Paraneoplastic Thrombocytosis in Ovarian Cancer
16 Feb 2012-The New England Journal of Medicine (Massachussetts Medical Society)-Vol. 366, Iss: 7, pp 610-618
TL;DR: Findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplasticThrombocytosis, which fuels tumor growth.
Abstract: From the Departments of Gynecologic Oncology and Reproductive Medicine (R.L.S., A.M.N., H.D.H., J.B.-M., W.H., H.G., K.M., M.M.K.S., E.R.K., A.K.S.), Cancer Biology (R.R., G.L.-B., A.K.S.), Experimental Therapeutics (G.N.A.-P., I.T., B.O., G.L.-B.), Hematology and Oncology (C.V.P.), Pathology (M.T.D.), Benign Hematology (H.G.V., V.A.-K.), Biostatistics (D.U.), and Leukemia (F.G.), and the Center for RNA Interference and Non-Coding RNA (H.D.H., G.L.-B.,
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TL;DR: It is asserted that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data and potential for novel cancer prevention and treatment strategies.
Abstract: Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
836 citations
TL;DR: How a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment is discussed.
Abstract: Recent pre-clinical and clinical research has provided evidence that cancer progression is driven not only by a tumour's underlying genetic alterations and paracrine interactions within the tumour microenvironment, but also by complex systemic processes. We review these emerging paradigms of cancer pathophysiology and discuss how a clearer understanding of systemic regulation of cancer progression could guide development of new therapeutic modalities and efforts to prevent disease relapse following initial diagnosis and treatment.
713 citations
TL;DR: Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS and with lower response rates in patients with metastatic NSCLC treated with nivolumab independently of other prognostic factors.
563 citations
TL;DR: A high PLR is associated with worse OS in various solid tumors and is a readily available and inexpensive biomarker with independent prognostic value in solid tumors.
Abstract: Background: Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, we quantify the prognostic impact of this biomarker.
Methods: A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling.
Results: Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups ( 300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 [HR = 1.87; 95% confidence interval (CI, 1.49–2.34); P < 0.001] and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97–1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HR[group 1] = 2.0; 95% CI, 1.6–2.7; HR[group 2] = 1.6; 95% CI, 1.1–2.4) than for early-stage disease (HR[group 1] = 1.5; 95% CI, 1.0–2.2; HR[group 2] = 1.0; 95% CI, 0.8–1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2.
Conclusion: A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted.
Impact: PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors. Cancer Epidemiol Biomarkers Prev; 23(7); 1204–12. ©2014 AACR .
This article is featured in Highlights of This Issue, [p. 1137][1]
[1]: /lookup/volpage/23/1137?iss=7
501 citations
Cites background from "Paraneoplastic Thrombocytosis in Ov..."
...In patients with ovarian cancer, high IL6 level is an independent predictor of poor prognosis (8)....
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...Platelets are also part of the inflammatory response and thrombocytosis is common in patients with solid tumors (7, 8)....
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...57, both thrombocytosis and elevated inflammatory markers have been linked to poor prognosis (4, 8)....
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TL;DR: The basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes.
450 citations
Cites background from "Paraneoplastic Thrombocytosis in Ov..."
...High platelet count is associated with increased mortality in a variety of cancers, including malignant mesothelioma; gynecological malignancies; and lung, renal, gastric, colorectal, and breast cancers.(62,76-83) We should seek to discern the roles played by platelets in stimulating different cellular compartments within the tumor, which has the potential to expand therapeutic use of cardiovascular inhibitors in oncology....
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...In a cohort of patients with ovarian cancer that was enriched for those with recurrent disease, elevated platelet counts correlated with decreased overall survival and resistance to chemotherapy.(62,63) The study further demonstrated that platelet transfusion resulted in significantly greater tumorweight innudemiceharboringA2780 tumors than in untreatedmice; this effectwas completely reversed bypretreating the platelets with aspirin before transfusion....
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References
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TL;DR: Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy, and benefit increased with scheduled duration of treatment.
1,208 citations
TL;DR: Chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model, and β-adrenergic activation of the cAMP–PKA signaling pathway is identified as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth.
Abstract: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma
1,046 citations
TL;DR: The role of alpha-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined.
901 citations
TL;DR: See also Machin SJ, Briggs C. Mean platelet volume: a quick, easy determinant of thrombotic risk?
886 citations
TL;DR: Levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer, and functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low Dicer expression.
Abstract: BACKGROUND We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer. METHODS We measured messenger RNA (mRNA) levels of Dicer and Drosha in specimens of invasive epithelial ovarian cancer from 111 patients, using a quantitative reverse-transcriptase-polymerase-chain-reaction assay, and compared the results with clinical outcomes. Validation was performed with the use of published microarray data from cohorts of patients with ovarian, breast, and lung cancer. Mutational analyses of genomic DNA from the Dicer and Drosha genes were performed in a subgroup of ovarian-cancer specimens. Dicer-dependent functional assays were performed by means of in vitro transfection with small interfering RNA (siRNA) and short hairpin RNA (shRNA). RESULTS Levels of Dicer and Drosha mRNA correlated with the levels of expression of the corresponding protein and were decreased in 60% and 51% of ovarian-cancer specimens, respectively. Low Dicer expression was significantly associated with advanced tumor stage (P=0.007), and low Drosha expression with suboptimal surgical cytoreduction (P=0.02). Cancer specimens with both high Dicer expression and high Drosha expression were associated with increased median survival (>11 years, vs. 2.66 years for other subgroups; P<0.001). We found three independent predictors of reduced disease-specific survival in multivariate analyses: low Dicer expression (hazard ratio, 2.10; P=0.02), high-grade histologic features (hazard ratio, 2.46; P=0.03), and poor response to chemotherapy (hazard ratio, 3.95; P<0.001). Poor clinical outcomes among patients with low Dicer expression were validated in additional cohorts of patients. Rare missense mutations were found in the Dicer and Drosha genes, but their presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low Dicer expression. CONCLUSIONS Our findings indicate that levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer.
697 citations