IDH wild-type lower-grade gliomas with glioblastoma molecular features: a systematic review and meta-analysis.

The WHO 2021 classification defines IDH wild type (IDHw) histologically lower-grade glioma (hLGG) as molecular glioblastoma (mGBM) if TERT promoter mutation (pTERTm), EGFR amplification or chromosome seven gain and ten loss aberrations are indicated. We systematically reviewed articles of IDHw hLGGs studies (49 studies, N = 3748) and meta-analyzed mGBM prevalence and overall survival (OS) according to the PRISMA statement. mGBM rates in IDHw hLGG were significantly lower in Asian regions (43.7%, 95% confidence interval [CI: 35.8-52.0]) when compared to non-Asian regions (65.0%, [CI: 52.9-75.4]) (P = 0.005) and were significantly lower in fresh-frozen specimen when compared to formalin-fixed paraffin-embedded samples (P = 0.015). IDHw hLGGs without pTERTm rarely expressed other molecular markers in Asian studies when compared to non-Asian studies. Patients with mGBM had significantly longer OS times when compared to histological GBM (hGBM) (pooled hazard ratio (pHR) 0.824, [CI: 0.694-0.98], P = 0.03)). In patients with mGBM, histological grade was a significant prognostic factor (pHR 1.633, [CI: 1.09-2.447], P = 0.018), as was age (P = 0.001) and surgical extent (P = 0.018). Although bias risk across studies was moderate, mGBM with grade II histology showed better OS rates when compared to hGBM.

Diagnostic accuracy of cerebrospinal fluid liquid biopsy and MRI for leptomeningeal metastases in solid cancers: A systematic review and meta-analysis.

Background: Cerebrospinal fluid (CSF) cytology remains the gold standard approach for diagnosing of leptomeningeal metastases (LM), but has clinical problems due to its low sensitivity. This systemic review and meta-analysis evaluated the diagnostic accuracy of the novel CSF biomarkers of liquid biopsy and magnetic resonance imaging (MRI) for detecting LM in patients with solid cancers. Methods: A systematic search of electronic databases was conducted to identify all published diagnostic accuracy studies on CSF liquid biopsies and MRI since January 2000 with registration for PROSPERO (#CRD42022301988). Articles were selected based on pre-defined inclusion and exclusion criteria following the PRISMA 2020 statement. Results: The search yielded 3790 citations, and 10 studies with 668 patients were included in the final analysis. The pooled prevalence of LM was 50.9% (340/668). The respective sensitivity and specificity for index tests were as follows: circulating tumor cells (CTC), 87.0% (95% confidence interval [CI] 77.9-92.6%) and 93.8% (86.9-97.2%); cell-free tumor DNA, 97.9% (19.3-100%) and 89.0% (25.3-99.5%); MRI 59.4% (60.7-76.9%) and 97.6% (77.3-99.8%); cytology, 71.9% (54.7-82.9%) and 100%. The diagnostic odds ratio was 100.6 (29.38-344.09) for CTC and 93.3 (88.42-1034.05) for MRI. Conclusion: Novel CSF liquid biopsies and MRI may offer improved diagnostic accuracy for LM from solid cancers; however, further research is required to specify the threshold values and to construct standards for individual primary cancers.

Incidental diffuse low-grade gliomas: A systematic review and meta-analysis of treatment results with correction of lead-time and length-time biases.

Background: Better overall survival (OS) reported in patients with incidental diffuse low-grade glioma (iLGG) in comparison to symptomatic LGG (sLGG) may be overestimated by lead-time and length-time. Methods: We performed a systematic review and meta-analysis of studies on adult hemispheric iLGGs according to the PRISMA statement to adjust for biases in their outcomes. Survival data were extracted from Kaplan-Meier curves. Lead-time was estimated by 2 methods: Pooled data of time to become symptomatic (LTs) and time calculated from the tumor growth model (LTg). Results: We selected articles from PubMed, Ovid Medline, and Scopus since 2000. Five compared OS between patients with iLGG (n = 287) and sLGG (n = 3117). The pooled hazard ratio (pHR) for OS of iLGG to sLGG was 0.40 (95% confidence interval [CI] {0.27-0.61}). The estimated mean LTs and LTg were 3.76 years (n = 50) and 4.16-6.12 years, respectively. The corrected pHRs were 0.64 (95% CI [0.51-0.81]) by LTs and 0.70 (95% CI [0.56-0.88]) by LTg. In patients with total removal, the advantage of OS in iLGG was lost after the correction of lead-time. Patients with iLGG were more likely to be female pooled odds ratio (pOR) 1.60 (95% CI [1.25-2.04]) and have oligodendrogliomas (pOR 1.59 [95% CI {1.05-2.39}]). Correction of the length-time bias, which increased the pHR by 0.01 to 0.03, preserved the statistically significant difference in OS. Conclusions: The reported outcome in iLGG was biased by lead-time and length-time. Although iLGG had a longer OS after correction of biases, the difference was less than previously reported.

Malignant Progression of Diffuse Low-grade Gliomas: A Systematic Review and Meta-analysis on Incidence and Related Factors.

Malignant progression of diffuse low-grade glioma (LGG) is a critical event affecting patient survival; however, the incidence and related factors have been inconsistent in literature. According to the PRISMA guidelines, we systematically reviewed articles from 2009, meta-analyzed the incidence of malignant progression, and clarified factors related to the transformation. Forty-one articles were included in this study (n = 7,122; n, number of patients). We identified two definitions of malignant progression: histologically proven (Htrans) and clinically defined (Ctrans). The malignant progression rate curves of Htrans and Ctrans were almost in parallel when constructed from the results of meta-regression by the mean follow-up time. The true transformation rate was supposed to lie between the two curves, approximately 40% at the 10-year mean follow-up. Risk of malignant progression was evaluated using hazard ratio (HR). Pooled HRs were significantly higher in tumors with a larger pre- and postoperative tumor volume, lower degree of resection, and notable preoperative contrast enhancement on magnetic resonance imaging than in others. Oligodendroglial histology and IDH mutation (IDHm) with 1p/19q codeletion (Codel) also significantly reduced the HRs. Using Kaplan-Meier curves from eight studies with molecular data, we extracted data and calculated the 10-year malignant progression-free survival (10yMPFS). The 10yMPFS in patients with IDHm without Codel was 30.4% (95% confidence interval [95% CI]: 22.2-39.0) in Htrans and 38.3% (95% CI: 32.3-44.3) in Ctrans, and that with IDHm with Codel was 71.7% (95% CI: 61.7-79.5) in Htrans and 62.5% (95% CI: 55.9-68.5) in Ctrans. The effect of adjuvant radiotherapy or chemotherapy could not be determined.

Outcomes of Preserving the Hypertrophic Arachnoid Membrane in the Brain-meningioma Interface: Long-term Follow-up.

Abnormal hypertrophic arachnoid membranes are often observed in the brain-meningioma interface during microsurgery. They contain fibrosis and tumor cell clusters; however, preservation of the membranes does not always cause recurrence from the brain surface, and the optimal treatments in the interface remain unclear. We investigated the incidence of recurrence on the brain surface following extra-arachnoid dissection with an approach emphasizing preservation of the arachnoid membranes in meningiomas of World Health Organization (WHO) Grade I. The features of dissection cleavages in the interface were prospectively recorded at surgery. The patients were followed up with MR imaging regularly. In total, 111 patients were included. The median follow-up time was 97.0 (interquartile range [IQR] 70.0-124.0) months. The cleavages in the interface were classified into three subgroups: the Extra-H group (n = 56) with extra-arachnoid resection and preservation of hypertrophic arachnoid membranes, the Extra-N group (n = 39) with extra-arachnoid resection having normal membranes, and the Subpial resection group (n = 16). Tumors recurred in 13 (11.7%) patients at both the brain and dura mater (n = 1) or at the dura mater alone (n = 12). The median recurrence-free survival (RFS) of all recurrences was significantly related to the Simpson grades (P <0.01). For brain surface recurrence, the median RFS was not related to the subgroups. The Karnofsky Performance Scores (KPSs) significantly improved in the patients except for the Subpial group at 3 months after surgery. This study revealed that hypertrophic arachnoid membranes preserved on the brain surface rarely caused recurrence from the brain in WHO Grade I meningiomas after a long-term follow-up.

Prevalence of incidental meningiomas and gliomas on MRI: a meta-analysis and meta-regression analysis.

BACKGROUND: The chance of incidentally detecting brain tumors is increasing as the utilization of magnetic resonance imaging (MRI) becomes more prevalent. In this background, knowledge is accumulating in relation to the prediction of their clinical sequence. However, their prevalence-especially the prevalence of glioma-has not been adequately investigated according to age, sex, and region. METHOD: We systematically reviewed the articles according to the PRISMA statement and calculated the prevalence of meningiomas and diffuse gliomas in adults using a generalized linear mixed model. Specifically, the differences related to age, sex, and region were investigated. RESULTS: The pooled prevalence of incidental meningiomas in MRI studies was 0.52% (95% confidence interval (CI) [0.34-0.78]) in 37,697 individuals from 36 studies. A meta-regression analysis showed that the prevalence was significantly higher in elderly individuals, women, and individuals outside Asia; this remained statistically significant in the multivariate meta-regression analysis. The prevalence reached to 3% at 90 years of age. In contrast, the prevalence of gliomas in 30,918 individuals from 18 studies was 0.064% (95%CI [0.040 - 0.104]). The meta-regression analysis did not show a significant relationship between the prevalence and age, male sex, or region. The prevalence of histologically confirmed glioma was 0.026% (95%CI [0.013-0.052]). CONCLUSIONS: Most of meningiomas, especially those in elderlies, remained asymptomatic, and their prevalence increased with age. However, the prevalence of incidental gliomas was much lower and did not increase with age. The number of gliomas that developed and the number that reached a symptomatic stage appeared to be balanced.

Leptomeningeal Metastasis in ER + HER2- Advanced Breast Cancer Patients: A Review of the Cases in a Single Institute Over a 15-year Period.

PURPOSE: While leptomeningeal metastasis (LM) from estrogen receptor-positive, HER2-negative advanced breast cancer (ER + HER2-ABC) has a poor prognosis, the details of ER + HER2-LM are unclear. We therefore retrospectively investigated patients with LM from ER + HER2-ABC. METHODS: ER + HER2-ABC patients who received any therapy at Shizuoka Cancer Center between October 2002 and December 2017 were retrospectively analyzed. Patients with central nervous system (CNS) metastases were divided into three groups: brain metastasis (BM) only (B group); BM with LM (BL group); and LM only (L group). RESULTS: Among 369 patients, 102 developed CNS metastases: 70 (68.6%), 13 (12.8%), and 19 (18.6%) in the B, BL, and L groups, respectively. The L group showed a later onset, poorer performance status, more symptoms, and more skull metastasis than the other groups. Radiotherapy as the initial treatment was introduced to 13/13 (100%) and 15/19 (78.9%) in the BL and L groups, respectively. Subsequent systemic therapy excluding best supportive care was introduced to 5/13 (38.5%) and 5/19 (26.3%) in the BL and L groups, respectively. The median overall survival from the diagnosis of CNS lesions was 295.0, 146.0, and 99.0 days in the B, BL, and L groups, respectively, and worsening of CNS lesions was the major cause of death in the BL and L groups. Multivariate analyses showed that concurrent soft tissue metastasis (hazard ratio, 4.620) and subsequent systemic therapy (hazard ratio, 0.063) were prognostic for the L group. CONCLUSION: Management of LM from ER + HER2-ABC remains challenging, so a multimodal approach with novel systemic therapy is warranted.

Prognostic significance of brain invasion in meningiomas: systematic review and meta-analysis.

The WHO 2016 classification introduced brain invasion as a standalone criterion for grade II meningioma (GIIM). We systematically reviewed studies published after 2000 and performed a PRISMA-compliant meta-analysis of the hazard ratios (HRs) for progression-free survival (PFS) between brain-invasive and noninvasive meningiomas. In five studies that included both benign and higher-grade meningiomas, brain invasion was a significant risk factor for recurrence (HR = 2.45, p = 0.0004). However, in 3 studies comparing "brain-invasive meningioma with otherwise benign histology (BIOB)" with grade I meningioma, brain invasion was not a significant predictor of PFS (HR = 1.49, p = 0.23). Among GIIM per the WHO 2000 criteria, brain invasion was a significant predictor of shorter PFS than noninvasive GIIM (HR = 3.40, p = 0.001) but not per the WHO 2016 criteria (HR 1.13, p = 0.54), as the latter includes BIOB. Meta-regression analysis of seven studies of grade II meningioma showed that more frequent BIOB was associated with lower HRs (p < 0.0001). Hence, there is no rationale for brain invasion as a standalone criterion for grade II meningioma, although almost all studies were retrospective and exhibited highly heterogeneous HRs due to differences in brain-tumor interface data availability.

Malignant transformation of WHO grade I meningiomas after surgery or radiosurgery: systematic review and meta-analysis of observational studies.

BACKGROUND: The incidence and clinical features of the malignant transformation of benign meningiomas are poorly understood. This study examined the risk of the malignant transformation of benign meningiomas after surgery or stereotactic radiosurgery. METHODS: We systematically reviewed studies published between 1979 and 2019 using PubMed, Scopus, and other sources. We analyzed pooled data according to the PRISMA guideline to clarify the incidence rate of malignant transformation (IMT) and factors affecting malignant transformation in surgically or radiosurgically treated benign meningiomas. RESULTS: IMT was 2.98/1000 patient-years (95% confidence interval [CI] = 1.9-4.3) in 13 studies in a single-arm meta-analysis. Although the evidence level of the included studies was low, the heterogeneity of the incidence was mostly explained by the tumor location. In meta-regression analysis, skull base tumors had a significantly lower IMT than non-skull base tumors, but no gender association was observed. IMT after radiosurgery in 9 studies was 0.50/1000 person-years (95% CI = 0.02-1.38). However, a higher proportion of skull base tumors, lower proportion of males, and lower salvage surgery rate were observed in the radiosurgery group than in the surgery group. The median time to malignant change was 5 years (interquartile range = 2.5-8.2), and the median survival after malignant transformation was 4.7 years (95% CI = 3.7-8) in individual case data. CONCLUSION: IMT of benign meningioma was significantly affected by the tumor location. Radiosurgery did not appear to increase IMT, but exact comparisons were difficult because of differences in study populations.

＜Editors' Choice＞ Impact of maintenance of postoperative performance status on survival in elderly patients over 70 with high-grade astrocytoma.

This study aimed to identify the elderly generation with the worst prognoses for high-grade astrocytoma and find independent predictors of good outcomes. We conducted a retrospective analysis of 91 patients, ≥65 years old, with anaplastic astrocytoma or glioblastoma. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method and compared using log-rank test or multivariate Cox regression analysis. We included 21 (23%) and 70 (77%) patients aged 65-69 years and ≥70 years. In the two generations, significant differences were found in the Charlson comorbidity index, extent of resection, chemoradiotherapy (CRT) as adjuvant therapy, and radiation dose (all P < 0.05). The median PFS was 9.9 and 6.9 months in patients aged 65-69 and ≥70 years (P = 0.10). The median OS was 22.8 and 11.6 months in patients aged 65-69 and ≥70 years (P = 0.009). In the multivariate analyzes in patients ≥70 years, only postoperative Karnofsky performance status (KPS) scores ≥70 were significantly related to prolonged PFS (hazard ratio [HR]: 0.48, P = 0.04), and postoperative KPS, CRT as adjuvant therapy, and salvage therapy were significantly related to prolonged OS (HR: 0.45, P = 0.03, HR: 0.38, P = 0.002, and HR: 0.43, P = 0.01, respectively). In conclusion, in patients ≥70 with high-grade astrocytoma, OS was significantly shorter compared to those aged 65-69. Postoperative KPS score was significantly related to prolonged PFS and OS. Postoperative CRT and salvage therapy at recurrence may be effective in the selected elderly.

FLAIR hyperintensity along the brainstem surface in leptomeningeal metastases: a case series and literature review.

BACKGROUND: The incidence of leptomeningeal metastasis (LM) is underestimated because of its non-specific signs and the low sensitivity of clinical diagnostic modalities. Cerebrospinal magnetic resonance (MR) imaging with and without contrast enhancement (CE) is a gold standard for the neuroradiological assessment of patients with suspected LM. Previous studies suggested that some LM cases show changes of the brainstem surface on non-contrast MR images without or before the appearance of abnormalities on CE images. We assessed the features of this non-contrast MR finding in a cohort of LM patients in this retrospective single-institution study. METHODS: We reviewed head MR images and clinical data of 142 consecutive patients in whom the final diagnosis was LM. RESULTS: We found that 11 of these 142 patients (7.7%) with LM had band-like hyperintensity on the brainstem surface on non-enhanced FLAIR images, which looked like bloomy rind on cheese. Three of seven patients who were examined using diffusion-weighted imaging showed restricted diffusion in the corresponding lesion site. The above-mentioned 11 patients included 10 women and 1 man, with a median age of 61 years. All 11 patients had primary lung adenocarcinoma. Seven patients had symptomatic hydrocephalus. Ten patients had EGFR-mutated and one had ALK-rearrangement adenocarcinomas. Before the diagnosis of LM, 10 patients had undergone systemic therapy with EGFR-TKI or pemetrexed, and 1 patient with ALK inhibitor and bevacizumab. CONCLUSIONS: We present a series of patients with bloomy rind sign that is non-enhancing LM reliably detected by FLAIR hyperintensity on the brainstem surface. This finding is rare, but may reflect the spread of cancer cells in both the leptomeningeal membrane and the surface of the brain parenchyma specifically in patients with lung adenocarcinomas. Further study is needed to determine the clinical significance of this sign, and the pathophysiological factors associated with it may be clarified by analyzing serial MR images in a larger cohort of patients treated for LM.

Alpha-type-1 Polarized Dendritic Cell-based Vaccination in Newly Diagnosed High-grade Glioma: A Phase II Clinical Trial.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is an intractable tumor that has a very poor prognosis despite intensive treatment with temozolomide plus radiotherapy. PATIENTS AND METHODS: Sixteen newly diagnosed patients with high-grade gliomas were enrolled in a phase II study of the α-type-1 DC vaccine. Briefly, DCs obtained from the culture of enriched monocytes in the presence of a cytokine cocktail, were pulsed with a cocktail of 5 synthetic peptides and cryopreserved until injection into patients. RESULTS: The amount of IL-12 produced by activated DCs was higher than that previously reported. Among 15 evaluable patients, 10 showed positive CTL responses to any peptides in an ELISPOT assay. After 6 years of observation, five patients were still alive, and two of these patients were relapse-free. Moreover, a significant survival-prolonging effect was verified in DC-treated glioma patients. CONCLUSION: Peptide-cocktail-pulsed α-type-1 DC vaccines have a potential therapeutic effect on survival when used in combination with the standard regimen, which is partly based on IL-12-IFN-γ-mediated T-cell activation.

Surgical outcome and graded prognostic assessment of patients with brain metastasis from adult sarcoma: multi-institutional retrospective study in Japan.

BACKGROUND: Brain metastasis (BM) is an uncommon complication of sarcomas with a poor prognosis. Little information is available about the feasibility and prognostic factors of surgical resection of BM from sarcomas. METHODS: This study involved a retrospective analysis of 22 patients with BM from sarcomas who underwent resection at six institutes in Japan. Prognostic factors were analyzed to develop a graded prognostic assessment (GPA) using the log-rank test and Cox regression analysis. For validation of this GPA, we collected data on 100 surgical cases from 48 published reports. RESULTS: Postoperative Karnofsky Performance Status (KPS) improved in 50% of our patients. Median overall survival (OS) was 21 months. Multivariate analysis showed age and alveolar soft part sarcoma (ASPS) were significant preoperative prognostic factors (P < 0.05). RTOG-RPA classification had no significant prognostic value. We developed a GPA system for OS after resection of BM. A score of 0 was assigned to patients aged 18-29 years with non-ASPS, 2 to patients aged 18-29 years with ASPS or 30-76 years with non-ASPS, and 4 to patients aged 30-76 years with ASPS. Median OS for patients with GPA scores of 0, 2, and 4 were 6.5, 16.0, and 44.0 months, respectively (P = 0.002). The results were validated by the data of 100 cases compiled (P < 0.001). CONCLUSION: Median OS of patients with BM from sarcomas was comparable to that from carcinomas after resection. A new sarcoma-specific GPA may help patients and clinicians to select resection as an option for treatment of BM from sarcomas.

Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone.

PURPOSE: This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonß (IFNß) plus temozolomide (TMZ) with that of TMZ alone. EXPERIMENTAL: DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations. RESULTS: Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNß + Radiotherapy (RT) group were found. CONCLUSION: This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNß addition were identified.

Retrospective analysis of salvage surgery for local progression of brain metastasis previously treated with stereotactic irradiation: diagnostic contribution, functional outcome, and prognostic factors.

BACKGROUND: Stereotactic irradiation (STI) is a primary treatment for patients with newly diagnosed brain metastases. Some of these patients experience local progression, which is difficult to differentiate from radiation necrosis, and difficult to treat. So far, just a few studies have clarified the prognosis and effectiveness of salvage surgery after STI. We evaluated the diagnostic value and improvement of functional outcomes after salvage surgery. Based on these results, we reconsidered surgical indication for patients with local progression after STI. METHODS: We evaluated patients with brain metastases treated with salvage surgery for local progression from October 2002 to July 2019. These patients had undergone salvage surgery based on magnetic resonance imaging findings and/or clinical evidence of post-STI local progression and stable systemic disease. We employed two prospective strategies according to the eloquency of the lesions. Lesions in non-eloquent areas had been resected completely with a safety margin, utilizing a fence-post method; while lesions in eloquent areas had been treated with minimal resection and postoperative STI. Kaplan-Meier curves were used for the assessment of overall survival. Prognostic factors for survival were analyzed. RESULTS: Fifty-four salvage surgeries had been performed on 48 patients. The median age of patients was 63.5 years (range 36-79). The median interval from STI to surgery was 12 months. The median overall survival was 20.2 months from salvage surgery and 37.5 months from initial STI. Primary cancers were lung 31, breast 9, and others 8. Local recurrence developed in 13 of 54 lesions (24%). Leptomeningeal dissemination occurred after surgery in 3 patients (5.6%). Primary breast cancer (breast vs. lung: HR: 0.17), (breast vs. others: HR: 0.08) and RPA class 1-2 (RPA 1 vs. 3, HR:0.13), (RPA 2 vs 3, HR:0.4) were identified as good prognostic factors for overall survival (OS) in multivariate analyses. The peripheral neutrophil-to-lymphocyte ratio (NLR) of ≤3.65 predicted significantly longer OS (median 25.5 months) than an NLR > 3.65 (median 8 months). CONCLUSION: We insist that salvage surgery leads to rapid improvement of neurological function and clarity of histological diagnosis. Salvage surgery is recommended for large lesions especially with surrounding edema either in eloquent or non-eloquent areas.

Natural History of Meningiomas: Review with Meta-analyses.

Observation has been a mainstay in asymptomatic meningiomas, but it may increase the risk associated with treatment due to tumor enlargement and the aging of patients. Understanding the natural course of meningiomas is important to provide appropriate treatment. The majority of previous studies investigated factors related to their growth, but failed to demonstrate their relationship with symptomatic progression (sympP) because of its rarity. We reviewed and meta-analyzed 27 studies that investigated natural courses in asymptomatic or untreated meningiomas to find clinico-radiological factors predictive of radiological progression (radioP), growth speed, and sympP. In results of time-growth analysis, two-thirds of meningiomas showed radioP defined by a volume criterion and the rate approached a plateau at 4-5 years. In growth curve analyses, about half of incidental meningiomas presented decelerating or no growth, while less than one-quarter of them grew exponentially. RadioP, growth speed [annual volume change (AVC) or relative growth rate], and sympP each had different factors related to them. Younger age, non-calcification, and high intensity on T2-weighted image were related to radioP and rapid growth speed, but not to sympP. Tumors in males and those of larger size were likely to be symptomatic in the meta-analysis. AVC (≥2.1 cm3/year) was the strongest indicator of sympP. Apart from perifocal edema, radiological features at up-front imaging may not be useful for predicting sympP. This may be due to dynamic changes of those radiological markers in the long term. Quantified tumor size and growth speed, especially AVC, are important markers for deciding on treatment.

A practical predictor of the growth potential of benign meningiomas: Hypointensity of surface layer in T2-weighted magnetic resonance imaging.

BACKGROUND: Accurate evaluation of proliferative potential is particularly important in the clinical management of individual patients with meningiomas. We introduce a new feature in the parenchyma of meningioma, namely, hypointensity of the surface layer (HSL), on T2-weighted MR images and compare it with a cellular proliferation index and growth speed. MATERIALS AND METHODS: We retrospectively analyzed the records of consecutive patients with WHO grade I meningiomas in two institutes: an operated group with 124 meningiomas resected in one institute, and an observed group with 89 meningiomas monitored without surgery in the other. Proliferative potential was evaluated using the MIB-1 labeling index (MIB-1 LI) for the operated group and using the relative growth rate on serial MR images for the observed group. RESULTS: In the operated group, 60 (48.4%) meningiomas exhibited HSL. HSL-positive meningiomas were significantly smaller in size and more often calcified than HSL-negative ones. Univariate analysis showed that HSL negativity, large size, no calcification, and surrounding brain edema were significantly associated with high MIB-1 LI (p < 0.05). Multivariate analysis demonstrated that only HSL was significantly related to MIB-1 LI (p = 0.001). HSL did not correlate with tumor recurrence after resection. In the observed group, 43 (48.3%) meningiomas exhibited HSL and they presented a significantly slow relative growth rate. CONCLUSIONS: HSL is a simple and new radiological feature indicative of low proliferative potential and a low risk of enlargement of meningiomas. The presence or absence of HSL may serve as a key parameter for the selection of aggressive treatment or active observation.

Pretreatment intratumoral susceptibility signals correlate with response to high-dose methotrexate and progression-free survival in primary central nervous system lymphoma.

We aimed to estimate the frequency of intratumoral susceptibility signals (ITSS) in susceptibility-weighted imaging (SWI) in consecutive patients with primary central nervous system lymphoma (PCNSL), and to determine if pretreatment heterogeneity of PCNSL is predictive of response to chemotherapy by using ITSS on SWI. We retrospectively examined 29 immunocompetent patients with PCNSL who underwent SWI-MRI before treatment. A univariate analysis was conducted with Fisher's exact test. Progression free survival (PFS) was calculated by the Kaplan-Meier method and compared by the log rank test. The patients, including 16 males, were initially treated at a median age of 69 years. All tissue types were diffuse large B-cell lymphoma. Nineteen patients (66%) presented lesions with ITSS. Sixteen patients (55%) received initial treatment with R-MTX (rituximab plus high-dose methotrexate). Seven out of nine patients with ITSS exhibited a poor response, whereas all seven without ITSS exhibited a good response to R-MTX. Regarding the absence of ITSS, the sensitivity, specificity, and diagnostic accuracy for a good response to R-MTX were 0.78, 1.00, and 0.88, respectively. Patients without ITSS showed significantly longer PFS compared to patients with ITSS (median PFS: 28.9 vs 2.1 months, P < 0.01). In conclusion, ITSS in PCNSL patients were more common than previously reported. We have to be careful to use ITSS for differentiating PCNSL and glioblastoma. Presence of ITSS correlated significantly with therapeutic response to R-MTX. ITSS may be a new marker for the response to chemotherapy in patients with PCNSL. A prospective multi-institutional analysis is needed.

Optimal Sequence of Local and EGFR-TKI Therapy for EGFR-Mutant Non-Small Cell Lung Cancer With Brain Metastases Stratified by Number of Brain Metastases.

PURPOSE: It is unclear whether local therapy (LT) or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) should take precedence for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases (BMs). The number of BMs is important in the choice of LT, including whole-brain radiation therapy, stereotactic radiosurgery, and surgery. METHODS: We retrospectively evaluated cases of EGFR-mutant non-small cell lung cancer with BMs from a single site. Patients were divided into 2 groups based on upfront therapy-EGFR-TKI (TKI) or LTs-and subsequently stratified by the number of BMs. RESULTS: Among 176 patients, 61% received upfront EGFR-TKI, and 39% received upfront LT. The number of patients with 1 to 4 BMs was similar (56% vs 52%; P = .61). All patients with 1 to 4 BMs in the LT group, except for surgical cases, received stereotactic radiosurgery (n = 31). Among those with ≥5 BMs, most (n = 27; 82%) received whole-brain radiation therapy. There was no significant difference in OS between LT and TKI groups (median overall survival, 28 vs 23 months; hazard ratio, 0.75; 95% confidence interval, 0.52-1.07). In patients with 1 to 4 BMs, the LT group showed significantly better OS compared with the TKI group (median overall survival, 35 vs 23 months; hazard ratio, 0.54; 95% confidence interval, 0.32-0.90). There was no difference in OS between the LT and TKI groups for patients with ≥5 BMs. Multivariable analysis showed that upfront LT yielded significantly better OS for patients with 1 to 4 BMs. CONCLUSION: Upfront LT followed by EGFR-TKI is more effective than upfront EGFR-TKI for the survival of untreated patients harboring EGFR mutations with 1 to 4 BMs.

Identification of a neoantigen epitope in a melanoma patient with good response to anti-PD-1 antibody therapy.

Recent advances in next-generation sequencing have enabled rapid and efficient evaluation of the mutational landscape of cancers. As a result, many cancer-specific neoantigens, which can generate antitumor cytotoxic T-cells inside tumors, have been identified. Previously, we reported a metastatic melanoma case with high tumor mutation burden, who obtained complete remission after anti-PD-1 therapy and surgical resection. The rib metastatic lesion, which was used for whole-exome sequencing and gene expression profiling in the HOPE project, showed upregulated expression of PD-L1 mRNA and a high single-nucleotide variants number of 2712. In the current study, we focused on a metastatic melanoma case and candidate epitopes among nonsynonymous mutant neoantigens of 1348 variants were investigated using a peptide-HLA binding algorithm, in vitro cytotoxic T-cell induction assay and HLA tetramer staining. Specifically, from mutant neoantigen data, a total of 21,066 9-mer mutant epitope candidates including a mutated amino acid anywhere in the sequence were applied to the NetMHC binding prediction algorithm. From in silico data, we identified the top 26 mutant epitopes with strong-binding capacity. A cytotoxic T-cell induction assay using 5 cancer patient-derived PBMCs revealed that the mutant ARMT1 peptide sequence (FYGKTILWF) with HLA-A*2402 restriction was an efficient neoantigen, which was detected at a frequency of approximately 0.04% in the HLA-A24 tetramer stain. The present success in identifying a novel mutant antigen epitope might be applied to clinical neoantigen screening in the context of an NGS-equipped medical facility for the development of the next-generation neoantigen cancer vaccines.