Glioblastoma with novel EGFR mutations (T790M and exon 20 insertion) yet unresponsive to osimertinib: A case report.

Glioblastoma (GBM) is a high-grade adult-type IDH-wildtype diffuse glioma, commonly harboring epidermal growth factor receptor (EGFR) amplification. Here, we describe a case of a 49-year-old man with a GBM harboring a TERT promoter mutation. Despite surgical and chemoradiation therapy, the tumor recurred. At that time, comprehensive genomic profiling by next-generation sequencing identified two rare mutations in EGFR: T790M and an exon 20 insertion. Based on these findings, the patient elected to undergo off-label therapy with osimertinib, a third-generation EGFR tyrosine kinase inhibitor that has shown promising results in non-small cell lung carcinoma, including metastatic to brain, with exactly the same EGFR mutations. Moreover, the drug has excellent central nervous system penetration. Even so, no clinical response was observed, and the patient succumbed to the disease. The lack of response may be related to the specific nature of the EGFR mutations, and/or other unfavorable tumor biology overriding any benefit from osimertinib.

Pediatric fibromyxoid tumor with PLAG1 fusion: An emerging entity with a novel intracranial location.

Translocations involving PLAG1 occur in several tumors, most commonly pleomorphic adenoma and lipoblastoma. Recently, a distinctive soft tissue tumor with a PLAG1 fusion has been reported in the pediatric age group. These are low grade tumors with a fibroblastic or mixed fibroblastic and myxoid morphology but no other lines of differentiation. They are typically immunopositive for desmin and CD34. The partner genes for these tumors have included YWHAZ, EEF1A1, ZFHX4l, CHCHD7, and PCMTD1. We report another case of this fibromyxoid tumor with a PLAG1 fusion, this time with COL3A1 as the partner gene. The fusion placed expression of a full-length PLAG1 protein under the control of the constitutively active COL3A1 promoter. Overexpression of PLAG1 was confirmed by diffusely positive immunostaining for PLAG1. The most novel aspect of this tumor is the intracranial location. Opinion has been divided over whether these tumors are a specific entity, or related to lipoblastoma, since that tumor also typically occurs in soft tissue in the pediatric age group and shows many of the same gene fusions. However, lipoblastoma has never been reported in an intracranial location and, thus, our case provides compelling evidence that this fibromyxoid tumor is indeed a distinct entity.

Value of Diffusion-Weighted Imaging and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Prediction of Treatment Outcomes in Nasopharyngeal Carcinoma.

OBJECTIVE: Magnetic resonance imaging (MRI) parameters that reflect the tumor microenvironment of nasopharyngeal carcinoma (NPC) may predict treatment response and facilitate treatment planning. This study aimed to evaluate the diffusion-weighted imaging and dynamic contrast-enhanced MRI (DCE-MRI) values for predicting the treatment outcomes in NPC patients. METHODS: Eighty-three patients with NPC underwent pretreatment MRI simulation with diffusion-weighted imaging and dynamic contrast-enhanced MRI. Average values of the apparent diffusion coefficient (ADC), Ktrans, Kep, Ve, Vp, and tumor volume of the primary tumors were measured. Other potential clinical characteristics (age, sex, staging, pathology, pretreatment Epstein-Barr virus level, and treatment type) were analyzed. Patients underwent follow-up imaging 6 months after treatment initiation. Treatment responses were assigned according to the Response Evaluation Criteria in Solid Tumors guideline (version 1.1). RESULTS: Fifty-one patients showed complete response (CR), whereas 32 patients did not (non-CR). Univariable logistic regression with variables dichotomized by optimal cutoff values showed that ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, tumor volume of ≥14.05 mL, high stage (stages III and IV), and Epstein-Barr virus level of ≥2300 copies/mL were predictors of non-CR ( P = 0.008, 0.05, 0.01, 0.009, and 0.04, respectively). The final multivariable model, consisting of a combination of ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, and high stage, could predict non-CR with a good discrimination ability (area under the receiver operating characteristic curve, 0.76 [95% confidence interval, 0.66-0.87]; sensitivity, 62.50%; specificity, 80.39%; and accuracy 73.49%). CONCLUSIONS: A multivariable prediction model using a combination of ADC ≥1.45 × 10 -3 mm 2 /s, Vp ≥0.14, and high stage can be effective for treatment response prediction in NPC patients.

Depressive symptoms due to stroke are strongly predicted by the volume and location of the cerebral infarction, white matter hyperintensities, hypertension, and age: A precision nomothetic psychiatry analysis.

OBJECTIVES: To delineate the effects of white matter hyperintensities (WMHs) as measured by Fluid-attenuated inversion recovery (FLAIR) and infarction volume as measured by Diffusion-weighted imaging (DWI) on post-stroke depression symptoms. METHODS: Baseline National Institutes of Health Stroke Score (NIHSS) and Modified Rankin Scale (mRS) scores, and FLAIR and DWI MRIs to assess WMHs and acute infarct volumes, respectively, were assessed in 47 patients (≥55 years) with acute ischemic stroke and 17 normal controls. The Montgomery-Åsberg Depression Rating Scale (MDRS) was assessed three months after the stroke. RESULTS: The MADRS score was significantly increased in stroke patients as compared with normal controls. The MADRS scale is not unidimensional and cannot be used as an accurate indicator of depression severity in stroke patients. Three months after stroke, key depressive (sadness and inability to feel) and concentration-tension symptoms, and lassitude are significantly predicted by the infarct volume. Right side infarction strongly predicts key depressive symptoms and left side infarction strongly predicts concentration-tension and lassitude scores. Total WMHs significantly predict key depressive and concentration-tension symptoms, and lassitude, with these effects being mediated by right and left DWI stroke volumes and associated disabilities. CONCLUSIONS: Interactions between age, hypertension, a chronic atherosclerotic process, and acute stroke account for the onset of key depressive symptoms three months after the acute infarct. Chronic and acute neuro-immune and neuro-oxidative stress pathways associated with the formation of WMHs and acute stroke may explain the incidence of post-stroke key depressive and concentration-tension symptoms, and lassitude.

Utility of diffusion-weighted magnetic resonance imaging in predicting the treatment response of nasopharyngeal carcinoma.

OBJECTIVE: Predicting the treatment response in patients with nasopharyngeal carcinoma (NPC) is challenging. This study evaluated the utility of diffusion-weighted imaging (DWI) in predicting the treatment response in patients with NPC. METHODS: We prospectively enrolled 33 patients with newly diagnosed NPC who underwent magnetic resonance imaging with the propeller DWI and apparent diffusion coefficient (ADC) map before and at 5 weeks after chemoradiation. The following ADC values of the primary tumor were calculated: pre-treatment ADC (pre-ADC), pre-treatment ADC ratio (pre-ADC ratio), ADC change (▵ADC), ADC change ratio (▵ADC ratio), and percentage of ADC change (▵%ADC). The correlations between these parameters and treatment outcomes were explored, and the patients were classified as good responders (complete response) and poor responders (stable disease, partial response, or progressive disease) based on the Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: The ▵ADC, ▵ADC ratio, and ▵%ADC were significantly lower in the poor-responder group (n = 12) than in the good-responder group (n = 21; p = 0.001, p = 0.002, and p = 0.004, respectively). There was no significant difference between groups in the pre-ADC and pre-ADC ratios (p = 0.602 and p = 0.685, respectively). The optimal ▵ADC, ▵ADC ratio, and ▵%ADC cutoff values for predicting poor response were >0.65 mm2/sec, 0.28, and 60%, respectively (sensitivity: 83.3%, 75%, and 83.3%; specificity: 71.4%, 85.7%, and 71.4%, respectively). CONCLUSION: The ▵ADC, ▵ADC ratio, and ▵%ADC obtained during the pre-treatment and mid-treatment periods could be potential biomarkers for predicting treatment response in patients with NPC.

Value of dynamic contrast-enhanced magnetic resonance imaging for determining the plasma Epstein-Barr virus status and staging of nasopharyngeal carcinoma.

AIM: To determine the associations between dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) parameters and plasma Epstein-Barr virus (EBV) DNA status and nasopharyngeal carcinoma (NPC) stages. METHODS: We prospectively studied the DCE-MRI results of 47 patients with newly diagnosed NPC and their pre-treatment plasma EBV DNA levels. We recruited all patients who had undergone MRI (1.5 T) simulation at the radiation therapy department of our institute between January 2018-2019. Regions of interest were drawn at primary tumors, and DCE-MRI parameters, including mean values of Ktrans, Kep, Ve, and Vp, were recorded. Spearman's rank correlation was used to identify significant associations between the DCE-MRI parameters and the plasma EBV DNA level and NPC stages. Mann-Whitney U tests and unpaired t-test were performed to compare the DCE-MRI parameters among different groups and to identify optimal cut-off values using receiver operating characteristic curves. RESULTS: We found that the DCE-MRI parameters correlated with the plasma EBV DNA levels and NPC stages. Positive plasma EBV DNA was correlated with lower Kep (optimal cut-off value, 2.1 min-1; area under the curve [AUC], 0.714) and higher Ve (optimal cut-off value, 0.675; AUC, 0.706). Ve higher than 0.765 (AUC, 0.678) was correlated with plasma EBV DNA (≥2300 copies mL-1). Higher Ktrans (cut-off value, 1.495 min-1) was correlated with high-T stage (AUC, 0.767) and high-stage group (AUC, 0.711). CONCLUSIONS: The DCE-MRI parameters are correlated with the plasma EBV DNA status and NPC stages. Therefore, DCE-MRI findings may be used as imaging biomarkers for patients with NPC.

Comparison between the seventh and eighth edition of the AJCC/UICC staging system for nasopharyngeal cancer integrated with pretreatment plasma Epstein-Barr virus DNA level in a non-Chinese population: secondary analysis from a prospective randomized trial.

OBJECTIVE: To validate the eighth edition of the AJCC/UICC staging system in nasopharyngeal cancer (NPC) patients who were uniformly treated in a prospective randomized study using intensity-modulated radiation therapy and to investigate the prognostic value of plasma Epstein-Barr virus (EBV) DNA level when incorporated into the TNM staging. METHODS: Between October 2010 and September 2015, non-metastatic NPC patients were treated with concurrent chemoradiation followed by adjuvant chemotherapy. Pretreatment images of 205 patients were reviewed by two radiologists to determine the TNM classification according to the seventh and eighth editions of the AJCC/UICC staging system. Overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated. Harrell's C concordance index (C-index) and Akaike information criterion (AIC) were used to compare the staging models. Recursive partitioning analysis (RPA) was conducted and incorporated with plasma EBV DNA. RESULTS: Overall, the eighth edition showed higher C-indexes and lower AIC values in nodal classification and stage groups, indicating a better discrimination performance and better goodness of fit, but showed similar separation for T classification compared with the seventh edition. The integration of pretreatment EBV values (<2300 vs ≥2300 copies/ml) to the eighth edition AJCC/UICC staging system allowed the classification of patients into three RPA categories and further lowered the AIC value and increased the C-index for OS. CONCLUSION: The eighth edition of the AJCC/UICC staging system had higher prognostic values in terms of OS, PFS and DMFS than the previous edition. An integration of pretreatment plasma EBV DNA into the next AJCC/UICC staging could improve the outcome prediction especially in poor risk groups who might benefit from treatment intensification.

Dynamic contrast-enhanced MRI of orbital and anterior visual pathway lesions.

PURPOSE: The accurate diagnosis of orbital and anterior visual pathway lesions has clinical significance. We determined whether dynamic contrast-enhanced MRI could differentiate benign from malignant lesions and compared model-independent and model-dependent methods of data analysis. METHODS: We retrospectively reviewed dynamic contrast-enhanced MRI studies of 37 enhancing orbital and anterior visual pathway lesions. The data were processed using model-independent analysis and model-dependent analysis using a 2-compartment pharmacokinetic model. The time-signal intensity curve and semiquantitative parameters from the model-independent method (area under the curve [AUC] after the initial 60, 90, and 120 s; time to peak; maximum signal enhancement ratio; maximum slope of increase; and washout ratio) and the quantitative parameters from the model-dependent method (Ktrans, kep, and ve) were derived for comparison with pathologic diagnoses. RESULTS: The time-signal intensity curves demonstrated different perfusion characteristics and were classified into 4 types. All the lesions that demonstrated curve types 1 and 4 were benign, while type 3 lesions were significantly associated with malignancy (P = 0.001). AUC60, AUC90, AUC120, and kep were significantly lower in benign lesions than in malignant lesions (P = 0.020, 0.018, 0.015, and 0.018, respectively). Receiver operating characteristic analysis indicated that AUC120 yielded the best diagnostic accuracy (area under the curve, 0.80; 95% CI, 0.64-0.96) in differentiating between benign and malignant lesions. CONCLUSIONS: Dynamic contrast-enhanced MRI is useful in evaluating orbital and anterior visual pathway lesions. The model-independent analysis method is equivalent to the model-dependent method in differentiating benign from malignant lesions.

Prognostic Role of Conventional and Dynamic Contrast-Enhanced MRI in Optic Pathway Gliomas.

BACKGROUND AND PURPOSE: The natural history of optic pathway glioma (OPG) is highly variable and unpredictable. We present a pilot study of the prognostic role of conventional and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) in the evaluation of OPG. METHODS: We retrospectively reviewed 17 patients with 20 pretreatment OPG lesions who underwent conventional and DCE MRI between January 2010 and December 2016. Conventional MRI was evaluated for enhancement pattern, cystic component, optic nerve tortuosity, optic nerve dural ectasia, and optic nerve perineural thickening. The DCE MRI data were analyzed for quantitative parameters using the two-compartment pharmacokinetic model (Ktrans , kep , and ve ) and for semiquantitative parameters based on time-signal intensity curve (AUC60 , peak, and wash-in). The results were compared with the clinically progressive or nonprogressive tumor. RESULTS: Five progressive OPGs and 15 nonprogressive OPGs were included. Conventional MRI findings of diffuse enhancement and cystic component were significantly correlated with progressive OPGs (both P = .01). Conventional MRI yielded sensitivity of 60%, specificity of 100%, and accuracy of 90%. Ktrans , kep , and ve as well as AUC60 , peak, and wash-in were significantly higher in progressive OPGs (P < .05). Using DCE MRI increased diagnostic performance up to a sensitivity of 100%, specificity of 93%, and accuracy of 95%. CONCLUSION: DCE MRI accurately distinguished progressive and nonprogressive OPGs, with high sensitivities and specificities. DCE MRI has a significant prognostic role in predicting progressive OPGs, thus making it useful for the identification of patients who need close clinical and imaging follow-up.

Orbital oncocytoma: evaluation with dynamic contrast-enhanced magnetic resonance imaging using a time-signal intensity curve and positive enhancement integral images.

Oncocytomas, which are benign epithelial tumors filled with abundant mitochondria, arise from ductal cells. Oncocytomas rarely occur in the orbit. We present a case of pathologically proven orbital oncocytoma of the lacrimal gland studied by dynamic contrast-enhanced magnetic resonance imaging (DCE MRI). DCE MRI has potential as an adjunct to conventional MRI in the differential diagnosis and tumor margin delineation of orbital oncocytoma. Simple assessments of the time-signal intensity curve, semiquantitative parameters, and post-processing positive enhancement integral images should be considered in the evaluation of orbital masses found on MRI.

SHP-1 promoter 2 methylation in cerebrospinal fluid for diagnosis of leptomeningeal epithelial-derived malignancy (carcinomatous meningitis).

Current diagnostic methods for leptomeningeal metastasis (LM) from epithelial-derived malignancy (EDM) have limited sensitivity. Here, we explored SHP-1 promoter 2 methylation (SHP1P2)-an epithelial-specific methylation marker previously proven as risk stratification and potential diagnostic marker in non-small cell lung cancer-for EDM with LM. We prospectively recruited 136 patients who were diagnosed EDM with LM (n = 25), EDM without LM (n = 14), non-EDM with LM (n = 8), and benign meningeal diseases (n = 89). The primary cancer sites for EDM with LM were lung (n = 17), breast (n = 5), and colon (n = 3). We performed quantitative analyses of cell-free (cfSHP1P2) and whole fraction (wSHP1P2) from cerebrospinal fluid (CSF); results were correlated with the clinicopathological data, including CSF cytology. Median cfSHP1P2 and wSHP1P2 were 3.08 [range: 0-163.5] and 9.35 [0.69-91.63] ng/ml, respectively, in EDM with LM; 0 [0-0.08] and 0.23 [0-7.84] ng/ml in EDM without LM; and were undetectable in most cases of benign meningeal diseases and non-EDM with LM. The cut-off values of 0.22 ng/ml for methylated cfSHP1P2 and 0.59 ng/ml for wSHP1P2 were the best to discriminate EDM with LM from EDM without LM (sensitivity: 79-100 %; specificity: 83-100 %), as well as from other benign conditions (sensitivity: 85-100 % specificity: 78-100 %). CSF cytology yielded 76 % sensitivity for diagnosing EDM with LM. Further validation of CSF SHP1P2 methylation detection as a role of adjunctive tool for LM from EDM should be interested based on our study.