Higher Karnofsky Performance Score Research Articles

Tumour growth rate predicts overall survival in patients with recurrent WHO grade 4 glioma.

Accurate prognostication may aid in the selection of patients who will benefit from surgery at recurrent WHO grade 4 glioma. This study aimed to evaluate the role of serial tumour volumetric measurements for prognostication at first tumour recurrence. We retrospectively analyzed patients with histologically-diagnosed WHO grade 4 glioma at initial and at first tumour recurrence at a tertiary hospital between May 2000 and September 2018. We performed auto-segmentation using ITK-SNAP software, followed by manual adjustment to measure serial contrast-enhanced T1W (CE-T1W) and T2W lesional volume changes on all MRI images performed between initial resection and repeat surgery. Thirty patients met inclusion criteria; the median overall survival using Kaplan-Meier analysis from second surgery was 10.5 months. Seventeen (56.7%) patients received treatment post second surgery. Univariate cox regression analysis showed that greater rate of increase in lesional volume on CE-T1W (HR = 2.57; 95% CI [1.18, 5.57]; p = 0.02) in the last 2 MRI scans leading up to the second surgery was associated with a higher mortality likelihood. Patients with higher Karnofsky Performance Score (KPS) (HR = 0.97; 95% CI [0.95, 0.99]; p = 0.01) and who received further treatment following second surgery (HR = 0.43; 95% CI [0.19, 0.98]; p = 0.04) were shown to have a better survival. Higher rate of CE-T1W lesional growth on the last 2 MRI images prior to surgery at recurrence was associated with increase mortality risk. A larger prospective study is required to determine and validate the threshold to distinguish rapidly progressive tumour with poor prognosis.

Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma

Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. The primary end point was objective response rate. The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. ClinicalTrials.gov Identifier: NCT03219775.

Tumors Affect the Metabolic Connectivity of the Human Brain Measured by 18F-FDG PET.

18F-FDG PET captures the relationship between glucose metabolism and synaptic activity, allowing for modeling brain function through metabolic connectivity. We investigated tumor-induced modifications of brain metabolic connectivity. Forty-three patients with left hemispheric tumors and 18F-FDG PET/MRI were retrospectively recruited. We included 37 healthy controls (HCs) from the database CERMEP-IDB-MRXFDG. We analyzed the whole brain and right versus left hemispheres connectivity in patients and HC, frontal versus temporal tumors, active tumors versus radiation necrosis, and patients with high Karnofsky performance score (KPS = 100) versus low KPS (KPS < 70). Results were compared with 2-sided t test (P < 0.05). Twenty high-grade glioma, 4 low-grade glioma, and 19 metastases were included. The patients' whole-brain network displayed lower connectivity metrics compared with HC (P < 0.001), except assortativity and betweenness centrality (P = 0.001). The patients' left hemispheres showed decreased similarity, and lower connectivity metrics compared with the right (P < 0.01), with the exception of betweenness centrality (P = 0.002). HC did not show significant hemispheric differences. Frontal tumors showed higher connectivity metrics (P < 0.001) than temporal tumors, but lower betweenness centrality (P = 4.5-7). Patients with high KPS showed higher distance local efficiency (P = 0.01), rich club coefficient (P = 0.0048), clustering coefficient (P = 0.00032), betweenness centrality (P = 0.008), and similarity (P = 0.0027) compared with low KPS. Patients with active tumor(s) (14/43) demonstrated significantly lower connectivity metrics compared with necroses. Tumors cause reorganization of metabolic brain networks, characterized by formation of new connections and decreased centrality. Patients with frontal tumors retained a more efficient, centralized, and segregated network than patients with temporal tumors. Stronger metabolic connectivity was associated with higher KPS.

Sex-specific Differences in IDH1-Wildtype Glioblastoma patients in the ReSPOND Consortium.

Understanding sex-based differences in glioblastoma patients is necessary for accurate personalized treatment planning to improve patient outcomes. To investigate sex-specific differences in molecular, clinical and radiological tumor parameters, as well as survival outcomes in glioblastoma, isocitrate dehydrogenase-1 wildtype (IDH1-WT), grade 4 patients. Retrospective data of 1832 glioblastoma, IDH1-WT patients with comprehensive information on tumor parameters was acquired from the Radiomics Signatures for Precision Oncology in Glioblastoma (ReSPOND) consortium. Data imputation was performed for missing values. Sex-based differences in tumor parameters, such as, age, molecular parameters, pre-operative KPS score, tumor volumes, epicenter and laterality were assessed through non-parametric tests. Spatial atlases were generated using pre-operative MRI maps to visualize tumor characteristics. Survival time analysis was performed through log-rank tests and Cox proportional hazard analyses. GBM was diagnosed at a median age of 64 years in females compared to 61.9 years in males (FDR = 0.003). Males had a higher Karnofsky Performance Score (above 80) as compared to females (60.4% females Vs 69.7% males, FDR = 0.044). Females had lower tumor volumes in enhancing (16.7 cm3 Vs. 20.6 cm3 in males, FDR = 0.001), necrotic core (6.18 cm3 Vs. 7.76 cm3 in males, FDR = 0.001) and edema regions (46.9 cm3 Vs. 59.2 cm3 in males, FDR = 0.0001). Right temporal region was the most common tumor epicenter in the overall population. Right as well as left temporal lobes were more frequently involved in males. There were no significant differences in survival outcomes and mortality ratios. Higher age, unmethylated O6-methylguanine-DNAmethyltransferase (MGMT) promoter and undergoing subtotal resection increased the mortality risk in both males and females. Our study demonstrates significant sex-based differences in clinical and radiological tumor parameters of glioblastoma, IDH1-WT, grade 4 patients. Sex is not an independent prognostic factor for survival outcomes and the tumor parameters influencing patient outcomes are identical for males and females. IDH1-WT = isocitrate dehydrogenase-1 wildtype; MGMTp = O6-methylguanine-DNA-methyltransferase promoter; KPS = Karnofsky performance score; EOR = extent of resection; WHO = world health organization; FDR = false discovery rate.

Fractionated stereotactic radiotherapy of intracranial postoperative cavities after resection of brain metastases – Clinical outcome and prognostic factors

Background and PurposeAfter surgical resection of brain metastases (BM), radiotherapy (RT) is indicated. Postoperative stereotactic radiosurgery (SRS) reduces the risk of local progression and neurocognitive decline compared to whole brain radiotherapy (WBRT). Aside from the optimal dose and fractionation, little is known about the combination of systemic therapy and postoperative fractionated stereotactic radiotherapy (fSRT), especially regarding tumour control and toxicity. MethodsIn this study, 105 patients receiving postoperative fSRT with 35 Gy in 7 fractions performed with Cyberknife were retrospectively reviewed. Overall survival (OS), local control (LC) and total intracranial brain control (TIBC) were analysed via Kaplan-Meier method. Cox proportional hazards models were used to identify prognostic factors. ResultsMedian follow-up was 20.8 months. One-year TIBC was 61.6% and one-year LC was 98.6%. Median OS was 28.7 (95%-CI: 16.9–40.5) months. In total, local progression (median time not reached) occurred in 2.0% and in 20.4% radiation-induced contrast enhancements (RICE) of the cavity (after median of 14.3 months) were diagnosed. Absence of extracranial metastases was identified as an independent prognostic factor for superior OS (p = <0.001) in multivariate analyses, while a higher Karnofsky performance score (KPS) was predictive for longer OS in univariate analysis (p = 0.041). Leptomeningeal disease (LMD) developed in 13% of patients. ConclusionFSRT after surgical resection of BM is an effective and safe treatment approach with excellent local control and acceptable toxicity. Further prospective randomized trials are needed to establish standardized therapeutic guidelines.

Molecular signature to predict quality of life and survival with glioblastoma using Multiview omics model.

Glioblastoma multiforme (GBM) patients show a variety of signs and symptoms that affect their quality of life (QOL) and self-dependence. Since most existing studies have examined prognostic factors based only on clinical factors, there is a need to consider the value of integrating multi-omics data including gene expression and proteomics with clinical data in identifying significant biomarkers for GBM prognosis. Our research aimed to isolate significant features that differentiate between short-term (≤ 6 months) and long-term (≥ 2 years) GBM survival, and between high Karnofsky performance scores (KPS ≥ 80) and low (KPS ≤ 60), using the iterative random forest (iRF) algorithm. Using the Cancer Genomic Atlas (TCGA) database, we identified 35 molecular features composed of 19 genes and 16 proteins. Our findings propose molecular signatures for predicting GBM prognosis and will improve clinical decisions, GBM management, and drug development.

OS04.4.A LONG- AND SHORT-TERM SURVIVORS AMONG ADULT PATIENTS WITH DIFFUSE WHO GRADE 2-3 GLIOMA: CLINICAL FEATURES, MOLECULAR RECLASSIFICATION AND DNA METHYLATION PATTERNS

Abstract BACKGROUND Diffuse gliomas show considerable heterogeneity in terms of survival. The WHO classifications of 2016 and 2021 improved prognostic stratification due to the definition of biologically and clinically homogeneous tumor entities. However, further prognostic models considering clinical and molecular factors are needed to balance survival benefit with adverse treatment-related long-term effects in therapeutic decisions. MATERIALS AND METHODS Patients with diffuse gliomas of WHO grades 2 and 3 diagnosed in 2000 - 2019 have been included. Long term survivors (LTS) were defined as patients with an overall survival (OS) of &amp;gt;10 years after radiological diagnosis, whereas short-term survivors (STS) had an OS of &amp;lt;1 year. Histological diagnosis was performed by a board-certified neuropathologist. DNA methylation analysis of formalin-fixed, paraffin-embedded tumor tissue was conducted using the Illumina EPIC 850k platform. The Heidelberg Methylation Classifier was applied to obtain methylation-based diagnoses. RESULTS Of 697 patients with WHO grade 2 and 3 glioma, 182 (26.1%) were LTS, and 42 (6.0%) were STS. LTS were younger than STS (median age: 36 vs. 59.5; p&amp;lt;0.001) and had a higher Karnofsky Performance Score at diagnosis (median: 90% vs. 80%; p&amp;lt;0.001). LTS more frequently presented with epileptic seizures (p&amp;lt;0.001), while more STS had motoric (p&amp;lt;0.001), sensory (p=0.021), and visual deficits (p=0.027) as well as aphasia (p&amp;lt;0.001) and behavioral changes (p=0.009). Histological diagnoses (including pre-2016) showed astrocytic histology in 117 (70.9% LTS, 29.1% STS), oligodendroglial in 61 (93.4% LTS, 6.6% STS), oligo-astroglial in 43 (97.7% LTS, 2.3% STS) and not otherwise specified in 3 (all STS; p&amp;lt;0.001). Molecular reclassification of pre-2016 diagnoses (n = 143) yielded divergent entities in 46 (32.2%) cases. Overall, integrated molecular diagnoses included astrocytoma (isocitrate dehydrogenase [IDH]-mutant] in 65 patients (95.4% LTS and 4.6% STS), oligodendroglioma (IDH-mutant, 1p/19q-codeleted) in 64 patients (98.4% LTS and 1.6% STS), IDH-wildtype gliomas in 24 patients (100% STS), anaplastic pilocytic astrocytoma in 2 STS, diffuse midline glioma (H3K27-altered) in 1 STS, and dysembryoplastic neuroepithelial tumor in 1 LTS, while not otherwise specified diagnoses were found in 4 patients (75% LTS, 25% STS; p&amp;lt;0.001). Unsupervised clustering based on DNA methylation profiling revealed two major clusters consisting of IDH-wildtype STS (cluster A) and IDH-mutant patients (cluster B; 94.6% LTS, 5.4% STS). In cluster B, one subcluster (n = 8) contained 3/4 IDH-mt STS. Further analyses of these cases including validation with publicly available DNA methylation data are ongoing. CONCLUSION LTS and STS show distinct clinical and molecular features. Further profiling of cases with divergent survival could provide more refined prognostic stratification.

Prognostic and Predictive Markers of Limited (1–4) Brain Metastases in Patients with Lung Adenocarcinoma After Stereotactic Radiosurgery: A Retrospective Analysis

Owing to the complexities of brain metastases (BMs), accurate and reliable prognostic and predictive factors remain critical roadblocks in patients with lung adenocarcinoma (LUAD) BMs who undergo stereotactic radiosurgery (SRS). In total, 132 patients with LUAD BMs who underwent SRS were retrospectively analyzed; Cox proportional hazards analysis of imaging and clinical characteristics was used to identify independent predictors related to overall survival (OS) and progression-free survival (PFS). Our data indicated that initial brain metastasis velocity (iBMV), Karnofsky performance score (KPS), and Rvol (the sum of peritumoral edema volume/cumulative intracranial tumor volume) could potentially be independent prognostic factors for OS. iBMV ≥2 (P=0.000), KPS <80 (P=0.042), and Rvol ≥5.7 (P=0.017) were strongly associated with unsatisfactory OS. The KPS and BM contrast enhancement were also identified as independent prognostic factors for PFS. A higher KPS (P=0.004) and homogeneous BM contrast enhancement (P=0.026) were strongly associated with longer PFS. Collectively, iBMV and Rvol are highly related to OS and could be used as potential prognostic indices in patients with LUAD BMs who underwent SRS. Furthermore, we also revealed that the KPS and BM contrast enhancement could be potential indices of PFS in LUAD BMs.

Erectile Dysfunction in Cirrhosis: Its Prevalence and Risk Factors

Erectile dysfunction (ED) is common in men with cirrhosis. The aim of this study was to assess the prevalence of ED and the factors associated with ED in men with cirrhosis. 400 men with cirrhosis [Child-Turcotte-Pugh (CTP) class A, 44.0%; CTP class B, 41.0%; and CTP class C, 15.0%] having high Karnofsky performance score, and living in a stable monogamous relationship with a female partner were included in the study. International Index of Erectile Function (IIEF) questionnaire, and Short-Form (36) Health Survey (SF-36) were used to assess erectile function and the health-related quality of life (HRQOL), respectively. ED was found in 289 (72.3%) patients. Patients with ED reported significantly lower SF-36 scores across all the eight domains of SF-36 (i.e., physical functioning score, role physical score, bodily pain score, general health perception score, vitality score, social functioning score, role emotional score, and mental health score); physical component summary score, and mental physical component summary score, compared with those without ED. On multivariate analysis, factors associated with ED were older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher hepatic venous pressure gradient (HVPG), presence of generalized anxiety disorder (GAD), presence of major depression, and lower appendicular skeletal muscle index measured by dual-energy X-ray absorptiometry (DEXA ASMI). ED is common in men with cirrhosis, and men with ED have poor HRQOL compared with those without ED. Older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher HVPG, presence of GAD, presence of major depression, and lower DEXA ASMI are associated with ED.

Safety and Efficacy of Sorafenib and Lenvatinib in Patients Who Underwent Surgery or Whole-Brain Radiotherapy for Brain Metastasis of Hepatocellular Carcinoma.

Surgery or whole-brain radiotherapy (WBRT) for the management of brain metastasis of hepatocellular carcinoma (HCC) is associated with improved survival. However, the efficacy of multi-tyrosine kinase inhibitors (TKIs) and possible bleeding complications have not been studied in these patients. Therefore, this study aimed at investigating TKI safety and efficacy in these patients. We retrospectively reviewed 39 patients who underwent surgery or WBRT for brain metastasis of HCC. Intracranial tumor bleeding rates were compared between patients who did and did not receive TKIs. Survival outcomes were analyzed using the log-rank and Cox regression tests. A total of 22 and 7 patients received sorafenib and lenvatinib, respectively. The intracranial tumor bleeding rates were 61.5% and 70% in patients who did and did not receive TKIs, respectively (p > 0.99). Survival analysis revealed craniotomy (adjusted odds ratio [AOR]: 0.45, p = 0.04), a higher Karnofsky Performance Score (AOR: 0.97, p < 0.01), and TKI use (AOR: 0.26, p < 0.01) were positive prognostic factors for overall survival. TKIs were associated with better survival outcomes in patients who underwent surgery or WBRT for brain metastasis of HCC and did not increase intracranial bleeding. Therefore, TKIs are efficacious and safe for treating brain metastasis of HCC.

Predictors of Long-Term Survival Among Patients With Brain Metastases

The prognosis for patients with brain metastases (BrM) remains guarded, with population-based data indicating a median survival of 3-12 months. However, a subset of patients with BrM display prolonged survival. We sought to characterize the likelihood and predictors associated with survival ≥ 5 years after BrM diagnosis.We identified 1,370 patients diagnosed with BrM at a tertiary cancer center between 2008 and 2015 who either died or survived ≥ 5 years. Patients censored before 5 years were excluded from the analysis (N = 66). Multivariable logistic regression was used to characterize predictors of long-term (i.e., ≥ 5 years) survival after BrM diagnosis (odds ratios > 1 indicated a greater odds of long-term survival). Median survival for subgroups was calculated with the Kaplan-Meier method; comparisons were made with the log-rank test.Among all 1,304 patients, median survival after BrM diagnosis was 10.8 months. In total, 123 patients (9.4%) survived ≥ 5 years. On multivariable logistic regression, significant predictors of survival ≥ 5 years included: breast as the primary tumor site vs. the reference of non-small cell lung cancer (NSCLC) (OR: 2.44 [95% CI, 1.23-4.83], P = 0.01), high Karnofsky performance score (KPS) (90-100) vs. low KPS (< 90) (OR: 2.32 [95% CI, 1.48-3.62], P < 0.001), and lack of progressive extracranial disease at time of BrM diagnosis (OR: 2.33 [95% CI, 1.47-3.70], P < 0.001). Factors significantly associated with not surviving ≥ 5 years included: receipt of whole brain radiation therapy vs. the reference of SRT as initial management (OR: 0.30 [95% CI, 0.13-0.70], P = 0.005), presence of 2-4 BrM vs. 1 BrM (OR: 0.63 [95% CI, 0.40-1.00], P = 0.05), an increasing number of extracranial sites of disease (OR: 0.73 per additional site [95% CI, 0.59-0.90], P = 0.003), and an increasing number of systemic therapy regimens for metastatic disease prior to diagnosis of BrM (OR: 0.64 per additional regimen [95% CI, 0.50-0.84], P = 0.001). When limiting to patients with NSCLC for whom EGFR and ALK status were known, there were significant differences in survival among patients with an ALK rearrangement, EGFR mutation, or neither (median survival of 30.9, 15.0, and 12.7 months, respectively, P = 0.04). Subsetting patients with breast cancer based on receptor subtype, there were significant differences in survival among patients with HER2-positive, hormone receptor-positive/HER2-negative, or triple-negative breast cancer (median survival of 26.0, 11.2, and 6.5 months, respectively, P < 0.001).Although patients with BrM generally have a poor prognosis, select patients live for ≥ 5 years. Multidisciplinary teams caring for favorable sub-populations should consider the long-term impact of oncologic therapy when formulating treatment recommendations.N. Lamba: None. D.N. Cagney: Research Grant; NhTheraguix, Viewray. P.J. Catalano: None. P. Wen: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics.

Optimal Timing of SBRT for Treatment of Oligometastatic Disease: A Single Institution Retrospective Analysis

There is mounting evidence that curative-intent stereotactic body radiation therapy (SBRT) may improve overall survival (OS) in patients with oligometastatic disease. However, the optimal sequencing and timing of radiation in this setting remains unclear. Delaying SBRT in favor of upfront systemic therapy can reduce tumor burden whilst allowing for the oligometastatic state to declare itself. However, there is also data to suggest that early upfront SBRT may confer a survival benefit. In this study, we explored the optimal timing of SBRT in the setting of oligometastatic disease.Patients who were initially diagnosed from 1991-2018 at a single institution and treated with curative intent SBRT to ≤5 extracranial metastatic lesions were included in this study. All primary tumor locations and histologies were included. Chi-squared and Wilcoxon rank-sum tests were used to compare clinical and demographic data. Variables associated with improved OS were examined using univariate and multivariate Cox proportional hazards models.A total of 70 patients treated with curative intent SBRT in the oligometastatic setting were included. The majority of patients had metachronous disease (n = 62). Median follow up time, OS, and progression free survival (PFS) were 27.0 months, 33.9 months, and 8.9 months respectively. Median time from diagnosis to treatment with SBRT was 2.7 months. Patients were categorized as those who received concurrent therapy (upfront systemic therapy and SBRT within 3 months of the date of diagnosis, n = 14), those who received sequential therapy (upfront systemic therapy followed by SBRT outside 3 months of the date of diagnosis, n = 20), or those who received upfront SBRT (n = 36). On univariate analysis, a trend between receipt of upfront systemic therapy and improved survival was observed (HR: 0.59, 95% CI: 0.32-1.09, P = 0.096). Sequential therapy (HR: 2.74, 95% CI: 0.89-8.42, P = 0.079) and upfront SBRT (HR: 3.30, 95% CI: 1.14-9.54, P = 0.027) were associated with worse survival compared to concurrent therapy. Higher Karnofsky Performance Score (KPS) (HR:0.96, 95% CI: 0.92-0.99, P = 0.018) was associated with improved survival. Older age was associated with worse survival (HR:1.02, 95% CI: 1.00-1.05, P = 0.020). Multivariate Cox analysis included variables with P < 0.1 and showed that sequential therapy (HR: 3.22, 95% CI: 1.01-10.28, P = 0.049) as well as upfront SBRT (HR: 3.28, 95% CI:1.10-9.76, P = 0.033) were associated with worse survival compared to upfront systemic therapy and early SBRT.Our results suggest that concurrent systemic therapy and SBRT may be associated with better survival compared to upfront SBRT in the oligometastatic setting. Amongst patients who received upfront systemic therapy, those who received early SBRT performed better than those who delayed SBRT. Given the retrospective nature of our work and small sample size more work will be needed to corroborate our findings.

BICD Cargo Adaptor 1 (BICD1) Downregulation Correlates with a Decreased Level of PD-L1 and Predicts a Favorable Prognosis in Patients with IDH1-Mutant Lower-Grade Gliomas.

Simple SummaryThe hypoxic inducible factor 1A (HIF1A) pathway has been known to play an important role in tumor progression in various cancers, including lower-grade (Grade II/III) gliomas (LGGs). An in silico analysis using 34 genes associated with the activity of the HIF1A pathway demonstrated that the BICD cargo adaptor 1 (BICD1) gene is a potential prognostic marker in LGGs. Moreover, BICD1 gene (BICD1) expression was positively correlated with CD274, GSK3B, HGF, and STAT3 expression in LGGs. Importantly, BICD1 downregulation was significantly associated with well-known favorable prognostic markers, such as a higher Karnofsky performance score (KPS), IDH1/TP53/ATRX mutations, wild-type EGFR and younger patient age, in LGGs. Therefore, our findings present BICD1 as a new prognostic biomarker to more precisely predict the clinical outcomes of LGG patients in coordination with those well-known biomarkers.Although several biomarkers have been identified to predict the prognosis of lower-grade (Grade II/III) gliomas (LGGs), we still need to identify new markers to facilitate those well-known markers to obtain more accurate prognosis prediction in LGGs. Bioinformatics data from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Cancer Cell Line Encyclopedia (CCLE) datasets were used as the research materials. In total, 34 genes associated with the HIF1A pathway were analyzed using the hierarchical method to search for the most compatible gene. The BICD cargo adaptor 1 (BICD1) gene (BICD1) was shown to be significantly correlated with The hypoxic inducible factor 1A (HIF1A) expression, the World Health Organization (WHO) grade, and IDH1 mutation status. In addition, BICD1 downregulation was significantly correlated with a higher Karnofsky performance score (KPS), IDH1/TP53/ATRX mutations, wild-type EGFR, and younger patient age in the enrolled LGG cohort. Moreover, BICD1 expression was significantly upregulated in wild-type IDH1 LGGs with EGFR mutations. Kaplan–Meier survival analysis revealed that BICD1 downregulation predicts a favorable overall survival (OS) in LGG patients, especially in those with IDH1 mutations. Intriguingly, we found a significant correlation between BICD1 downregulation and a decreased level of CD274, GSK3B, HGF, or STAT3 in LGGs. Our findings suggest that BICD1 downregulation could be a potential biomarker for a favorable prognosis of LGGs.

The Effect of Conditioning Regimen Dose Reduction in Obese Patients Undergoing Autologous Transplantation

There are limited data on whether to adjust high-dose chemotherapy prior to autologous transplant in overweight patients. We performed a registry-based retrospective analysis on the effect of dose adjustment on the outcomes of patients with body mass index (BMI) ≥ 30 kg/m2. Dose adjustment was defined as a reduction in standard dosing of ≥ 20%. We studied autologous transplant recipients with myeloma (n=1696) treated with high-dose melphalan and lymphomas (Hodgkin/non-Hodgkin; n=781) who received carmustine, etoposide, cytarabine, and melphalan (BEAM) conditioning, respectively. In the myeloma group, chemotherapy dose was adjusted in 1324 (78%). Age, sex, BMI, race, Karnofsky performance score (KPS), co-morbidity score (HCT-CI), and disease features (stage at diagnosis, disease status and time to transplant) were similar between adjusted and unadjusted dose groups. In the multivariate analysis (Table) for myeloma patients, adjusting (reducing) the melphalan dose was not an independent predictor of survival and treatment-related mortality (TRM), whereas there was a reduction in relapse and improvement in progression-free survival in myeloma patients who received an unadjusted chemotherapy dose. In the myeloma group, younger age, early disease stage at diagnosis, higher KPS, and chemotherapy sensitive disease were independent predictors of superior survival. In the lymphoma cohort, chemotherapy dose was adjusted in 608 (78%). There was a similar distribution of age, sex, BMI, race, KPS, and HCT-CI between patients with dose adjusted and unadjusted groups. In addition, the distribution of lymphoma subtypes, chemotherapy sensitivity, time from diagnosis to transplant, and year of transplant were similar between dose adjusted and unadjusted groups. In the multivariate analysis (Table) for lymphoma patients, adjusting the conditioning regimen chemotherapy dose did not affect survival, PFS, relapse or TRM. In the lymphoma group, younger age and higher KPS were independent predictors of superior survival. There found center effect on the outcomes of both myeloma and lymphoma groups. Our study demonstrates that adjusting (reducing) the conditioning regimen chemotherapy dose for autologous transplant patients with BMI ≥ 30 with myeloma receiving melphalan and lymphoma receiving BEAM did not influence survival. Myeloma patients receiving unadjusted, and thus higher dose chemotherapy, experienced less early relapse. In summary, our data suggest that patients with high BMI undergoing autologous transplantation with melphalan or BEAM do not require dose adjustment. [Display omitted] DisclosuresBrunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Savani:Jazz Pharmaceuticals: Speakers Bureau.

Stereotactic radiosurgery (SRS) for brain metastasis (BM) in hormone receptor positive (HR+) HER2 negative breast cancer (BC).

1069 Background: With the increase of the utilization of SRS for the treatment of oligometastatic BM over surgical reaction or whole brain radiation therapy (WBRT), we sought to evaluate the impact of SRS on overall survival in HR+Her2- BC and prognostic factors associated with SRS. Methods: We reviewed prospectively collected data in the electronic data bases of the breast medical, surgical and radiation oncology departments at MD Anderson cancer center. We aimed at identifying HR+HER2- BC patients who received upfront SRS for BM’s between 08/10/2009 and 02/27/2018.Overall survival was defined as the time from the first SRS to last follow-up/death. Multivariate analysis by the Cox proportional hazards regression analysis was performed to evaluate the prognostic factors (age at BM, stage, Karnofsky performance score (KPS), symptomatic BM, BM at 1stdistant metastatic presentation, extracranial Disease, treatment history, salvage therapy, number of brain lesion treated) of SRS that influenced survival. Results: A total of 125 patients were identified, and we are reporting on 68 with completed analysis. Median age at time of first SRS was 53.86 years. 51 patients of the 68 were deceased at the time of this analysis and 17 patients were alive at the time of last follow-up. 49 patients (72.06 %) presented with radiation necrosis after SRS; 36 patients (52.94 %) presented with BM as 1st distant metastasis including metastasis to other sites. Number of BM’s lesions &lt;4 was 60 (88.2%) and &gt;=4 was 7 (10.3%). The median follow-up from time of first SRS for survivors was 10.84 months. 24 (35.29%) received two or more sessions of SRS and the mean time between first and second SRS sessions for these patients was 14.24 months. Median time from first SRS to second SRS for ER+HER2− patients was 10.84 months (n = 24); on multivariable analysis, higher Karnofsky performance score (KPS) was associated with better survival compared to no salvage therapy. Patients with KPS&gt;90 (p=0.005) had better survival and reduced the hazard by a factor of 0.33 (or 67%). Receiving SRS (p=0.0003) or SRS+WBRT (0.0001) as salvage therapy reduced the hazard (risk of death) by 86% and 85%, respectively. Conclusions: SRS is an effective treatment modality for HR+HER2- BM from BC. Patients who received SRS or SRS and WBRT, KPS &gt;90 had better survival than patients who didn’t receive any salvage therapy. Updated data will be available at the time of the presentation.[Table: see text]

PSYCHOMETRIC VALIDATION OF THE BAHASA MALAYSIA VERSION OF THE EORTC QLQ-C30 IN MALAYSIAN COLORECTAL CANCER PATIENTS

This study aimed to assess the validity and reliability of the Bahasa Malaysia (BM) version of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire core (QLQ-C30) (version 3.0) in Malaysian patients with colorectal cancer. A cross sectional study design was used to obtain data from patients receiving treatment at two teaching hospitals in Kuala Lumpur, Malaysia. Self-administered method was used. Statistical analysis included reliability, convergent and discriminant validity and known-groups comparisons. Statistical significance was based on p value ≤ 0.05. The internal consistency Cronbach’s alpha coefficient (α) was acceptable (&gt; 0.70) in all scales but cognitive (α = 0.56) and pain in patients with stoma bag (α = 0.35). Test-retest coefficients were high (r = 0.93 to 1.00). All items showed adequate convergent validity (r &gt; 0.40) except for questionnaire item 5 “needs help in eating/dressing/washing”. Similarly, criteria for discriminant validity were achieved in all but item 10 “need rest”. Patients with high Karnofsky Performance Scores (KPS) scores reported significantly less dyspnoea (p = 0.021) and appetite loss (p = 0.047) compared to patients with low KPS scores. There was no significant difference between patients with and without stomas. The psychometric properties of the BM version of the QLQ-C30 were comparable to previous studies in other settings. Therefore, the questionnaire could be used to measure quality of life in Malaysian patients with colorectal cancer.

Survival analysis after intramedullary stabilization for metastatic disease of the femur: prognostic value of common laboratory parameters.

Metastatic disease of the femur confers significant morbidity and with improved survival due to advances in oncological treatment the prevalence in increasing. The aim of this study was to report on the outcomes of intramedullary stabilization for metastatic disease of the femoral shaft in a New Zealand centre and identify predictors of mortality. Ten-year retrospective review of clinical and radiographic records of patients treated with intramedullary stabilization for metastatic disease of the femur from a single tertiary referral hospital. Data on demographics, clinical and radiographic disease, laboratory markers, complications and mortality were collected. Univariate and multivariate analyses were used to determine predictors of mortality. A total of 82 patients were reviewed (median age 72.5 years; 51% female). The most common primary tumour type was breast cancer (33%). Mortality rate was 15% and 77% at 30 days and 1 year, respectively. Multivariate analysis determined higher albumin (hazard ratio (HR) 0.51; P = 0.014) and higher Karnofsky Performance Score (HR 0.95; P < 0.001) were associated with reduced mortality risk; higher platelet count (HR 2.14; P = 0.009) and higher platelet : lymphocyte ratio (HR 1.87; P = 0.027) were associated with increased mortality risk. Mortality rates were similar to those reported in other regions. Simple laboratory markers including serum albumin, platelet count and the platelet : lymphocyte ratio can aid clinicians in providing prognosis with surgical intervention.

LINC00909 promotes tumor progression in human glioma through regulation of miR-194/MUC1-C axis

Long non‐coding RNAs (lncRNAs) play important roles in tumor progression. Whereas the roles and underlying mechanisms of LINC00909 (a newly discovered lncRNA) are still unclear in glioma progression. In the present study, we identified that LINC00909 expression was significantly elevated in glioma tissues and cell lines. High LINC00909 expression was associated with advanced WHO grade, high Karnofsky Performance Score (KPS), and poor prognosis in patients with glioma. Function assays showed that LINC00909 depletion inhibited glioma cells proliferation, invasion in vitro and reduced tumor growth in vivo. In the mechanism, we found that LINC00909 could act as a ceRNA to interact with miR-194 and thereby up‐regulate the expression of MUC1-C, thus promoting the proliferation and invasion of glioma cells. Collectively, these data demonstrated that LINC00909/miR-194/MUC1-C axis regulated glioma progression and might act as a novel therapeutic target.

Postoperative local fractionated radiotherapy for resected single brain metastases.

Evaluation of postoperative fractionated local 3D-conformal radiotherapy (3DRT) of the resection cavity in brain metastases. Between 2011 and 2016, 57patients underwent resection of asingle, previously untreated (37/57, 65%) or recurrent (20/57, 35%) brain metastasis (median maximal diameter 3.5 cm [1.1-6.5 cm]) followed by 3DRT. For definition of the gross tumor volume (GTV), the resection cavity was used and for the clinical target volume (CTV), margins of 1.0-1.5cm were added. Median dose was 48.0 Gy (30.0-50.4 Gy) in 25 (10-28) fractions; most patients had 36.0-42.0 Gy in 3.0 Gy fractions (n = 16, EQD210Gy 39.0-45.5 Gy) or 40.0-50.4 Gy in 1.8-2.0 Gy fractions (n = 37, EQD210Gy 39.3-50.0 Gy). Median follow-up was 18months. Local control rates were 83% at 1year and 78% at 2years and were significantly influenced by histology (breast cancer 100%, non-small lung cancer 87%, melanoma 80%, colorectal cancer 26% at 2years, p = 0.006) and resection status (p < 0.0001), but not by EQD210Gy or size of the planning target volume (median 96.7 ml [16.7-282.8 ml]). At 1 and 2years, 74% and 52% of the patients were free from distant brain metastases. Salvage procedures were applied in 25/27 (93%) of recurrent patients. Survival was 68% at 1year and 41% at 2years and was significantly improved in younger patients (p = 0.006) with higher Karnofsky performance score (p < 0.0001) and without prior radiotherapy (54% vs. 9% at 2years, p = 0.006). No cases of radiographic or symptomatic radionecrosis were observed. Adjuvant fractionated local 3DRT is highly effective in radiosensitive, completely resected metastases and should be considered for treating large resection cavities as an alternative to postoperative stereotactic single dose or hypofractionated radiosurgery.

Higher Plasma Fibrinogen Levels are Associated with Malignant Phenotype and Worse Survival in Patients with Glioblastomas.

Preoperative plasma fibrinogen levels were associated with poor clinical outcomes in malignancies. There were few data about the prognostic value of plasma fibrinogen in glioblastomas (GBMs). The objective of our study was to investigate the association between fibrinogen and patients' clinicopathological factors and overall survival (OS). From 2008 to 2016, 315 patients with GBMs who had a surgical treatment at our institute, were retrospectively involved in this study. IDH (isocitrate dehydrogenase) mutations and ATRX (alpha thalassemia/mental retardation syndrome X-linked) loss were detected with IHC (Immunohistochemistry). The preoperative plasma fibrinogen levels ranged from 1.00 to 5.22 g/L, with a mean of were 2.57 g/L. There were increased levels of plasma fibrinogen in patients aged ≥ 65 years, secondary GBMs, IDH mutation (p = 0.033) and ATRX loss (p = 0.040). Moreover, the plasma fibrinogen level was the highest in the subtype of IDH-1R132H wildtype - ATRX expression, which showed a shorter OS compared to the group of IDH-1R132H mut and IDH-1R132H wildtype - ATRX loss (p = 0.001, log-rank test). ROC curves for fibrinogen and IDH-1R132H wildtype - ATRX expression was also plotted, and indicated a potential diagnostic value of fibrinogen in molecular pathology. Univariate analysis found that younger age, higher KPS (Karnofsky Performance Score), gross total resection, complete chemoradiotherapy, IDH-1R132H mutations and lower levels of fibrinogen were associated with favorable outcomes. Multivariate analysis proved that chemoradiotherapy, IDH-1R132H and fibrinogen were independent prognostic factors. In conclusion, plasma fibrinogen could predict clinical outcome and molecular subtype in GBMs.