Yingjie Zou

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.

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

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

Prognostic Factors in Patients With Spinal Chordoma: An Integrative Analysis of 682 Patients

BACKGROUND: The low incidence of spinal chordoma precludes a prospective study of prognostic factors with a large patient cohort. OBJECTIVE: To perform a comprehensive integrative analysis on the prognostic factors, treatment, and outcomes of patients with spinal chordoma using data from 2 institutions and the literature. METHODS: Appropriate studies were identified per search criteria. The local database was retrospectively searched to include a similar patient cohort. RESULTS: Overall, 108 studies from the literature and 30 patients from our local institution were identified, resulting in a total of 682 patients. The median age was 57 years old and 35.2% were female. The median follow‐up was 46 months (range: 1‐408). The median progression‐free survival (PFS) and overall survival (OS) were 72 months and 115 months, respectively. Significant prognostic factors for PFS on multivariate analysis included age (pediatric vs adult, hazard ratio [HR]: 2.00‐14.36), tumor location (mobile spine vs sacral spine, HR: 0.31‐0.87), pathology (differentiated vs classic, HR: 2.48‐10.90),and chemotherapy (HR:1.11‐3.85). Significant prognostic factors for OS on multivariate analysis included age (geriatric vs adult, HR: 1.52‐3.45 and pediatric vs adult, HR: 1.73‐9.36), bladder or bowel dysfunction (HR: 1.27‐5.43), pathology (dedifferentiated vs classic, HR: 2.38‐11.09), recurrence or progression (HR: 1.72‐4.48), and metastases (HR: 1.11‐2.47). CONCLUSION: In patients with spinal chordoma, young age, location in sacral spine, dedifferentiated pathology, and chemotherapy were negative predictors of PFS, while young and old age, bladder or bowel dysfunction at presentation, dedifferentiated pathology, recurrence or progression, and metastases portended a worse OS.

Does morphological assessment have a role in classifying oligoastrocytoma as 'oligodendroglial' versus 'astrocytic'?

A. C. Araujo Lemos de Silva: wrote the manuscript, and interpreted stains and data. F. J. Rodriguez: participated in writing the manuscript, and interpreted stains and data. I. Aldecoa: participated in writing the manuscript, and interpreted stains and data. W. McDonald: participated in writing the manuscript, and interpreted stains and data. T. Ribalta: participated in writing the manuscript, and interpreted stains and data.

Biopsy versus resection in the management of high-grade gliomas in the elderly

We read with interest a recent paper by Almenawer et al.1 The authors performed a meta-analysis on biopsy versus partial versus gross total resection (GTR) in older patients with high-grade gliomas (HGGs). The authors compared patients undergoing overall resection (of any extent) with patients undergoing biopsy and found significantly longer overall survival and progression-free-survival, higher postoperative Karnofsky performance status (KPS), and lower morbidity and mortality. GTR was found to be superior to subtotal resection in terms of overall survival, postoperative KPS, and progression-free survival with no difference in morbidity and mortality. The authors concluded that maximum resections are safe and are associated with longer survival time, delayed tumor progression rates, and improved functional recovery. n nWe would like to commend the authors on their efforts to examine the impact of extent of resection on survival and functional outcomes for elderly patients with HGG. The benefit of maximal resection is uncertain in this age group since older patients tend to have more comorbidities, higher complication rates, and poorer prognosis overall. In addition, fundamental differences in tumor biology may explain some of the correlation between age and outcome.1 However, we have some doubts about the methodology and the conclusions reached by the authors. First, it is quite possible that biopsy was used for diagnostic purposes only in some of the studies included in the meta-analysis. In fact, this was clearly stated in the methods section of 3 studies.2–4 We believe it is not meaningful to include these studies in the meta-analysis since the goal of the paper was to compare outcomes in elderly patients who underwent different extents of resection, not between patients who had surgery versus those who did not. n nSecondly, the authors admitted that the greatest limitation in their meta-analysis was the inability to account for similar distribution of patient characteristics. We agree with the authors that variables such as patient age, brain tumor location and size, adjuvant therapy, and preoperative baseline functional status should be taken into account when performing meta-analyses. Without looking at these factors, the conclusion reached (ie, that increasing extents of tumor resection are associated with improved outcomes) suffers from selection bias. However, these variables were presented in such a way in the individual studies that it is almost impossible to incorporate them into the meta-analysis (eg, using meta-regression). Therefore, we attempted to compare age, preoperative KPS, tumor location and size, and adjuvant treatment between biopsy and resection cohorts in the individual studies via qualitative analysis (Tablexa01). In the 12 studies that separated the age groups for the biopsy and resection patients, 11 reported either a higher proportion of older patients undergoing biopsy,2,5–8 or a higher mean age for the biopsy group.4,9–12 The biopsy group had a lower preoperative KPS score in 5 of the 9 studies that reported this information.2,6,12–14 The resection group was associated with a larger tumor size in the 2 studies that listed tumor size separately for the resection and biopsy groups.8,13 In the 4 studies that compared tumor location between biopsy and resection groups, patients with corpus callosum, deep lesions (eg, brainstem), and bilateral lesions were more likely to undergo biopsy,8,13,15 while endangerment of the eloquent area seemed to play little role in the decision-making process.14 In the 6 studies that reported number of patients receiving chemotherapy in the 2 groups, the proportion of patients receiving chemotherapy was higher in the resection group than that in the biopsy group in all 6 studies,2,10,11,13,14,16 while the proportion of patients receiving radiotherapy was higher in only 4 studies.2,10,11,13 n n n nTablexa01. n nBiopsy versus resection in elderly patients with high-grade glioma n n n nIn summary, even among the elderly, older patients tended to undergo biopsy rather than resection of their HGGs. Tumors located in the corpus callosum, deep lesions, and bilateral lesions were more likely to be biopsied than resected. Elderly patients undergoing resection of their HGG were more likely to receive chemotherapy than those who underwent biopsy. Consequently, the favorable outcomes associated with greater extent of resection in elderly patients may be influenced by the patient selection factors listed above and should be interpreted with caution.

Radiation therapy after subtotal resection of pediatric grade II/III spinal ependymomas: what is the evidence?

Dear Editor: We read with interest a recent paper published by Yang et al. The authors reported their institutional experience of 15 grade II spinal cord ependymomas in children [1]. Gross total resection (GTR) was achieved in 12 cases. The remaining three underwent subtotal resection (STR) followed by radiotherapy (RT). While no tumor recurrence occurred in the GTR group, residual tumor regrowthwas observed in two STR cases. Consequently, the author concluded that postoperative radiotherapy should be considered carefully due to uncertain therapeutic efficacy. We agree with the authors that there is a paucity of published data on the use of adjuvant radiotherapy in children with grade II/III spinal ependymomas. Pediatric intraspinal ependymomas are considered more aggressive than their adult counterparts [2]. All efforts must be made to achieve GRT [3]. It is generally agreed that RT is not necessary if the tumor has been removed completed [4]. In adults, progression-free survival (PFS) has been shown to be significantly prolonged among those who received RT after STR in a meta-analysis [5]. However, the role of RT after STR is controversial. We reviewed the literature on pediatric patients with grade II/III spinal ependymoma and found 13 cases that were subtotally resected (Table 1) [4, 6–12]. The median age was 9 (range 1 to 20). There were 5 males and 8 females. All except three were located in the lower spinal cord (thoracic, lumbar, and conus). Ten received adjuvant RT with an average dose of 40 Gy. The rate of local recurrence in those who received RT was 40 % (4/10), while two of the three who did not receive RT had local recurrence. The median PFS was 68 months. For the three patients who had information on further treatment after local recurrence, two received STR followed by RT and postsalvage recurrence occurred in both cases. The other patient received RT only and experienced no recurrence. The median follow-up was 92 months. All patients were alive at the last followup except two. One received RT and the other one did not. Contrary to the opinion of Yang et al., our review of the literature suggests that there may be some evidence for beneficial effect of RT after STR in pediatric grade II/III intraspinal ependymomas. Because of the rarity of Y. Zou : Z. Wang : L. Yang (*) Department of Neurology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, 410011 Changsha, Hunan, People’s Republic of China e-mail: yangli762@gmail.com

Prognostic Factors in Clival Chordomas: An Integrated Analysis of 347 Patients

OBJECTIVEnTo investigate prognostic factors of clival chordoma using the largest patient set to date.nnnMETHODSnAppropriate studies were identified per search criteria, data satisfying criteria were extracted, and survival analysis was performed to investigate prognostic factors of clival chordoma.nnnRESULTSnA total of 347 patients from the literature cohort met our inclusion criteria. Of 346 cases in which extent of resection was reported, gross total resection (GTR), subtotal resection, and biopsy were achieved in 118 (34.1%), 205 (59.2%), and 21 (6.1%) cases, respectively. Two (0.6%) subjects did not undergo surgery. Of 185 cases in which surgical approach was reported, 56 (30.3%) underwent an endoscopic transoral approach, 17 (9.2%) microscopic transsphenoidal, 45 (24.3%) endoscopic or microscopic, 45 (24.3%) craniotomy, and 22 (11.9%) other approaches. There was no significant difference in GTR rates of different surgical approaches (Pxa0= 0.101). Median follow-up was 46.6 months. The 5- and 10-year rates for progression-free survival (PFS) were 59.2% and 47.9%, respectively. The 5- and 10-year rates for overall survival (OS) were 77.3% and 63.9%, respectively. On multivariate analysis for both PFS and OS, GTR demonstrated significantly improved outcomes when compared with subtotal resection (hazard ratio 0.45, 95% confidence interval 0.22-0.90, Pxa0= 0.025 for PFS; hazard ratio 0.20, confidence interval 0.06-0.65, Pxa0= 0.008 for OS).nnnCONCLUSIONSnGTR rates were comparable in different surgical approaches. GTR was a significant predictor of longer PFS and OS in clival chordoma.

Superior Mesenteric Artery Syndrome in a 20-year-old Athletic Female with Abdominal Pain

To the Editor: A 20-year-old female college student and soccer player presented to the Emergency Department with acute onset of abdominal pain, nausea, and vomiting. On the morning of presentation, she woke up with sudden onset of epigastric pain that was constant and 10/10 in severity. The patient denied any obstipation, constipation, diarrhea, any recent trauma to the abdomen, or any potential inciting event. Of note, the patient did endorse previous episodes of postprandial epigastric pain, but it was never this severe. Her past medical and surgical history was unremarkable.