The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis.
ABSTRACT: Background:Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods:We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results:Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. Conclusion:Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.
Project description:BACKGROUND:The value of early postoperative 18F-FET-PET in patients with glioblastoma (GBM) is unclear. Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections in these patients and previous data suggest that fluorescence and 18F-FET-PET both demarcate larger tumor volumes than gadolinium enhanced magnet resonance imaging (MRI). OBJECTIVE:To correlate fluorescence with enhancing volumes on postoperative MRI and 18F-FET-PET tumor volumes, and determine the value of postoperative 18F-FET-PET for predicting survival through observational study. METHODS:GBM patients underwent fluorescence-guided resection after administration of 5-ALA followed by early postoperative MRI and 18F-FET-PET for determination of residual tissue volumes. All patients were treated with standard temozolomide radiochemotherapy and monitored for progression-free and overall survival (PFS, OS). RESULTS:A total of 31 patients were included. For functional reasons, residual 5-ALA derived fluorescent tissue was left unresected in 18 patients with a median 18F-FET-PET volume of 17.82 cm3 (interquartile range 6.50-29.19). In patients without residual fluorescence, median 18F-FET-PET volume was 1.20 cm3 (interquartile range 0.87-5.50) and complete resection of gadolinium enhancing tumor was observed in 100% of patients. A 18F-FET-PET volume of above 4.3 cm3 was associated with worse OS (logrank P-value ? .05), also in patients with no residual contrast enhancing tumor on MRI. More patients in whom fluorescencing tissue had been removed completely had postoperative 18F-FET-PET tumor volumes below 4.3 cm3. CONCLUSION:Postoperative 18F-FET-PET volumes predict OS and PFS. Resection of 5-ALA derived fluorescence beyond gadolinium enhancing tumor tissue leads to lower postoperative 18F-FET-PET tumor volumes and improved OS and PFS without additional deficits.
Project description:The purpose of this study was to determine the impact of CT-determined pretreatment primary tumor volume on survival and disease control in T4a laryngeal squamous cell carcinoma (SCC).We retrospectively reviewed 124 patients with T4a laryngeal cancer from 2000-2011. Tumor volume measurements were collected and correlated with outcomes.Five-year overall survival (OS) for patients with tumor volume ?21 cm3 treated with larynx preservation (n = 26 of 41) was significantly inferior compared to <21 cm3 (42% vs 64%, respectively; P = .003). Five-year OS for patients with tumor volumes ?21 cm3 in the cohort treated with total laryngectomy followed by radiotherapy (RT; n = 42 of 83) was not statistically significant when compared to <21 cm3 (50% vs 63%, respectively; P = .058). On multivariate analysis, tumor volume ?21 cm3 was a significant independent correlate of worse disease-specific survival (DSS; P = .004), event-free survival (P = .005), recurrence-free survival (RFS; P = .04), noncancer cause-specific survival (P = .02), and OS (P = .0002).Pretreatment CT-based tumor volume is an independent prognostic factor of outcomes in T4a laryngeal cancer.
Project description:We evaluated prognostic factors of adult low-grade glioma (LGG) according to the new 2016 WHO classification. Records of 153 patients diagnosed with WHO grade II LGG between 2003 and 2015 were retrospectively reviewed. Based on the 2016 WHO classification, 80 patients (52.3%) had diffuse astrocytoma, IDH-mutant; 45 (29.4%) had oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG); and 28 (18.3%) had diffuse astrocytoma, IDH-wildtype. Gross total resection (GTR) was performed in 71 patients (46.4%), subtotal resection in 31 (20.3%), partial resection in 43 (28.1%), and biopsy in 8 (5.2%). One hundred two patients (66.7%) received postoperative radiotherapy. The 5- and 10-year progression-free survival (PFS) rates were 72.7% and 51.5%, respectively, and the 5- and 10-year overall survival (OS) rates were 82.5% and 63.5%, respectively. GTR and IDH-mutant and/or 1p/19q codeletion were favorable prognostic factors for PFS and OS. Patients with IDH-wildtype had significantly decreased OS. Among patients with ODG who underwent GTR, no recurrence was observed after radiotherapy. Patients who underwent non-GTR frequently experienced recurrence after radiotherapy (IDH-mutant: 47.6%, IDH-wildtype: 57.9%). In conclusion, molecular classification of LGG was of prognostic relevance, with IDH-wildtype patients having a particularly poor outcome, regardless of the treatment. Favorable results were observed in patients who underwent GTR.
Project description:BACKGROUND:For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15-39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS:This was a secondary analysis of Children's Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0-21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0-14 years old) or early AYAs (eAYAs, 15-21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS:Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs. 19.2%; p?=?0.015), without other significant differences in clinicopathological features. 5-year PFS rates for children and eAYA were 80.2% (95% confidence interval [95% CI], 76.1-83.7) and 83.0% (95% CI 68.8-91.1), respectively; 5-year OS rates were 97.3% (95% CI 95.2-98.5) and 95.4% (95% CI 82.7-98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (<?1.5 cm3, hazard ratio [HR] 5.93 [95% CI 3.45-10.18]) and (??1.5 cm3, HR 8.38 [95% CI 4.75-14.79]) (p?<?0.001), while midline-chiasmatic location (HR 9.69 [95% CI 3.05-30.75], p?<?0.001) and non-pilocytic astrocytoma histology (HR 6.77 [95% CI 2.35-19.49], p?<?0.001) were independent predictors of OS. CONCLUSION:Unlike several other cancers, LGG has similar presenting features and survival for both eAYAs and children. This support continuing a unified treatment approach and enrollment of eAYAs in pediatric clinical trials for LGGs.
Project description:Background and purpose:Inconsistent bladder and rectal volumes have been associated with motion uncertainties during prostate radiotherapy. This study investigates the impact of these volumes to determine the optimal bladder volume. Materials and methods:60 patients from two Asian hospitals were recruited prospectively. 1887 daily cone-beam computed tomography (CBCT) images were analysed. Intra-fraction motion of the prostate was monitored real-time using a four-dimension transperineal ultrasound (4D TPUS) Clarity® system. The impact of planned bladder volume, adequacy of daily bladder filling, and rectum volume on mean intra-fraction motion of the prostate was analysed. Patients' ability to comply with the full bladder hydration protocol and level of frustration was assessed using a questionaire. Acute side effects were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and quality of life (QoL) assessed using the International Prostate Symptom Score (IPSS). Results:The mean (SD) bladder and rectum volumes achieved during daily treatment were 139.7?cm3 (82.4?cm3) and 53.3?cm3 (18?cm3) respectively. Mean (SD) percentage change from planned CT volumes in bladder volume was reduced by 8.2% (48.7%) and rectum volume was increased by 12.4% (42.2%). Linear Mixed effect model analysis revealed a reduction in intra-fraction motion in both the Sup/Inf (p?=?0.008) and Ant/Post (p?=?0.0001) directions when the daily bladder was filled between 82 and 113% (3rd Quartiles) of the planned CT volumes. A reduction in intra-fraction motion of the prostate in the Ant/Post direction (z-plane) (p?=?0.03) was observed when the planned bladder volume was greater than 200?ml. Patients complied well with the hydration protocol with minimal frustration (mean (SD) scores of 2.1 (1.4) and 1.8 (1.2) respectively). There was a moderate positive correlation (0.496) between mean bladder volume and IPSS reported post-treatment urinary straining (p?=?0.001). Conclusions:A planned bladder volume >200?cm3 and daily filling between 82 and 113%, reduced intra-fraction motion of the prostate. The hydration protocol was well tolerated.
Project description:AbstractWe conducted an open label, single arm phase II clinical trial with with irinotecan and cisplatin (I/C) for pediatric patients with glial tumors (EudraCT:2009-010742-59).METHODSPatients diagnosed with high-risk (HR) gliomas at diagnosis (HGG, ependymomas, DIPG, or HR-LGG) received sixteen weekly outpatient iv. cycles of Cisplatin(30mg/m2) and Irinotecan(65mg/m2). Malignant gliomas received radiation at progression. Objective response was assessed with MRI plus volumetric analysis. Clinical and neurological changes were assessed.RESULTSSince November/2009 until December/2012, 39 patients (66,7% females), aged 7m-17y (mean=84-months), diagnosed with DIPG(n=7), HGG(n=5), anaplastic-ependymoma(n=6), atypical neurocytoma(n=1), LGG n=20: Pilocytic Astrocytoma(n=7), Pilomyxoid A.(n=1), Astrocytoma NOS(n=5), Grade-II astrocytoma (n=2), Ganglioglioma(n=2), LGG-NF1(n=3) were included. Most frequent events were nausea/vomiting, mostly grade 1–2, only 5/39 grade >2; 17 patients (43,6%) developed grade-1 diarrhea. At the end of follow-up 3/31 patients developed hypoacusia, all grade 1 (9,7%). Five (45.5%) patients with HGG, 1 relapsed HGG(100%), 7 DIPG(100%) and 3 LGG(15.0%) progressed during treatment, ending prematurely the study. Objective response rate (ORR) at the end of therapy (week 21), was by ITT / PP, of 54,4% for HGG, 0% for DIPG, and 85% for HR-LGG After a median follow-up time of 67.5 months, OS/EFS was 0/0% for relapsed HGG and DIPG, 62%/23% for High-grade glial tumors, and 95%/43% for HR-LGG. Radiation was avoided in 19/20 HR-LGG patients.CONCLUSIONThe I/C regimen was acceptably tolerated and shows activity for some children with HR-gliomas, mainly HR-LGG.
Project description:Background:Thalamic low-grade glioma (LGG) poses a special therapeutic challenge, as complete resection is often not possible. To determine the survival outcomes of mono- and bithalamic LGG, we analyzed a large cohort of pediatric patients. Methods:From 1996 until 2012, 2618 patients were registered in the HIT-LGG 1996 and the SIOP-LGG 2004 studies. A total of 102 of these 2618 patients (3.9%) were diagnosed with a thalamic LGG with a median age at diagnosis of 8.0 years (range, 0.4-17.5 years); 87 patients (85%) had monothalamic and 15 patients (15%) had bithalamic LGG. Results:Ninety patients received at least one surgical procedure. Thirty-one patients received radiotherapy and 24 patients received chemotherapy as a first-line, nonsurgical treatment indicated by radiological tumor progression or severe/progressive clinical symptoms. Patients with monothalamic tumors showed a 10-year overall survival (OS) rate of 91%, whereas patients with bithalamic tumors only reached 65% (P = .001). Bithalamic tumors more frequently showed diffuse histology than monothalamic tumors. Patients with diffuse astrocytoma had a lower 10-year OS (68%) than those with pilocytic astrocytoma (93%). The 10-year progression-free survival rate after the start of first nonsurgical treatment was 53% in the radiotherapy group and 34% in the chemotherapy group. Conclusions:Thalamic glioma was manageable using a strategy that included surgery, observation, chemotherapy, and/or radiotherapy. Radiotherapy could be successfully deferred or obviated in a number of patients. Survival was high in among patients with monothalamic tumors. The worse prognosis associated with bithalamic tumors correlates with the higher rate of diffuse histology in this subgroup, precluding total or near-total resection.
Project description:Background:Engrailed 1 (EN1), as a member of homeobox-containing transcription factors, participates in the development of the brain. High expressions of EN1 exist in various tumors. However, the role of EN1 in lower grade glioma (LGG) is still unknown. Methods:Coefficients of Cox regression were examined by data mining among 13 cancer types using OncoLnc to validate EN1 expressions in LGG patients from The Cancer Genome Atlas database (TCGA). Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on the data from 273 glioma cases in GSE16011 from GEO datasets and 530 cases of LGG patients in TCGA. Cases in GSE16011 were divided into two groups according to IDH1 mutation status. Cases in TCGA-LGG were classified to subtypes according to histopathological results, IDH1 mutation status and 1p19q status. The Kaplan-Meier survival curves were performed to analyze the relationship between EN1 expressions and clinicopathological characteristics and survival time respectively. Results:Cox regression results showed that LGG was ranked statistically first among 13 different cancer types according to the false discovery rate (FDR) correction. Results from GSE16011 showed that: glioma, LGG and LGG with IDH1 mutation patients with high EN1 expressions had significantly shorter 5, 10, and 15-year overall survival time (OS) (p < 0.001). Similar results from TCGA-LGG showed that LGG patients with high EN1 expressions had significantly shorter 15-year OS, irrespective of IDH1 mutation and 1p19q co-deletion (p < 0.001). The astrocytoma subgroup showed highest levels of EN1 expression and shortest 5, 10 and 15-year OS compared with oligoastrocytoma and oligodendroglioma (p < 0.05). Conclusion:EN1 can be used as a prognostic marker in LGG patients, combined with IDH1 mutation and 1p19q co-deletion.
Project description:BACKGROUND:Since most prostatic diseases are associated with the organ's enlargement, evaluation of prostatic size is a main criterion in the diagnosis of prostatic state of health. While enlargement is a non-uniform process, volumetric measurements are believed to be advantageous to any single dimensional parameter for the diagnosis of prostatomegaly. In a previous study, volume was analysed with a slice addition technique (SAT), which was validated as highly accurate. Irrespective of high accuracy, SAT represents a complex and time-consuming procedure, which limits its clinical use. Thus, demand exists for more practical volume assessment methods. In this study, the prostatic volume of 95 canine patients (58 intact males, 37 neutered males) were analysed retrospectively by using the ellipsoid formula (Formula) and an imaging "wrap" function tool (Wrap) to help assess accuracy and applicability. Accuracy was checked against phantom measurements and results were compared to SAT measurements of the same patient pool obtained from a previously published paper. Patients were grouped according to prostatic structure (H = homogeneous, I = inhomogeneous, C = cystic) and volume using the SAT (volume group = vg: 1, 2 and 3). RESULTS:High correlation between the Formula or Wrap volume and the phantom volume was found, the values being higher for the Formula. Mean Formula volumes (vg 1: 2.2 cm3, vg 2: 14.5 cm3, vg 3: 109.4 cm3, respectively) were significantly underestimated, while mean Wrap volumes (vg 1: 3.8 cm3, vg 2: 19.5 cm3, vg 3: 159.2 cm3) were statistically equivalent to SAT measurements (vg 1: 3.1 cm3, vg 2: 18.6 cm3, vg 3: 157.2 cm3, respectively). Differences between Formula and SAT volumes ranged from 22.4-31.1%, while differences between Wrap and SAT volumes were highest in small prostates (vg 1: 22.1%) and fell with increasing prostatic size (vg 3: 1.3%). CONCLUSION:The Wrap function is highly accurate, less time-consuming and complex compared to SAT and could serve as beneficial tool for measuring prostatic volume in clinical routine after further validation in future studies. The Formula method cannot be recommended as an alternative for volumetric measurements of the prostate gland due to its underestimation of volumes compared to SAT results.
Project description:Stereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry.Patients with liver metastases treated with SBRT were identified in the RSSearch® Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test.The study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31-91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm3 (1.6-877 cm3), median SBRT dose was 45 Gy (12-60 Gy) delivered in a median of 3 fractions [1-5]. At a median follow-up of 14 months (1-91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries (p?<?0.0001). Smaller tumor volumes (<?40 cm3) correlated with improved OS (25 months vs 15 months p?=?0.0014). BED10???100 Gy was also associated with improved OS (27 months vs 15 months p?<?0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED10???100 Gy (77.2% vs 59.6%) and the median LC was better for tumors <?40 cm3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor.In a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted.Clinicaltrials.gov: NCT01885299 .