scholarly journals A molecular signature associated with prolonged survival in glioblastoma patients treated with regorafenib

2020 ◽  
Author(s):  
Alessandra Santangelo ◽  
Marzia Rossato ◽  
Giuseppe Lombardi ◽  
Salvatore Benfatto ◽  
Denise Lavezzari ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Clinical Decision ◽  
Molecular Signature ◽  
Prolonged Survival ◽  
Second Step ◽  
Free Survival ◽  
Genome Wide ◽  
Potential Biomarker ◽  
Gene Transcripts ◽  
Recurrent Gbm

Abstract Background Patients with glioblastoma (GBM) have a dramatically poor prognosis. The recent REGOMA trial suggested an overall survival (OS) benefit of regorafenib in recurrent GBM patients. Considering the extreme genetic heterogeneity of GBMs, we aimed to identify molecular biomarkers predictive of differential response to the drug. Methods Total RNA was extracted from tumor samples of patients enrolled in the REGOMA trial. Genome-wide transcriptome and micro (mi)RNA profiles were associated with patients’ OS and progression-free survival. Results In the first step, a set of 11 gene transcripts (HIF1A, CTSK, SLC2A1, KLHL12, CDKN1A, CA12, WDR1, CD53, CBR4, NIFK-AS1, RAB30-DT) and 10 miRNAs (miR-93-5p, miR-203a-3p, miR-17-5p, let-7c-3p, miR-101-3p, miR-3607-3p, miR-6516-3p, miR-301a-3p, miR-23b-3p, miR-222-3p) was filtered by comparing survival between regorafenib and lomustine arms. In the second step, a mini-signature of 2 gene transcripts (HIF1A, CDKN1A) and 3 miRNAs (miR-3607-3p, miR-301a-3p, miR-93-5p) identified a subgroup of patients showing prolonged survival after regorafenib administration (median OS range, 10.6–20.8 mo). Conclusions The study provides evidence that a signature based on the expression of 5 biomarkers could help identify a subgroup of GBM patients exhibiting a striking survival advantage when treated with regorafenib. Although the presented results must be confirmed in larger replication cohorts, the study highlights potential biomarker options to help guide the clinical decision among regorafenib and other treatments in patients with relapsing GBM.

scholarly journals HOTAIR as a Prognostic Predictor for Diverse Human Cancers: A Meta- and Bioinformatics Analysis

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 778 ◽  
Author(s):  
Halil Ibrahim Toy ◽  
Didem Okmen ◽  
Panagiota I. Kontou ◽  
Alexandros G. Georgakilas ◽  
Athanasia Pavlopoulou
Keyword(s):  
Overall Survival ◽  
Cancer Patients ◽  
Bioinformatics Analysis ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Free Survival ◽  
Human Cancers ◽  
Potential Biomarker

Several studies suggest that upregulated expression of the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is a negative predictive biomarker for numerous cancers. Herein, we performed a meta-analysis to further investigate the prognostic value of HOTAIR expression in diverse human cancers. To this end, a systematic literature review was conducted in order to select scientific studies relevant to the association between HOTAIR expression and clinical outcomes, including overall survival (OS), recurrence-free survival (RFS)/disease-free survival (DFS), and progression-free survival (PFS)/metastasis-free survival (MFS) of cancer patients. Collectively, 53 eligible studies including a total of 4873 patients were enrolled in the current meta-analysis. Pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated to assess the relationship between HOTAIR and cancer patients’ survival. Elevated HOTAIR expression was found to be significantly associated with OS, RFS/DFS and PFS/MFS in diverse types of cancers. These findings were also corroborated by the results of bioinformatics analysis on overall survival. Therefore, based on our findings, HOTAIR could serve as a potential biomarker for the prediction of cancer patient survival in many different types of human cancers.

scholarly journals The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3591-3660 ◽  
Author(s):  
Fumihiko Ishikawa ◽  
Hiroaki Niiro ◽  
Tadafumi Iino ◽  
Shuro Yoshida ◽  
Noriyuki Saito ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Severe Combined Immunodeficiency ◽  
Molecular Signature ◽  
Newborn Mice ◽  
Nonobese Diabetic ◽  
Genome Wide ◽  
Gene Transcripts ◽  
Plasmacytoid Dcs ◽  
Human Dendritic Cells ◽  
Xenotransplantation Model

Abstract Two distinct dendritic cell (DC) subsets, conventional DCs (cDCs) and plasmacytoid DCs (pDCs), have been shown to develop via either the myeloid or the lymphoid pathway in murine hematopoiesis. Lineage-specific phenotypes or functions of “myeloid” and “lymphoid” DCs, however, still remain elusive. Furthermore, such analysis has been particularly difficult in humans, due to lack of an assay system appropriate for the analysis of human stem and progenitor cell differentiation. Here, using a highly efficient xenotransplantation model, we extensively analyze the origin and the molecular signature of human DCs. Purified human common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs) were intravenously transplanted into nonobese diabetic–severe combined immunodeficiency (NOD-scid)/IL2rγnull newborn mice. CMPs and CLPs displayed significant expansion in the xenogeneic host, and human cDC and pDC progeny were isolatable. Strikingly, each human DC subset possessed indistinguishable expression patterns of surface phenotype and gene transcripts regardless of their CMP or CLP origin, even at the genome-wide level. Thus, cDC and pDC normally develop after cells have committed to the myeloid or the lymphoid lineage in human hematopoiesis, while their transcriptional signatures are well preserved irrespective of their lineage origin. We propose that human DCs use unique and flexible developmental programs that cannot be categorized into the conventional myeloid or lymphoid pathway.

Local Ablative Therapies in Oligometastatic NSCLC: New Data and New Directions

2020 ◽  
Vol 41 (03) ◽  
pp. 369-376
Author(s):  
Pencilla Lang ◽  
Daniel R. Gomez ◽  
David A. Palma
Keyword(s):  
Clinical Decision Making ◽  
Treatment Phase ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Stereotactic Ablative Radiotherapy ◽  
Free Survival ◽  
Fractionated Radiotherapy ◽  
Disease States ◽  
Ablative Therapies ◽  
Clinical Scenarios

AbstractThe oligometastatic and oligoprogressive disease states have been recently recognized as common clinical scenarios in the management of non-small cell lung cancer (NSCLC). As a result, there has been increasing interest in treating these patients with locally ablative therapies including surgery, conventionally fractionated radiotherapy, stereotactic ablative radiotherapy, and radiofrequency ablation. This article provides an overview of oligometastatic and oligoprogressive disease in the setting of NSCLC and reviews the evidence supporting ablative treatment. Phase II randomized controlled trials and retrospective series suggest that ablative treatment of oligometastases may substantially improve progression-free survival and overall survival, and additional large randomized studies testing this hypothesis in a definitive context are ongoing. However, several challenges remain, including quantifying the possible benefits of ablative therapies for oligoprogressive disease and developing prognostic and predictive models to assist in clinical decision making.

scholarly journals Copy Number Alterations of Depressed Colorectal Neoplasm Predict the Survival and Response to Oxaliplatin in Proximal Colon Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1527
Author(s):  
Li-Chun Chang ◽  
Han-Mo Chiu ◽  
Bing-Ching Ho ◽  
Min-Hsuan Chen ◽  
Yin-Chen Hsu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Copy Number ◽  
Colorectal Neoplasm ◽  
Progression Free Survival ◽  
Proximal Colon ◽  
Copy Number Alterations ◽  
Free Survival ◽  
Marker Panel ◽  
Genome Wide ◽  
Prospective Trials

Depressed colorectal neoplasm exhibits high malignant potential and shows rapid invasiveness. We investigated the genomic profile of depressed neoplasms and clarified the survival outcome and treatment response of the cancers arising from them. We examined 20 depressed and 13 polypoid neoplasms by genome-wide copy number analysis. Subsequently, we validated the identified copy number alterations (CNAs) in an independent cohort of 37 depressed and 42 polypoid neoplasms. Finally, the CNAs were tested as biomarkers in 530 colorectal cancers (CRCs) to clarify the clinical outcome of depressed neoplasms. CNAs in MYC, CCNA1, and BIRC7 were significantly enriched in depressed neoplasms and designated as the D-marker panel. CRCs with a D-marker panel have significantly shorter progression-free survival compared with those without (p = 0.012), especially in stage I (p = 0.049), stages T1+2 (p = 0.027), and proximal cancers (p = 0.002). The positivity of the D-marker panel was an independent risk factor of cancer progression (hazard ratio (95% confidence interval) = 1.52 (1.09–2.11)). Furthermore, the proximal CRCs with D-marker panels had worse overall and progression-free survival when taking oxaliplatin as chemotherapy than those that did not. The D-marker panel may help to optimize treatment and surveillance in proximal CRC and develop a molecular test. However, the current result remains preliminary, and further validation in prospective trials is warranted in the future.

Level of activated circulating endothelial cells to predict progression-free survival of Anlotinib treatment in patients with NSCLC: Analysis on ALTER-0303 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20530-e20530 ◽  
Author(s):  
Kai LI ◽  
Jing Wang ◽  
Xinyue Wang ◽  
Zhujun Liu ◽  
Cuigui Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Initial Period ◽  
Progression Free Survival ◽  
Circulating Endothelial Cells ◽  
Free Survival ◽  
Time Points ◽  
Potential Biomarker ◽  
Nsclc Patients ◽  
Clinical Trial Information

e20530 Background: Activated circulating endothelial cells (aCECs) have been indicated as a potential biomarker of angiogenesis in a variety of cancers. Several studies have revealed that aCECs may reflect the extent of tumor angiogenesis, and the level of aCECs counts may has correlation with progression-free survival (PFS) in anti-angiogenesis therapy on NSCLC patients. Therefore, we investigated the association between aCECs and PFS of Anlotinib treatment in ALTER-0303 study. Methods: NSCLC patients with aCECs counts in ALTER-0303 study were observed. Samples were prospectively collected at six time points: before treatment (baseline), on the 7th, 15th, 21th, 42th, 63thday of Anlotinib treatment. aCECs was identified by Flow cytometry (FCM). The prognostic value of aCECs counts was analyzed and, the patients were stratified according to their ratio of the minimum aCECs counts in all time points and counts on baseline (aCECs min/baseline) as <1 and ≥1. Results: Forty-nine patients were included of which 35 and 14 had an aCECs min/baseline<1 and ≥1, respectively in Anlotinib arm. Median follow-up was 8.6 months. In univariate survival analysis, patients with min/baseline<1 had longer PFS [HR=0.439, 95% CI (0.211-0.912), P = 0.023], the median PFS for the patients with aCECs min/baseline <1 and ≥1 were 193 days and 124 days, respectively (shown in Table). However, there were no significant relation between PFS and such aCECs min/baseline ratio found in control arm of ALTER-0303 study. Conclusions: A decrease of aCECs counts from baseline during an initial period of Anlotinib therapy may predict longer PFS and good response in NSCLC patients. Information: NCT02029209, NCT02388919 Clinical trial information: NCT02029209. [Table: see text]

Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: A retrospective case series.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13538-e13538
Author(s):  
Marc C. Chamberlain ◽  
Bryan T. Kim
Keyword(s):  
Unmet Need ◽  
Case Series ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
Retrospective Case ◽  
Free Survival ◽  
Entire Cohort ◽  
First Recurrence ◽  
Grade 3 ◽  
Recurrent Gbm

e13538 Objective: A single institution retrospective evaluation of nivolumab following disease progression on bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). Background: There is no accepted therapy for recurrent GBM after failure of bevacizumab. Methods: 16 adults, ages 52-72 years (median 62), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, and post-radiotherapy temozolomide. Bevacizumab (with or without lomustine) was administered to all patients at first recurrence. Patients were treated with nivolumab only (3mg/kg) once every 2 weeks at second recurrence. One cycle of nivolumab was defined as 2 treatments. Neurological evaluation was performed bi-weekly and neuroradiographic assessment every 4 weeks. Results: A total of 37 treatment cycles (median 2) were administered of nivolumab in which there were 14 Grade 2 adverse events (AEs) and Grade 3 AEs in 2 patients. No Grade 4 or 5 AEs were seen. Following 1 month of nivolumab, 7 patients’ demonstrated progressive disease and discontinued therapy. No patient demonstrated a response though 9 patients demonstrated neuroradiographic stable response. Survival in the entire cohort ranged from 2 - 6 months with a median of 3.5 months (CI: 2.8, 4.2). Median and 6-month PFS at 6 months was 2.0 months (range 1-5 months; CI: 1.3, 2.7) and 0% respectively. Conclusions: Nivolumab salvage therapy demonstrated no survival advantage in patients with recurrent bevacizumab refractory GBM emphasizing a continued unmet need in neuro-oncology.

Association of dynamic changes of methylated SFRP2 in ctDNA with prognosis in advanced gastric cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15051-e15051
Author(s):  
Yan Haijiao ◽  
Kele Ge ◽  
Wenyu Chen ◽  
Xizheng Mao ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dynamic Change ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Suppressor Gene ◽  
Stage Iii ◽  
Dynamic Monitoring ◽  
Free Survival ◽  
Potential Biomarker

e15051 Background: Secreted frizzled-related protein 2 (SFRP2) is a tumor suppressor gene and its hyper methylation could cause its inactivation and promote cancer development. However, whether methylated SFRP2 (mSFRP2) in ctDNA could serve as prognostic biomarker for patients with gastric cancer has not been thoroughly studied. Methods: Stage III or IV gastric cancer patients treated with systemic chemotherapy in the Third Affiliated Hospital of Soochow University from 2015 to 2017 were included. The mSFRP2 before and during chemotherapy were dynamically detected from ctDNA by digital polymerase chain reaction-based technologies. Results: In total, 121 patients were enrolled, with 63 in stage III and 58 in stage IV. Baseline median mSFRP2 was higher in stage IV than stage III (64 VS 18 copies/ng, P < 0.001). In stage III GC, the top 50% mSFRP2 population had shorter median disease-free survival (DFS, 11.0 months VS NR; HR, 13.05; 95% CI, 3.05-55.95;) and overall survival (OS, 17.0 months VS NR; HR, 7.80; 95% CI, 1.81-33.60). Similar results were observed in stage IV GC that the median progression-free survival (PFS, 4.0 VS 7.0 months; HR, 2.74; 95% CI, 1.58-4.78) and OS (12.0 VS 16.0 months; HR, 3.14; 95% CI, 1.67-5.92) was shorter in patients with top 50% mSFRP2. During the dynamic monitor along treatment, elevated mSFPR2 was associated with worse PFS (5.0 VS 7.0 months; HR, 2.17; 95% CI, 1.25-3.76) and OS (12.0 VS 15.5 months; HR, 3.51; 95% CI, 1.94-6.35) in stage IV patients. Conclusions: Our study shows the association between SFRP2 methylation and its dynamic change and prognosis in patients with gastric cancer. Our results provide a potential biomarker in ctDNA for prognosis and dynamic monitoring in patients with gastric cancer.

scholarly journals Prospective validation of a molecular prognostication panel for clival chordoma

2019 ◽  
Vol 130 (5) ◽  
pp. 1528-1537 ◽  
Author(s):  
Georgios A. Zenonos ◽  
Juan C. Fernandez-Miranda ◽  
Debraj Mukherjee ◽  
Yue-Fang Chang ◽  
Klea Panayidou ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Clinical Decision Making ◽  
Cox Model ◽  
Wide Spectrum ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Homozygous Deletion ◽  
Ki 67 ◽  
Free Survival ◽  
Clival Chordoma

OBJECTIVEThere are currently no reliable means to predict the wide variability in behavior of clival chordoma so as to guide clinical decision-making and patient education. Furthermore, there is no method of predicting a tumor’s response to radiation therapy.METHODSA molecular prognostication panel, consisting of fluorescence in situ hybridization (FISH) of the chromosomal loci 1p36 and 9p21, as well as immunohistochemistry for Ki-67, was prospectively evaluated in 105 clival chordoma samples from November 2007 to April 2016. The results were correlated with overall progression-free survival after surgery (PFSS), as well as progression-free survival after radiotherapy (PFSR).RESULTSAlthough Ki-67 and the percentages of tumor cells with 1q25 hyperploidy, 1p36 deletions, and homozygous 9p21 deletions were all found to be predictive of PFSS and PFSR in univariate analyses, only 1p36 deletions and homozygous 9p21 deletions were shown to be independently predictive in a multivariate analysis. Using a prognostication calculator formulated by a separate multivariate Cox model, two 1p36 deletion strata (0%–15% and > 15% deleted tumor cells) and three 9p21 homozygous deletion strata (0%–3%, 4%–24%, and ≥ 25% deleted tumor cells) accounted for a range of cumulative hazard ratios of 1 to 56.1 for PFSS and 1 to 75.6 for PFSR.CONCLUSIONSHomozygous 9p21 deletions and 1p36 deletions are independent prognostic factors in clival chordoma and can account for a wide spectrum of overall PFSS and PFSR. This panel can be used to guide management after resection of clival chordomas.

scholarly journals DUSP6 regulates radio-sensitivity in glioblastoma by modulating the recruitment of p-DNAPKcs at DNA double-strand breaks

2021 ◽  
Author(s):  
Jyothi Nair ◽  
Safiulla Basha Syed ◽  
Tejashree Mahaddalkar ◽  
Madhura Ketkar ◽  
Rahul Thorat ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Clonogenic Survival ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Canonical Function ◽  
Free Survival ◽  
Strand Breaks ◽  
Radio Sensitivity ◽  
Recurrent Gbm

Glioblastoma (GBM) has poor median survival due to its resistance to chemo-radiotherapy regimen, resulting in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is up-regulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies (n=11) compared to primary biopsies (n=11). Importantly, although reported as cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse population of GBM cell lines generated from in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radio-sensitized primary and importantly, relapse GBM cells by inhibiting the recruitment of p-DNAPKcs, subsequently down-regulating the recruitment of γH2AX and 53BP1. This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM.

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