 and proinflammatory cytokines and increased the survival rate of mice. Collectively, these results suggest that the antiinflammatory effects of EPS were associated with the suppression of NF-κB and activator protein-1 activation and support its possible therapeutic role for the treatment of endotoxemia. Copyright © 2017 John Wiley & Sons, Ltd.

Building and Querying RDF/OWL Database of Semantically Annotated Nuclear Medicine Images.

As the use of positron emission tomography-computed tomography (PET-CT) has increased rapidly, there is a need to retrieve relevant medical images that can assist image interpretation. However, the images themselves lack the explicit information needed for query. We constructed a semantically structured database of nuclear medicine images using the Annotation and Image Markup (AIM) format and evaluated the ability the AIM annotations to improve image search. We created AIM annotation templates specific to the nuclear medicine domain and used them to annotate 100 nuclear medicine PET-CT studies in AIM format using controlled vocabulary. We evaluated image retrieval from 20 specific clinical queries. As the gold standard, two nuclear medicine physicians manually retrieved the relevant images from the image database using free text search of radiology reports for the same queries. We compared query results with the manually retrieved results obtained by the physicians. The query performance indicated a 98 % recall for simple queries and a 89 % recall for complex queries. In total, the queries provided 95 % (75 of 79 images) recall, 100 % precision, and an F1 score of 0.97 for the 20 clinical queries. Three of the four images missed by the queries required reasoning for successful retrieval. Nuclear medicine images augmented using semantic annotations in AIM enabled high recall and precision for simple queries, helping physicians to retrieve the relevant images. Further study using a larger data set and the implementation of an inference engine may improve query results for more complex queries.

Correlation of Uptake Patterns on Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and Treatment Response in Patients with Knee Pain.

PURPOSE: To determine whether treatment response in patients with knee pain could be predicted using uptake patterns on single-photon emission computed tomography/computed tomography (SPECT/CT) images. METHODS: Ninety-five patients with knee pain who had undergone SPECT/CT were included in this retrospective study. Subjects were divided into three groups: increased focal uptake (FTU), increased irregular tracer uptake (ITU), and no tracer uptake (NTU). A numeric rating scale (NRS-11) assessed pain intensity. We analyzed the association between uptake patterns and treatment response using Pearson's chi-square test and Fisher's exact test. Uptake was quantified from SPECT/CT with region of interest (ROI) counting, and an intraclass correlation coefficient (ICC) calculated agreement. We used Student's t-test to calculate statistically significant differences of counts between groups and the Pearson correlation to measure the relationship between counts and initial NRS-1k1. Multivariate logistic regression analysis determined which variables were significantly associated with uptake. RESULTS: The FTU group included 32 patients; ITU, 39; and NTU, 24. With conservative management, 64 % of patients with increased tracer uptake (TU, both focal and irregular) and 36 % with NTU showed positive response. Conservative treatment response of FTU was better than NTU, but did not differ from that of ITU. Conservative treatment response of TU was significantly different from that of NTU (OR 3.1; p = 0.036). Moderate positive correlation was observed between ITU and initial NRS-11. Age and initial NRS-11 significantly predicted uptake. CONCLUSIONS: Patients with uptake in their knee(s) on SPECT/CT showed positive treatment response under conservative treatment.

Chikusetsusaponin IVa Methyl Ester Isolated from the Roots of Achyranthes japonica Suppresses LPS-Induced iNOS, TNF-α, IL-6, and IL-1ß Expression by NF-κB and AP-1 Inactivation.

We investigated the effect of chikusetsusaponin IVa (CS) and chikusetsusaponin IVa methyl ester (CS-ME) from the roots of Achyranthes japonica NAKAI on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in RAW264.7 macrophages. CS-ME more potently inhibited LPS-induced NO and PGE2 production than CS. CS-ME concentration-dependently inhibited LPS-induced tumor necrosis factor (TNF)-α and interleukin (IL)-6 and IL-1ß production in RAW264.7 macrophages and mouse peritoneal macrophages. Consistent with these findings, CS-ME suppressed LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at protein level as well as iNOS, COX-2, TNF-α, IL-6, and IL-1ß at mRNA level. In addition, CS-ME suppressed LPS-induced transcriptional activity of nuclear factor (NF)-κB and activator protein (AP)-1. The anti-inflammatory properties of CS-ME might result from suppression of iNOS, COX-2, TNF-α, IL-6, and IL-1ß expression through downregulation of NF-κB and AP-1 in macrophages.