Prognostic Marker For Survival Research Articles

Prognostic markers for survival in patients with oligodendroglial tumors; a single-institution review of 214 cases.

BackgroundIn the 2016 WHO classification, the diagnosis of oligodendroglioma has been restricted to IDH mutated, 1p19q codeleted tumors (IDHmut-codel). IDHmut oligoastrocytoma is now classified either as oligodendroglioma or astrocytoma based on presence of 1p19q codeletion. There is growing evidence that this molecular classification more closely reflects patient outcome. Due to the strong association between IDHmut-codel with oligodendroglial morphology, the additional impact of these markers on prognostic accuracy is largely unknown. Our aim was to assess the prognostic impact of IDHmut-codel in an unselected cohort of morphologically classified oligodendroglial tumors.MethodsWe performed a retrospective chart review of oligodendroglial tumors (WHO grade II and III) operated since 1983. A total of 214 tumors were included, and molecular information was available for 96 tumors. The prognostic impact of IDHmut-codel together with clinical parameters was analyzed by multivariate Cox regression.ResultsIDHmut-codel was registered in 64 tumors while for 150 tumors the molecular profile was negative for IDHmut-codel, unknown or incomplete. Comparison between the two groups showed that patients with IDHmut-codel tumors were younger (42 vs. 48 years), had more frequent frontal tumor location (48 vs. 33%) and presented more often with seizures (72 vs. 51%) and no signs of neurological impairment (14 vs. 30%) than patients harboring tumors with unknown or incomplete molecular profile. Multivariate survival analysis identified young age (HR 1.78 ≥ 40 years), the absence of neurological deficits or personality changes (HR 0.57), frontal tumor location (HR 0.64) and the presence of IDHmut-codel (HR 0.50) as independent predictors for longer survival, whereas tumor grade was not.ConclusionIn this unselected single-institution cohort, the presence of IDHmut-codel was associated with more beneficial clinical parameters and was identified as an independent prognostic factor. We conclude that the classical oligodendroglioma genotype provides additional prognostic data beyond clinical characteristics, morphology and tumor grade.

Immunoparesis defined by heavy+light chain suppression is a novel marker of long-term outcomes in cardiac AL amyloidosis.

Cardiac involvement and presenting dFLC (difference between involved and uninvolved free light chains) are independent predictors of outcome in systemic AL amyloidosis. These markers have limited prognostic utility in patients surviving the initial months following diagnosis. Here we assessed immunoparesis, as determined by novel heavy+light chain (HLC) immunoassays, as a prognostic marker for survival in AL amyloidosis. HLC measurements identified immunoparesis of at least one immunoglobulin (Ig) isotype in 145 (85%) patients; and severe immunoparesis (≥2 Ig isotypes suppressed by >50% below normal levels) in 29 (17%) patients. Median overall survival (OS) on intention to treat (ITT) analysis was 26·2months. In the ITT cohort, dFLC >180mg/l was associated with shorter OS (P=0·05); whereas HLC immunoparesis was not prognostic. On a landmark analysis of 127 patients alive at 6months, presenting dFLC was not prognostic for OS (P=0·33) and severe HLC immunoparesis trended towards poorer survival (20·2 vs. 42·8months; P=0·09). In the subset of patients with cardiac involvement, severe HLC immunoparesis conferred very poor outcome (median OS 8·8 vs. 29·9months, P=0·007). In conclusion, severe HLC immunoparesis is an independent marker of long-term poor prognosis in AL patients with cardiac involvement. The pathophysiological significance of this observation needs further study.

TCT-551 Lactate Clearance is a Prognostic Marker for Survival in Cardiogenic Shock Receiving Early Percutaneous Mechanical Circulatory Support

The survival of patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) remains low despite early revascularization. The evolving percutaneous mechanical circulatory support (MCS) device options provide the possibility of a brighter future, however markers are needed to

P2776Unloading the mystery: serum lactate clearance used as an early prognostic marker for survival in severe cardiogenic shock requiring impella support

P2776Unloading the mystery: serum lactate clearance used as an early prognostic marker for survival in severe cardiogenic shock requiring impella support

Abstract 668: Evaluation of α-1-acid glycoprotein as a prognostic marker and as a predictive biomarker for severe neutropenia induced by docetaxel in esophageal carcinoma patients

Abstract Background: Serum α-1-acid glycoprotein (AAG) level is an independent predictor of response and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel chemotherapy. However, whether AAG is associated with the outcomes of esophageal cancer patients treated with docetaxel remains unclear. Methods: Between August 2009 and April 2014, pretreatment serum samples were obtained from patients with clinical stage II/III esophageal cancer. Individuals were subsequently treated with neoadjuvant DCF or CF followed by surgery. DCF consisted of docetaxel and cisplatin on day 1, and continuous infusion of 5-fluorouracil on days 1-5, with this regimen repeated every 3 weeks for up to three cycles. CF consisted of cisplatin and 5-fluorouracil. Patients were divided into groups based on the median value of baseline AAG levels. Response to chemotherapy, survival, and the most severe grade of neutropenia were compared between the high and low AAG groups at each regimen. Results: A total of 129 patients were enrolled (44 received neo DCF and 85 neo CF). The median serum AAG level was 95 g/L (range 57-228 g/L) and 95 g/L (range 46-197 g/L) in the patients with neo DCF and CF, respectively. For all patients, overall survival (OS) was significantly shorter in the high AAG group (AAG ≧ 95 g/L) than the low AAG group (AAG < 95 g/L) (HR 2.18, p=0.03). Both in the neo DCF and neo CF patients, there was a similar trend in OS between individuals with high and low AAG levels. Multivariate analysis demonstrated that AAG level (HR 1.98) and performance status (HR 2.20) were independent prognostic factors. However, the relationship between response to chemotherapy and AAG level were similar both in DCF and CF patients. In addition, grade 4 neutropenia was observed in 50% of patients with low AAG level and 23% with high AAG (p = 0.06) in DCF patients. A correlation analysis revealed a statistically significant correlation between serum AAG level and nadir absolute neutrophil count caused by DCF chemotherapy. However, in CF patients, there was no difference in the frequency of severe neutropenia between individuals with high and low AAG level, and there was no correlation between AAG and nadir neutrophil count. Conclusions: Serum AAG level may be a prognostic marker for survival in stage II/III esophageal cancer patients treated with neoadjuvant chemotherapy. In addition, low serum AAG level is a potential predictive biomarker of docetaxel-induced severe neutropenia. Citation Format: Yusuke Sasaki, Ken Kato, Hidekazu Hirano, Hirokazu Shoji, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Tetsuya Hamaguchi, Kengo Nagashima, Narikazu Boku. Evaluation of α-1-acid glycoprotein as a prognostic marker and as a predictive biomarker for severe neutropenia induced by docetaxel in esophageal carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 668. doi:10.1158/1538-7445.AM2017-668

Abstract 5715: Gene body methylation and expression of SHOX2 gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers

Abstract Background: Previous data indicated that low level of promoter methylation of the SHOX2 gene was a prognostic marker for worse progression-free survival for non-small cell lung cancer. Purpose: (a) to determine the relationship between SHOX2 gene methylation and expression; b) to determine whether SHOX2 gene methylation and expression were prognostic markers for other cancers. Methods: We examined multiple methylation and expression datasets available from The Cancer Genome Atlas (TCGA) and other previously published studies. Data from a total of more than 1000 intermediate grade gliomas and 1100 renal cancer cases were examined, along with smaller number of corresponding non-malignant tissues. We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression model analyses. Results: SHOX2 gene contains three CpG islands encompassing the promoter region and body. Methylation of various regions of SHOX2 gene body was significantly positively correlated with its expression in gliomas and renal cancer. Aberrantly high methylation and expression of SHOX2 gene, which were significantly higher than the corresponding nonmalignant tissues, were identified in subsets of gliomas and renal cancers. Survival analysis of patients indicated that the methylation and expression of SHOX2 gene in gliomas and renal cancer (both clear cell and papillary cell carcinomas) were highly potent markers for poor survival. We further investigated the combination of SHOX2 with other known clinically relevant glioma markers (IDH genotype status, TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of glioma patients with significantly favorable survival outcomes, especially in the subgroup (i.e., IDH wild-type) associated with worse prognosis for each individual marker. Multivariate analysis demonstrated that SHOX2 was a potent independent survival marker for gliomas. Conclusion: Gene body methylation and expression of SHOX2 gene are tightly positively correlated and are potent new markers for overall survival prognosis for intermediate grade gliomas and renal cancer. The combination of IDH or other relevant prognostic markers with SHOX2 identified intermediate grade glioma subsets with improved survival outcomes. Citation Format: Yu-An Zhang, Yunyun Zhou, Xin Luo, Guanghua Xiao, Adi F. Gazdar. Gene body methylation and expression of SHOX2 gene are potent prognostic markers for survival in intermediate grade gliomas and renal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5715. doi:10.1158/1538-7445.AM2017-5715

Abstract 371: Developing small molecule therapeutics to target AKT signaling in non-small cell lung cancer

Abstract Lung cancer remains a leading public health problem which is evidenced by its increasing death rate. Platinum-based chemotherapy is the first-line of treatment for patients in advanced stages of non-small cell lung cancer (NSCLC), however the success rates are not quite impressive. Hence, developing individualized treatment strategies for metastatic lung cancer gains momentum, such as Tyrosine kinase inhibitors erlotinib and gefitinib, or ALK inhibitors ceritinib and alectinib are commonly used in the clinic. Recent reports suggest that pAKT(ser473) is highly expressed in NSCLC and higher nuclear expression of pAKT correlated with poor prognosis and an independent prognostic marker for survival. Our lab is interested to develop novel small molecules which specifically inhibit AKT signaling in NSCLC. Structure-activity relationship (SAR) studies in our laboratory have recently ideintifed one such compound, AKS-407, that effectively inhibited cell growth at nanomolar concentration in NSCLC cell lines (A549 and H460; 250nM). Molecular studies revealed AKS-407 inhibited AKT signaling by down regulating pAKT(ser473) expression and downstream events including NFκB activation, BCl-2 expression in both the cell lines. As signaling through AKT regulates epithelial-mesenchymal transition (EMT) in NSCLC, we determined the effect of AKS-407 on EMT phenotype on NSCLC cells. Treatment of AKS-407 inhibited the mesenchymal markers includes snail, MMP9, N-cadherin, β-catenin and vimentin expression that resulted in blocking invasion and migration of A549 and H-460 cells. These results suggest AKS-407 to be a promising small molecule targeting AKT signaling pathway which remains an important target for the development of effective treatment of metastatic NSCLC. Validating in-vivo efficacy of this potential drug candidate would further support our overall goal of the study. Citation Format: Balaji Chandrasekaran, Deeksha Pal, Venkatesh Kolluru, Srinivasa R. Ramisetti, Arun K. Sharma, Murali Ankem, Chendil Damodaran. Developing small molecule therapeutics to target AKT signaling in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 371. doi:10.1158/1538-7445.AM2017-371

Abstract 4733: Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer

Abstract Background: The Cullin-RING ubiquitin ligases 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human cancer patients. Methods: 352 lung cancer and 62 benign lung specimens of Asian origin were constructed into tissue microarrays (TMAs) of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B and their substrates was detected by immunohistochemistry (IHC), and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Results: Both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A<0.001, PCUL4B<0.001), and significantly associated with tumor size (PCUL4A<0.001, PCUL4B=0.002), lymphatic invasion (PCUL4A=0.004, PCUL4B<0.001), metastasis (PCUL4A=0.019, PCUL4B=0.006), and advanced TNM stage (PCUL4A<0.001, PCUL4B<0.001), which parallels gene amplification and abnormal activation of the canonical Wnt signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (P=0.01), and inversely correlated with XPC and p21, both of which are substrates of CUL4A (PCUL4A=0.019, PCUL4B=0.006). Higher levels of CUL4A or CUL4B are significantly associated with patients’ OS (PCUL4A<0.001, PCUL4B<0.001) and PFS (PCUL4A<0.001, PCUL4B=0.001). Conclusion: Our findings revealed that CUL4A and CUL4B are differentially associated with etiological factors for pulmonary malignancies and are independent prognostic markers for survival of distinct lung cancer subtypes. Citation Format: Hui Li, Lei Jia, Fan Yan, Pengbo Zhou. Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4733. doi:10.1158/1538-7445.AM2017-4733

CSPG4: A Target for Selective Delivery of Human Cytolytic Fusion Proteins and TRAIL.

Chondroitin-sulfate proteoglycan 4 (CSPG4) is a transmembrane glycoprotein overexpressed on malignant cells in several cancer types with only limited expression on normal cells. CSPG4 is implicated in several signaling pathways believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Expression may serve as a prognostic marker for survival and risk of relapse in treatment-resistant malignancies including melanoma, triple negative breast cancer, rhabdomyosarcoma and acute lymphoblastic leukemia. This tumor-associated overexpression of CSPG4 points towards a highly promising therapeutic target for antibody-guided cancer therapy. Monoclonal αCSPG4 antibodies have been shown to inhibit cancer progression by blocking ligand access to the CSPG4 extracellular binding sites. Moreover, CSPG4-directed antibody conjugates have been shown to be selectively internalized by CSPG4-expressing cancer cells via endocytosis. CSPG4-directed immunotherapy may be approached in several ways, including: (1) antibody-based fusion proteins for the selective delivery of a pro-apoptotic factors such as tumor necrosis factor-related apoptosis-inducing ligand to agonistic death receptors 4 and 5 on the cell surface; and (2) CSPG4-specific immunotoxins which bind selectively to diseased cells expressing CSPG4, are internalized by them and induce arrest of biosynthesis, closely followed by initiation of apoptotic signaling. Here we review various methods of exploiting tumor-associated CSPG4 expression to improve targeted cancer therapy.

ST2 predicts survival in patients undergoing transcatheter aortic valve implantation

ObjectiveTo assess soluble suppression of tumorigenicity 2 (sST2) serum concentrations and predict mortality in patients undergoing transcatheter aortic valve implantation (TAVI). MethodsWe prospectively enrolled 74 patients with severe aortic stenosis (AS) who underwent TAVI and matched them to patients without aortic valve disease (n=74). AS patients underwent comprehensive echocardiographic and cardiac magnetic resonance imaging and laboratory examinations. sST2 levels were determined by enzyme-linked immunosorbent assay (ELISA), their association with post procedural mortality was investigated using logistic and Cox regression analyses, and the prognostic performance compared to established risk scores. ResultsAS patients had substantially higher sST2 levels than controls (39.5 vs. 17.8ng/mL, p<0.001). sST2 significantly correlated with left and right atrial sizes (r=0.25, p=0.033 and r=0.38, p=0.001). At one and two years, 10 (13.9%) and 18 (25%) patients had died, respectively. sST2 significantly predicted survival in uni- and multivariate Cox regression analyses in our cohort (p=0.005 and p=0.025). sST2 also predicted major adverse cardiovascular events (MACE, p=0.046). Adding sST2 to the established STS score improved prediction of two-year mortality in our cohort (ΔAUC=0.108; 95% CI −0.066–0.281; continuous NRI=0.778; 95% CI: 0.277–1.278 and IDI=0.141; 95% CI: 0.031–0.251), and a model containing both sST2 and the STS score had a negative predictive value of 96.1% and 86.3% regarding one and two-year mortality, respectively. ConclusionssST2 is elevated in AS patients and a prognostic marker of survival after TAVI. Implementation of this marker in routine pre-TAVI workup may improve risk prediction and patient selection.

Preoperative C-Reactive Protein Values as a Potential Component in Outcome Prediction Models of Metastasized Renal Cell Carcinoma Patients Receiving Cytoreductive Nephrectomy

Purpose: To validate preoperative C-reactive protein (CRP) levels as a prognostic marker for survival in a metastasized renal cell carcinoma (mRCC) patient cohort receiving cytoreductive nephrectomy (CN). Patients and Methods: By chart review, 146 mRCC patients receiving CN at our tertiary referral centre from 1997 to 2015 were identified retrospectively. All relevant clinicopathological features including laboratory parameters were collected and correlated to overall survival, progression-free survival and cancer-specific survival (CSS). The mean follow-up was 23 months (range 1-168 months). Results: Besides the already established scoring systems like the MSKCC criteria, an elevated preoperative CRP level (≥0.5 mg/dL) was an independent predictor of CSS in our study group including the chosen postoperative adjuvant therapies (TKI vs. immunotherapy vs. others). With regard to morbidity, patients with a good performance status, small tumour size and adequate renal function/haematopoiesis experienced less complication rates, thereby profiting more from CN. Conclusions: Our data provide indication that preoperative CRP levels should be implemented in nomograms regarding the outcome prediction in mRCC to identify candidates likely to profit from CN.

Computer extracted measurements of intra-tumoral heterogeneity on H&amp;E stained tissue images to distinguish short term and long term survivors in patients with non-small cell lung carcinoma.

e20052 Background: Molecular and morphologic heterogeneity is an important characteristic of cancer. This spatial and temporal tumor heterogeneity has important implications on tumor behavior and response to therapies. This study aims to evaluate the role of computer extracted features of intra-tumoral heterogeneity (ITH) from digitized whole slide H&amp;E stained images of early stage NSCLC patients treated with surgery as a prognostic marker for survival. Methods: A cohort of 89 early stage NSCLC patients treated with surgery with long term survival data were identified. 28 patients had OS&gt; 3 years from the date of definitive surgery and were defined as long term survivors and 61 patients had OS &lt; 3 years, and were defined as short term survivors. Corresponding H&amp;E stained whole mounted lung tissue images was digitally scanned and a thoracic pathologist marked the primary tumor margins on these images. Our computational approach involved determining the variance in measurements relating to nuclear size, shape, and texture across the tissue section; Each feature was then assigned a morphologic diversity score (MDS) based off the variance; the top predictive MDS features were identified via Wilcoxon Rank Sum Test and then evaluated via a quadratic classifier using 3-fold cross validation. Kaplan-Meier (KM) survival analysis was performed for the ITH features, as well as T- and N-stage. Results: The top ranked MDS features yielded a mean area under the receiver operating characteristic curve (AUC) of 0.66 in discriminating short term from long term survivors. A p=0.00657 (see Table) was obtained for KM-analysis of the ITH features. Conclusions: Computer extracted image features of ITH enabled differentiation of NSCLC patients with short and longer term survival. Large scale multi-site validation will need to be done to establish ITH measurements as a prognostic biomarker for NSCLC patients. [Table: see text]

Pre-treatment serum lactate dehydrogenase as a biomarker in small cell lung cancer.

Small cell lung cancer is a rapidly progressive disease with high fatality. No sensitive and specific biomarker to assist in managing this disease exists currently. Role of pretreatment serum lactate dehydrogenase as a biomarker in small cell lung cancer. A hospital-based cancer registry was used to identify eligible patients from 1999 to 2009. Demographic data, lactate dehydrogenase level and clinical outcome of patients were collected for analysis. One hundred and sixty-eight patients were identified: 61% (n = 103) males and 39% (n = 65) females. Majority had extensive stage (67%). High lactate dehydrogenase (≥230 U/L) was present in 60.4% (n = 75); mean reading 260 U/L (range 148-898 U/L) in limited stage and 470 U/L (range 116-5462 U/L) in extensive stage. Extensive stage patients with high lactate dehydrogenase had lower treatment response rate compared to those with normal lactate dehydrogenase (39% vs 79%, P = 0.002); no difference in treatment response was seen among patients with limited stage. High lactate dehydrogenase conferred a worse survival; mean overall survivals in limited and extensive stage were 8.0 and 5.2 months, respectively, in patients with elevated lactate dehydrogenase. Those with normal lactate dehydrogenase had an overall survival of 16.5 and 8.2 months, respectively. The association remained significant after adjustment for age, sex and treatment (HR 1.8, 95% CI 1.16-2.80, P = 0.009). High pretreatment lactate dehydrogenase is a prognostic marker of survival in both stages of small cell lung cancer. It is also a predictive marker of response to therapy in extensive stage. Larger prospective studies to validate our findings would be beneficial.

On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable. To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC. In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively. A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child-Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8-18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61-0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37-0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51-0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose. Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.

Dysregulation of Telomere Lengths and Telomerase Activity in Myelodysplastic Syndrome

BackgroundTelomere shortening is thought to be involved in the pathophysiology of myeloid malignancies, but telomere lengths (TL) during interphase and metaphase in hematopoietic malignancies have not been analyzed. We aimed to assess the TLs of interphase and metaphase cells of MDS and telomerase activity (TA) and to find out prognostic significances of TL and TA.MethodsThe prognostic significance of TA by quantitative PCR and TL by quantitative fluorescence in situ hybridization (QFISH) of interphase nuclei and metaphase chromosome arms of bone marrow cells from patients with MDS were evaluated.ResultsMDS patients had shorter interphase TL than normal healthy donors (P<0.001). Average interphase and metaphase TL were inversely correlated (P=0.013, p arm; P=0.029, q arm), but there was no statistically significant correlation between TA and TL (P=0.258). The progression free survival was significantly shorter in patients with high TA, but the overall survival was not different according to average TA or interphase TL groups. Multivariable Cox analysis showed that old age, higher International Prognostic Scoring System (IPSS) subtypes, transformation to AML, no history of hematopoietic stem cell transplantation and short average interphase TL (<433 TL) as independent prognostic factors for poorer survival (P=0.003, 0.001, 0.005, 0.005, and 0.013, respectively).ConclusionsThe lack of correlation between age and TL, TA, and TL, and the inverse relationship between TL and TA in MDS patients reflect the dysregulation of telomere status and proliferation. As a prognostic marker for leukemia progression, TA may be considered, and since interphase TL has the advantage of automated measurement by QFISH, it may be used as a prognostic marker for survival in MDS.

KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer.

Several angiogenic prognostic markers are under investigation because of their potential clinical utility, aiming to improve patient outcomes. We hypothesized that genetic variant in the VEGF pathway could be used as prognostic markers of survival in non-small cell lung cancer (NSCLC) patients undergoing pulmonary resection. We evaluated the relationship between genetic variants in the VEGF pathway and relapse-free survival (RFS, main endpoint) and overall survival (OS, secondary endpoint) among 131 patients with stage I-III NSCLC treated with surgical resection from 2009 to 2013. Clinical, pathological and surgical data were prospectively collected. Twenty-five variants in sixteen relevant genes were selected and genotyped in tumor samples by real time PCR. The Kaplan-Meier method with the log-rank test and Cox's regression models were used for RFS and OS analyses. With a median follow-up of 36 (min=2.8; max=67.4) months, there were 31 (24%) relapses and 31 (24%) deaths. Overall, median RFS was not reached and median OS was 65 [95% confidence interval (CI) 56-75] months. The KRAS rs1137282 and PIK3C2A rs4356203 variants were significantly associated with RFS. For KRAS rs1137282, the 3-year RFS was 76% [95% CI 64-84%] in patients harboring an A/A genotype compared to 53% [95% CI 37-69%] in patients harboring an A/G or G/G genotype (p=0.02). For PIK3C2A rs4356203, patients with an A/A or an A/G genotype had a 3-year RFS of 72% [95% CI 58-76%], whereas in patients with a G/G genotype was 49% [95% CI 28-70%] (p=0.02). These associations remained statistically significant after adjusting for all the relevant clinical parameters in the multivariable analysis. Genetic variants in VEGF pathway may be associated with recurrence in stage I-III NSCLC. Specifically, the KRAS rs1137282 could be considered as a prognostic factor for recurrence in resectable NSCLC patients. Although PIK3C2A rs4356203 was associated with RFS, further analyses are necessary to confirm these data.

Characteristics of long-term survivors in a randomized phase III trial (NAPOLI-1) of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan (nal-IRI; MM-398) + 5-FU/LV.

293 Background: nal-IRI, a liposomal formulation of irinotecan, plus 5-FU/LV is approved in the United States and Taiwan for patients (pts) with mPDAC previously treated with gemcitabine-based therapy. Primary analysis of the NAPOLI-1 trial (NCT01494506) showed that nal-IRI+5-FU/LV significantly improved median overall survival vs 5-FU/LV (6.1 vs 4.2 months; HR, 0.67; 95% CI, 0.49-0.92; P = 0.012; Wang-Gillam et al, Lancet. 2016). Herein we report baseline characteristics of pts surviving ≥1 year (data cutoff, Nov 2015). Methods: This analysis includes 117 pts assigned to treatment with nal-IRI 70 mg/m2 (free base) + 5-FU/LV 2400/400 mg/m2 q2w, and 119 pts assigned to treatment with 5-FU/LV 2000/200 mg/m2weekly for weeks 1-4 q6w. Results: A total of 29 (25%) pts in the nal-IRI+5-FU/LV arm and 17 (14%) in the 5-FU/LV arm survived ≥1 year. These pts typically had better performance status, lower CA19-9 (U/mL) levels, and were less likely to have liver metastases at baseline, compared with the overall population (Table). For long-term survivors in the nal-IRI+5-FU/LV arm, a higher proportion of pts had neutrophil-to-lymphocyte ratio (NLR) &gt;5, a marker of poor prognosis, suggesting that higher NLR may potentially be predictive of survival outcome with nal-IRI+5-FU/LV. Conclusions: More pts receiving nal-IRI+5-FU/LV versus 5-FU/LV were alive beyond 1 year. The most prominent prognostic markers of survival ≥1 year included lower CA19-9, KPS ≥90 and absence of liver metastases. These analyses may be limited by small sample sizes. Clinical trial information: NCT01494506. [Table: see text]

Abstract IA16: Current and emerging molecular diagnostic assays for colorectal cancer

Abstract IA16: Current and emerging molecular diagnostic assays for colorectal cancer

Circulating miR-30d Predicts Survival in Patients with Acute Heart Failure

Background/Aims: Identification of novel biomarkers to identify acute heart failure (AHF) patients at high risk of mortality is an area of unmet clinical need. Recently, we reported that the baseline level of circulating miR-30d was associated with left ventricular remodeling in response to cardiac resynchronization therapy in advanced chronic heart failure patients. However, the role of circulating miR-30d as a prognostic marker of survival in patients with AHF has not been explored. Methods: Patients clinically diagnosed with AHF were enrolled and followed up for 1 year. Quantitative reverse transcription polymerase chain reactions were used to determine serum miR-30d levels. The univariate logistic regression analysis and multivariate logistic regression analysis were used to determine the predictors for all-cause mortality in AHF patients. Kaplan–Meier survival analysis was used to analyze the role of miR-30d in prediction of survival. Results: A total of 96 AHF patients were enrolled and followed up for 1 year. Serum miR-30d was significantly lower in AHF patients who expired in the one year follow-up period compared to those who survived. Univariate logistic regression analysis yielded 18 variables that were associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 4 variables including heart rate, hemoglobin, serum sodium, and serum miR-30d level associated with mortality. ROC curve analysis showed that hemoglobin, heart rate and serum sodium displayed poor prognostic value for AHF (AUCs not higher than 0.700) compared to miR-30d level (AUC = 0.806). Kaplan–Meier survival analysis confirmed that patients with higher serum miR-30d levels had significantly lower mortality (P=0.001). Conclusion: In conclusion, this study shows evidence for the predictive value of circulating miR-30d as 1-year all-cause mortality in AHF patients. Large multicentre studies are further needed to validate our findings and accelerate the transition to clinical utilization.

CD68/macrosialin: not just a histochemical marker

CD68 is a heavily glycosylated glycoprotein that is highly expressed in macrophages and other mononuclear phagocytes. Traditionally, CD68 is exploited as a valuable cytochemical marker to immunostain monocyte/macrophages in the histochemical analysis of inflamed tissues, tumor tissues, and other immunohistopathological applications. CD68 alone or in combination with other cell markers of tumor-associated macrophages showed a good predictive value as a prognostic marker of survival in cancer patients. Lowression of CD68 was found in the lymphoid cells, non-hematopoietic cells (fibroblasts, endothelial cells, etc), and tumor cells. Cell-specific CD68 expression and differentiated expression levels are determined by the complex interplay between transcription factors, regulatory transcriptional elements, and epigenetic factors. Human CD68 and its mouse ortholog macrosialin belong to the family of LAMP proteins located in the lysosomal membrane and share many structural similarities such as the presence of the LAMP-like domain. Except for a second LAMP-like domain present in LAMPs, CD68/microsialin has a highly glycosylated mucin-like domain involved in ligand binding. CD68 has been shown to bind oxLDL, phosphatidylserine, apoptotic cells and serve as a receptor for malaria sporozoite in liver infection. CD68 is mainly located in the endosomal/lysosomal compartment but can rapidly shuttle to the cell surface. However, the role of CD68 as a scavenger receptor remains to be confirmed. It seems that CD68 is not involved in binding bacterial/viral pathogens, innate, inflammatory or humoral immune responses, although it may potentially be involved in antigen processing/presentation. CD68 could be functionally important in osteoclasts since its deletion leads to reduced bone resorption capacity. The role of CD68 in atherosclerosis is contradictory.