Identification of Molecular Biomarkers and Pathways for Risk Stratification in Human Papilloma Virus-Associated Cancers

Abstract Background: Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients’ response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. Methods: We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of the anatomical locations by analyzing the TCGA and GEO databases. In this study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high-risk and low-risk groups in HPV-associated CC and HNC, identifying a molecular biomarkers and pathways for the risk stratification. Results: Among the identified 174 DEGs, expression of the genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, LAMC1) were increased in high-risk groups in both HPV-associated CC and HNC while expression of the genes associated with the T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) were decreased vise versa. The individual genes showed statistically significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations, and distinct patterns of immune cell infiltration in tumor microenvironments. Conclusion: These results identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical locations. The identified targets are selectively working in only HPV-associated cancers, but not in HPV-negative cancers indicating possibility of the selective targets governing HPV-infective tumor microenvironments.

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Risk stratification in pediatric low-grade glioma and glioneuronal tumor treated with radiation therapy: an integrated clinicopathologic and molecular analysis

Neuro-Oncology ◽

10.1093/neuonc/noaa031 ◽

2020 ◽

Vol 22 (8) ◽

pp. 1203-1213 ◽

Cited By ~ 5

Author(s):

Sahaja Acharya ◽

Jo-Fen Liu ◽

Ruth G Tatevossian ◽

Jason Chiang ◽

Ibrahim Qaddoumi ◽

...

Keyword(s):

Overall Survival ◽

Radiation Therapy ◽

High Risk ◽

Risk Stratification ◽

Risk Groups ◽

Low Risk ◽

Glioneuronal Tumor ◽

Low Grade ◽

Diffuse Astrocytoma ◽

Prognostic Features

Abstract Background Management of unresectable pediatric low-grade glioma and glioneuronal tumor (LGG/LGGNT) is controversial. There are no validated prognostic features to guide use of radiation therapy (RT). Our study aimed to identify negative prognostic features in patients treated with RT using clinicopathologic and molecular data and validate these findings in an external dataset. Methods Children with non-metastatic, biopsy-proven unresectable LGG/LGGNT treated with RT at a single institution between 1997 and 2017 were identified. Recursive partitioning analysis (RPA) was used to stratify patients into low- and high-risk prognostic groups based on overall survival (OS). CNS9702 data were used for validation. Results One hundred and fifty patients met inclusion criteria. Median follow-up was 11.4 years. RPA yielded low- and high-risk groups with 10-year OS of 95.6% versus 76.4% (95% CI: 88.7%–98.4% vs 59.3%–87.1%, P = 0.003), respectively. These risk groups were validated using CNS9702 dataset (n = 48) (4-year OS: low-risk vs high-risk: 100% vs 64%, P < 0.001). High-risk tumors included diffuse astrocytoma or location within thalamus/midbrain. Low-risk tumors included pilocytic astrocytoma/ganglioglioma located outside of the thalamus/midbrain. In the subgroup with known BRAF status (n = 49), risk stratification remained prognostic independently of BRAF alteration (V600E or fusion). Within the high-risk group, delayed RT, defined as RT after at least one line of chemotherapy, was associated with a further decrement in overall survival (P = 0.021). Conclusion A high-risk subgroup of patients, defined by diffuse astrocytoma histology or midbrain/thalamus tumor location, have suboptimal long-term survival and might benefit from timely use of RT. These results require validation.

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Comparação da Aplicação da EER Hema-Obs a 250 Gestações da Consulta de Hematologia-Obstetrícia do Centro Hospitalar São João, Portugal Versus EER Galit Sarig a 90 Gestações no Rambam Health Care Campus, Israel

Acta Médica Portuguesa ◽

10.20344/amp.5200 ◽

2015 ◽

Vol 28 (2) ◽

pp. 189

Author(s):

Ana Salselas ◽

Inês Pestana ◽

Francisco Bischoff ◽

Mariana Guimarães ◽

Joaquim Aguiar Andrade

Keyword(s):

High Risk ◽

Risk Stratification ◽

Pregnant Women ◽

Receiver Operating Characteristic ◽

Operating Characteristic ◽

Characteristic Curve ◽

Risk Groups ◽

Low Risk ◽

Very High ◽

Receiver Operating

Introduction: Pregnant women with thromboembolic diseases, previous thrombotic episodes or thrombophilia family history were supervised in a multidisciplinary Obstetrics/ Hematology consultation in Centro Hospitalar São João EPE, Porto, Portugal. For the evaluation and medication of these women, a risk stratification scale was used. Purposes: The aim of this study was to validate a Risk Stratification Scale and thromboprophylaxis protocol by means of comparing it with a similar scale, developed and published by Sarig. Material and Methods: We have compared: The distribution, by risk groups, obtained through the application of the two scales on pregnant women followed at Centro Hospitalar São João, Porto, Portugal, consultation; the sensibility and specificity for each one of the scales (DeLong scale, applied to Receiver Operating Characteristic) curves; the outcomes in pregnancies followed in Hospital São João, Porto, Portugal Results: According to our Hema-Obs risk stratification scale, 29% were allocated to low-risk, 47% to high-risk and 24% to very-high-risk groups. According to Galit Sarig risk stratification scale, 24% were considered low-risk, 53% moderate, 16% high-risk and 7% as very high-risk group. In our study we observed 9% of spontaneous abortions, in comparison with 18% in the Galit Sarig cohort. From the application of Receiver Operating Characteristic curve to both risk stratification scales, the results of the calculated areas were 58,8% to our Hema-Obs risk stratification scale and 38,7% to Galit Sarig risk stratification scale, with a Delong test significancie of p = 0.0006. Conclusions: We concluded that Hema-Obs risk stratification scale is an effective support for clinical monitoring of therapeutic strategies.

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Risk stratification of normotensive pulmonary embolism: prognostic impact of copeptin

European Respiratory Journal ◽

10.1183/13993003.00857-2015 ◽

2015 ◽

Vol 46 (6) ◽

pp. 1701-1710 ◽

Cited By ~ 18

Author(s):

Kristian Hellenkamp ◽

Johanna Schwung ◽

Heidi Rossmann ◽

Anja Kaeberich ◽

Rolf Wachter ◽

...

Keyword(s):

Pulmonary Embolism ◽

High Risk ◽

Risk Stratification ◽

Adverse Outcome ◽

Troponin T ◽

High Sensitivity ◽

High Risk Group ◽

Low Risk ◽

Prognostic Impact ◽

Increased Risk

The prognostic value of copeptin, the C-terminal fragment of the precursor protein of vasopressin which is released upon stress, and hypotension in pulmonary embolism is unknown, especially if combined with biomarkers reflecting different pathophysiological axes such as myocardial injury (high-sensitivity troponin T (hsTnT)) and stretch (N-terminal pro-brain natriuretic peptide (NT-proBNP)).We prospectively studied 268 normotensive pulmonary embolism patients included in a single-centre cohort study.Patients with an adverse 30-day outcome (5.6%) had higher copeptin levels than patients with a favourable course (median (interquartile range) 51.8 (21.6–90.8) versus 13.2 (5.9–39.3) pmol·L−1; p=0.020). Patients with copeptin levels above the calculated optimal cut-off value of 24 pmol·L−1 had a 5.4-fold increased risk for an adverse outcome (95% CI 1.68–17.58; p=0.005). We developed a strategy for risk stratification based on biomarkers. None of 141 patients (52.6%) with hsTnT <14 pg·mL−1 or NT-proBNP <600 pg·mL−1 had an adverse outcome (low risk). Copeptin ≥24 pmol·L−1 stratified patients with elevated hsTnT and NT-proBNP as intermediate–low and intermediate–high risk (5.6% and 20.0% adverse outcome, respectively). Compared to the algorithm proposed by the 2014 European Society of Cardiology guideline, more patients were classified as low risk (52.8% versus 17.5%, p<0.001) and more patients in the intermediate–high risk group had an adverse outcome (20.0% versus 11.6%).Copeptin might be helpful for risk stratification of normotensive patients with pulmonary embolism, especially if integrated into a biomarker-based algorithm.

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A Risk Score Integrating BAALC, ERG and WT1 Expression Can Be Used To Improve Risk Stratification In Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v122.21.1323.1323 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1323-1323

Author(s):

Anna Hecht ◽

Florian Nolte ◽

Daniel Nowak ◽

Verena Nowak ◽

Benjamin Hanfstein ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Risk Stratification ◽

Risk Score ◽

Risk Group ◽

Risk Groups ◽

Low Risk ◽

Expression Levels ◽

Improve Risk Stratification

Abstract Introduction With current therapy regimens over 75% of patients with de novo acute promyelocytic leukemia (APL) can be cured. Approaches to further improve patient outcome by stratifying patients at the time of initial diagnosis according to their individual risk and to adjust therapy accordingly have been based on clinical features only. Molecular markers have not been established for risk stratification as yet. Recently, we have shown that high expression levels of the genes brain and acute leukemia, cytoplasmic (BAALC) and ets related gene (ERG) are associated with inferior outcome in APL patients. In addition, data indicate that aberrant expression of the gene Wilms’ tumor 1 (WT1) is a negative prognostic factor with regard to overall survival (OS) after complete remission (CR) and relapse free survival (RFS) in APL. In this study we evaluated the prognostic relevance of a combined score integrating the expression levels of the above mentioned genes to further improve risk stratification in APL patients. Methods Expression levels of BAALC, ERG and WT1 of 62 patients with newly diagnosed APL were retrospectively analyzed in bone marrow mononuclear cells using multiplex reverse transcriptase quantitative real-time PCR (qRT-PCR). Median age of patients was 47 years (range: 19 to 82y). All patients gave informed consent. Patients were diagnosed and treated in the German AML Cooperative Group (AMLCG) study with a treatment of simultaneous ATRA and double induction chemotherapy including high-dose ara-C, consolidation and maintenance chemotherapy. The following gene expression levels were identified as negative risk factors in preceding studies: BAALC expression ≥25th percentile (BAALChigh), ERG expression >75th percentile (ERGhigh) and WT1 expression ≤25th percentile or ≥75th percentile (WT1low/high). A risk score was developed as follows: for the presence of one of the mentioned risk factors one scoring point was assigned to a respective patient, i.e. a maximum of 3 points (one point for BAALChigh, ERGhigh and WT1low/high, respectively) and a minimum of 0 points (i.e. presenting with none of the aforementioned risk factors) could be allocated to one patient. Accordingly, patients were divided into four risk groups: 7 patients scored 0 points (= low risk), 27 patients scored 1 point (= intermediate 1 risk), 19 patients scored 2 points (= intermediate 2 risk) and 9 patients scored 3 points (= high risk). Subsequently, OS, RFS and relapse free interval (RFI) were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the four risk groups (p<0.05). Results The integrative risk score divided patients into four groups with significantly different outcome. The low risk group showed a RFS of 100% at 10 years of follow-up compared to the intermediate 1 risk group with 81%, the intermediate 2 risk group with 58% and the high risk group with a RFS of 42% only (median survival: 4.6y) (p=0.02). In accordance, the RFI differed significantly between the four groups: low risk 100%, intermediate 1 risk 100%, intermediate 2 risk 89% and high risk 71% (p=0.049). There was no statistically significant difference between the 4 groups with regard to OS in the entire patient cohort. However, there was a clear trend towards a difference in OS in patients who achieved a CR after induction therapy: low risk 100%, intermediate 1 risk 81%, intermediate 2 risk 68% and high risk 53% survival at 10 years of follow-up (p=0.09). Conclusion Integration of expression levels of the genes BAALC, ERG and WT1 into a scoring system identifies 4 risk groups with significantly different outcome with regard to RFS and RFI. It might be a promising approach to guide therapeutic decisions in patients with APL. However, multivariate analyses and validation of these data in an independent patient cohort is warranted. Disclosures: No relevant conflicts of interest to declare.

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Identification of a Gene-Related Risk Signature in Melanoma Patients Using Bioinformatic Profiling

Journal of Oncology ◽

10.1155/2020/7526204 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Jing Wang ◽

Peng-Fei Kong ◽

Hai-Yun Wang ◽

Di Song ◽

Wen-Qing Wu ◽

...

Keyword(s):

Gene Expression ◽

High Risk ◽

Expression Patterns ◽

Prognostic Significance ◽

Gene Signature ◽

Low Risk ◽

Gene Set Enrichment Analysis ◽

Prognostic Impact ◽

Related Risk ◽

Melanoma Patients

Introduction. Gene signature has been used to predict prognosis in melanoma patients. Meanwhile, the efficacy of immunotherapy was correlated with particular genes expression or mutation. In this study, we systematically explored the gene expression pattern in the melanoma-immune microenvironment and its relationship with prognosis. Methods. A cohort of 122 melanoma cases with whole-genome microarray expression data were enrolled from the Gene Expression Omnibus (GEO) database. The findings were validated using The Cancer Genome Atlas (TCGA) database. A principal component analysis (PCA), gene set enrichment analysis (GSEA), and gene oncology (GO) analysis were performed to explore the bioinformatic implications. Results. Different gene expression patterns were identified according to the clinical stage. All eligible gene sets were analyzed, and the 8 genes (GPR87, KIT, SH3GL3, PVRL1, ATP1B1, CDAN1, FAU, and TNFSF14) with the greatest prognostic impact on melanoma. A gene-related risk signature was developed to distinguish patients with a high or low risk of an unfavorable outcome, and this signature was validated using the TCGA database. Furthermore, the prognostic significance of the signature between the classified subgroups was verified as an independent prognostic predictor of melanoma. Additionally, the low-risk melanoma patients presented an enhanced immune phenotype compared to that of the high-risk gene signature patients. Conclusions. The gene pattern differences in melanoma were profiled, and a gene signature that could independently predict melanoma patients with a high risk of poor survival was established, highlighting the relationship between prognosis and the local immune response.

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Cytogenetic Prognostication Within Medulloblastoma Subgroups

Journal of Clinical Oncology ◽

10.1200/jco.2013.50.9539 ◽

2014 ◽

Vol 32 (9) ◽

pp. 886-896 ◽

Cited By ~ 168

Author(s):

David J.H. Shih ◽

Paul A. Northcott ◽

Marc Remke ◽

Andrey Korshunov ◽

Vijay Ramaswamy ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Prognostic Significance ◽

Molecular Biomarkers ◽

Low Risk ◽

Chromosome 11 ◽

Group 4 ◽

Clinical Biomarkers ◽

Group 3 ◽

Very High

Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

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P2757Embolic risk stratification and prognostic impact of early surgery in left-sided infective endocarditis

European Heart Journal ◽

10.1093/eurheartj/ehz748.1074 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

V Scheggi ◽

N Ceschia ◽

V Andrei ◽

P L Stefano

Keyword(s):

Infective Endocarditis ◽

High Risk ◽

Risk Stratification ◽

Imaging Techniques ◽

Low Risk ◽

Early Surgery ◽

Optimal Timing ◽

Prognostic Impact ◽

Telephone Interviews ◽

Similar Survival

Abstract Background Surgery is performed in 50% to 60% of infective endocarditis. In patients with definite surgical indication for hearth failure and with large vegetation, early surgery prevents embolic events. The optimal timing of surgery for other indications is still debated. Moreover, patients with large vegetation as unique indication to surgery, have a weak class of recommendation to it. Accurate risk stratification for embolic events is desirable to optimize selection of surgical candidates. Materials and methods We retrospectively analyzed 195 consecutive patients (72 women and 123 men) admitted to our department between 2013 and 2017 with definite IE according to modified Duke University criteria. Transesophageal echocardiography and blood cultures were performed in all patients for confirmation of diagnosis. Systemic embolism was soughton admission clinically and with imaging techniques (Brain and chest CT plus abdominal CT or US scan). Seventy-seven percent of patients underwent surgery (valve repair or replacement). Outcome following discharge was systematically assessed by structured telephone interviews. Results Of the 195 patients with left sided IE, 151 underwent surgery, 29 were low risk and treated medically, 5 refused surgery and 10 were not operated due to high surgical risk. Overall survival was 78% at 4 years. Patients excluded from surgery had the worst prognosis, while operated patients with high-risk IE showed comparable survival to non-complicated infections treated medically. Early surgery (<2 weeks from diagnosis) was associated with similar survival compared to later intervention. Euroscore II was the main predictor of mortality when above a threshold of 7 before 2015 and 16 after 2015, reflecting surgical management of higher risk patients over time.In left sided IE, mean vegetation length was 11.1 mm; embolic events before diagnosis occurred in 35% of cases and Staphylococcus aureus etiologywas the main risk factor associated with embolism (OR 4, p<0.05). Vegetation size >10 mm was also independently associated with embolic risk (p=0.033) whereas renal failure, age, sex, endocarditis location (mitral or aortic), type of valve (native or prosthetic), perivalvular extension and degree of valveregurgitation were not. Conclusions Compared to low-risk IE patients treated medically, those at high-risk showed comparable survival when managed surgically, whereas a conservative approach was associated with adverse prognosis. In patients with left sided IE and intermediate vegetation length, S. aureus infection was the best independent predictor of systemic embolic events. Our data support extensive surgical referral in high risk IE and suggest that its etiology represents an important factor in decision-making.

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Preclinical markers of carotid atherosclerosis and cardiovascular risk assessed by the ESH/ESC scale (2003, 2007, 2009)

CARDIOVASCULAR THERAPY AND PREVENTION ◽

10.15829/1728-8800-2011-4-14-20 ◽

2011 ◽

Vol 10 (4) ◽

pp. 14-20 ◽

Cited By ~ 1

Author(s):

S. Sh. Urazalina ◽

A. N. Rogoza ◽

T. V. Balakhonova ◽

R. P. Myasnikov ◽

T. E. Kolmakova ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

European Society ◽

Risk Group ◽

Intima Media Thickness ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Intermediate Risk ◽

European Society Of Cardiology

Aim. To assess the degree of cardiovascular (CV) risk adjustment in patients with low and intermediate risk by the SCORE scale, who were further examined in accordance with the European Society of Hypertension/European Society of Cardiology Guidelines (2003, 2007, 2009), and also underwent carotid artery (CA) ultrasound, as an extension of the ambulatory examination protocol. Material and methods. The study included 600 individuals aged 30-65 years (445 women, 155 men), with low to intermediate SCORE-assessed risk, and without diagnosed atherosclerosis or diabetes mellitus. The algorithm of CV risk stratification included SCORE scale, the ESH/ESC Guidelines (2003, 2007, 2009) and duplex CA ultrasound, with intima-media thickness (IMT) and atherosclerotic plaque (AP) assessment. Results. At the first stage of CV risk classification, which included routine examinations only, 73,8 % of the patients remained in the “low-risk” group, 14,5 % remained in the “intermediate-risk” group, and 11,7 % were moved to the “high-risk” group. After taking into account the duplex CA ultrasound results, the “low-risk”, “intermediaterisk”, and “high-risk” groups included 35,7 %, 33,5 %, and 30,8 % of the patients, respectively. In the “low-risk” and “intermediate-risk” groups, most patients had normal blood pressure levels (72,8 % and 83,5 %, respectively), while most patients in the “high-risk” group had arterial hypertension (56,7 %). The reason for moving the patients to the “high-risk” group was visualization of AP in CA (100 %). The percentage of subjects with one AP in this group was 22,7 %. In total, AP were visualized in 358 out of 600 participants (59,6 %). Out of these 358 patients, 26 (7,2 %) had IMT value >0,9 mm. Out of 242 patients without AP in CA, 2 (0,8 %) had IMT value >0,9 mm. Conclusion. At both risk stratification stages, the most prevalent causes of moving the patients to the groups of higher CV risk were dyslipidemia (81,3 % and 92,5 %, respectively), smoking (26,7 % and 22,2 %), abdominal obesity (77,7 %), and metabolic syndrome (98,5 %). The level of CV risk was affected by AP presence to a substantially greater extent than by IMT.

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Plasma Biomarker Profiling In Langerhans Cell Histiocytosis: Risk-Stratifying The Inflammatory Storm

Blood ◽

10.1182/blood.v122.21.2854.2854 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2854-2854

Author(s):

Miguel Dario Cantu ◽

Tricia L Peters ◽

Karen Phaik-Har Lim ◽

Albert Shih ◽

Rikhia Chakraborty ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Langerhans Cell Histiocytosis ◽

Risk Groups ◽

Langerhans Cell ◽

Response To Therapy ◽

Low Risk ◽

Clinical Risk ◽

Clinical Risk Groups ◽

Single Lesion

Abstract Introduction Despite indistinguishable histology and the common feature of Birbeck granules in lesion biopsies, clinical presentation of patients with Langerhans Cell Histiocytosis (LCH) is highly variable, from single lesion cured by curretage, to multi-system disease requiring aggressive chemotherapy or stem cell transplant. Risk stratification for Langerhans Cell Histiocytosis has historically assigned clinical risk groups based on anatomic location and extent of LCH lesions, which is the basis for dose and duration of chemotherpy on recent Histiocyte Society trials. In this study, we test the hypothesis that distinct subgroups of patients with LCH may be identified by relative levels of circulating biomarkers. Methods Pre-therapy plasma was collected on 97 patients with LCH (82 Pediatric: 17 High-Risk, 23 Multisystem/Multifocal “Non-risk”, 42 Single Lesion “Non-risk”; 15 Adult: 5 High-Risk, 5 Multisystem/Multifocal “Non-risk”, 5 Single Lesion “Non-risk”) and 49 control subjects (32 Pediatric, 17 Adult). Quantitative levels of plasma proteins (158 analytes) was determined by multiplex analysis with Millipore MagPix kits and the Luminex plate reader. Data were analyzed with both unsupervised and supervised methodologies. Results Consensus clustering with non-negative matrix factorization (NMF) clusters identified three groups which were analyzed along with clinical categories. Significant clinical variables included age (adult samples clustered in NMF group 1) and LCH risk category (High-Risk LCH samples clustered in NMF group 3). Samples from patients with the BRAF-V600Emutation or relapse within 1 year did not cluster into any NMF group with signifiance. Additionally, supervised analysis identified specific molecules that were significantly differentially expressed between different clinical categories after multiple testing correction (FDR<0.10): Pediatric LCH vs Adult LCH (72 molecules significant, largest differences in MMP-3, MMP-2 and osteopontin); Pediatric Control vs Pediatric LCH (66 molecules significant, largest differences in SDF-1a, IL-20, MIP-1d, FGF-2 and sIL-4R); Pediatric Low-Risk vs Pediatric High-Risk (47 molecules significant, largest differences in sTNF-R11, sTNF-RI, I-309, sIL2Ra and osteopontin). While previous studies have analyzed expression differences of cytokines in LCH lesions and plasma, in this study the most striking differences are between control vs LCH samples are chemokine molecules. The largest differences between Low-Risk and High-Risk LCH patients include inflammatory cytokines and receptors. Conclusions Despite mounting evidence supporting pathogenesis of LCH as a myeloid neoplasia arising from immature dendritic cell precursors, these results are consistent with exuberant chemokine and cytokine expression in patients with active LCH, supporting a potential role for inflammation in pathogenesis. This study demonstrates the feasibility of identifying novel LCH sub-groups according to plasma protein profiles with unsupervised analysis, and significant differences can be detected in protein levels between clinical risk groups. Future studies will validate the clinical utility of plasma biomarkers in diagnosis, risk-stratification and determining response to therapy. Finally, feasibility of collecting plasma compared to viable lesions makes plasma studies ideal for prospective collection and analysis in cooperative group studies. Disclosures: No relevant conflicts of interest to declare.

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Risk Stratification and Individualized Chemotherapy for Elderly Patients with Locoregionally Advanced Nasopharyngeal Carcinoma

10.21203/rs.3.rs-530771/v1 ◽

2021 ◽

Author(s):

Jia Kou ◽

Lu-Lu Zhang ◽

Dan-Wan Wen ◽

Guan-Qun Zhou ◽

Chen-Fei Wu ◽

...

Keyword(s):

High Risk ◽

Nasopharyngeal Carcinoma ◽

Risk Stratification ◽

Elderly Patients ◽

Risk Group ◽

Disease Free Survival ◽

Risk Groups ◽

High Risk Group ◽

Low Risk ◽

Individualized Treatment

Abstract Backgroud: The optimal treatment strategy for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains unclear. We aimed to develop individualized treatment strategies for such patients according to their pretreatment risk stratification and the degree of comorbidities.Methods: A total of 583 elderly LA-NPC patients diagnosed between January 2011 and January 2018 were retrospectively studied. Based on prognostic factors confirmed by multivariate analysis, we constructed a nomogram for disease-free survival (DFS). The entire cohort was then divided into two groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities was assessed by Charlson Comorbidity Index (CCI). We performed subgroup analysis based on the degree of complications in the low- and high-risk groups to compare the survival outcomes of different treatment regimens using the Kaplan-Meier method and the log-rank test.Results: A nomogram for DFS was constructed with T/N classification, Epstein-Barr virus DNA and albumin. The high-risk group had significantly poorer survival compared with the low-risk group. The 3-year DFS and overall survival (OS) of the low-risk group and the high-risk group were 76.7% vs. 44.6%, 81.5% vs. 51.0% (both P <0.001) respectively. Only high-risk patients with fewer comorbidities (CCI =2) would benefit from induction chemotherapy combined with concurrent chemoradiotherapy, while patients in the low-risk group or the high-risk group with more comorbidities (CCI >2) would not have.Conclusion: We constructed a prognostic nomogram for DFS and generated two risk groups. Combining risk stratification and degree of comorbidities can better guide individualized treatment for elderly LA-NPC patients.

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