Comparison of the clinical features and treatment outcomes of pilocytic astrocytoma in pediatric and adult patients.

PURPOSE: Pilocytic astrocytoma is a slow-growing tumor that predominantly develops in children, but has a broad age spectrum. A notable characteristic of pilocytic astrocytoma is that the tumor arises in diverse locations and the clinical course is not always benign. Therefore, it is necessary to elucidate the clinical spectrum of the disease and analyze the relevant prognostic factors. METHODS: Demographic and treatment-related factors were retrospectively reviewed in a cohort of 254 patients with histologically confirmed pilocytic astrocytoma. Clinical features were compared between the pediatric group (N = 208; age < 18 years) and the adult group (N = 46; age ≥ 18 years). Cox regression analysis was performed to identify relevant prognostic factors. RESULTS: There was no difference in progression-free survival (PFS) between the pediatric and adult groups (p = 0.36); however, patients under 8 years of age exhibited worse PFS (p < 0.01). Leptomeningeal seeding at diagnosis and pilomyxoid histology was observed only in pediatric patients. In the pediatric group, nine patients experienced recurrence after complete resection. Increasing age (hazard ratio (HR) = 0.89, p < 0.01) and adjuvant therapy (HR = 0.32, p < 0.01) were protective factors against tumor progression. In the adult group, no progression occurred after complete resection. Age and adjuvant therapy were not significant factors in the adult group. CONCLUSION: Pilocytic astrocytoma presents with a diverse clinical spectrum. Complete resection is of utmost importance, and appropriate adjuvant treatment is recommended if complete resection cannot be achieved. Children with younger age are associated with more aggressive tumors, and recurrence may occur even after complete resection.

Sporadic and Lynch syndrome-associated mismatch repair-deficient brain tumors.

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options.

Molecular subgrouping of medulloblastoma in pediatric population using the NanoString assay and comparison with immunohistochemistry methods.

PURPOSE: Molecular subgrouping of medulloblastoma has become important due to its impact on risk group stratification. Immunohistochemistry (IHC) has been widely used but it has innate limitations. The NanoString assay has been proposed as an alternative method. This study aims to present the characteristics of medulloblastoma subgrouped by the NanoString assay and to compare the subgrouping results with the IHC method. METHODS: Pediatric patients with histological diagnosis of medulloblastoma who underwent surgery from 2007 to 2021 were included. Clinical characteristics, pathological findings were reviewed. Molecular subgrouping was performed by IHC and by NanoString nCounter Elements TagSets assay. Test for concordance between two methods was made. RESULTS: Among a total of 101 patients analyzed, subgrouping using the NanoString assay resulted in 14 (13.8%) WNT, 20 (19.8%) SHH, 18 (17.8%) Group 3, and 39 (38.6%) Group 4 subgroup cases. Survival analysis revealed the following from best to worse prognosis: WNT, Group 4, SHH, and Group 3. In SHH subgroup the large cell/anaplastic histology was present in 30% of cases. Seventy-one cases were analyzed for concordance between NanoString and IHC. Cohen's kappa value indicated moderate agreement but identification of Groups 3 and 4 with IHC using NPR3 and KCNA1 markers exhibited poor results. CONCLUSIONS: The NanoString assay of Korean medulloblastoma patients revealed a more aggressive clinical course in the SHH subgroup which may be explained by a higher proportion of large cell/anaplastic histology being present in this subgroup. IHC did not distinguish Group 3 or 4 accurately. The NanoString assay may represent a good alternative method for practical use in the clinical field.

Toxic leukoencephalopathy with axonal spheroids caused by chemotherapeutic drugs other than methotrexate.

BACKGROUND: The objective of this report is to share the clinicopathological features of chemotherapy-induced toxic leukoencephalopathy, which is a rare and under-recognized disease, clinically characterized by rapidly progressive cognitive loss that often leads to sudden death. CASE PRESENTATION: A 64-year-old woman and a 63-year-old man, who had both suffered from a rapid deterioration of consciousness, were autopsied under the clinical impressions of either the central nervous system graft versus host disease (CNS-GVHD), infectious encephalitis, or autoimmune encephalitis. Both patients had been treated with multiple chemotherapy regimens, including adriamycin, cytarabine arabinoside, daunorubicin, fludarabine, azacitidine, and allogeneic peripheral blood stem cell transplantation to treat hematological malignancies (acute myelogenous leukemia and myelodysplastic syndrome). Neuropathological findings at autopsy revealed rarefaction and vacuolar changes of the white matter with axonal spheroids, reactive gliosis, and foamy macrophage infiltration, predominantly in the visual pathways of the occipital and temporal lobes. Damaged axons exhibited immunoreactivity to beta-amyloid, consistent with axonopathy. However, there was no lymphocyte infiltration that suggested CNS-GVHD or any type of encephalitis. CONCLUSION: The neuropathology found in the presented cases had the characteristic features of toxic leukoencephalopathy (chemobrain). Our cases showed that toxic leukoencephalopathy can also be caused by chemotherapy drugs other than methotrexate.

Occult tethered cord syndrome: a rare, treatable condition.

PURPOSE: Occult tethered cord syndrome (OTCS) is an entity that shows tethered cord syndrome (TCS) with normal spinal MRI findings. The definition and treatment of OTCS have been controversial since first proposal. The purpose of this study was to evaluate the existence, prevalence, histological characteristics, and surgical outcomes of OTCS. METHODS: We retrospectively analyzed patients who underwent untethering surgery for OTCS from January 2010 to December 2019. Inclusion criteria were (1) clinical manifestation of TCS; (2) supported by urodynamic study (UDS) or electromyography/nerve conduction study; (3) no structural lesions in the urological tract or spinal cord, and no developmental delay; and (4) postoperative follow-up for > 6 months. Sectioned fila from OTCS patients were histologically compared with those from cases of thickened filum or low-lying conus. RESULTS: Five (four female, one male) of 439 patients (1.1%) who underwent untethering surgeries for occult spinal dysraphism corresponded to OTCS. Mean age at the time of surgery was 16 years (7-22 years). Mean postoperative follow-up duration was 45 months (15-114 months). The main symptom was urinary dysfunction in four patients and leg pain in one. All patients had detrusor-sphincter dyssynergia. Fila from OTCS patients revealed increased fibrous tissue as in TCS patients. Four patients showed postoperative improvement and one with preoperative static course had no improvement. CONCLUSIONS: This study suggests that OTCS is a definitely existing entity although rare. OTCS is curable when timely treatment is given. Sudden onset with rapid progression of symptom seems the best indication for surgery.

Absolute quantification of tumor-infiltrating immune cells in high-grade glioma identifies prognostic and radiomics values.

PURPOSE: To understand the tumor immune microenvironment precisely, it is important to secure the quantified data of tumor-infiltrating immune cells, since the immune cells are true working unit. We analyzed unit immune cell number per unit volume of core tumor tissue of high-grade gliomas (HGG) to correlate their immune microenvironment characteristics with clinical prognosis and radiomic signatures. METHODS: The number of tumor-infiltrating immune cells from 64 HGG core tissue were analyzed using flow cytometry and standardized. After sorting out patient groups according to diverse immune characteristics, the groups were tested if they have any clinical prognostic relevance and specific radiomic signature relationships. Sparse partial least square with discriminant analysis using multimodal magnetic resonance images was employed for all radiomic classifications. RESULTS: The median number of CD45 + cells per one gram of HGG core tissue counted 865,770 cells which was equivalent to 8.0% of total cells including tumor cells. There was heterogeneity in the distribution of immune cell subpopulations among patients. Overall survival was significantly better in T cell-deficient group than T cell-enriched group (p = 0.019), and T8 dominant group than T4 dominant group (p = 0.023). The number of tumor-associated macrophages (TAM) and M2-TAM was significantly decreased in isocitrate dehydrogenase mutated HGG. Radiomic signature classification showed good performance in predicting immune phenotypes especially with features extracted from apparent diffusion coefficient maps. CONCLUSIONS: Absolute quantification of tumor-infiltrating immune cells confirmed the heterogeneity of immune microenvironment in HGG which harbors prognostic impact. This immune microenvironment could be predicted by radiomic signatures non-invasively.

Coexistence of dentatorubral-pallidoluysian atrophy and Parkinson's disease: An autopsy case report.

We report an autopsy case of a 56-year-old male patient with the coexistence of dentatorubral-pallidoluysian atrophy (DRPLA) and Parkinson's disease (PD). He presented with gait instability and dysarthria for 10 years. The removed brain showed general atrophy (988 g) with depigmentation of the substantia nigra. The neocortex and deep gray matter, including the red nucleus, subthalamic nuclei, and globus pallidus, were atrophic, and grumose degeneration of the cerebellar dentate nucleus was observed. Polyglutamine- and p62-positive neuronal inclusions were present and widespread in the areas mentioned above. Interestingly, this case also had brainstem-predominant PD pathology with α-synuclein-positive Lewy bodies and Lewy neurites. Generalized white matter atrophy with patchy loss of astrocytes in the white matter suggested glial dysfunction by elongated CAG repeats in the atrophin 1 gene (atrophin 1). Polymerase chain reaction (PCR) fragment analysis revealed increased CAG repeats (61) on atrophin 1 encoding atrophin 1. The patient had a family history of DRPLA, including his daughter, who was confirmed positive on genetic testing (CAG repeat: 65). His father, brother, and niece were suspected of having the disease. Clinicopathologically, all of the above findings are consistent with the coexistence of DRPLA and PD. So far, various overlapping neurodegenerative disorders have been reported, but the coexistence of DRPLA and PD has never been demonstrated in the published literature. Even though the exact time of PD development is unknown in this case, PD might develop after DRPLA, and the overwhelming symptoms of DRPLA might mask those of PD. Here, we report a clinicopathologically definite case of the coexistence of DRPLA and PD. White matter degeneration with patchy loss of astrocytes was another remarkable finding of this case.

Prognostication of anaplastic astrocytoma patients: application of contrast leakage information of dynamic susceptibility contrast-enhanced MRI and dynamic contrast-enhanced MRI.

PURPOSE: To examine the applicability of contrast leakage information from dynamic susceptibility contrast-enhanced (DSC) MRI and dynamic contrast-enhanced (DCE) MRI to determine which one is the most valuable surrogate imaging biomarker for predicting disease progression in anaplastic astrocytoma (AA) patients. MATERIALS AND METHODS: This study was approved by the institutional review board (IRB), which waived informed consent. A total of seventy-three AA patients who had undergone preoperative DCE and DSC MRI and received standard treatment, including partial resection or biopsy followed by radiation therapy, were included in this retrospective study. Based on Response Assessment in Neuro-Oncology (RANO), patients were sorted into progression (n = 21) and non-progression (n = 52) groups. Tumor boundaries were defined as high-signal intensity (SI) lesions on fluid-attenuated inversion recovery (FLAIR) imaging, where we analyzed mean pharmacokinetic parameters (Ktrans, Vp, and Ve) from DCE MRI and contrast leakage information (mean extraction fraction (EF)) from DSC MRI. RESULTS: Mean Ve and mean EF were significantly higher in patients with progression-free survival (PFS) < 18 months than in those with PFS ≥ 18 months. For distinguishing the group with PFS < 18 months, AUC values were calculated using the mean Ve value (AUC = 0.716). The Kaplan-Meier survival analysis revealed that mean Ve value was significantly correlated with PFS. In Cox proportional-hazards regression, only the mean Ve value was found to be significantly associated with PFS. CONCLUSION: We found that the mean Ve value based on high-SI tumor lesions on FLAIR imaging was capable of predicting outcomes of AA patients as a potential surrogate imaging biomarker. KEY POINTS: • Mean Ve(2.152 ± 1.857 vs. 1.173 ± 1.408) was significantly higher in anaplastic astrocytoma patients with PFS < 18 months that in those with PFS ≥ 18 months (p = 0.02). • Cox proportional-hazards regression showed that only mean Ve(p = 0.034) was significantly associated with PFS, regardless of IDH mutation status, in anaplastic astrocytoma patients.

Arterial spin labeling perfusion-weighted imaging aids in prediction of molecular biomarkers and survival in glioblastomas.

OBJECTIVES: Prediction of progression-free survival (PFS) and overall survival (OS) and early identification of molecular biomarkers with prognostic information are clinically important in glioblastoma (GBM) patients. We aimed to explore the utility of arterial spin labeling perfusion-weighted imaging (ASL-PWI) in the prediction of molecular biomarkers and survival in GBM patients. METHODS: We retrospectively analyzed 149 consecutive GBM patients, who had undergone maximal surgical resection or biopsy followed by concurrent chemoradiotherapy and adjuvant chemotherapy using temozolomide between November 2010 and June 2016. On preoperative ASL-PWI, cerebral blood flow (CBF) within contrast-enhancing (CE) and nonenhancing (NE) portions were evaluated both qualitatively (perfusion pattern[CE] and perfusion pattern[NE]) and quantitatively (nCBFCE and nCBFNE). ASL-PWI findings were correlated with molecular biomarkers, including isocitrate dehydrogenase (IDH) and O6-methylguanine-DNA methyltransferase (MGMT) methylation statuses, and survival, using the Mann-Whitney U-test, Spearman rank correlation, Kaplan-Meier analysis, and receiver operating characteristics analysis. RESULTS: nCBFCE was significantly higher in the IDH wild-type group than in the IDH mutant group (p = .013) and in the MGMT unmethylated group than in the methylated group (p = .047). Areas under the receiver operating characteristic curve were 0.678 for IDH mutation (p = .022) and 0.601 for MGMT promoter methylation (p = .043). Hyperperfusion was associated with the shortest median PFS for both perfusion pattern[CE] (7.6 months) and perfusion pattern[NE] (4.0 months). The perfusion pattern[NE] remained an independent predictor for PFS and OS even after adjusting for clinical and molecular predictors, unlike perfusion pattern[CE]. CONCLUSIONS: ASL-PWI can aid to predict survival and molecular biomarkers including IDH mutation and MGMT promoter methylation statuses in GBM patients. KEY POINTS: • ASL-PWI can aid to predict survival in GBM patients. • ASL-PWI can aid to predict IDH and MGMT promoter methylation statuses in GBM.

Association of pathway mutation with survival after recurrence in colorectal cancer patients treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy.

BACKGROUND: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR. METHODS: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-ß, and PI3K). RESULTS: Mutation of genes within the WNT, P53, RTK-RAS, TGF-ß, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-ß pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-ß pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p <  0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-ß pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-ß pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation. CONCLUSIONS: Mutation in genes within TGF-ß pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.

Parathyroid adenoma with prominent lymphocytic infiltrate having histological features highly suggestive of IgG4-related disease: a case report and literature review.

Parathyroid adenoma with prominent lymphocytic infiltrate is a rare disease. Until now, 11 patients have been reported. Herein, we report a 57-year-old man who had a neck mass that was incidentally found. Aspiration cytology and subsequent needle biopsy of the tumor were performed and suggested papillary thyroid carcinoma. From the resected specimen, however, the patient was finally diagnosed with parathyroid adenoma with prominent lymphocytic infiltrate, characterized by hyperplastic parathyroid cells with nuclear atypia within fibrotic stroma along with numerous lymphocytes forming germinal centers. Some eosinophils and plasma cells were also observed with some histological features highly suggestive of IgG4-related disease (IgG4-RD), including increased IgG4-positive plasma cells and IgG4/IgG-positive plasma cell ratio, storiform-type fibrosis, and obliterative phlebitis. It turned out that microfollicular or trabecular architecture and cellular atypia with high expression of HBME-1 observed in the aspiration cytology and needle biopsy had been misinterpreted as a thyroid malignancy. This is the first report describing microscopic features of aspiration cytology and needle biopsy of parathyroid adenoma with prominent lymphocytic infiltrate, warning that it can mimic papillary thyroid carcinoma in biopsy specimens. Furthermore, the IgG4-RD-like features of the present case and previous reports imply that parathyroid adenoma with prominent lymphocytic infiltrate may be a type of IgG4-RD.

Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers.

Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8-PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease.

Differentiation of High-Grade from Low-Grade Astrocytoma: Improvement in Diagnostic Accuracy and Reliability of Pharmacokinetic Parameters from DCE MR Imaging by Using Arterial Input Functions Obtained from DSC MR Imaging.

Purpose To evaluate whether arterial input functions (AIFs) derived from dynamic susceptibility-contrast (DSC) magnetic resonance (MR) imaging, or AIFDSC values, improve diagnostic accuracy and reliability of the pharmacokinetic (PK) parameters of dynamic contrast material-enhanced (DCE) MR imaging for differentiating high-grade from low-grade astrocytomas, compared with AIFs obtained from DCE MR imaging (AIFDCE). Materials and Methods This retrospective study included 226 patients (138 men, 88 women; mean age, 52.27 years ± 15.17; range, 24-84 years) with pathologically confirmed astrocytomas (World Health Organization grade II = 21, III = 53, IV = 152; isocitrate dehydrogenase mutant, 11.95% [27 of 226]; 1p19q codeletion 0% [0 of 226]). All patients underwent both DSC and DCE MR imaging before surgery, and AIFDSC and AIFDCE were obtained from each image. Volume transfer constant (Ktrans), volume of vascular plasma space (vp), and volume of extravascular extracellular space (ve) were processed by using postprocessing software with two AIFs. The diagnostic accuracies of individual parameters were compared by using receiver operating characteristic curve (ROC) analysis. Intraclass correlation coefficients (ICCs) and the Bland-Altman method were used to assess reliability. Results The AIFDSC-driven mean Ktrans and ve were more accurate for differentiating high-grade from low-grade astrocytoma than those derived by using AIFDCE (area under the ROC curve: mean Ktrans, 0.796 vs 0.645, P = .038; mean ve, 0.794 vs 0.658, P = .020). All three parameters had better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.737 vs 0.095; vp, 0.848 vs 0.728; ve, 0.875 vs 0.581, respectively). In AIF analysis, maximal signal intensity (0.837 vs 0.524) and wash-in slope (0.800 vs 0.432) demonstrated better ICCs with AIFDSC than AIFDCE. Conclusion AIFDSC-driven DCE MR imaging PK parameters showed better diagnostic accuracy and reliability for differentiating high-grade from low-grade astrocytoma than those derived from AIFDCE. © RSNA, 2017 Online supplemental material is available for this article.

Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.

Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group. CONCLUSION: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855-868).

Comparison of Immunohistochemistry and Direct Sequencing Methods for Identification of the BRAFV600E Mutation in Papillary Thyroid Carcinoma.

BACKGROUND: BRAFV600E mutation is the most common somatic variant in papillary thyroid carcinoma (PTC) and is associated with aggressive prognostic factors. The conventional detection method for BRAF mutations is polymerase chain reaction followed by Sanger sequencing. Recently, an immunohistochemistry (IHC) method using a BRAFV600E-specific antibody (VE1) has been developed and widely adopted in the clinics; however, there is a lack of evidence regarding the comparability of the IHC and Sanger sequencing methods. METHODS: Our institution began using the BRAFV600E IHC test in January 2013. We retrospectively analyzed 697 samples that were tested using both the IHC and sequencing methods, and evaluated their concordance. RESULTS: BRAF mutation was detected in 90.0% (627/697) of samples using IHC and 83.4% (581/697) of samples using direct sequencing. The diagnostic parameters of IHC compared with Sanger sequencing were as follows: 100% sensitivity (581/581), 60.3% specificity (70/116), 92.7% positive predictive value (581/627), and 100% negative predictive value (70/70). No false negative results were recorded using IHC. The overall concordance rate between the two methods was 93.4% (651/697). Discordant results were found in 46 samples (6.6%), 29 of which were from cases with small tumors (< 6 mm), 8 were from cases with low tumor cellularity, and 9 were specimens yielding low-quality DNA. CONCLUSIONS: IHC using the VE1 antibody is a reliable and highly sensitive method for detecting the BRAFV600E mutation in classic PTC.

Association Between Fusobacterium nucleatum, Pathway Mutation, and Patient Prognosis in Colorectal Cancer.

BACKGROUND: There is a close link between Fusobacterium nucleatum and colorectal cancer (CRC) tumorigenesis and chemoresistance. However, the genetic characteristics and clinical significance of CRC related with F. nucleatum remains unclear. This study evaluated the relationship between F. nucleatum, pathway mutation, and patient prognosis. METHODS: Fusobacterium nucleatum amount in the tumor tissue and adjacent normal tissue were measured by quantitative polymerase chain reaction in adjuvant (N = 128) and metastatic (N = 118) cohorts. Patients were divided into binary (F. nucleatum-high and F. nucleatum-low) according to F. nucleatum amount. Targeted next-generation sequencing of 40 genes included in the 5 critical pathways (WNT, P53, RTK-RAS, PI3 K, and TGF-ß) was performed in the adjuvant cohort. RESULTS: Patients with MSI-H and CIMP-H had higher amount of F. nucleatum in tumor tissue. Fusobacterium nucleatum-high patients had higher rates of transition mutation and C to T (G to A) nucleotide change regardless of MSI status. In addition, mutation rate of AMER1 and ATM genes, and TGF-ß pathway was higher in F. nucleatum-high patients. Fusobacterium nucleatum-high was associated with poor overall survival (OS) in the palliative cohort (26.4 vs. 30.7 months, p = 0.042). Multivariate analysis revealed F. nucleatum-high as an independent negative prognostic factor for OS [adjusted hazard ratio of 1.69 (95% confidence interval 1.04-2.75), p = 0.034]. However, F. nucleatum amount was not associated with recurrence in the adjuvant cohort. CONCLUSIONS: F. nucleatum-high was associated with poor survival in metastatic CRC. In addition, we identified mutational characteristics of colorectal cancer according to F. nucleatum amount.

Prevention of total thyroidectomy in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) based on combined interpretation of ultrasonographic and cytopathologic results.

OBJECTIVE: To explore the potential preoperative ultrasonography (US) and cytopathological features to avoid total thyroidectomy in NIFTP. CONTEXT: Recently, it has been proposed that that noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) be classified as tumours, rather than cancer. PATIENTS: A total of 142 surgically proven follicular variant papillary thyroid carcinomas (FVPTCs; 45 NIFTP, 97 non-NIFTP; mean size: 20.4±11.0 mm, range: 10.0-65.0 mm) from 142 patients were included in this study. MEASUREMENTS: Three preoperative features of thyroid nodules (each US finding, US and Bethesda category) were compared in NIFTP and non-NIFTP groups. The preoperative decision-making process to avoid total thyroidectomy in NIFTP was evaluated based on combination of those features. RESULTS: In each US finding, there was only significantly less macrocalcification in the NIFTP group than in the non-NIFTP group (8.8% [4/45] vs 32.0% [31/97], P = .006). In US category, all of the NIFTP nodules were a low or intermediate suspicion (100% [45/45]). In Bethesda category, 26.7% [12/45] of the NIFTP was diagnosed as either suspicious malignancy or malignant, which increased the risk of a total thyroidectomy. In our study, a total thyroidectomy might be avoided in all of the NIFTP cases if lobectomy was selected for the nodules classified as a low or intermediate suspicion in US, despite being classified as a suspicious malignancy or malignant by cytopathology. CONCLUSIONS: Combining the US and cytopathological results could sensitively reduce total thyroidectomy in cases of NIFTP.

Radiogenomics correlation between MR imaging features and major genetic profiles in glioblastoma.

OBJECTIVES: To assess the association between MR imaging features and major genomic profiles in glioblastoma. METHODS: Qualitative and quantitative imaging features such as volumetrics and histogram analysis from normalised CBV (nCBV) and ADC (nADC) were evaluated based on both T2WI and CET1WI. The imaging parameters of different genetic profile groups were compared and regression analyses were used for identifying imaging-molecular associations. Progression-free survival (PFS) was analysed by a Kaplan-Meier test and Cox proportional hazards model. RESULTS: An IDH mutation was observed in 18/176 patients, and ATRX loss was positive in 17/158 of the IDH-wt cases. The IDH-mut group showed a larger volume on T2WI and a higher volume ratio between T2WI and CET1WI than the IDH-wt group (p < 0.05). In the IDH-mut group, higher mean nADC values were observed compared with the IDH-wt tumours (p < 0.05). Among the IDH-wt tumours, IDH-wt, ATRX-loss tumours revealed higher 5th percentile nADC values than the IDH-wt, ATRX-noloss tumours (p = 0.03). PFS was the longest in the IDH-mut group, followed by the IDH-wt, ATRX-loss groups and the IDH-wt, ATRX-noloss groups, consecutively (p < 0.05). We found significant associations of PFS with the genetic profiles and imaging parameters. CONCLUSION: Major genetic profiles of glioblastoma showed a significant association with MR imaging features, along with some genetic profiles, which are independent prognostic parameters for GBM. KEY POINTS: • Significant correlation exists between radiological parameters such as volumetric and ADC values and major genomic profiles such as IDH mutation and ATRX loss status • Radiological parameters such as the ADC value were feasible predictors of glioblastoma patients' prognosis • Imaging features can predict major genomic profiles of the tumours and the prognosis of glioblastoma patients.

Acute invasive fungal rhinosinusitis: MR imaging features and their impact on prognosis.

PURPOSE: Acute invasive fungal rhinosinusitis (AIFRS) is a life-threatening disease that is difficult to diagnose. Its overall imaging features have not been evaluated and the prognostic impact is unclear. The purpose of our study was to present MR imaging features and their impact on prognosis of AIFRS. METHODS: MR images and clinical records of 23 patients with AIFRS were retrospectively evaluated to identify the imaging features and to determine the factors affecting patients' survival. A multivariable Cox proportional hazard model was used to estimate the hazard ratio of the prognostic factors, and Kaplan-Meier survival curves were compared by using a log-rank test. RESULTS: All cases showed extra-sinonasal involvement and the orbit was the most common (65.2%, 15/23) location. The lesion enhancement pattern was classified into lack of contrast enhancement (LoCE) (47.8%, 11/23) and homogeneous (34.8%, 8/23) and heterogeneous (17.4%, 4/23) enhancement. Although LoCE showed variable signal intensity (SI), homogeneously or heterogeneously enhancing lesions showed exclusively low SI (100%, 12/12) on T2WI. Among various clinical and imaging factors, LoCE was correlated with coagulation necrosis, probably provoked by numerous fungal hyphae, and was found to be a sole independent prognostic factor for disease-specific mortality (hazard ratio = 16.819; 95% CI, 1.646-171.841, p = 0.017). In addition, patients with LoCE showed worse survival than patients without LoCE (p = 0.008). CONCLUSION: AIFRS showed frequent extra-sinonasal involvement and variable MR enhancement patterns. An enhancement pattern of LoCE was seen in about half of the cases and was a unique prognostic factor among the various clinico-radiologic factors.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor ß [TGF-ß]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-ß pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23. © 2017 American Cancer Society.