Prognosis In Solid Tumors Research Articles

Original Article Non-Hematological Malignancies Seeding in Bone Marrow

Background: Bone marrow is the site of origin for primary haematological malignancies and is the third common preferred site metastasized by the solid tumors. The malignant infiltration of the hematopoietic tissue alters the clinical course of disease, response of the treatment and influences the overall survival. The aim of this study was to assess pattern of bone marrow involvement by different solid tumors and their correlation with hematological parameters.
 Methods: In this retrospective study, 8064 bone marrow examinations from Jan 2011-Aug 2017 at tertiary health and research centre of Northern India were evaluated to access spectrum of different solid tumors infiltrating the bone marrow alongwith their clinical, hematological and histopathological findings.
 Result: Total 38 cases of non-hematological malignancies metastasizing to bone marrow were evaluated with main indications of lytic lesions, cytopenia and Pyrexia of Unknown Origin. The most common metastasis were adenocarcinoma of prostate and lung. In 33 cases, the clinical, cytomorphological and immunohistochemical analysis findings were correlated to know primary site, while in remaining five patients, even after complete diagnostic evaluation, the definitive origin could not be ascertained, therefore categorized as Carcinoma of Unknown Primary Site (CUPS).
 Conclusion: Our series showed that anemia as commonest parameter, followed by leukopenia, thrombocytopenia. Many cases were misdiagnosed as multiple myeloma due to lytic lesion, anemia and hypercalcemia. We concluded that unexplained cytopenia are strong indicators of bone marrow examination; an easy, convenient, sensitive, effective procedure of staging of tumor, monitoring the course and prognosis of solid tumors.

Neutrophil-to-lymphocyte ratio as a prognostic indicator for overall and cancer-specific survival in squamous cell carcinoma of the head and neck.

Neutrophil-to-lymphocyte ratio (NLR) is a biomarker that is correlated with systemic inflammation and poor prognosis in solid tumors. We investigated the value of NLR in predicting survival in a large population of head and neck cancer patients in the United States. We performed a retrospective cohort study of Veterans Affairs patients with head and neck squamous cell carcinoma (HNSCC) diagnosed between January 2000 and December 2017. We compared 5-year overall survival and cancer-specific survival for different NLR tertiles using cox proportional hazards modeling with adjustment for covariates. The primary cohort consisted of 14 644 subjects of which 99% were male. Relative to patients with NLRs in the lower tertile, patients with NLRs in the top tertile had an 71% increased hazard of all-cause mortality (P < .001) and 44% increased hazard of cancer-specific mortality (P < .001) at 5 years. Elevated NLR in HNSCC confers a poor prognosis.

The prognostic value of IDO expression in solid tumors: a systematic review and meta-analysis

BackgroundIndoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the metabolism of tryptophan into kynurenine. It is considered to be an immunosuppressive molecule that plays an important role in the development of tumors. However, the association between IDO and solid tumor prognosis remains unclear. Herein, we retrieved relevant published literature and analyzed the association between IDO expression and prognosis in solid tumors.MethodsStudies related to IDO expression and tumor prognosis were retrieved using PMC, EMbase and web of science database. Overall survival (OS), time to tumor progression (TTP) and other data in each study were extracted. Hazard ratio (HR) was used for analysis and calculation, while heterogeneity and publication bias between studies were also analyzed.ResultsA total of 31 studies were included in this meta-analysis. Overall, high expression of IDO was significantly associated with poor OS (HR 1.92, 95% CI 1.52–2.43, P < 0.001) and TTP (HR 2.25 95% CI 1.58–3.22, P < 0.001). However, there was significant heterogeneity between studies on OS (I2 = 81.1%, P < 0.001) and TTP (I2 = 54.8%, P = 0.007). Subgroup analysis showed lower heterogeneity among prospective studies, studies of the same tumor type, and studies with follow-up periods longer than 45 months.ConclusionsThe high expression of IDO was significantly associated with the poor prognosis of solid tumors, suggesting that it can be used as a biomarker for tumor prognosis and as a potential target for tumor therapy.

Phase Ib/II trial of tisotumab vedotin (TV) ± bevacizumab (BEV), pembrolizumab (PEM), or carboplatin (CBP) in recurrent or metastatic cervical cancer (innovaTV 205/ENGOT-cx8/GOG-3024).

TPS6095 Background: Patients (pts) with recurrent/metastatic cervical cancer (r/mCC) receive paclitaxel/platinum or paclitaxel/topotecan ± BEV as first-line standard-of-care therapy. Tissue factor (TF) expression has been associated with poor prognosis in solid tumors, and TF is highly expressed in r/mCC. TV is an investigational antibody-drug conjugate composed of a fully human, TF-directed monoclonal antibody covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Upon internalization, MMAE is released resulting in cell cycle arrest and apoptotic cell death. In pts with previously treated r/mCC, TV monotherapy (IV 2.0 mg/kg Q3W) demonstrated a manageable safety profile and encouraging antitumor activity (investigator-assessed confirmed ORR, 24%; median DOR, 4.2 mo) [Hong DS et al. Clin Cancer Res. 2019. doi: 10.1158/1078-0432.CCR-19-2962]. The preliminary safety and efficacy data for TV monotherapy suggest a positive benefit/risk profile and warrant further investigation of TV in combination with therapies commonly administered to pts with r/mCC. The global, open-label, phase Ib/II trial innovaTV 205/ENGOT-cx8/GOG-3024 (NCT03786081) evaluates the safety and antitumor activity of TV monotherapy and TV in combination with BEV, PEM, or CBP in pts with untreated or previously treated r/mCC. This abstract presents the new TV monotherapy weekly dosing schedule. Results from this study will inform the further clinical development of TV in the treatment of r/mCC. Methods: Approximately 170 adult pts with recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma of the cervix; measurable disease; and ECOG PS 0-1 will be enrolled. The phase I part of the study will consist of 3 dose-escalation arms for identification of the recommended phase II dose (RP2D) of TV administered Q3W with BEV, PEM, or CBP. In this part, previously treated pts will receive escalating doses of TV (IV Q3W) in combination with escalating doses of BEV (IV Q3W), a fixed dose of PEM (IV Q3W), or a fixed dose of CBP (IV Q3W). The phase II part will include 4 expansion arms. In this phase, pts who have not received prior systemic therapy for r/mCC will receive 1) TV RP2D + PEM or 2) TV RP2D + CBP; pts who received 1-2 prior treatments for r/mCC will receive 3) TV RP2D + PEM or 4) TV monotherapy with weekly dosing (IV 3Q4W). The primary endpoint of phase II is ORR by RECIST v1.1. Secondary endpoints include DOR, time to response, PFS, OS, and safety. Clinical trial information: NCT03786081.

SUN-122 Nuclear PDCD4 Expression Predicts Good Clinical Outcome in Luminal A-Like and Luminal B-Like Breast Cancer Subtypes

Hormone receptor-positive (HR+, estrogen and/or progesterone receptor-positive) and HER2-negative breast cancer (BC) subtype is a biologically heterogeneous entity that comprises 70% of BCs. This subtype includes both luminal (Lum) A- and B-like subtypes, which have differences in prognosis and sensitivity to endocrine therapies. The development of biomarkers guiding treatment decisions in these settings is required. Tumor suppressor PDCD4 (programmed cell death 4), which can be found both in the nucleus (NPDCD4) or the cytoplasm (CPDCD4), inhibits tumor growth and metastasis, and its loss is associated with poor prognosis in solid tumors. To explore the clinical relevance of PDCD4 in BC, we analyzed its expression by immunohistochemistry in a cohort of 619 patients with primary invasive BC. We found that 34.7% of patients showed NPDCD4 and 21.3% showed CPDCD4. NPDCD4 positivity, but not CPDCD4, was associated with lower clinical stage (P = 0.0003), with presence of more differentiated tumors (P = 6.4x10-6), and with estrogen and progesterone receptor (PR) expression (P = 9.2x10-9 and P = 2.8x10-9, respectively). Kaplan-Meier analysis revealed that NPDCD4 expression was associated with a longer overall survival (OS) and disease-free survival (DFS) in LumA-like (P = 0.008 and P = 0.028, respectively) and LumB-like (P = 0.004 and P = 0.012, respectively) subtypes. Interestingly, patients with LumB-like tumors displaying NPDCD4 presented estimated OS and DFS rates similar to the ones observed in patients with LumA-like tumors also expressing NPDCD4, indicating that its presence improves the clinical outcome of LumB-like patients. Multivariate Cox regression analysis identified NPDCD4 as an independent predictor of good clinical outcome in both LumA-like (HR: 0.45, 95% CI 0.22-0.96, P = 0.038) and LumB-like (HR: 0.28, 95% CI 0.10-0.80, P = 0.018) subtypes. We validated our results by in silico analysis using expression data from the METABRIC cohort. Bioinformatics analysis of BC cells from the Cancer Cell Line Encyclopedia revealed a positive correlation between PDCD4 and PR expression (P = 0.015). Since LumB-like tumors present a higher risk of resistance to endocrine therapy and both PR and PDCD4 levels in this subtype are lower than in the LumA-like one, we postulated that the presence of PR may modulate PDCD4 expression. Silencing of PR expression in HR+ cells decreased PDCD4 protein levels while reconstitution of PR in a PR-null cell line increased them, confirming PR requirement for PDCD4 modulation. In line with PDCD4 physiological function, its knockdown increased cell migration capability of HR+ BC cells, whereas its restoration led to a decrease in cell migration of HR-negative BC models. Our findings identified NPDCD4 positivity as a novel biomarker of clinical outcome in LumA- and B-like subtypes and revealed PDCD4 reconstitution as a novel therapeutic strategy in BC.

The role of SOX2 overexpression in prognosis of patients with solid tumors: A meta-analysis and system review.

Background:Many studies have been done to reported the value of SRY-related HMG-box Gene 2 (SOX2) in prognosis of solid tumors. But results were not particularly consistent among these studies because of the limitations of the small sample data.Methods:We searched relevant studies published before November 2018 by PubMed, Web of Science and EMBASE. In this meta-analysis, hazard ratio (HR) values for overall survival (OS) were cumulatively pooled and quantitatively analyzed.Results:A meta-analysis based on 12 studies with 3318 patients was conducted to assess the potential correlation between SOX2 overexpression and OS in human solid tumors. A total of 12 studies (n = 3318) were assessed in the meta-analysis. It suggested that the high expression of SOX2 obviously indicates poor survival and prognosis in both univariate and multivariate analysis. In the univariate analysis, the combined HR for OS was 1.66 (95% confidence interval [CI]: 1.46–1.89, P < .001). The pooled HR of multivariate analysis for OS was 1.51 (95% confidence interval [CI]: 1.32–1.71, P < .001).Conclusions:This meta-analysis indicated that the high expression level of SOX2 is significantly associated with a decline in survival of human with solid tumors. On the basis of the expression level in solid tumors, SOX2 is expected to be a meaningful prognostic biomarker and effective therapeutic target.

Integrin ανβ6 Protein Expression and Prognosis in Solid Tumors: A Meta-Analysis.

Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ανβ6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ανβ6 integrin protein expression in solid tumors. A systematic search of electronic databases identified publications exploring the effect of ανβ6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ανβ6 integrins on OS. Seventeen studies comprising 5795 patients met the inclusion criteria. High ανβ6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran'sQ p < 0.001, I2 = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ανβ6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods. High expression of ανβ6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ανβ6 integrin and its role as a therapeutic target are warranted.

LncRNA NORAD as a Novel Predictor of Lymph Node Metastasis and Prognosis in Solid Tumors: A Systematic Review and Meta-Analysis.

Background:Non-coding RNA-activated by DNA damage (NORAD), a novel identified lncRNA, was found to be aberrantly expressed in various types of cancer. This meta-analysis was performed to evaluate the value of lncRNA NORAD as a prognostic biomarker in human cancers.Methods:We searched PubMed, Web of Science, PMC, and Embase databases thoroughly for eligible literatures. Studies which explored the relationship of lncRNA NORAD expression with clinical outcomes in human cancers were included in our meta-analysis. Review Manager version 5.3 and Stata SE 12.0 were used to perform the data analyses.Results:Our meta-analysis results indicated that cancer patients with high lncRNA NORAD expression tended to have unfavorable overall survival (OS) (HR = 1.67; 95% CI, 1.44-1.95; P < 0.00001). Moreover, elevated lncRNA NORAD expression showed a significant relationship with poor tumor grade (OR = 1.61; 95% CI, 1.01-2.56; P = 0.05) and more lymph node metastasis (LNM) (OR = 2.66; 95% CI, 1.60-4.43; P = 0.0002).Conclusions:LncRNA NORAD could serve as a valuable biomarker to predict poor prognosis and LNM in various human tumors.

Validation and clinical usefulness of pre- and postoperative systemic inflammatory parameters as prognostic markers in patients with potentially resectable pancreatic cancer

BackgroundSeveral preoperative systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), prognostic nutritional index (PNI), and Glasgow prognostic score, have been reported to be associated with the prognosis of solid tumors. In this study, we compared pre- and postoperative hematological inflammatory parameters and validated their prognostic significance in pancreatic cancer patients who underwent surgical resection. MethodsClinical records from 211 consecutive pancreatic cancer patients who underwent surgical resection at our institution were retrospectively analyzed. The optimal cutoff values of hematological inflammatory parameters, including lymphocyte count, NLR, PLR, LMR, and PNI, were determined by time-dependent receiver-operating characteristic analysis. ResultsThe postoperative neutrophil count and serum albumin level were significantly decreased in patients who underwent pancreatoduodenectomy (PD group) and in those who underwent distal pancreatectomy (DP group) compared to the levels at baseline. The postoperative lymphocyte count, monocyte count, and platelet count were significantly increased in the DP group compared to those at baseline. As a result, the postoperative NLR and PNI significantly decreased in both groups. The multivariate analysis identified intraoperative peritoneal washing cytology, administration of adjuvant therapy, tumor size, extrapancreatic nerve plexus invasion, and preoperative PLR as independent prognostic factors for overall survival. ConclusionsSystemic inflammatory responses were altered after pancreatic resection in pancreatic cancer patients. Preoperative PLR may be a useful prognostic marker in pancreatic cancer patients undergoing surgical resection.

Hypermethylation of Circulating Free DNA in Cutaneous Melanoma

Changes in DNA methylation are well documented in cancer development and progression and are typically identified through analyses of genomic DNA. The capability of monitoring tumor-specific methylation changes in circulating tumor DNA (ctDNA) has the potential to improve the sensitivity of ctDNA for the diagnosis and prognosis of solid tumors. In this study we profiled the methylation of seven gene targets (all known to be hypermethylated in metastatic melanoma) within the plasma of patients with advanced melanoma using amplicon-based next generation sequencing of bisulfite-treated DNA. Hypermethylation of 6/7 gene targets, including paraoxonase 3 (PON3) was significantly elevated in patients with metastatic melanoma (n = 4) compared to healthy control samples (n = 5). In addition, the degree of hypermethylation of PON3 and MEOX2 were significantly correlated with ctDNA copy number in melanoma patients, confirming the utility of methylated ctDNA in the absence of tumor mutation data for genes such as BRAF, RAS or EGFR.

GDF-15 in solid vs non-solid treatment-naïve malignancies.

AimGDF‐15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF‐15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF‐15 to other cardiac biomarkers and the general association of GDF‐15 on prognosis in an unselected cohort of treatment‐naïve cancer patients.MethodsWe prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF‐15 concentrations were determined alongside other cardiac and routine laboratory markers. All‐cause mortality was defined as primary endpoint.ResultsGDF‐15 levels were 338 ng/L (IQR:205‐534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF‐15 [435 ng/L (IQR:279‐614) vs 266 ng/L (IQR:175‐427), P < .001]. GDF‐15 correlated positively with inflammatory status reflected by CRP, SAA and IL‐6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT‐proBNP, hsTnT, MR‐proADM and CT‐proET‐1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF‐15 was significantly associated with all‐cause mortality after multivariate adjustment [adj.HR for ln(GDF‐15) 1.78, 95%CI:1.47‐2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF‐15 with outcome in myelodysplastic and myeloproliferative disease.ConclusionsElevated plasma GDF‐15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment‐naïve cancer patients. GDF‐15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF‐15 represents a promising target for our pathophysiologic understanding in cardio‐oncology linking conditions of both cardiac and neoplastic disease.

Prognostic role of secreted protein acidic and rich in cysteine in patients with solid tumors

Objectives:To analyze the heterogeneous functions of secreted protein acidic and rich in cysteine (SPARC) from different origins and in different tumor microenvironments with the purpose of determining its clinical significance.Methods:The PubMed, CINAHL, Cochrane, Web of Science and Embase databases were utilized. Studies that focused on the effects of SPARC expression on solid tumor progression and clinical implications were used. The different outcomes including overall survival and disease-free survival were analyzed to evaluate their relations with tumor- and stroma-derived SPARC expression.Results:A total of 26 studies including 5,939 patients were enrolled in the present meta-analysis. Tumor-derived SPARC overexpression was significantly related with poor overall survival (hazard ratio: 1.478; 95% CI: 1.143-1.910; p=0.003), and a similar tendency was also observed in disease-free survival (hazard ratio: 1.476; 95% CI: 0.993-2.195; p=0.054). However, the hazard ratios for overall survival and disease-free survival did not present a statistical trend in stromal SPARC overexpression. Tumor type subgroup analysis revealed marked heterogeneity among outcomes. In pancreatic cancer, SPARC overexpression in the stroma was significantly associated with poorer overall survival and disease-free survival. In colorectal cancer, SPARC overexpression in the stroma was associated with better disease-free survival.Conclusion:For the majority of solid tumors, SPARC in cancer cells may be an unfavorable indicator for long-term survival for patients. As for stromal expression, SPARC indicates a poorer prognosis in pancreatic cancer, but a better disease-free survival in colorectal cancer. Secreted protein acidic and rich in cysteine might be a potential biomarker for solid tumor prognosis.

Prognostic Value of Inducible Nitric Oxide Synthase (iNOS) in Human Cancer: A Systematic Review and Meta-Analysis.

Background Inducible nitric oxide synthase (iNOS) is confirmed to regulate the production of nitric oxide (NO) when cells are exposed to external stimulus. Recent publications revealed that overexpression of iNOS predicted poor clinical outcomes for patients with malignant cancers, e.g., gastric, bladder, and colorectal cancers; however, several studies reported no obvious relationship between iNOS expression and prognosis of solid tumors. The aim of our study was to investigate the pooled effect of the prognostic value of iNOS expression. Materials and Methods We performed a systematic search of PubMed, Web of Science, and Embase databases up to January 15, 2019. The concerned outcomes of interest included overall survival (OS), cancer-special survival (CSS), and recurrence-free survival (RFS). Results Fourteen studies with 1,758 patients were included in this meta-analysis, and we reached the conclusion that increased iNOS expression was significantly associated with worse OS (HR: 1.89, 95% CI: 1.57 - 2.28, p ≤ 0.001), worse CSS (HR: 3.13, 95% CI: 1.88 - 5.20, p ≤ 0.001), and worse RFS (HR: 2.16, 95% CI: 1.29 - 3.62, p = 0.003) in solid tumors. Furthermore, the subgroup analysis identified the significant relationship of high iNOS expression with poor OS in gastric cancer. No obvious publication bias was detected by Begg's tests. Conclusion In summary, the results drawn in our meta-analysis demonstrated that elevated expression of iNOS had a significant association with poor survival in human cancer. iNOS might serve as a promising predictive biomarker of prognosis in cancer patients, and well-designed prospective studies are further needed to substantiate the prognostic value of iNOS.

PS1323 HIGH SERUM LEVELS OF IL‐2R, IL‐6 AND TNF ARE ASSOCIATED WITH HIGHER TUMOR BURDEN AND POORER OUTCOME IN PATIENTS WITH NEWLY DIAGNOSED FOLLICULAR LYMPHOMA

Background:Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL‐2R), interleukin 6 (IL‐6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL‐2R has been associated with shorter progression‐free survival (PFS) in FL, but the impact of the levels of IL‐6 and TNF is not known in this disease specifically.Aims:To determine the prognostic significance of the serum levels of sIL‐2R, IL‐6 and TNF in patients with newly diagnosed FL.Methods:We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL‐2R, IL‐6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines.Results:Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL‐6 or TNF levels were older and those with elevated IL‐6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL‐2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2‐microglobulin (β2m) levels or a high‐risk FLIPI score. A Ki67 index &gt;30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R‐CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single‐agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL‐2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10‐year PFS was significantly lower for patients with high levels of either sIL‐2R, IL‐6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10‐year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion:FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.image

PS1324 GENETIC SIMILARITY BETWEEN WALDENSTRÖM MACROGLOBULINEMIA AND IGG-TYPE LYMPHOPLASMACYTIC LYMPHOMA. TARGETED NEXT-GENERATION SEQUENCING RESULTS OF FORMALIN-FIXED PARAFFIN EMBEDDED SAMPLES

Background: Follicular lymphoma (FL), the most frequent type of indolent non Hodgkin lymphoma, exhibits a heterogeneous clinical behavior. Predictive biological variables are eagerly sought, in an effort to better anticipate outcomes for each individual patient. Cytokines are small proteins involved in cell signaling and immune regulation. The levels of soluble interleukin 2 receptor (sIL-2R), interleukin 6 (IL-6), and tumor necrosis factor (TNF) have been correlated with tumor burden and prognosis in solid tumors and some lymphomas. High sIL-2R has been associated with shorter progression-free survival (PFS) in FL, but the impact of the levels of IL-6 and TNF is not known in this disease specifically. Aims: To determine the prognostic significance of the serum levels of sIL-2R, IL-6 and TNF in patients with newly diagnosed FL. Methods: We identified 300 patients (132 males/168 females; median age: 60 years) diagnosed with FL at our institution between January 2002 and December 2017 who had available information about serum cytokine levels (sIL-2R, IL-6 and TNF), determined by ELISA, before the initiation of frontline treatment. Baseline patient and disease characteristics, type of frontline treatment, PFS and overall survival (OS) were assessed retrospectively and compared between patients with normal vs. elevated levels (above the upper normal limit) of each one of the three evaluated cytokines. Results: Baseline characteristics, treatment, response, PFS and OS data are detailed in the table. Patients with elevated IL-6 or TNF levels were older and those with elevated IL-6 had a worse performance status and higher rate of B symptoms. An advanced stage was more frequently seen in patients with any elevated cytokine, while secondary extranodal involvement, and specifically, bone marrow involvement, was more frequent if either sIL-2R or TNF were raised. Patients with any elevated cytokine were more likely to have elevated LDH or β2-microglobulin (β2m) levels or a high-risk FLIPI score. A Ki67 index >30% was more frequently seen among patients with high TNF levels. Patients requiring frontline treatment with R-CHOP showed higher levels of any one of the 3 evaluated cytokines, while those who were not treated or received single-agent rituximab were more likely to have normal levels. The complete response (CR) rate was higher for patients with normal levels of sIL-2R and TNF. Median PFS was 10 years for treated patients in the entire series. 10-year PFS was significantly lower for patients with high levels of either sIL-2R, IL-6 or TNF. Similarly, patients who had elevated levels of any one of the 3 evaluated cytokines had a lower 10-year OS. However, in a multivariate analysis including FLIPI score, β2m and cytokine levels, only FLIPI and β2m retained statistical significance for PFS and OS.Summary/Conclusion: FL patients with elevated levels of cytokines are more symptomatic and have a higher tumor burden. Despite being treated more aggressively, they are less likely to achieve a CR after treatment or to maintain it after 2 years. PFS and OS are also significantly shorter in patients with elevated cytokine levels compared to those with normal levels. Determination of serum cytokine levels is simple and could become an additional factor informing about response to treatment, early progression, and survival.

CD146 contributes the metastatic properties and antitumor immunity of human colon adenocarcinoma cells

Abstract CD146 (MCAM) expressed on not only vascular endothelial and smooth muscle cells but also various malignant tumor cells. It has been shown that overexpression of CD146 predicts poor prognosis of solid tumor. Several reports by using transfectants or gene silencing technique have shown that CD146 is involved in cell adhesion and inflammatory cell migration. However, contribution of CD146 in tumor metastasis and antitumor immunity are still unknown. To investigate the effect of CD146 on tumor metastatic properties, we establish two subclones from DLD-1 (human colon adenocarcinoma cells) expressing CD146 or not. Both cell lines express epithelial tumor marker EpCAM and TROP2 equally, while CD146 (+) DLD-1 could only express CD44 variant v8–v10 and EphA2. Using metabolic assay, we found enhanced metabolism and decreased lactate production in CD146 (+) DLD-1. Consist with the morphological changes to mesenchymal features CD146 (+) DLD-1, the expression of E-cadherin and claudin-3 in tight junction were decreased in CD146 (+) DLD-1. In addition, CD146 (+) DLD-1 significantly increased the production of VEGF and the induction of various genes (slug, twist and zeb1) which are involved in epithelial to mesenchymal transition (EMT). Interestingly, the expression of immune checkpoint molecules including B7-H1, B7-DC (both PD-1 ligands), CD155 and IDO were up-regulated in CD146 (+) DLD-1 inducing the resistance of cytotoxic effect of activated lymphocytes. These results indicate that CD146 (+) DLD-1 strongly induces immune escape mechanism, thus demonstrating a new relationship between CD146 and EMT and anti-tumor immunity, which would be a new treatment and diagnostic target for immunotherapy.

Systemic inflammation and immunological microenvironment in prognosis of solid tumors

The purpose of the research. To study prognostic significance of indicators of systemic inflammation of peripheral blood and relative indicators: neutrophil‑lymphocytic and platelet‑lymphocytic ratio, the course of squamous cell carcinoma of the oral mucosa and gastric adenocarcinoma.Materials and methods. Prospective analysis of patients with squamous cell carcinoma of the oral mucosa and disseminated gastric adenocarcinoma was performed. Patients with verified diagnosis, without signs of inflammatory diseases in anamnesis, not receiving antibacterial and immunomodulatory therapy were selected. Overall survival and survival without progression were considered as the main estimated parameters.Results. The selection criteria were met by 32 patients with disseminated gastric adenocarcinoma and 60 patients with squamous cell carcinoma of the oral mucosa. The prognostic value of relative indicators is determined: overall survival of patients with gastric adenocarcinoma with a low value of the neutrophil‑lymphocytic index is significantly higher than that of the rest of the cohort of patients: 16 months vs. 8 and 7 months (95 % CI (confidence interval) from 12 to 23 months, p=0.0382). Overall survival of patients with low platelet‑lymphocytic index was also higher: 16 months vs. 8 months (95 % CI from 11 to 24 months, р=0,0026). Different relapse‑free survival was noted in the group of patients with squamous cell head and neck cancer: patients with low index value it is 7 months vs. 2 months (95 % CI from 5 to 9 months, p=0.0499).Conclusions. The results show the possibility of using immunological microenvironment of the tumor and indices, characterizing the systemic inflammation, for prognosis of gastric adenocarcinoma and squamous cell carcinoma of the oral mucosa.

Association of Preoperative Platelet-to-Lymphocyte Ratio with Poor Outcome in Patients with Distal Cholangiocarcinoma

Background: Several preoperative systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and Glasgow Prognostic Score, have been reported to be associated with the prognosis of solid tumors. However, there are conflicting survival data regarding these parameters in cholangiocarcinoma. Objectives: In this study, we performed a retrospective cohort analysis of patients with distal cholangiocarcinoma (DCC) who underwent surgical resection to evaluate the prognostic value of a cluster of preoperative hematological inflammatory parameters for survival. Method: Fifty-three patients with DCC who underwent pancreaticoduodenectomy with curative intent were enrolled. The optimal cutoff values of hematological inflammatory parameters, including the absolute lym­phocyte count, NLR, PLR, and LMR, were determined by time-dependent receiver operating characteristic analysis. ­Results: The univariate analysis for overall survival (OS) of conventional factors and hematological inflammatory parameters identified that portal vein invasion and PLR had p values of ≤0.1. The univariate analysis for disease-free survival (DFS) identified that lymph node metastasis, PLR, lymphocyte count, and number of positive lymph nodes (≥3) had p values of ≤0.1. These factors were incorporated into the full model and variables were selected using the backward stepwise method. The multivariate analysis identified portal vein invasion and high PLR as independent prognostic factors for OS (p = 0.033 and 0.039, respectively) and high PLR and number of positive lymph nodes (≥3) as independent prognostic factors for DFS (p = 0.016 and 0.004, respectively). Conclusions: Preoperative PLR assessment may be useful for detecting high-risk DCC patients undergoing surgical resection for aggressive adjuvant therapy.

Prognostic significance of X-linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta-analysis.

X-linked inhibitor of apoptosis protein (XIAP) is aberrantly expressed in solid tumors. Considering conflicting data, we conducted this meta-analysis to investigate its prognostic role. Electronic databases were searched to collect studies about associations between XIAP expressions and survival outcomes. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) were utilized as effect size estimates. A total of 3,794 patients from 21 published studies were included. The results revealed that high XIAP expressions correlated with age (OR = 2.02; 95% CI, 1.07-3.84), lymph node metastasis (OR = 1.69; 95% CI, 1.02-2.77), histological grade (OR = 2.04; 95% CI, 1.01-4.11), and tumor stage (OR = 2.18; 95% CI, 1.20-3.96). The combined HR revealed that high XIAP expressions associated with poor overall survival (OS) (HR = 1.60; 95% CI, 1.22-2.10). Our study suggested high XIAP expressions may be indicative of poor prognosis in solid tumors.

The Correlation of Clinicopathological Findings and Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in Papillary Thyroid Carcinoma

Objectives:Inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been recently introduced as potential biomarkers for tumor pathogenesis, development and prognosis in solid tumors. Our aim was to assess the correlation of clinicopathological features and NLR and PLR in patients with papillary thyroid carcinoma (PTC).Methods:A total of 201 papillary thyroid carcinoma patients were divided into groups with a cut-off preoperative median NLR and PLR value of 1,92 and 123.9, respectively. The correlation of NLR and PLR and clinicopathological features including age, tumor size, extra-thyroidal extension, thyroid capsule invasion, surgical margin positivity, multifocality, bilaterality of the patients were analyzed.Results:The mean NLR and PLR were 2.11±0.94, 129.69±42.81, respectively. Larger tumor size and higher positivity of extra-thyroidal spread were correlated with higher NLR values. No significant relationship was found between NLR and age, presence of thyroid capsule invasion, surgical margin positivity, multifocality, bilaterality, and lymph node metastasis. Also no significant association was observed between the clinicopathological features and PLR.Conclusion:High NLR was found to correlate with tumor size and extra-thyroidal extension. NLR may be used as a marker to determine the clinical behavior of disease in patients with papillary thyroid carcinoma (PTC).