Early therapy evaluation of intra-arterial trastuzumab injection in a human breast cancer xenograft model using multiparametric MR imaging.

PURPOSE: To investigate the treatment efficacy of intra-arterial (IA) trastuzumab treatment using multiparametric magnetic resonance imaging (MRI) in a human breast cancer xenograft model. MATERIALS AND METHODS: Human breast cancer cells (BT474) were stereotaxically injected into the brains of nude mice to obtain a xenograft model. The mice were divided into four groups and subjected to different treatments (IA treatment [IA-T], intravenous treatment [IV-T], IA saline injection [IA-S], and the sham control group). MRI was performed before and at 7 and 14 d after treatment to assess the efficacy of the treatment. The tumor volume, apparent diffusion coefficient (ADC), and dynamic contrast-enhanced (DCE) MRI parameters (Ktrans, Kep, Ve, and Vp) were measured. RESULTS: Tumor volumes in the IA-T group at 14 d after treatment were significantly lower than those in the IV-T group (13.1 mm3 [interquartile range 8.48-16.05] vs. 25.69 mm3 [IQR 20.39-30.29], p = 0.005), control group (IA-S, 33.83 mm3 [IQR 32.00-36.30], p<0.01), and sham control (39.71 mm3 [IQR 26.60-48.26], p <0.001). The ADC value in the IA-T group was higher than that in the control groups (IA-T, 7.62 [IQR 7.23-8.20] vs. IA-S, 6.77 [IQR 6.48-6.87], p = 0.044 and vs. sham control, 6.89 [IQR 4.93-7.48], p = 0.004). Ktrans was significantly decreased following the treatment compared to that in the control groups (p = 0.002 and p<0.001 for vs. IA-S and sham control, respectively). Tumor growth was decreased in the IV-T group compared to that in the sham control group (25.69 mm3 [IQR 20.39-30.29] vs. 39.71 mm3 [IQR 26.60-48.26], p = 0.27); there was no significant change in the MRI parameters. CONCLUSION: IA treatment with trastuzumab potentially affects the early response to treatment, including decreased tumor growth and decrease of Ktrans, in a preclinical brain tumor model.

Bright diffusion sign: A sensitive and specific radiologic biomarker for multinodular and vacuolating neuronal tumor.

BACKGROUND AND PURPOSE: Accurate differentiation between multinodular and vacuolating neuronal tumor (MVNT) and dysembryoplastic neuroepithelial tumor (DNET) is important for treatment decision-making. We aimed to develop an accurate radiologic diagnostic model for differentiating MVNT from DNET using T2WI and diffusion-weighted imaging (DWI). MATERIALS AND METHODS: A total of 56 patients (mean age, 47.48±17.78 years; 31 women) diagnosed with MVNT (n = 37) or DNET (n = 19) who underwent brain MRI, including T2WI and DWI, were included. Two board-certified neuroradiologists performed qualitative (bubble appearance, cortical involvement, bright diffusion sign, and bright apparent diffusion coefficient [ADC] sign) and quantitative (nDWI and nADC) assessments. A diagnostic tree model was developed with significant and reliable imaging findings using an exhaustive chi-squared Automatic Interaction Detector (CHAID) algorithm. RESULTS: In visual assessment, the imaging features that showed high diagnostic accuracy and interobserver reliability were the bright diffusion sign and absence of cortical involvement (bright diffusion sign: accuracy, 94.64 %; sensitivity, 91.89 %; specificity, 100.00 %; interobserver agreement, 1.00; absence of cortical involvement: accuracy, 92.86 %; sensitivity, 89.19 %; specificity, 100.00 %; interobserver agreement, 1.00). In quantitative analysis, nDWI was significantly higher in MVNT than in DENT (1.52 ± 0.34 vs. 0.91 ± 0.27, p < 0.001), but the interobserver agreement was fair (intraclass correlation coefficient = 0.321). The overall diagnostic accuracy of the tree model with visual assessment parameters was 98.21 % (55/56). CONCLUSION: The bright diffusion sign and absence of cortical involvement are accurate and reliable imaging findings for differentiating MVNT from DNET. By using simple, intuitive, and reliable imaging findings, such as the bright diffusion sign, MVNT can be accurately differentiated from DNET.

Clinical Relevance of Computed Tomography Perfusion-Estimated Infarct Volume in Acute Ischemic Stroke Patients within the 6-h Therapeutic Time Window.

INTRODUCTION: Although the estimated infarct volume on baseline computed tomography perfusion (CTP) can identify patients who are likely to benefit from endovascular thrombectomy (EVT) in late time window strokes, the role of CTP imaging in early time windows has not been established. We assessed the clinical impact of CTP-estimated infarct volume on long-term prognosis after EVT, particularly in patients with early time window stroke. METHODS: We retrospectively reviewed patients who underwent pretreatment CTP and EVT for large vessel occlusion in the anterior circulation within 6 h after symptom onset between March 2014 and February 2019. The infarct volume at baseline CTP was estimated using commercially available software (RAPID, iSchemaView, Menlo Park, CA, USA) with a cerebral blood flow threshold <30% of the normal brain. Risk factors for poor outcome after EVT were evaluated, and a receiver operating characteristic (ROC) curve analysis was used to identify CTP-estimated infarct volumes that optimally predicted the development of symptomatic intracranial hemorrhage (sICH) and poor outcomes (modified Rankin Scale [mRS] 3-6) at 90 days. RESULTS: Of 120 patients, successful recanalization was achieved in 89 (74.2%) patients, while 61 (50.8%) showed poor outcomes at 90 days. Among 89 patients with successful recanalization after EVT, age, diabetes, clinical stroke severity, CTP-estimated infarct volume, and sICH development were independently associated with 90-day clinical outcomes. ROC analysis identified infarct volumes of ≥88.5 mL and ≥74 mL as the optimal thresholds for predicting poor outcome and development of sICH, respectively. Patients with large infarct volumes showed poorer outcomes (odds ratio [OR], 7.704; 95% confidence interval [CI], 1.528-38.839) and higher rates of sICH development (OR, 10.857; 95% CI, 1.835-64.235). Among patients with large infarction volumes (≥88.5 mL), the 90-day mRS demonstrated a shift toward better outcomes in patients with successful recanalization. CONCLUSION: Larger initial infarct volumes are significantly associated with worse clinical outcomes in patients who underwent EVT because of early time window stroke. Furthermore, our study of 6-h data demonstrated that an initial infarction of more than a certain volume might be an independent risk factor for sICH development and poor outcomes even in patients with successful recanalization. However, we still observed benefits of EVT in patients with large ischemic cores. The CTP-estimated infarct volume might be an important prognostic factor after EVT rather than a biomarker predicting treatment effectiveness.

Cervical necrotic lymphadenopathy: a diagnostic tree analysis model based on CT and clinical findings.

OBJECTIVES: To establish a diagnostic tree analysis (DTA) model based on computed tomography (CT) findings and clinical information for differential diagnosis of cervical necrotic lymphadenopathy, especially in regions where tuberculous lymphadenitis and Kikuchi disease are common. METHODS: A total of 290 patients (147 men and 143 women; mean age (years), 46.2 ± 19.5; range, 3-91) with pathologically confirmed metastasis (n = 110), tuberculous lymphadenitis (n = 73), Kikuchi disease (n = 71), and lymphoma (n = 36) who underwent contrast-enhanced neck CT were included. The patients were randomly divided into training (86%, 248/290) and validation (14%, 42/290) datasets to assess diagnostic performance of the DTA model. Two sorts of DTA models were created using a classification and regression tree algorithm on the basis of CT findings alone and that combined with clinical findings. RESULTS: In the DTA model based on CT findings alone, perinodal infiltration, number of the necrotic foci, percentage of necrotic lymph node (LN), degree of necrosis, margin and shape of the necrotic portion, shape of the LN, and enhancement ratio (cutoff value, 1.93) were significant predictors for differential diagnosis of cervical necrotic lymphadenopathy. The overall accuracy was 80.6% and 73.8% in training and validation datasets. In the model based on imaging and clinical findings, tenderness, history of underlying malignancy, percentage of necrotic LN, degree of necrosis, and number of necrotic foci were significant predictors. The overall accuracy was 87.1% and 88.1% in training and external validation datasets. CONCLUSIONS: The DTA model based on CT imaging and clinical findings may be helpful for the diagnosis of cervical necrotic lymphadenopathy. KEY POINTS: • The diagnostic tree analysis model based on CT may be useful for differential diagnosis of cervical necrotic lymphadenopathy. • Perinodal infiltration, number of necrotic foci, percentage of necrotic lymph nodes, degree of necrosis, margin and shape of necrotic portion, lymph node shape, and enhancement ratio were the most significant predictors.

Wnt and the cancer niche: paracrine interactions with gastrointestinal cancer cells undergoing asymmetric cell division.

OBJECTIVE: Stem-like cancer cells contribute to cancer initiation and maintenance. Stem cells can self-renew by asymmetric cell division (ACD). ACD with non-random chromosomal cosegregation (ACD-NRCC) is one possible self-renewal mechanism. There is a paucity of evidence supporting ACD-NRCC in human cancer. Our aim was to investigate ACD-NRCC and its potential interactions with the cancer niche (microenvironment) in gastrointestinal cancers. DESIGN: We used DNA double and single labeling approaches with FACS to isolate live cells undergoing ACD-NRCC. RESULTS: Gastrointestinal cancers contain rare subpopulations of cells capable of ACD-NRCC. ACD-NRCC was detected preferentially in subpopulations of cells previously suggested to be stem-like/tumor-initiating cancer cells. ACD-NRCC was independent of cell-to-cell contact, and was regulated by the cancer niche in a heat-sensitive paracrine fashion. Wnt pathway genes and proteins are differentially expressed in cells undergoing ACD-NRCC vs. symmetric cell division. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in suppression of ACD-NRCC. However, using a Wnt-agonist did not increase the relative proportion of cells undergoing ACD-NRCC. CONCLUSION: Gastrointestinal cancers contain subpopulations of cells capable of ACD-NRCC. Here we show for the first time that ACD-NRCC can be regulated by the Wnt pathway, and by the cancer niche in a paracrine fashion. However, whether ACD-NRCC is exclusively associated with stem-like cancer cells remains to be determined. Further study of these findings might generate novel insights into stem cell and cancer biology. Targeting the mechanism of ACD-NRCC might engender novel approaches for cancer therapy.

Isolation of live label-retaining cells and cells undergoing asymmetric cell division via nonrandom chromosomal cosegregation from human cancers.

The ability to retain DNA labels over time is a property proposed to be associated with adult stem cells. Recently, label retaining cells (LRC) were indentified in cancer. LRC were suggested to be the result of either slow-cycling or asymmetric-cell-division with nonrandom-chromosomal-cosegregation (ACD-NRCC). ACD-NRCC is proposed to segregate the older template DNA strands into daughter stem cells and newly synthesized DNA into daughter cells destined for differentiation. The existence of cells undergoing ACD-NRCC and the stem-like nature of LRC remain controversial. Currently, to detect LRC and ACD-NRCC, cells need to undergo fixation. Therefore, testing the stem-cell nature and other functional traits of LRC and cells undergoing ACD-NRCC has been limited. Here, we show a method for labeling DNA with single and dual-color nucleotides in live human liver cancer cells avoiding the need for fixation. We describe a novel methodology for both the isolation of live LRC and cells undergoing ACD-NRCC via fluorescence-activated cell sorting with confocal microscopy validation. This has the potential to be a powerful adjunct to stem-cell and cancer research.