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Purpose: To compare CT, MRI, and [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET/MRI) for nodal status, regarding quantity and location of metastatic locoregional lymph nodes in patients with newly diagnosed breast cancer. Materials and methods: One hundred eighty-two patients (mean age 52.7 ± 11.9 years) were included in this prospective double-center study. Patients underwent dedicated contrast-enhanced chest/abdomen/pelvis computed tomography (CT) and whole-body ([18F]-FDG PET/) magnet resonance imaging (MRI). Thoracal datasets were evaluated separately regarding quantity, lymph node station (axillary levels I–III, supraclavicular, internal mammary chain), and lesion character (benign vs. malign). Histopathology served as reference standard for patient-based analysis. Patient-based and lesion-based analyses were compared by a McNemar test. Sensitivity, specificity, positive and negative predictive values, and accuracy were assessed for all three imaging modalities. Results: On a patient-based analysis, PET/MRI correctly detected significantly more nodal positive patients than MRI (p < 0.0001) and CT (p < 0.0001). No statistically significant difference was seen between CT and MRI. PET/MRI detected 193 lesions in 75 patients (41.2%), while MRI detected 123 lesions in 56 patients (30.8%) and CT detected 104 lesions in 50 patients, respectively. Differences were statistically significant on a lesion-based analysis (PET/MRI vs. MRI, p < 0.0001; PET/MRI vs. CT, p < 0.0001; MRI vs. CT, p = 0.015). Subgroup analysis for different lymph node stations showed that PET/MRI detected significantly more lymph node metastases than MRI and CT in each location (axillary levels I–III, supraclavicular, mammary internal chain). MRI was superior to CT only in axillary level I (p = 0.0291). Conclusion: [18F]-FDG PET/MRI outperforms CT or MRI in detecting nodal involvement on a patient-based analysis and on a lesion-based analysis. Furthermore, PET/MRI was superior to CT or MRI in detecting lymph node metastases in all lymph node stations. Of all the tested imaging modalities, PET/MRI showed the highest sensitivity, whereas CT showed the lowest sensitivity, but was most specific. [ABSTRACT FROM AUTHOR]

Objectives: To compare the diagnostic accuracy of contrast-enhanced thoraco-abdominal computed tomography and whole-body 18F-FDG PET/MRI in N and M staging in newly diagnosed, histopathological proven breast cancer. Material and methods: A total of 80 consecutive women with newly diagnosed and histopathologically confirmed breast cancer were enrolled in this prospective study. Following inclusion criteria had to be fulfilled: (1) newly diagnosed, treatment-naive T2-tumor or higher T-stage or (2) newly diagnosed, treatment-naive triple-negative tumor of every size or (3) newly diagnosed, treatment-naive tumor with molecular high risk (T1c, Ki67 >14%, HER2neu over-expression, G3). All patients underwent a thoraco-abdominal ceCT and a whole-body 18F-FDG PET/MRI. All datasets were evaluated by two experienced radiologists in hybrid imaging regarding suspect lesion count, localization, categorization and diagnostic confidence. Images were interpreted in random order with a reading gap of at least 4 weeks to avoid recognition bias. Histopathological results as well as follow-up imaging served as reference standard. Differences in staging accuracy were assessed using Mc Nemars chi2 test. Results: CT rated the N stage correctly in 64 of 80 (80%, 95% CI:70.0–87.3) patients with a sensitivity of 61.5% (CI:45.9–75.1), a specificity of 97.6% (CI:87.4–99.6), a PPV of 96% (CI:80.5–99.3), and a NPV of 72.7% (CI:59.8–82.7). Compared to this, 18F-FDG PET/MRI determined the N stage correctly in 71 of 80 (88.75%, CI:80.0–94.0) patients with a sensitivity of 82.1% (CI:67.3–91.0), a specificity of 95.1% (CI:83.9–98.7), a PPV of 94.1% (CI:80.9–98.4) and a NPV of 84.8% (CI:71.8–92.4). Differences in sensitivities were statistically significant (difference 20.6%, CI:-0.02–40.9; p = 0.008). Distant metastases were present in 7/80 patients (8.75%). 18 F-FDG PET/MRI detected all of the histopathological proven metastases without any false-positive findings, while 3 patients with bone metastases were missed in CT (sensitivity 57.1%, specificity 95.9%). Additionally, CT presented false-positive findings in 3 patients. Conclusion: 18F-FDG PET/MRI has a high diagnostic potential and outperforms CT in assessing the N and M stage in patients with primary breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Methods Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as „cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. Results EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Conclusions Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.

Introduction: To correlate tumour grading and prognostic immunohistochemical markers of lung cancer with simultaneously acquired standardised uptake values (SUV) and apparent diffusion coefficient (ADC) derived from hybrid PET/MRI. Methods: In this retrospective study, 55 consecutive patients (mean age 62.5 ± 9.2 years) with therapy‐naïve, histologically proven lung cancer were included. All patients underwent whole‐body PET/MRI using 18F‐flourdeoxyglucose (18F‐FDG) as a radiotracer. Diffusion‐weighted imaging of the chest (DWI, b‐values: 0, 500, 1000 s/mm2) was performed simultaneously with PET acquisition. Histopathological tumour grading was available in 43/55 patients. In 15/55 patients, immunohistochemical markers, that is, phospho‐AKT Ser473 (pAKTS473), phosphorylated extracellular signal‐regulated kinase (pERK), phosphatase and tensin homolog (PTEN), and human epidermal growth factor receptor 2 (erbB2) were available. Results: The average SUVmax, SUVmean, ADCmin and ADCmean in lung cancer primaries were 12.6 ± 5.9, 7.7 ± 4.6, 569.9 ± 96.1 s/mm2 and 825.8 ± 93.2 s/mm2, respectively. We found a significant inverse correlation between the ADCmin and SUVmax (r = −0.58, P < 0.001) as well as between the ADCmin and SUVmean (r = −0.44, P < 0.001). Tumour grading showed a significant positive correlation with SUVmax and SUVmean (R = 0.34 and R = 0.31, both P < 0.05) and a significant inverse correlation with ADCmin and ADCmean (r = −0.30 and r = −0.40, both P < 0.05). In addition, erbB2 showed a significant inverse correlation with SUVmax and SUVmean (r = −0.50 and r = −0.49, both P < 0.05). The other immunohistochemical markers did not show any significant correlation. Conclusion: 18F‐FDG‐PET/MRI showed weak to moderate correlations between SUV, ADC, tumour grading and erbB2‐expression of lung cancer. Hence, 18F‐FDG‐PET/MRI may, to some extent, offer complementary information to the histopathology of lung cancer, for the evaluation of tumour aggressiveness and treatment response. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate and compare the diagnostic potential of whole-body MRI and whole-body 18F-FDG PET/MRI for N and M staging in newly diagnosed, histopathologically proven breast cancer. Material and methods: A total of 104 patients (age 53.4 ± 12.5) with newly diagnosed, histopathologically proven breast cancer were enrolled in this study prospectively. All patients underwent a whole-body 18F-FDG PET/MRI. MRI and 18F-FDG PET/MRI datasets were evaluated separately regarding lesion count, lesion localization, and lesion characterization (malignant/benign) as well as the diagnostic confidence (5-point ordinal scale, 1–5). The N and M stages were assessed according to the eighth edition of the American Joint Committee on Cancer staging manual in MRI datasets alone and in 18F-FDG PET/MRI datasets, respectively. In the majority of lesions histopathology served as the reference standard. The remaining lesions were followed-up by imaging and clinical examination. Separately for nodal-positive and nodal-negative women, a McNemar chi2 test was performed to compare sensitivity and specificity of the N and M stages between 18F-FDG PET/MRI and MRI. Differences in diagnostic confidence scores were assessed by Wilcoxon signed rank test. Results: MRI determined the N stage correctly in 78 of 104 (75%) patients with a sensitivity of 62.3% (95% CI: 0.48–0.75), a specificity of 88.2% (95% CI: 0.76–0.96), a PPV (positive predictive value) of 84.6% % (95% CI: 69.5–0.94), and a NPV (negative predictive value) of 69.2% (95% CI: 0.57–0.8). Corresponding results for 18F-FDG PET/MRI were 87/104 (83.7%), 75.5% (95% CI: 0.62–0.86), 92.2% (0.81–0.98), 90% (0.78–0.97), and 78.3% (0.66–0.88), showing a significantly better sensitivity of 18F-FDG PET/MRI determining malignant lymph nodes (p = 0.008). The M stage was identified correctly in MRI and 18F-FDG PET/MRI in 100 of 104 patients (96.2%). Both modalities correctly staged all 7 patients with distant metastases, leading to false-positive findings in 4 patients in each modality (3.8%). In a lesion-based analysis, 18F-FDG PET/MRI showed a significantly better performance in correctly determining malignant lesions (85.8% vs. 67.1%, difference 18.7% (95% CI: 0.13–0.26), p < 0.0001) and offered a superior diagnostic confidence compared with MRI alone (4.1 ± 0.7 vs. 3.4 ± 0.7, p < 0.0001). Conclusion: 18F-FDG PET/MRI has a better diagnostic accuracy for N staging in primary breast cancer patients and provides a significantly higher diagnostic confidence in lesion characterization than MRI alone. But both modalities bear the risk to overestimate the M stage. [ABSTRACT FROM AUTHOR]

Objectives: To compare the diagnostic performance of 18F-FDG PET/MRI and 18F-FDG PET/CT for primary and locoregional lymph node staging in non-small cell lung cancer (NSCLC).Methods: In this prospective study, a total of 84 patients (51 men, 33 women, mean age 62.5 ± 9.1 years) with histopathologically confirmed NSCLC underwent 18F-FDG PET/CT followed by 18F-FDG PET/MRI in a single injection protocol. Two readers independently assessed T and N staging in separate sessions according to the seventh edition of the American Joint Committee on Cancer staging manual for 18F-FDG PET/CT and 18F-FDG PET/MRI, respectively. Histopathology as a reference standard was available for N staging in all 84 patients and for T staging in 39 patients. Differences in staging accuracy were assessed by McNemars chi2 test. The maximum standardized uptake value (SUVmax) and longitudinal diameters of primary tumors were correlated using Pearson's coefficients.Results: T stage was categorized concordantly in 18F-FDG PET/MRI and 18F-FDG PET/CT in 38 of 39 (97.4%) patients. Herein, 18F-FDG PET/CT and 18F-FDG PET/MRI correctly determined the T stage in 92.3 and 89.7% of patients, respectively. N stage was categorized concordantly in 83 of 84 patients (98.8%). 18F-FDG PET/CT correctly determined the N stage in 78 of 84 patients (92.9%), while 18F-FDG PET/MRI correctly determined the N stage in 77 of 84 patients (91.7%). Differences between 18F-FDG PET/CT and 18F-FDG PET/MRI in T and N staging accuracy were not statistically significant (p > 0.5, each). Tumor size and SUVmax measurements derived from both imaging modalities exhibited excellent correlation (r = 0.963 and r = 0.901, respectively).Conclusion: 18F-FDG PET/MRI and 18F-FDG PET/CT show an equivalently high diagnostic performance for T and N staging in patients suffering from NSCLC. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare the diagnostic value of a one-step to a two-step staging algorithm utilizing 18F-FDG PET/MRI in breast cancer patients.Methods: A total of 38 patients (37 females and one male, mean age 57 ± 10 years; range 31-78 years) with newly diagnosed, histopathologically proven breast cancer were prospectively enrolled in this trial. All PET/MRI examinations were assessed for local tumor burden and metastatic spread in two separate reading sessions: (1) One-step algorithm comprising supine whole-body 18F-FDG PET/MRI, and (2) Two-step algorithm comprising a dedicated prone 18F-FDG breast PET/MRI and supine whole-body 18F-FDG PET/MRI.Results: On a patient based analysis the two-step algorithm correctly identified 37 out of 38 patients with breast carcinoma (97%), while five patients were missed by the one-step 18F-FDG PET/MRI algorithm (33/38; 87% correct identification). On a lesion-based analysis 56 breast cancer lesions were detected in the two-step algorithm and 44 breast cancer lesions could be correctly identified in the one-step 18F-FDG PET/MRI (79%), resulting in statistically significant differences between the two algorithms (p = 0.0015). For axillary lymph node evaluation sensitivity, specificity and accuracy was 93%, 95 and 94%, respectively. Furthermore, distant metastases could be detected in seven patients in both algorithms.Conclusion: The results demonstrate the necessity and superiority of a two-step 18F-FDG PET/MRI algorithm, comprising dedicated prone breast imaging and supine whole-body imaging, when compared to the one-step algorithm for local and whole-body staging in breast cancer patients. [ABSTRACT FROM AUTHOR]

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next‐generation sequencing, conducted in situ and immunohistochemical analyses (including PD‐L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan‐Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5‐year overall survival (OS) of 58% and recurrence‐free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR‐deficiency (MMR‐d)/MSI‐high (MSI‐h), whereas 10 of 63 cases (16%) expressed PD‐L1. Therefore, anti‐PD‐1/PD‐L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti‐EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer. [ABSTRACT FROM AUTHOR]

Circadian disruption is associated with the development of diabetes. Non-obese diabetic (NOD) mice show abnormal diurnal profiles in energy balance and locomotor activity suggesting circadian misalignment. Therefore, we analyzed cFos and mPER1 as markers for rhythmic neuronal activity within the suprachiasmatic nucleus (SCN) of wildtype (WT) and non-diabetic (nNOD) as well as acutely diabetic NOD (dNOD) mice. cFos levels show a day/night difference in both WT and nNOD but not in dNOD. mPER1 levels did not show a day/night difference in both nNOD and dNOD. This suggests that disruption of SCN rhythmicity in NOD mice precedes the actual onset of diabetes. [ABSTRACT FROM AUTHOR]

Introduction: Heat shock factor 1 (HSF1) is a ubiquitous heat-sensitive transcription factor that mediates heat shock protein transcription in response to cellular stress, such as increased temperature, in order to protect the organism against misfolded proteins. In this study, we analysed the effect of HSF1 deficiency on core body temperature regulation. Materials and Methods: Body temperature, locomotor activity, and food consumption of wild-type mice and HSF1- deficient mice were recorded. Prolactin and thyroid-stimulating hormone levels were measured by ELISA. Gene expression in brown adipose tissue was analysed by quantitative real-time PCR. Hypothalamic HSF1 and its co-localisation with tyrosine hydroxylase was analysed using confocal laser scanning microscopy. Results: HSF1-deficient mice showed an increase in core body temperature (hyperthermia), decreased overall locomotor activity, and decreased levels of prolactin in pituitary and blood plasma reminiscent of cold adaptation. HSF1 could be detected in various hypothalamic regions involved in temperature regulation, suggesting a potential role of HSF1 in hypothalamic thermoregulation. Moreover, HSF1 co-localises with tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, suggesting a potential role of HSF1 in the hypothalamic control of prolactin release. In brown adipose tissue, levels of prolactin receptor and uncoupled protein 1 were increased in HSF1-deficient mice, consistent with an up-regulation of heat production. Conclusion: Our data suggest a role of HSF1 in systemic thermoregulation. [ABSTRACT FROM AUTHOR]

Overexpression of the classical homeobox transcription factor HOXC6 is frequent in prostate cancers and correlates with adverse clinical parameters. Since surprisingly many HOXC6 target genes are downregulated in prostate cancer, it has been posited that oncogenic effects of HOXC6 in prostate cancer may be unmasked by concurrent epigenetic downregulation of target genes exerting tumor suppressive effects. To test this hypothesis, we have studied the expression of three HOXC6 target genes, CNTN1 (encoding a cell adhesion protein), DKK3 and WIF1 (encoding WNT growth factor antagonists) as well as DNA methylation of DKK3 and WIF1. HOXC6 upregulation and association with poor prognosis were confirmed in our tissue series. The three target genes were each significantly downregulated in cancer tissues and expression of each one correlated inversely with that of HOXC6. Cases with lower WIF1 expression showed significantly earlier recurrence (p = 0.021), whereas no statistical significance was reached for CNTN1 and DKK3. Hypermethylation of DKK3 or WIF1 gene promoters was observed in a subset of cancers with downregulated expression, but was often weak. Our data support the hypothesis that HOXC6 target genes exerting tumor-suppressive effects are epigenetically downregulated in prostate cancer, but DNA methylation appears to follow or bolster rather than to cause their transcriptional inactivation. [ABSTRACT FROM AUTHOR]

Background: The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Methods: Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as "cortical cytoskeleton" genes) as well as ERG was measured by quantitative RTPCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. Results: EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Conclusions: Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is considered the leading cancer type and main cause of cancer death in women. In this study, we assess simultaneous 18F-FDG PET/MRI of the breast as a platform for comprehensive radiomics analysis for breast cancer subtype. The radiomics-based analysis comprised prediction of molecular subtype, hormone receptor status, proliferation rate and lymphonodular and distant metastatic spread. Our results demonstrated high accuracy for multiparametric MRI alone as well as 18F-FDG PET/MRI as an imaging platform for high-quality non-invasive tissue characterization. Background: This study investigated the performance of simultaneous 18F-FDG PET/MRI of the breast as a platform for comprehensive radiomics analysis for breast cancer subtype analysis, hormone receptor status, proliferation rate and lymphonodular and distant metastatic spread. Methods: One hundred and twenty-four patients underwent simultaneous 18F-FDG PET/MRI. Breast tumors were segmented and radiomic features were extracted utilizing CERR software following the IBSI guidelines. LASSO regression was employed to select the most important radiomics features prior to model development. Five-fold cross validation was then utilized alongside support vector machines, resulting in predictive models for various combinations of imaging data series. Results: The highest AUC and accuracy for differentiation between luminal A and B was achieved by all MR sequences (AUC 0.98; accuracy 97.3). The best results in AUC for prediction of hormone receptor status and proliferation rate were found based on all MR and PET data (ER AUC 0.87, PR AUC 0.88, Ki-67 AUC 0.997). PET provided the best determination of grading (AUC 0.71), while all MR and PET analyses yielded the best results for lymphonodular and distant metastatic spread (0.81 and 0.99, respectively). Conclusion: 18F-FDG PET/MRI enables comprehensive high-quality radiomics analysis for breast cancer phenotyping and tumor decoding, utilizing the perks of simultaneously acquired morphologic, functional and metabolic data. [ABSTRACT FROM AUTHOR]

The circadian rhythms of body functions in mammals are controlled by the circadian system. The suprachiasmatic nucleus (SCN) in the hypothalamus orchestrates subordinate oscillators. Time information is conveyed from the retina to the SCN to coordinate an organism's physiology and behavior with the light/dark cycle. At the cellular level, molecular clockwork composed of interlocked transcriptional/translational feedback loops of clock genes drives rhythmic gene expression. Mice with targeted deletion of the essential clock gene Bmal1 (Bmal1−/−) have an impaired light input pathway into the circadian system and show a loss of circadian rhythms. The red house (RH) is an animal welfare measure widely used for rodents as a hiding place. Red plastic provides light at a low irradiance and long wavelength—conditions which affect the circadian system. It is not known yet whether the RH affects rhythmic behavior in mice with a corrupted circadian system. Here, we analyzed whether the RH affects spontaneous locomotor activity in Bmal1−/− mice under standard laboratory light conditions. In addition, mPER1- and p-ERK-immunoreactions, as markers for rhythmic SCN neuronal activity, and day/night plasma corticosterone levels were evaluated. Our findings indicate that application of the RH to Bmal1−/− abolishes rhythmic locomotor behavior and dampens rhythmic SCN neuronal activity. However, RH had no effect on the day/night difference in corticosterone levels. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of disability and death worldwide. There is increasing evidence that occurrence of ischemic stroke is affected by circadian system and sex. However, little is known about the effect of these factors on structural recovery after ischemic stroke. Therefore, we studied infarction in cerebral neocortex of male and female mice with deletion of the clock gene Bmal1 (Bmal1−/−) after focal ischemia induced by photothrombosis (PT). The infarct core size was significantly smaller 14 days (d) as compared to seven days after PT, consistent with structural recovery during the sub-acute phase. However, when sexes were analyzed separately 14 days after PT, infarct core was significantly larger in wild-type (Bmal1+/+) female as compared to male Bmal1+/+ mice, and in female Bmal1+/+, as compared to female Bmal1−/− mice. Volumes of reactive astrogliosis and densely packed microglia closely mirrored the size of infarct core in respective groups. Estradiol levels were significantly higher in female Bmal1−/− as compared to Bmal1+/+ mice. Our data suggests a sex-dependent effect and an interaction between sex and genotype on infarct size, the recruitment of astrocytes and microglia, and a relationship of these cells with structural recovery probably due to positive effects of estradiol during the subacute phase. [ABSTRACT FROM AUTHOR]

Objectives: To investigate a correlation between 68Ga-DOTATOC PET/MR imaging parameters such as arterial and venous contrast enhancement, diffusion restriction, and maximum standardized uptake value (SUVmax) with histopathological tumor grading in patients with neuroendocrine neoplasms (NEN).Material and Methods: A total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwent 68Ga-DOTATOC PET/MRI. Images were evaluated regarding NEN lesion number and location, predominant tumor signal intensity on precontrast T1w and T2w images and on postcontrast arterial and portal venous phase T1w images, apparent diffusion coefficient (ADC) and SUVmax. Histopathological tumor grading was assessed and related to PET/MRI features using Pearson's correlation coefficient and Fisher's exact t-test. A binary logistic regression analysis was performed to evaluate a potential relation with an aggressive tumor biology and odds ratios (OR) were calculated.Results: There was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001).Conclusion: The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68 Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68 Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUV max ) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68 Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68 Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUV max greater than 10 for all tumor regions. Results: 68 Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUV max ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68 Ga-FAPI versus 18 F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68 Ga-FAPI was higher than that of 18 F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68 Ga-FAPI uptake and the histopathologic FAP expression score ( n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68 Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18 F-FDG PET. 68 Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

We present an overview of our prospective fibroblast-activation protein inhibitor (FAPI) registry study across a 3-y period, with head-to-head comparison of tumor uptake in 68 Ga-FAPI and 18 F-FDG PET, as well as FAP immunohistochemistry. Methods: This is an interim analysis of the ongoing 68 Ga-FAPI PET prospective observational trial at our department. Patients who underwent clinical imaging with 68 Ga-FAPI PET between October 2018 and October 2021 were included. Tracer uptake was quantified by SUV max for tumor lesions and by SUV mean for normal organs. PET tumor volume (40% isocontour) and tumor-to-background ratios were calculated. Correlation between SUV max and FAP staining in tissue samples was analyzed. Results: In total, 324 patients with 21 different tumor entities underwent 68 Ga-FAPI imaging; 237 patients additionally received 18 F-FDG PET. The most common tumor entities were sarcoma (131/324, 40%), pancreatic cancer (67/324, 21%), and primary tumors of the brain (22/324, 7%). The mean primary tumor SUV max was significantly higher for 68 Ga-FAPI than 18 F-FDG among pancreatic cancer (13.2 vs. 6.1, P < 0.001) and sarcoma (14.3 vs. 9.4, P < 0.001), and the same was true for mean SUV max in metastatic lesions of pancreatic cancer (9.4 vs. 5.5, P < 0.001). Mean primary tumor maximum tumor-to-background ratio was significantly higher for 68 Ga-FAPI than 18 F-FDG across several tumor entities, most prominently pancreatic cancer (14.7 vs. 3.0, P < 0.001) and sarcoma (17.3 vs. 4.7, P < 0.001). Compared with 18 F-FDG, 68 Ga-FAPI showed superior detection for locoregional disease in sarcoma (52 vs. 48 total regions detected) and for distant metastatic disease in both sarcoma (137 vs. 131) and pancreatic cancer (65 vs. 57), respectively. Among 61 histopathology samples, there was a positive correlation between 68 Ga-FAPI SUV max and overall FAP immunohistochemistry score ( r = 0.352, P = 0.005). Conclusion: 68 Ga-FAPI demonstrates higher absolute uptake in pancreatic cancer and sarcoma, as well as higher tumor-to-background uptake along with improved tumor detection for pancreatic cancer, sarcoma, and other tumor entities when compared with 18 F-FDG. 68 Ga-FAPI is a new tool for tumor staging with theranostic potential., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Expression levels of collagens have been implicated in the progression of various cancers and interaction with cytokeratins but are not well studied in bladder cancer (BC). Therefore, we analyzed the gene and protein expression levels of collagen 1A1 (Col1a1/COL1A1), collagen 3A1 (col3a1/COL3A1), collagen 5A2 (col5a2/COL5A2), cytokeratin 14 (krt14/CK14), and cytokeratin 17 (krt17/CK17) in urothelial BC samples of different stages., Methods: In total, 102 fresh frozen and 190 formalin-fixed and paraffin-embedded (FFPE) samples were tested using immunohistochemistry and RT-qPCR. Expression levels were correlated with clinicopathological and follow-up data., Results: Col1a1, col3a1, col5a2 and krt14 mRNA levels were significantly overexpressed in high-grade and muscle-invasive BC (MIBC) compared to low-grade and non-muscle invasive BC (NMIBC) cases. Disease-specific survival (DSS) was shorter in patients with high expression levels of col1a1 (p = 0.004), col3a1 (p = 0.004), and col5a2 (p = 0.028). CK14 (p = 0.020), COL3A1 (p = 0.006), and Col5A2 (p = 0.006) protein expression levels were significantly higher and protein expression levels of CK17 (p = 0.05) were significantly lower in MIBC compared to NMIBC. Furthermore, CK14 (p = 0.002) and COL5A2 (p = 0.006) protein expression level were significantly higher in high-grade compared to low-grade BC. DSS was shorter in patients with high expression levels of COL5A2 (p = 0.033) and CK14 (p = 0.042)., Conclusion: Expression changes of collagens and cytokeratins are univariable prognostic markers in BC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To compare the diagnostic accuracy of contrast-enhanced thoraco-abdominal computed tomography and whole-body 18F-FDG PET/MRI in N and M staging in newly diagnosed, histopathological proven breast cancer., Material and Methods: A total of 80 consecutive women with newly diagnosed and histopathologically confirmed breast cancer were enrolled in this prospective study. Following inclusion criteria had to be fulfilled: (1) newly diagnosed, treatment-naive T2-tumor or higher T-stage or (2) newly diagnosed, treatment-naive triple-negative tumor of every size or (3) newly diagnosed, treatment-naive tumor with molecular high risk (T1c, Ki67 >14%, HER2neu over-expression, G3). All patients underwent a thoraco-abdominal ceCT and a whole-body 18F-FDG PET/MRI. All datasets were evaluated by two experienced radiologists in hybrid imaging regarding suspect lesion count, localization, categorization and diagnostic confidence. Images were interpreted in random order with a reading gap of at least 4 weeks to avoid recognition bias. Histopathological results as well as follow-up imaging served as reference standard. Differences in staging accuracy were assessed using Mc Nemars chi2 test., Results: CT rated the N stage correctly in 64 of 80 (80%, 95% CI:70.0-87.3) patients with a sensitivity of 61.5% (CI:45.9-75.1), a specificity of 97.6% (CI:87.4-99.6), a PPV of 96% (CI:80.5-99.3), and a NPV of 72.7% (CI:59.8-82.7). Compared to this, 18F-FDG PET/MRI determined the N stage correctly in 71 of 80 (88.75%, CI:80.0-94.0) patients with a sensitivity of 82.1% (CI:67.3-91.0), a specificity of 95.1% (CI:83.9-98.7), a PPV of 94.1% (CI:80.9-98.4) and a NPV of 84.8% (CI:71.8-92.4). Differences in sensitivities were statistically significant (difference 20.6%, CI:-0.02-40.9; p = 0.008). Distant metastases were present in 7/80 patients (8.75%). 18 F-FDG PET/MRI detected all of the histopathological proven metastases without any false-positive findings, while 3 patients with bone metastases were missed in CT (sensitivity 57.1%, specificity 95.9%). Additionally, CT presented false-positive findings in 3 patients., Conclusion: 18F-FDG PET/MRI has a high diagnostic potential and outperforms CT in assessing the N and M stage in patients with primary breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To compare breast magnetic resonance imaging (MRI), thoracal MRI, thoracal 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET)/MRI and axillary sonography for the detection of axillary lymph node metastases in women with newly diagnosed breast cancer. Materials and Methods: This prospective double-center study included patients with newly diagnosed breast cancer between March 2018 and December 2019. Patients underwent thoracal ( 18 F-FDG PET/)MRI, axillary sonography, and dedicated prone breast MRI. Datasets were evaluated separately regarding nodal status (nodal+ vs. nodal-). Histopathology served as reference standard in all patients. The diagnostic performance of breast MRI, thoracal MRI, thoracal PET/MRI and axillary sonography in detecting nodal positive patients was tested by creating receiver-operating-characteristic curves (ROC) with a calculated area under the curve (AUC). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for all four modalities. A McNemar test was used to assess differences. Results: 112 female patients (mean age 53.04 ± 12.6 years) were evaluated. Thoracal PET/MRI showed the highest ROC-AUC with a value of 0.892. The AUC for breast MRI, thoracal MRI and sonography were 0.782, 0.814 and 0.834, respectively. Differences between thoracal PET/MRI and axillary sonography, thoracal MRI and breast MRI were statistically significant (PET/MRI vs. axillary sonography, P = 0.01; PET/MRI vs. thoracal MRI, P = 0.02; PET/MRI vs. breast MRI, P = 0.03). PET/MRI showed the highest sensitivity (81.8%, 36/44) (95%-CI: 67.29-91.81%) while axillary sonography had the highest specificity (98.5%, 65/66), 95%-CI: 91.84-99.96%). Conclusion: 18 F-FDG PET/MRI outperforms axillary sonography, breast MRI and thoracal MRI in determining the axillary lymph node status. In a clinical setting, the combination of 18 F-FDG PET/MRI and axillary sonography might be considered to provide even more accuracy in diagnosis., (Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: To investigate a correlation between 68 Ga-DOTATOC PET/MR imaging parameters such as arterial and venous contrast enhancement, diffusion restriction, and maximum standardized uptake value (SUVmax) with histopathological tumor grading in patients with neuroendocrine neoplasms (NEN)., Material and Methods: A total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwent 68 Ga-DOTATOC PET/MRI. Images were evaluated regarding NEN lesion number and location, predominant tumor signal intensity on precontrast T1w and T2w images and on postcontrast arterial and portal venous phase T1w images, apparent diffusion coefficient (ADC) and SUVmax. Histopathological tumor grading was assessed and related to PET/MRI features using Pearson's correlation coefficient and Fisher's exact t-test. A binary logistic regression analysis was performed to evaluate a potential relation with an aggressive tumor biology and odds ratios (OR) were calculated., Results: There was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001)., Conclusion: The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The concept of "controlled oxygenated rewarming" (COR) using ex vivo machine perfusion after cold storage was evaluated as tool to improve renal graft function after transplantation. Renal function after 20 min warm ischemia and 21 h cold storage was studied in an auto-transplant model in pigs (25-30 kg, n = 6 per group). In the study group, preimplant ex vivo machine perfusion for 90 min was added after cold storage, including gentle warming up of the graft to 20°C (COR). Kidneys that were only cold stored for 21 h served as controls. In vivo follow up was one week; the remaining native kidney was removed during transplantation. COR significantly improved cortical microcirculation upon early reperfusion and reduced free radical mediated injury and cellular apoptosis. Post-transplant kidney function (peak levels in serum) was also largely and significantly improved in comparison to the control group. A weak inverse correlation was found between renal flow during COR and later peak creatinine after transplantation (r 2  = 0.5), better values were seen for oxygen consumption, measured during machine perfusion at 20°C (r 2  = 0.81). Gentle graft rewarming prior to transplantation by COR improves post-transplant graft outcome and may also be a valuable adjunct in pretransplant graft assessment., (© 2018 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)