Li Yang

MRI features predict survival and molecular markers in diffuse lower-grade gliomas

BackgroundnPrevious studies have shown that MR imaging features can be used to predict survival and molecular profile of glioblastoma. However, no study of a similar type has been performed on lower-grade gliomas (LGGs).nnnMethodsnPresurgical MRIs of 165 patients with diffuse low- and intermediate-grade gliomas (histological grades II and III) were scored according to the Visually Accessible Rembrandt Images (VASARI) annotations. Radiomic models using automated texture analysis and VASARI features were built to predict isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion status, histological grade, and tumor progression.nnnResultsnInterrater analysis showed significant agreement in all imaging features scored (k = 0.703-1.000). On multivariate Cox regression analysis, no enhancement and a smooth non-enhancing margin were associated with longer progression-free survival (PFS), while a smooth non-enhancing margin was associated with longer overall survival (OS) after taking into account age, grade, tumor location, histology, extent of resection, and IDH1 1p/19q subtype. Using logistic regression and bootstrap testing evaluations, texture models were found to possess higher prediction potential for IDH1 mutation, 1p/19q codeletion status, histological grade, and progression of LGGs than VASARI features, with areas under the receiver-operating characteristic curves of 0.86 ± 0.01, 0.96 ± 0.01, 0.86 ± 0.01, and 0.80 ± 0.01, respectively.nnnConclusionnNo enhancement and a smooth non-enhancing margin on MRI were predictive of longer PFS, while a smooth non-enhancing margin was a significant predictor of longer OS in LGGs. Textural analyses of MR imaging data predicted IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression with high accuracy.

Imaging genomics in cancer research: limitations and promises.

Recently, radiogenomics or imaging genomics has emerged as a novel high-throughput method of associating imaging features with genomic data. Radiogenomics has the potential to provide comprehensive intratumour, intertumour and peritumour information non-invasively. This review article summarizes the current state of radiogenomic research in tumour characterization, discusses some of its limitations and promises and projects its future directions. Semi-radiogenomic studies that relate specific gene expressions to imaging features will also be briefly reviewed.

Residual Convolutional Neural Network for Determination of IDH Status in Low- and High-grade Gliomas from MR Imaging

Purpose: Isocitrate dehydrogenase (IDH) mutations in glioma patients confer longer survival and may guide treatment decision making. We aimed to predict the IDH status of gliomas from MR imaging by applying a residual convolutional neural network to preoperative radiographic data. Experimental Design: Preoperative imaging was acquired for 201 patients from the Hospital of University of Pennsylvania (HUP), 157 patients from Brigham and Womens Hospital (BWH), and 138 patients from The Cancer Imaging Archive (TCIA) and divided into training, validation, and testing sets. We trained a residual convolutional neural network for each MR sequence (FLAIR, T2, T1 precontrast, and T1 postcontrast) and built a predictive model from the outputs. To increase the size of the training set and prevent overfitting, we augmented the training set images by introducing random rotations, translations, flips, shearing, and zooming. Results: With our neural network model, we achieved IDH prediction accuracies of 82.8% (AUC = 0.90), 83.0% (AUC = 0.93), and 85.7% (AUC = 0.94) within training, validation, and testing sets, respectively. When age at diagnosis was incorporated into the model, the training, validation, and testing accuracies increased to 87.3% (AUC = 0.93), 87.6% (AUC = 0.95), and 89.1% (AUC = 0.95), respectively. Conclusions: We developed a deep learning technique to noninvasively predict IDH genotype in grade II–IV glioma using conventional MR imaging using a multi-institutional data set. Clin Cancer Res; 24(5); 1073–81. ©2017 AACR.

Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients

Early brain biopsy may be indicated in HIV patients with focal brain lesion. This study aimed to evaluate and compare the safety and diagnostic value of brain biopsy in HIV patients in the pre-highly active antiretroviral therapy (HAART) versus post-HAART era via meta-analysis. Appropriate studies were identified per search criteria. The local database was retrospectively reviewed to select a similar patient cohort. Patient demographics, brain biopsy technique, histopathology and patient outcomes were extracted from each study. Study-specific outcomes were combined per random-effects model. Outcomes were compared between the pre-HAART and post-HAART era. Correlations between outcomes and baseline characteristics were assessed via meta-regression analysis. The proportions of histopathological diagnosis were tabulated and compared between the pre- and post-HAART era. Survival analysis was performed for patients in the post-HAART era. A total of 26 studies (including the local database) with 1209 patients were included in this meta-analysis. The most common indications for brain biopsy were diagnosis unlikely to be toxoplasmosis (n=8, 42.1%), focal brain lesion (n=5, 26.3%) or both (n=3, 15.8%). The weighted proportions for diagnostic success were 92% (95% CI 90.0% to 93.8%), change in management 57.7% (45.9% to 69.1%) and clinical improvement 36.6% (26.3% to 47.5%). Morbidity and mortality were 5.7% (3.6% to 8.3%) and 0.9% (0.3% to 1.9%), respectively. Diagnostic success rate was significantly higher in the post-HAART than the pre-HAART era (97.5% vs 91.9%, p=0.047). The odds ratio (OR) for diagnostic success in patients with contrast-enhanced lesions was 2.54 ((1.25 to 5.15), p<0.01). The median survival for HIV patients who underwent biopsy in the post-HAART era was 225u2005days (90–2446). Brain biopsy in HIV patients is safe with high diagnostic yield. Early brain biopsy should be considered in patients without classic presentation of toxoplasmosis encephalitis.

Stroke-like Migraine Attacks after Radiation Therapy Syndrome.

Objective: To summarize the clinical presentation, pathogenesis, neuroimaging, treatment, and outcome of stroke-like migraine attacks after radiation therapy (SMART) syndrome, and to propose diagnostic criteria for this disorder. Data Sources: We searched the PubMed database for articles in English published from 1995 to 2015 using the terms of “stroke-like AND migraine AND radiation.” Reference lists of the identified articles and reviews were used to retrieve additional articles. Study Selection: Data and articles related to late-onset effects of cerebral radiation were selected and reviewed. Results: SMART is a rare condition that involves complex migraines with focal neurologic deficits following cranial irradiation for central nervous system malignancies. The recovery, which ranges from hours to days to weeks, can be partial or complete. We propose the following diagnostic criteria for SMART: (1) Remote history of therapeutic external beam cranial irradiation for malignancy; (2) prolonged, reversible clinical manifestations mostly years after irradiation, which may include migraine, seizures, hemiparesis, hemisensory deficits, visuospatial defect, aphasia, confusion and so on; (3) reversible, transient, unilateral cortical gadolinium enhancement correlative abnormal T2 and fluid-attenuated inversion recovery signal of the affected cerebral region; (4) eventual complete or partial recovery, the length of duration of recovery ranging from hours to days to weeks; (5) no evidence of residual or recurrent tumor; (6) not attributable to another disease. To date, no specific treatment has been identified for this syndrome. Conclusions: SMART is an extremely rare delayed complication of brain irradiation. However, improvements in cancer survival rates have resulted in a rise in its frequency. Hence, awareness and recognition of the syndrome is important to make a rapid diagnosis and avoid aggressive interventions such as brain biopsy and cerebral angiography.

Comparison of immunohistochemistry and DNA sequencing for the detection of IDH1 mutations in gliomas

We read with interest a recent paper published by Chen et al on building a multivariable model to predict the likelihood of an IDH1/2 mutation in diffuse gliomas.1 Incorporating patient age, glioblastoma diagnosis, and prior history of grade II or III gliomas, the model was shown to have high sensitivity and specificity for predicting the presence of an IDH1/2 mutation, either with or without an immunostain, and high accuracy for predicting the presence of a less common IDH1 or IDH2 mutation when the immunostain was negative. The authors suggested that the model will help triage diffuse gliomas that would benefit from mutation testing in both clinical and research settings. n nWe commend the authors for their effort to create such a model since IDH1/2 mutation has been shown to have both diagnostic and prognostic implications in diffuse gliomas. IDH1 in adult patients is associated with younger age at diagnosis, TP53 mutation, combined 1p/19q deletion, MGMT promoter hypermethylation, and favorable patient survival.2 Detection of an IDH mutation has also been shown to be reliable for differentiating glioma from reactive gliosis.2 There are even proposals to include IDH mutation status in the next version of the WHO classification of gliomas (Gupta 2011).3 However, the utility of such a model to predict IDH mutation status in both clinical and research settings must be interpreted in the context of sensitivity and specificity of the 2 most common methods currently being used in the laboratory to detect this mutation: immunohistochemistry (IHC) and Sanger sequencing. n nWe identified 8 studies in the literature that directly compared IHC and sequencing in their detection of IDH1/2 mutation in gliomas (Tablexa01). The number of samples ranged from 49 to 343. Six studies included gliomas of all grades,4–9 while 2 studies focused only on oligodendrogliomas.10,11 The antibody used for IHC was DIA-H09 in 6 studies4,5,8–11 and Imab in one study;7 another study used both antibodies.6 The concordance rate between IHC and sequencing ranged from 88% to 99%. In 5 of 8 studies, the number of mutations detected by IHC was greater than those detected by sequencing.4,6–8,10 This was explained by the fact that only IHC can detect the mutation if there is only a small population of IDH1-R132H mutation-possessing tumor cells in the sample. Under model B proposed by Chen et al the predicted probability of IDH1 is 100% if IHC is positive. This makes the implicit assumption that as long as there are a few cells in the sample that stain positive for IDH-1 on IHC, the sample should be considered IDH1 positive. However, there is no study in the literature showing that glioma samples with only a small population of IDH1-R132H mutation-possessing tumor cells exhibit the same properties as those that are unequivocally IDH1 positive. In the remaining 3 studies, in which the number of mutations detected by sequencing was greater than those detected by IHC,5,9,11 the most frequently cited reason for false negatives was that IHC had failed to detect the other types of IDH1 mutations including R132C (4%), R132L (1%), R132S (2%), R132G (2%), and IDH2 mutations.2 To some extent in cases where immunostain is negative, the model proposed by Chen et al will generate the possibility of harboring a less common mutation n n n nTablexa01. n nComparison of immunohistochemistry with sequencing for IDH1 testing in gliomas n n n nAt our institution, we first test all diffuse glioma samples with IHC and only sequence the negative samples. If the model given by Chen et al predicts only a 20% likelihood of an IDH1 mutation in a negative IHC sample, will that change our decision to sequence the sample? The answer will be “no” if we believe that accurate assessment of the IDH1 status will factor significantly into how we prognosticate and manage the patient. The answer will only be “yes” if we are so resource constrained that the cost of sequencing outweighs the benefit provided by the information gained from accurate IDH mutation testing. Similarly, in a research setting, it is highly unlikely that any researcher would base the decision to immunostain or sequence the sample on what the model predicts. n nIn conclusion, we suggest that the models proposed by Chen et al demonstrating the clinical and pathological factors, which can be important for predicting IDH1/2 mutation in diffuse gliomas, currently have limited utility in both the clinical and research settings.

The role of radiotherapy in the treatment of spinal chordomas: an integrative analysis of 523 cases

We read with great interest a recent paper by Meng et al on the clinical features and prognostic factors of patients with chordoma of the spine. The authors performed a retrospective analysis of 153 patients in a single center. They found that tumor location of C3–L5, dedifferentiated chordoma, preoperative Frankel scores A–C, and total spondylectomy were independent prognostic factors for local relapse-free survival (LRFS), while total en bloc spondylectomy and KPS .80% were favorable factors for overall survival (OS). We commend the authors for performing the largest study in the literature on spinal chordomas, as the disease is rare and previous published series were limited to a small number of patients. Meng et al argued that having a cohort of patients from a single center reduced the heterogeneity of the data. However, one disadvantage of this approach is that subgroup analysis, with its potential to reveal factors which could have affected LRFS and OS, cannot be performed due to the small sample size. We noted that Meng et al did not find radiotherapy to be an independent prognostic factor for spinal chordomas. This contradicts previous studies that showed the beneficial effect of adjuvant radiotherapy after tumor resection. – 4 Therefore, we aimed to further define the role of radiotherapy in patients with spinal chordoma by performing an integrative analysis of 519 cases from the literature with 14 additional cases from our local institution. We included papers from 1990 to 2015 that presented data on LRFS and OS for individual patients. Studies with incomplete patient information were excluded. We performed univariate and multivariate analysis of prognostic factors on our dataset according to the protocol described by Meng et al. Our cohort comprised 312 men and 179 women; gender was not reported for 42 patients. The mean age was 55 years (median, 57; range, 6–89). Of these patients, 364 presented with primary chordoma, while 37 presented with chordoma recurrences after initial surgical treatment. Three hundred chordomas were located in the sacrum, with 20 in C1–L2 and 82 cases in C3–L5. Out of 498 (96.0%) patients who underwent surgical treatment, 171 (34.3%) had positive margins; 327 (65.7%) had negative margins. The mean follow-up period was 60 months (median, 48 mo; range, 0 –408 mo). Recurrence was detected in 253 (48.4%) patients, and 165 (31.5%) died in the follow-up period. The mean time from surgery to recurrence was 34 months (median, 24; range, 0.1–204). The mean follow-up for the deceased patients was 61 months (median, 50; range, 0–408). We found that the LRFS rate was significantly lower in patients with tumor located in C1– C2 compared with other tumor sites (P1⁄4 .03). Other factors that affected LRFS rate on univariate analysis included age, history of previous treatment, pathology (classical vs dedifferentiated type), resection margin, and the use of adjuvant radiotherapy and/or chemotherapy. Only pathology remained significant on multivariate Cox regression analysis. We found the same trend in adjuvant

The effectiveness of immunomodulating treatment on Miller Fisher syndrome: a retrospective analysis of 65 Chinese patients

Dear Editor, Owing to the rarity of Miller Fisher syndrome (MFS), the efficacy of different immunomodulating agents on its natural course is uncertain. In an analysis of 92 patients with MFS, Mori et al. demonstrated that intravenous immunoglobulin (IVIg) slightly hastened the amelioration of ophthalmoplegia and ataxia but had no effect on recovery outcomes (Mori et al., 2007). They also showed that plasmapheresis did not affect either the speed or the rate of recovery from these symptoms (Mori et al., 2002). However, these studies all came from the same geographic area (Japan) and the treatments were limited to IVIg and plasmapheresis. Because MFS has a good natural recovery, the efficacy of these treatments must be carefully judged. In this study, we conducted a retrospective analysis of 65 Chinese patients who were diagnosed with MFS. Sixty-eight patients with MFS were seen at the First and Second Xiangya Hospitals in Changsha, China from January 2003 to June 2012. All presented with ophthalmoplegia, ataxia, and areflexia, and had acute onset without major limb weakness or other signs indicative of central nervous system (CNS) involvement. Three of the 68 patients later developed profound limb weakness and were excluded from analysis. Institutional Review Board approval was obtained from the relevant institutions. Eight patients with MFS were treated with IVIg (0.4 g per kilogram per day for 5 days). Three underwent two sessions of plasmapheresis with a second filter (Bellco Micropes, HOXEN Co Ltd., Shanghai, China) (each of 50 ml per kilogram of body weight) within 7–14 days. Twenty-three patients received IV methylprednisolone (500 mg per day for 5 days and tapered over 6 weeks). Four

NK-/T-cell lymphoma resembling hydroa vacciniforme with positive CD4 marker expression: a diagnostic difficulty.

A 35-year-old Chinese woman presented with a 2.5-year history of facial swelling in the left lower quadrant and a 10-month history of relapsing red papules and vesicles in the perioral area resembling hydroa vacciniforme. Histologically, a tissue biopsy showed a dense infiltration of medium-sized atypical lymphocytic cells expressing CD4 and CD56. A diagnosis of cutaneous NK-/T-cell lymphoma was made. The patient was treated with alpha-interferon, valaciclovir hydrochloride, and low-dose prednisone for 2 months. Her skin lesions and lymphoadenopathy resolved initially, but she succumbed to the disease shortly after starting chemotherapy treatment 11 months later. To our knowledge, this is the first case of CD4CD56 NK-/T-cell lymphoma with clinical features resembling hydroa vacciniforme.

Anaplastic oligoastrocytoma: is molecular stratification based on 1p/19q status alone appropriate?

We read with interest a recent paper published by Jiang et al. on molecular classification for high-grade oligodendroglial tumors (HGOs) based on 1p/19q status. Using 117 tumors with histological diagnosis of primary HGOs, the authors divided these patients into four subtypes which conferred remarkably distinct prognosis based on the number of risk factors (higher tumor grade, 1p/19q maintenance and 1q/19p copolysomy). The authors concluded that the molecular classification scheme based on 1p/19q status alone can serve as a supplement of the current World Health Organization classification system and contribute to the personalized treatment decision-making. An oligoastrocytoma (OA) is defined as a tumor with a conspicuous mixture of two distinct neoplastic cell types resembling oligodendrocytes and astrocytes. Due to the heterogenous morphology, the histological diagnosis of OA is often subjective. No guidelines currently exist regarding the minimum percentage of either part required for the diagnosis. Consequently, the frequency of OA diagnosis varies widely among different institutions and the interobserver agreement of OA diagnosis is low and the diagnosis is made of varying frequencies in different institutions. The often limited amount of material available for histopathological diagnosis further contributes to the diagnostic uncertainty. It is still unclear if the oligodendroglial and astrocytic areas of OA are derived from a common cell origin or from two different cell clones during neoplastic transformation. Previous studies have shown that the vast majority of OAs, in addition to harboring mutations in IDH1/2, exhibit the molecular signature of either pure oligodendroglioma (1p/19q codeletion, CIC and FUBP1 mutation) or astrocytoma (ATRX mutation, p53 mutation) with almost complete mutual exclusivity. This supports the notion that OA, as an independent biological entity, does not truly exist. We found three studies in the literature that examined the molecular genotypes of the two components of OA separately [1–3]. In 1995, Kraus et al. demonstrated in three OAs that both areas of oligodendroglial and of astrocytic differentiation had 1p/19q codeletion [1]. In 2007, Qu et al. used microdissection techniques to examine the two different components of 11 OAs in comparison with the histological diagnosis of the specific tumor area for 1p19q codeletion and TP53 mutation [2]. They found that the oligodendroglial and astrocytic components of an Y. Zou L. Yang (&) Department of Neurology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha 410011, Hunan, People’s Republic of China e-mail: yangli762@gmail.com