scholarly journals TAMI-54. THE PRESENCE OF IMMUNE CELL INFILTRATES IN THE TISSUE MICROENVIRONMENT OF HIGH-GRADE GLIOMAS AND THEIR ASSOCIATION WITH OVERALL SURVIVAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii225-ii225
Author(s):  
Anupam Rishi ◽  
Homan Mohammadi ◽  
Daniela Martir ◽  
Eric Welsh ◽  
Timothy Robinson ◽  
...  

Abstract OBJECTIVE Tumor-associated microglia and macrophages (TAMs) influence brain tumor biology and promote tumor-proliferating phenotype. Studies have shown these cell types predict outcomes in various tumor sites with limited evidence in high-grade gliomas (HGG). In this study, we assessed the presence of immune cell infiltrate (ICI) and overall survival (OS) in HGGs. METHODS A total of 97 consecutively treated patients with primary HGG with complete gene expression profiling were identified from our IRB-approved institutional tissue biorepository. Patients underwent primary surgical resection between 02/2004 and 03/2011. Gene expression levels were assessed by Affymetrix Hu-RSTA assays (Affymetrix; Santa Clara, CA). CIBERSORT estimated the presence of ICI via gene expression deconvolution. Tumor characteristics and the presence of 22 individual ICI subtypes were assessed with respect to OS. Time-to-event analyses were performed with Kaplan-Meier estimates and compared via log-rank test. Associations between the ICI and outcomes were explored using Cox-regression. P< 0.05 (two-tailed) was considered statistically significant. RESULTS Median follow-up from primary surgical resection was 12.8 months (range: 0.1-162.8), and median age was 58 years (20-85). Most patients were male (n=63; 65%) and had grade 4 tumors (n=71; 73%). OS differed by grade with 24-month actuarial OS rates of 81% and 34% (P< 0.0001) for grade 3 and 4 gliomas, respectively. The presence of M0 (HR 2.2; 95% CI 1.4-3.6; P=0.001), M1 (HR 1.8; 95%CI 1.1-2.9; P=0.01), and M2 macrophages (HR 1.9; 95%CI 1.2-3.2; P=0.007) predicted OS. No other ICI subtypes were predictive of OS. The presence of M0- and M2-polarized macrophages were more common in grade 4 compared to grade 3 gliomas 46% vs. 11% (P=0.002) and 69% vs. 31% (P=0.0007), respectively. CONCLUSION The increased presence of non-polarized or M2 TAMs within the glioma microenvironment was significantly associated with OS in HGG. Their presence may serve as unique stratification and a potential therapeutic target.

2020 ◽  
Vol 10 ◽  
Author(s):  
Zhen Lin ◽  
Xianyi Meng ◽  
Jinming Wen ◽  
José María Corral ◽  
Darja Andreev ◽  
...  

BackgroundHuman malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA).MethodsClonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level.ResultsTumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011).ConclusionsHighly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.


2020 ◽  
Author(s):  
Longqing Li ◽  
Lianghao Zhang ◽  
Manhas Adbul Khader ◽  
Yan Zhang ◽  
Xinchang Lu ◽  
...  

Abstract Background: Osteosarcoma is a malignant bone tumor common in children and adolescents. Metastatic status remains the most important guideline for classifying patients and making clinical decisions. Despite many efforts, newly diagnosed patients receive the same therapy that patients have received over the last 4 decades. With the development of high-throughput sequencing technology and the rise of immunotherapy, it is necessary to deeply explore the immune molecular mechanism of osteosarcoma.Methods: We obtained RNA-seq data and clinical information of osteosarcoma patients from TCGA database and TARGET database. With the help of co-expression analysis we identified immune-related lncRNA and then by means of univariate Cox regression analysis prognostic-related lncRNA was screened out. And also by using least absolute shrinkage and selection operator regression method a model based on immune-related lncRNA was constructed. The differences in overall survival, immune infiltration, immune checkpoint gene expression, and tumor microenvironmental immunity type between the two groups were evaluated.Results: We constructed a signature consisting of 13 lncRNA. Our results show that signatures can reliably predict the overall survival of patients with osteosarcoma and can bring net clinical benefits. Further more, the signatures can be used for further risk stratification of the metastasis patients. Patients in the low-risk group had higher immune cell infiltration and immune checkpoint gene expression. The results from gene set variation analysis show that patients in low-risk group are closely related to immune-related pathways when compared with patients in high-risk group. Finally, patients in the low-risk group are more likely to be classified as TMIT I and hence more likely to benefit from immunotherapy.Conclusion: Our signature may be a reliable marker for predicting the overall survival of patients with osteosarcoma.


2018 ◽  
Vol 09 (03) ◽  
pp. 312-316 ◽  
Author(s):  
Meenu Gupta ◽  
Saurabh Bansal ◽  
Deep Shankar Pruthi ◽  
Manju Saini ◽  
Nadia Shirazi ◽  
...  

ABSTRACT Background and Objectives: Due to the aging of the population, diagnosis of high-grade gliomas (HGGs) in the elderly is becoming more common. The purpose of this study was to report our experience in 24 elderly patients with HGGs and evaluate the value of different prognostic factors. Design and Setting: Retrospective analysis of 24 elderly patients of ≥60 years with newly diagnosed HGGs, who were treated at our department between January 2009 and December 2012, was done. Patients and Methods: Age, gender, Karnofsky performance scale (KPS) score, extent of surgery, and use of temozolomide were evaluated using univariate and multivariate analyses. Survival was determined using the Kaplan–Meier method, and differences were compared using the log-rank test. Cox regression analysis was conducted to identify the independent prognostic factors. Results: The median overall survival of the patient cohort was 10 months. The 1- and 2-year survival rates were 45.8% and 16.6%, respectively. The analysis revealed that KPS score and use of concomitant chemotherapy were significant prognostic factors. Conclusion: The results of our analyses demonstrate that KPS score and use of concomitant chemotherapy yield encouraging outcomes in elderly patients with HGGs, validating the results published in research papers.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14500-e14500
Author(s):  
Rixci Ramirez ◽  
Daniel Estuardo Rosales Lopez ◽  
Jennifer Dominguez ◽  
Marisol Gramajo ◽  
Carolina Camey

e14500 Background: In previous studies separately, it has already been determined how the inflammatory response measured by it neutrophilia and also lymphopenia s with temozolamide have determined that they are important at the time of initiation of treatment and have a prognostic value in patients with high-grade gliomas, the objective This study was the prognostic value of leukocyte disorders, absolute neutrophil count and absolute lymphocyte count in a retrospective cohort of patients with high-grade glioma who receive concomitant temozolomide and radiation plus maintenance. Methods: Clinical records of patients treated at the Guatemalan Social Security Institute were registered in the Oncology service within the period from January 1, 2013 to December 2018, the treatment consisted of temozolomide (75 mg / m2 per day) and concomitant radiation and subsequent maintenance with temozolomide (150 mg / m2 D1-5) every 28 days for 6 cycles. The prognostic value of neutrophilia and lymphopenia, prior to treatment in survival, was defined as a neutrophil count greater than 7x10 3 / uL and lymphopenia less than 2 x10 3 / uL. The analysis was performed using Kapplan Mayer curves, log rank test and Cox analysis. Results: We identified 64 high-grade patients (grades III and IV according to WHO), all treatments with concomitant chemoradiotherapy based on temozolomide and subsequent maintenance with temozolamide. The initial surgery was lost in the majority (75%), with resection > 90% in 25 patients (34%). 79.4% were treated with radiotherapy plus concomitant chemotherapy followed by adjuvant chemotherapy with temozolamide of these, 69% completed the treatment, thirty-two patients (50%) with pre-treatment neutrophilia. The overall survival at 2 years was 55%. In the univariate analysis, neutrophilia is associated with a worse overall survival (p = 0.019), as well as lymphopenia (p = 0.003), in addition to the age ≥65 years (p = 0.0001), surgical resection < 90% (p = 0.045) and prednisolone consumption ≥50mg / day (p = 0.045). In the multivariate analysis, neutrophilia (p = 0.017), age ≥65 (p = 0.001), lymphopenia (p = 0.0056) were associated with a worse prognosis with reduced survival. Conclusions: In high-grade gliomas treated with temozolomide and concomitant radiation followed by maintenance with temozolamide, neutrophilia and lymphopenia can be a significant prognostic factor for overall survival, with the advantage that it is not an expensive test and is accessible at all times of patient follow-up.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4108-4108
Author(s):  
Diana Hsu ◽  
Sidney Le ◽  
Alex Chang ◽  
Austin Spitzer ◽  
George Kazantsev ◽  
...  

4108 Background: Pancreatic neuroendocrine tumors (PNET) are a heterogeneous group of tumors that represent 1-2% of all pancreatic neoplasms. Their biologic behaviors are unpredictable with high grade, nodal metastasis, or liver metastasis lending an unfavorable prognosis. Current guidelines recommend resection for functioning tumors and those 2 cm or larger but are less straightforward regarding tumors < 2 cm in size. Previous data show that observation for nonfunctioning tumors < 2 cm can be safe and feasible; however, a significant portion of these patients may have nodal involvement or metastatic disease. Methods: A retrospective review was undertaken to identify patients with pancreatic neuroendocrine tumors treated at Northern California Kaiser Permanente (KP-NCAL) between February 2010 and December 2018. Univariate and multivariate analyses were performed with the log-rank test and Cox regression. Chi-squared test of relevant clinicopathologic factors determined which factors were predictive for overall survival (OS). Results: Mean age was 61 years in our cohort of 354 patients, with 29% over the age of 70. Mean tumor size was 3.43 cm; 32% of tumors were 2 cm or smaller. 51% of the patients had localized disease; 32% of the patients presented with metastatic disease. The pancreatic tail was the most common tumor location (38%), followed by the head of the pancreas (24%). On multivariate survival analysis, stage, location of the tumor, and surgical resection were statistically significant in terms of overall survival ( p<.001). Mean OS for patients with localized and metastatic disease was 93 months versus 37 months ( p<.001). Surgery was utilized in 8.9% of patients with metastatic disease ( p<.001). All patients with PNET smaller than 1 cm in our study group had localized disease only. However, in patients with tumor size between 1 and 2 cm, 11% had nodal or metastatic spread. Conclusions: PNETs are indolent but have malignant potential at any size. In our retrospective study, all of the patients with tumor size < 1 cm had localized disease. For those with PNETs 1-2 cm in size, 11% had nodal or metastatic spread. Based on our findings, we suggest a more aggressive surgical resection size criteria of 1 cm.[Table: see text]


2018 ◽  
Vol 17 (3) ◽  
pp. 266-273
Author(s):  
Lubna Sheazadi ◽  
Robert Appleyard ◽  
Natalie Foley ◽  
Bernadette Foran

AbstractPurposeTo evaluate the extent to which intensity-modulated arc therapy (IMAT) for high-grade gliomas is comparable with three-dimensional conformal radiotherapy (3DCRT) in relation to the dose delivered to normal brain tissue (NBT), planning target volume (PTV) conformity and the dose delivered to brainstem and optic chiasma.MethodA total of 16 randomly selected 3DCRT treatment plans of grade 3 gliomas were re-planned using an IMAT planning technique and dose–volume histograms were compared. Primary outcomes were maximum, mean, 1/3 and 2/3 doses to NBT outside the PTV. Also the maximum, mean, D50 and D20 doses to PTV. Secondary outcomes were maximum and mean doses to the brainstem and optic chiasm. Wilcoxon signed rank test was used to compare data.ResultsIMAT led to a statistically significant increase in mean dose to NBT (34·4 versus 33·3 Gy, (p=0·047) but a statistically significant reduction in maximum dose to NBT (62·7 versus 63·8 Gy, p=0·004) compared with 3DCRT. IMAT led to statistically significant reductions in maximum, D50 and D20 doses to the PTV (63·3 versus 64·7 Gy, p=0·001; 60·0 versus 60·7 Gy, p=0·001 and 60·5 versus 61·8 Gy, p=0·002, respectively). No statistically significant differences were seen in doses to brainstem and optic chiasm.ConclusionIMAT is at least comparable with 3DCRT in relation to minimising dose to NBT and ensuring good PTV conformity. Doses delivered to organs at risk using IMAT were also comparable with 3DCRT. This study supports the continued use of IMAT for the treatment of high-grade gliomas.


2021 ◽  
Vol 12 ◽  
Author(s):  
Qunying Yang ◽  
Chengcheng Guo ◽  
Xiaoping Lin ◽  
Lili Luo ◽  
Zhenqiang He ◽  
...  

Background: Anlotinib is a multi-target anti-angiogenic agent. This retrospective study aimed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide for the treatment of recurrent high-grade glioma.Materials and Methods: The clinical data of patients with recurrent high-grade glioma treated with anlotinib alone or in combination with temozolomide in our cancer center were collected and analyzed. Treatment response was evaluated according to the response assessment for neuro-oncology criteria. Progression-free survival, progression-free survival at 6 months, overall survival, and overall survival at 12 months were evaluated by Kaplan–Meier method and compared by log-rank test.Results: Between August 2019 and December 2020, 31 patients with recurrent high-grade glioma (21 of grade 4 and 10 of grade 3) were enrolled in this study. Seventeen patients received anlotinib alone and 14 received anlotinib plus temozolomide. All patients were heavily treated, the median lines of previous treatments were 2, and the median Karnofsky score was 60. At the data cutoff date, the median progression-free survival was 4.5 months and the progression-free survival at 6 months was 43.5%. The median overall survival was 7.7 months, and the overall survival at 12 months was 26.7%. The progression-free survival at 6 months and the overall survival at 12 months for 21 patients with grade 4 glioma was 40.2 and 27.9%, respectively. The tumor objective response rate was 41.9% in all patients and 33.3% in patients with grade 4 glioma. No grade 3 or worse treatment-related adverse events were recorded during the treatment.Conclusion: Anlotinib alone or in combination with temozolomide showed encouraging efficacy and favorable tolerability in patients with recurrent high-grade glioma who had been heavily treated.


2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yue Zhao ◽  
Shao-Min Yang ◽  
Yu-Lan Jin ◽  
Guang-Wu Xiong ◽  
Pin Wang ◽  
...  

The objective of this research was to develop a robust gene expression-based prognostic signature and scoring system for predicting overall survival (OS) of patients with high-grade serous ovarian cancer (HGSOC). Transcriptomic data of HGSOC patients were obtained from six independent studies in the NCBI GEO database. Genes significantly deregulated and associated with OS in HGSOCs were selected using GEO2R and Kaplan–Meier analysis with log-rank testing, respectively. Enrichment analysis for biological processes and pathways was performed using Gene Ontology analysis. A resampling/cross-validation method with Cox regression analysis was used to identify a novel gene expression-based signature associated with OS, and a prognostic scoring system was developed and further validated in nine independent HGSOC datasets. We first identified 488 significantly deregulated genes in HGSOC patients, of which 232 were found to be significantly associated with their OS. These genes were significantly enriched for cell cycle division, epithelial cell differentiation, p53 signaling pathway, vasculature development, and other processes. A novel 11-gene prognostic signature was identified and a prognostic scoring system was developed, which robustly predicted OS in HGSOC patients in 100 sampling test sets. The scoring system was further validated successfully in nine additional HGSOC public datasets. In conclusion, our integrative bioinformatics study combining transcriptomic and clinical data established an 11-gene prognostic signature for robust and reproducible prediction of OS in HGSOC patients. This signature could be of clinical value for guiding therapeutic selection and individualized treatment.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9006-9006
Author(s):  
Hirotsugu Kenmotsu ◽  
Seiji Niho ◽  
Masahiro Tsuboi ◽  
Masashi Wakabayashi ◽  
Genichiro Ishii ◽  
...  

9006 Background: In the WHO classification, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are considered as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Although there were no randomized trials evaluating adjuvant chemotherapy for patients (pts) with resected HGNEC, EP was considered to be a standard regimen for this population. A phase III study showed the superiority of IP to EP in pts with extensive stage SCLC (JCOG9511). Methods: Pts with completely resected HGNEC were randomized in a 1:1 ratio to receive either etoposide (100 mg/m2, days 1-3)/cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15)/cisplatin (60 mg/m2, day 1), using the minimization method according to sex, pathologic stage, histology and institution. The primary endpoint was changed from overall survival (OS) to relapse-free survival (RFS) during the study period. We assumed a 3-year RFS of 59% of EP arm and 72% of IP arm (hazard ratio (HR) of 0.623). Planned sample size was 220 in total to give a power of 80% with a one-sided alpha of 5%, an accrual period of 6 years and a follow-up period of 3 years. Results: Between April 2013 and October 2018, 221 pts with a median age of 66 years, pathological stage I (54%), SCLC (53%), were randomly assigned to the EP arm (n = 111) or the IP arm (n = 110). In the second interim analysis, the predictive probability that IP would be superior to EP at the time of the primary analysis was 15.9%, which led to early termination of the trial. With a median follow-up of 24.1 months, 3-year RFS was 65.4% versus 69.0% with HR of 1.076 (95% CI, 0.666-1.738; log-rank test, one-sided P= 0.619). In the subgroup analyses of histology, 3-year RFS in SCLC was 65.2% versus 66.5% with HR of 1.029 (95% CI, 0.544-1.944), and 3-year RFS in LCNEC was 66.5% versus 72.0% with HR of 1.072 (95% CI, 0.517-2.222). Overall survival at 3 years was 84.1% versus 79.0% with HR of 1.539 (95% CI, 0.760-3.117). Proportions of treatment completion were 87.4% (EP) and 72.7% (IP). Incidences (EP/IP) of grade 3 or 4 febrile neutropenia (20.2/3.7%) or neutropenia (97.2/35.8%) were more common in EP. Grade 3 or 4 diarrhea (0.9/8.3%) or anorexia (6.4/11.1%) were more common in IP. One treatment-related death due to tracheal bleeding was observed in IP. Conclusions: This study failed to show the superiority of IP to EP in RFS for pts with completely resected HGNEC. EP is still a standard treatment for this population. Clinical trial information: UMIN000010298.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sicheng Zhou ◽  
Qiang Feng ◽  
Jing Zhang ◽  
Haitao Zhou ◽  
Zheng Jiang ◽  
...  

Abstract Background This study aimed to evaluate the impact of postoperative complications on long-term survival in patients with peritoneal metastasis (PM) arising from colorectal cancer (CRC) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Methods Patients with PM arising from CRC treated with CRS and HIPEC were systematically reviewed at the China National Cancer Center and Huanxing Cancer Hospital from June 2017 to June 2019. High-grade complications that occurred within 30 days were defined as grade 3 to 4 events according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Univariate and multivariable Cox regression models for overall survival were created. Predictors of high-grade postoperative complications were evaluated with univariate and multivariate logistic regression analyses. Results In all, 86 consecutive cases were included in this study. Forty-one patients (47.7%) developed postoperative complications, while 22 patients (25.6%) experienced high-grade complications. No mortality occurred during the postoperative period. The median survival of all patients was 25 months, and the estimated 3-year overall survival (OS) rate was 35.0%. In the multivariable Cox regression analysis, a high peritoneal carcinomatosis index (PCI) score (HR, 1.07, 95% CI, 1.01–1.14; P=0.015) and grade 3–4 postoperative complications (HR, 1.86, 95% CI, 1.22–3.51; P=0.044) correlated with worse overall survival. High estimated blood loss (OR, 1.01, 95% CI, 1.01–1.02; P< 0.001) was identified as an independent risk factor for developing high-grade complications. Conclusion Careful patient selection, high levels of technical skill and improved perioperative management are crucial to ensure patient survival benefits after CRS+HIPEC.


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