Adverse Prognostic Indicator Research Articles

Tumour budding with and without admixed inflammation: two different sides of the same coin?

Background:Tumour budding is an adverse prognostic indicator in colorectal cancer (CRC). Marked overall peritumoural inflammation has been associated with favourable outcome and may lead to the presence of isolated cancer cells due to destruction of invading cancer cell islets.Methods:We assessed the prognostic significance of tumour budding and peritumoural inflammation in a cohort of 381 patients with CRC applying univariate and multivariate analyses.Results:Patients with high-grade budding and marked inflammation had a significantly better outcome compared with patients with high-grade budding and only mild inflammation. Outcome in these cases, however, was still worse compared with cases with low-grade budding, in which the extent of peritumoural inflammation had no further prognostic effect.Conclusions:Tumour budding proved to be a powerful prognostic variable in patients with CRC. Scattering of invading cancer cell islets by marked overall peritumoural inflammation seems to have a minor role.

Kidney Disease among Patients with Sickle Cell Disease, Hemoglobin SS and SC

Sickle cell disease (SCD) is an inherited anemia that afflicts millions worldwide. Kidney disease is a major contributor to its morbidity and mortality. We examined contemporary and historical SCD populations to understand how renal disease behaved in hemoglobin SS (HbSS) compared with HbSC. Kidney function was examined in the multicentered Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) Trial (HbSS=463; HbSC=127; years 2007-2009) and historical comparator populations from the Cooperative Study of Sickle Cell Disease (CSSCD; HbSS=708) and the Multicenter Study of Hydroxyurea in Sickle Cell Disease (MSH; HbSS=299). In adults with SCD, eGFR was lower among older individuals: -1.78 ml/min per 1.73 m(2) per year of age (95% confidence interval [95% CI], -2.06 to -1.50; Walk-PHaSST Trial), -1.75 ml/min per 1.73 m(2) per year of age (95% CI, -2.05 to -1.44; MSH), and -1.69 ml/min per 1.73 m(2) per year of age (95% CI, -2.00 to -1.38; CSSCD) in HbSS compared with -1.09 ml/min per 1.73 m(2) per year of age (95% CI, -1.39 to -0.75) in HbSC (Walk-PHaSST Trial). Macroalbuminuria was seen in 20% of participants with SCD (HbSS or HbSC; P=0.45; Walk-PHaSST Trial), but microalbuminuria was more prevalent in HbSS (44% versus 23% in HbSC; P<0.002). In the Walk-PHaSST Trial, albuminuria was associated with hemolysis (higher lactate dehydrogenase, P<0.001; higher absolute reticulocyte count, P<0.02; and lower Hb, P=0.07) and elevated systolic BP (P<0.001) in HbSS. One half of all participants with HbSS (20 of 39) versus one fifth without (41 of 228) elevated tricuspid regurgitant jet velocity (≥3 m/s; adverse prognostic indicator in SCD) had macroalbuminuria (P<0.001). In the CSSCD, overt proteinuria, detected (less sensitively) by urine dipstick, associated with higher 3-year mortality (odds ratio, 2.48; 95% CI, 1.07 to 5.77). Serum bicarbonate was lower in HbSS (23.8 versus 24.8 mEq/dl in HbSC; P<0.05) and associated with reticulocytopenic anemia and decreased renal function. In SCD, albuminuria or proteinuria was highly prevalent, in HbSS more than in HbSC. Proteinuria associated with mortality in HbSS. Older individuals had a lower than expected eGFR, and this was more prominent in HbSS. Current management does not routinely address renal complications in SCD, which could plausibly reduce morbidity and mortality.

Impact of Molecular Clonality on Survival in Acute Myeloid Leukemia

Background: Tumor heterogeneity has been documented in several malignancies and is generally associated with more aggressive disease and poorer prognosis. While heterogeneity has been documented in acute myeloid leukemia (AML), risk prognosis in AML is currently assessed by cytogenetics and the presence of recurrent mutations in genes such as FLT3 and NPM1, which are typically tested on a single gene basis. Prior approaches to identify molecular clonality have been laborious and therefore of limited clinical utility. The advent of next generation sequencing (NGS), however, allows for the rapid assessment of subclones within tumor populations. Currently, the prognostic significance of tumor heterogeneity in AML is not well defined. Therefore, this pilot study assessed the clinical significance of molecular clonality in AML using data generated by an NGS platform.Methods: We selected patients with de novo AML who had blood or bone marrow submitted for sequencing at initial diagnosis. Patients who subsequently elected for comfort measures only without receiving AML-directed therapy were excluded. Study patients were sequenced with a 25 gene NGS panel on the Ion Torrent platform. This panel included genes that have been shown to be frequently mutated in AML and which lead to increased cellular proliferation or impaired differentiation, with particular emphasis on therapeutic and prognostic mutations. Germline mutations, identified by allelic fraction and/or minor allele frequency, were excluded. Remaining somatic mutations were analyzed with software employing a variational Bayesian algorithm to predict tumor heterogeneity such that patients were assessed for the presence of tumor heterogeneity (≥2 predicted clones) at the time of diagnosis. Heterogeneity was recorded and compared to several clinical parameters, including post-chemotherapy survival at 120 days, patient age, gender, karyotype, and association with the recurrent genetic mutations NPM1, FLT3-ITD, and CEBPA.Results: Twenty patients met the study criteria of de novo AML and elected to receive therapy. The mean age at diagnosis was 59 years (38-77 years); overall survival was 75% at 120 days. Half of the patients (n=10) were determined to have ≥2 clones. Patients with either a complex karyotype or the FLT3-ITD mutation were classified as high risk (n=11). While survival at 120 days was lower in the high risk group (64%) compared to normal risk subjects (89%), this difference did not reach statistical significance (p=0.19). By contrast, patients with tumor heterogeneity (≥2 clones) had significantly lower 120 day survival (50%) when compared to AML patients with a single clone (100%) (p=0.01). There was no correlation between patients with multiple clones and high risk classification (p=0.18).Conclusions: These pilot data present some of the first prospective evidence that heterogeneity detected by NGS is an adverse prognostic indicator for early survival in de novo AML post-chemotherapy. This finding may not be surprising given that the presence of tumor heterogeneity has been shown to confer adverse prognostic risk in several solid malignancies. Still, this early impact of molecular clonality in AML may have important consequences on choice of therapy. Further prospective studies are needed to confirm our findings and to determine the long-term outcomes in AML patient subsets, as well as examining whether a distinct approach to therapy in AML patients with clonal heterogeneity leads to improved early survival. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The prognostic significance of tumour-stroma ratio in endometrial carcinoma.

BackgroundHigh tumour stromal content has been found to predict adverse clinical outcome in a range of epithelial tumours. The aim of this study was to assess the prognostic significance of tumour-stroma ratio (TSR) in endometrial adenocarcinomas and investigate its relationship with other clinicopathological parameters.MethodsClinicopathological and 5-year follow-up data were obtained for a retrospective series of endometrial adenocarcinoma patients (n = 400). TSR was measured using a morphometric approach (point counting) on digitised histologic hysterectomy specimens. Inter-observer agreement was determined using Cohen’s Kappa statistic. TSR cut-offs were optimised using log-rank functions and prognostic significance of TSR on overall survival (OS) and disease-free survival (DFS) were determined using Cox Proportional Hazards regression analysis and Kaplan-Meier curves generated. Associations of TSR with other clinicopathological parameters were determined using non-parametric tests followed by Holm-Bonferroni correction for multiple comparisons.ResultsTSR as a continuous variable associated with worse OS (P = 0.034) in univariable Cox-regression analysis. Using the optimal cut-off TSR value of 1.3, TSR-high (i.e. low stroma) was associated with worse OS (HR = 2.51; 95 % CI = 1.22–5.12; P = 0.021) and DFS (HR = 2.19; 95 % CI = 1.15–4.17; P = 0.017) in univariable analysis. However, TSR did not have independent prognostic significance in multivariable analysis, when adjusted for known prognostic variables. A highly significant association was found between TSR and tumour grade (P < 0.001) and lymphovascular space invasion (P < 0.001), both of which had independent prognostic significance in this study population.ConclusionsLow tumour stromal content associates with both poor outcome and with other adverse prognostic indicators in endometrial cancer, although it is not independently prognostic. These findings contrast with studies on many - although not all - cancers and suggest that the biology of tumour-stroma interactions may differ amongst cancer types.

Abstract A1-67: Prognostic significance of copy number aberrations in Wilms tumor

Abstract Background and Purpose: Treatment of Wilms tumor (WT) patients under International Society of Paediatric Oncology (SIOP) protocols is currently stratified by staging and histopathology at nephrectomy after neoadjuvant chemotherapy. However, most relapses occur in cases without specific histopathological risk factors, and there is a clinical need for better prognostic biomarkers. Combined loss of heterozygosity (LOH) of 1p and 16q has recently been introduced in the US as an adverse prognostic indicator, while previous work in our and other laboratories suggests that 1q gain may have a similar association with poor outcome. To examine the clinical significance of 1q gain and assess its potential as a WT biomarker, we developed a simple, effective assay that measures its genomic copy number together with that of several other loci of interest, and applied it to a large tumor series. Methods: 686 frozen tumor samples from the SIOP WT 2001 trial (from a total of 7 countries) were assayed using a rapid multiplex ligation-dependent probe amplification (MLPA) assay that was developed and optimized in association with MRC-Holland b.v. to assess the copy number status of 1p, 1q, 16q, WT1, WTX, TP53, MYCN and FBXW7. Analyses were conducted in 3 laboratories, with exchange of a blinded quality assurance sample set. Results: 1q gain was present in 28% (190/686) of the cases. The 5- year Event Free Survival (EFS) rate was 72.6% (95% Confidence Interval (CI), 66.3%-85%) for those with 1q gain and 86.4% (95% CI, 83.4%-89.6%) for those who lacked 1q gain (p=&amp;lt;0.0001). The Overall Survival (OS) rate for 1q gain cases was 86.9% (95% CI, 82.1%-92.1%) compared to 93.8% (95% CI, 91.7%-92.1%) for cases without the aberration (p=0.01). Both the EFS and OS analysis showed a statistically significant poorer outcome for cases with 1q gain, but there was no association with disease stage. 1q gain was associated with a significantly increased risk of disease recurrence (HR = 2.18, p&amp;lt;0.0001). In this analysis the proportions of samples with 1p and 16q loss were respectively 8% and 16%. Both were marginally significant for EFS but in the OS analysis 1p lost its significance. MYCN gain, 4q (FBXW7) loss and 17p (TP53) loss were also associated with adverse outcome. Conclusion: Gain of 1q is a potential adverse biomarker for WT. Its association with high risk histological features after pre-operative chemotherapy and independent impact on survival require assessment in a larger number of patients before consideration for clinical use. Citation Format: Tasnim Chagtai, Christina Zill, Linda Dainese, Jenny Wegert, Mariana Maschietto, Gordan Vujanic, Neil Sebire, Ivo Leuschner, Peter Ambros, Maureen O'Sullivan, Christophe Bergeron, David Gisselsson, Marcel Kool, Marry van den Heuvel-Eibrink, Norbert Graf, Harm van Tinteren, Aurore Coulomb, Manfred Gessler, Richard Williams, Kathy Pritchard-Jones. Prognostic significance of copy number aberrations in Wilms tumor. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-67.

S100A16 is a Prognostic Marker for Lung Adenocarcinomas.

Many functional molecules controlling diverse cellular function are included in low-molecular weight proteins and peptides. To identify proteins controlling function in lung adenocarcinomas (AC), we performed two-dimensional gel electrophoresis employing tricine-SDS polyacrylamide in the second dimension (tricine 2-DE). This system was able to detect proteins under 1 kDa even with post- translational modifications. To confirm the utility of detected proteins as novel tumor markers for AC, we performed immunohistochemical analysis using 170 formalin-fixed and paraffin-embedded lung AC tissues. Tricine 2-DE revealed that five proteins including S100A16 were overexpressed in lung AC-derived cells compared with lung squamous cell carcinoma, small cell carcinoma, and large cell neuroendocrine carcinoma- derived cells. Immunohistochemically, S100A16 showed various subcellular localization in lung cancer tissues and a membranous staining status was correlated with the T-factor (P=0.0008), pathological stage (P=0.0015), differentiation extent (P=0.0001), lymphatic invasion (P=0.0007), vascular invasion (P=0.0001), pleural invasion (P=0.0087), and gender (P=0.039), but not with the age or smoking history. More importantly, membranous staining of S100A16 was significantly correlated with a poorer overall survival of either stage I (P=0.0088) or stage II / III (P=0.0003) lung AC patients, and multivariate analysis confirmed that membranous expression of S100A16 was an independent adverse prognostic indicator (P=0.0001). The present results suggest that S100A16 protein is a novel prognostic marker for lung AC.

Tumor budding in colorectal cancer—ready for diagnostic practice?

Tumor budding is an important additional prognostic factor for patients with colorectal cancer (CRC). Defined as the presence of single tumor cells or small clusters of up to 5 cells in the tumor stroma, tumor budding has been likened to an epithelial-mesenchymal transition. Based on well-designed retrospective studies, tumor budding is linked to adverse outcome of CRC patients in 3 clinical scenarios: (1) in malignant polyps, detection of tumor buds is a risk factor for lymph node metastasis indicating the need for colorectal surgery; (2) tumor budding in stage II CRC is a highly adverse prognostic indicator and may aid patient selection for adjuvant therapy; (3) in the preoperative setting, presence of tumor budding in biopsy material may help to identify high-risk rectal cancer patients for neoadjuvant therapy. However, lack of consensus guidelines for standardized assessment still limits reporting in daily diagnostic practice. This article provides a practical and comprehensive overview on tumor budding aimed at the practicing pathologist. First, we review the prognostic value of tumor budding for the management of colon and rectal cancer patients. Second, we outline a practical, evidence-based proposal for the assessment of tumor budding in the daily sign-out. Last, we summarize the current knowledge of the molecular characteristics of high-grade budding tumors in the context of personalized treatment approaches and biomarker discovery.

P2X7 receptor predicts postoperative cancer-specific survival of patients with clear-cell renal cell carcinoma.

The P2X7 receptor, an ATP-gated plasma membrane ion channel, is involved in inflammation, apoptosis and cell proliferation, and thereby plays a crucial role during oncogenic transformation in various malignancies. This study aims to evaluate the impact of P2X7 receptor expression on postoperative cancer-specific survival of patients with clear-cell renal cell carcinoma (ccRCC). A total of 273 patients with ccRCC undergoing nephrectomy at a single institution were retrospectively enrolled in this study, among which 86 patients died of this disease and six patients died of other causes. Clinicopathologic features and cancer-specific survival (CSS) were recorded. P2X7 expression was assessed by immunohistochemistry in clinical specimens. Kaplan–Meier method with log rank test was performed to compare survival curves. Cox regression models were used to evaluate the prognostic values of variables on CSS. Concordance index was calculated to assess prognostic accuracy of prognostic models. Median follow-up period was 90 months (range, 11–120 months). Intratumoral P2X7 expression was significantly lower than peritumoral tissues (P < 0.001). Moreover, high intratumoral P2X7 expression, which was significantly associated with shorten CSS (P < 0.001), high TNM stage (P = 0.038), Fuhrman grade (P = 0.035), SSIGN (stage, size, grade, and necrosis) score (P = 0.021) and University of California Integrated Staging System (UISS) score (P = 0.007), was indicated to be an independent prognostic factor for CSS (hazard ratio [HR], 1.693; P = 0.034). The prognostic accuracy of TNM stage, UISS and SSIGN scoring models was improved when intratumoral P2X7 expression was added. Intratumoral P2X7 expression is a potential independent adverse prognostic indicator for postoperative CSS of patients with ccRCC.

Prognostic value of lymph node ratio and extramural vascular invasion on survival for patients undergoing curative colon cancer resection.

Background:Increasing lymph node ratio (LNR) (ratio of metastatic lymph nodes to the total number of harvested lymph nodes) and extramural vascular invasion (EMVI) have been proposed as adverse prognostic indicators in colorectal cancer, although their use remains variable and controversial. The aim of the present study was to assess the prognostic value of LNR and EMVI in predicting survival for patients undergoing curative colon cancer resection.Methods:Between 2006 and 2012, 922 patients underwent curative colon cancer resection. Surgical technique and pathological assessment did not change during the study period. Clinical and pathological data were collected from a prospectively maintained database. The primary outcome measure was overall survival and disease-free survival. LNR was separated into five categories based on three previously calculated cutoff values: LNR 0 (no lymph nodes involved), LNR 1 (ratio 0.01<0.17), LNR 2 (ratio 0.18–0.41), LNR 3 (ratio 0.42–0.69), and LNR 4 (ratio >0.70).Results:Nine hundred and twenty-two patients underwent colon cancer resection. The median follow-up for survivors was 52.8 months (IQR 34.6–77.6). The median total number of lymph nodes harvested was 16 (IQR13-22). On multivariate analysis, both pN and LNR were strongly associated with overall and disease-free survival. Using the Akaike information criterion (AIC), LNR had greater prognostic value compared with pN. For overall survival, compared with patients in LNR category 0, hazard ratios (95% CI) for those in categories 1, 2, 3 and 4 were 1.37 (1.03,1.82), 2.37 (1.70,3.30), 2.40 (1.57,3.65) and 5.51 (3.16,9.58), respectively. For disease-free survival, patients had hazard ratios (95% CI) of 1.78 (1.25,2.52), 3.79 (2.56,5.61), 2.60 (1.50,4.48) and 4.76 (2.21,10.27), respectively. The presence of EMVI was a significant predictor of decreased overall and disease-free survival (P<0.001).Conclusions:This study demonstrated, in the presence of high surgical, oncology and pathological standards, EMVI and increasing LNR were independent predictors of decreased overall and disease-free survival for patients undergoing curative colon cancer resection. LNR was superior to pN stage in predicting overall and disease-free survival.

Prognostic significance of the BAALC gene expression in adult patients with acute myeloid leukemia: A meta-analysis.

Numerous studies have investigated the prognostic role of brain and acute leukemia, cytoplasmic (BAALC) gene expression in adult patients with acute myeloid leukemia (AML); however, the results are inconclusive. A meta-analysis was conducted to provide a comprehensive evaluation of the prognostic role of BAALC gene expression in AML. Eligible studies were searched through PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and the China Biology Medicine Disc. Correlations between the BAALC gene expression and clinicopathological features and prognosis were analyzed. A total of 15 studies were examined. The pooled results suggest that high BAALC expression had an unfavorable outcome in AML. The combined hazard ratio (HR) for overall survival (OS) was 1.53 and the summary HR for the disease-free survival rate was 1.64. In addition, subgroup analyses considering cytogenetic and survival analysis were also conducted. High BAALC gene expression appeared to be an adverse prognostic indicator in patients with cytogenetically normal AML (HR for OS, 1.43) and in subgroups of survival analysis with multivariate analysis (HR for OS, 2.35). These results indicate that high BAALC gene expression served as an independent poor prognostic indicator in adult patients with AML.

Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle-Invasive Micropapillary Bladder Cancer?

Introduction: We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. Patients and Methods: This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. Results: Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). Conclusions: MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation.

(371) - Initial Results of the Prospective Registry of Sarcoidosis Associated Pulmonary Hypertension (ReSAPH)

s S143 artery pressure (mPAP) ≥ 25 mmHg, pulmonary artery wedge pressure (PAWP) 3 Wood Units. Data reported as mean ± standard deviation. Results: Of 5420 patients with Sjogren’s Syndrome evaluated between 1995 and 2014, 100 had evidence of right ventricular systolic pressure (RVSP) > 40 mmHg on transthoracic echocardiography. Of those 100 patients, 40 underwent right heart catheterization (RHC); and 36 (90%) had mPAP ≥ 25 mmHg. Of those 36 all-female patients, the average age was 65 ± 9 years. 20 (56%) had primary SS, and 16 (44%) had secondary SS. An underlying lung disorder was present in 13 (36%), with five carrying a diagnosis of interstitial lung disease. A left ventricular ejection fraction (EF) < 45% was present in 14 (39%). Transthoracic echocardiography for the 36 patients revealed a right atrial pressure (RAP) of 13 ± 4 mmHg and a mean RVSP of 72 ± 21 mmHg. Moderate-severe right atrial enlargement was present in 21 (58%) with moderate-severe right ventricular enlargement present in 21 (58%) also. 19 (53%) had ≤ mild right ventricular (RV) dysfunction and 17 (47%) had moderate-severe RV dysfunction. RHC in the 36 patients demonstrated a mPAP of 45 ± 10 mmHg, RAP of 11 ± 7 mmHg, PAWP of 14 ± 8 mmHg, and PVR of 7.3 ± 4.7 Wood Units. 16 (44%) had PAH and 15 (42%) were treated with PAH-specific medications. Median survival of patients with PAH was 39 months. Adverse prognostic indicators for those 36 patients with coexisting SS and PH included moderate-severe right atrial enlargement (p= 0.03), moderate-severe RV dysfunction (p= 0.035), and pre-capillary pulmonary arterial hypertension (p= 0.05). Conclusion: In patients with primary or secondary Sjogren’s Syndrome, a minority develop pulmonary hypertension. There is no significant difference in outcome between primary or secondary SS in the setting of concomitant PH. Right atrial enlargement, RV dysfunction, and pre-capillary pulmonary arterial hypertension are associated with worse survival.

Prognostic value of carbonic anhydrase VII expression in colorectal carcinoma

BackgroundCarbonic anhydrases (CAs) have been implicated in the pathogenesis of human cancers. Carbonic anhydrase VII (CA7), a member of the CA gene family, was recently demonstrated to be expressed in several human tissues including colon. Nevertheless, the expression and clinical relevance of CA7 in colorectal carcinoma (CRC) has not been investigated.MethodsReal-time PCR, western blot, and immunohistochemistry analyses were used to determine CA7 expression in CRC clinical samples. The correlation of CA7 expression with clinicopathologic features was assessed in 228 patients from Luoyang, China (training cohort) and validated in 151 patients from Shanghai, China (validation cohort). Kaplan-Meier and Cox proportional regression analyses were used to estimate the association between CA7 expression and patients’ survival.ResultsCA7 expression was frequently downregulated in CRC tissues at both the mRNA and protein levels. Reduced expression of CA7 was significantly correlated with poor differentiation, positive lymph node metastasis, advanced TNM stage and unfavorable clinical outcome not only in the training cohort but also in the validation set. Survival analysis indicated that patients with lower CA7 expression had a significantly shorter disease-specific survival (DSS) than those with higher CA7 expression. Importantly, further stage-based analyses revealed that decreased CA7 expression significantly predicted poor DSS and was an independent adverse prognostic indicator for patients with early stage tumors in both cohorts.ConclusionsOur results indicate that decreased expression of CA7 correlates with disease progression and predicts poor prognosis in CRC, especially for patients with early stage tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1216-y) contains supplementary material, which is available to authorized users.

Increased levels of symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease

Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry. The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively). The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome

Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.

Scientific Prize Papers

Objective Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD). Methods In 238 patients with symptomatic PAD and an ABI of Results The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality ( P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI ( r = −0.236, N = 216, P r = −0.209, N = 208, P = .002, respectively). Conclusions The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Evaluation of absolute and normalized apparent diffusion coefficient (ADC) values within the post-operative T2/FLAIR volume as adverse prognostic indicators in glioblastoma.

To evaluate the association of normalized and absolute ADC metrics with progression free survival (PFS) and overall survival (OS) in patients treated for glioblastoma multiforme (GBM). Fifty-two patients with preradiotherapy diffusion weighted imaging treated with post-operative chemoradiation for GBM were evaluated. Region of interest analysis for ADC metrics including mean and minimum ADC value (ADCmean) and (ADCmin) was performed within the T2/FLAIR volume. Normalized (N)ADC values were generated relative to contralateral white matter. PFS and OS were analyzed relative to ADC parameters using a regression model. Kaplan-Meier and Cox proportional hazards analysis with respect to (N)ADCmean, and (N)ADCmin was performed. A (N)ADC threshold <1.3 within the T2/FLAIR volume was analyzed with respect to PFS and OS. Regression analysis indicated that normalized ADC values provide the strongest association with PFS and OS. Kaplan-Meier analysis revealed a non-significant trend toward inferior PFS and OS associated with (N)ADCmean <1.7, and a significant decrement to PFS and OS associated with (N)ADCmin <0.3. (N)ADCmin was a significant prognostic factor when taking into account age, performance status, and extent of resection. ADC thresholding analysis revealed that a retained volume of >0.45 cc per mL FLAIR volume was associated with a trend toward inferior PFS and OS. In the post-operative, pre-radiotherapy setting, the (N)ADCmin is the strongest predictor of outcomes in patients treated for GBM. ADC thresholding analysis indicates that a large volume of normalized ADC value <1.3 may be associated with adverse outcomes.

Prognostic significance of diagnosed WT1 level in acute myeloid leukemia: a meta-analysis.

The Wilms' tumor 1 (WT1) expression has been recognized in a substantial number of acute myeloid leukemia (AML) patients. Some studies indicated the association of diagnosed WT1 higher expression (WT1(H)) and poor outcome in the AML patients, while other studies had different opinions. Therefore, we performed a meta-analysis to evaluate the controversial prognostic significance of diagnosed WT1(H) in AML. Eligible studies were identified from several databases including PubMed, Embase, Web of Science, and the Cochrane Library (up to September 2014). The primary end point was overall survival (OS) and disease-free survival (DFS) was chosen as secondary end point. If possible, we would pool estimate effects (hazard ratio [HR] with 95% confidence interval [CI]) of outcomes in bothfixed and random effects models. Eleven studies, covering 1497 AMLpatients, were included in this meta-analysis. Pooled HRs indicated that diagnosed WT1(H) had a poor impact on the survival of AML patients (HR for OS, 1.37; HR for DFS, 1.38). Furthermore, diagnosed WT1(H) appeared to be an adverse prognostic indicator in adult AML (HR for OS, 1.43; HR for DFS, 1.41) and non-promyelocytic AML (non-M3 AML) (HR for OS, 1.46; HR for DFS, 1.41). Diagnosed WT1(H) had slightly but significantly poor prognostic impact on OS and DFS of patients with AML in total population and some specific subgroups.

Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systematic review.

Fetal liver tyrosine kinase 3 (FLT3)-internal tandem duplications (ITDs) has been used as a powerful adverse prognostic indicator for acute myeloid leukemia (AML) in any age group. Evidence is mixed regarding the effects of allogeneic transplantation (allo-HSCT) in first complete remission (CR) for patients with FLT3/ITD AML. To fill this gap, this study provides a systematic review and meta-analysis of patients with FLT3/ITD AML receiving HSCT. A search of PubMed, Embase, and OVID yielded 1706 abstracts, two researchers screening the trials based on inclusion and exclusion criteria, and assessed the methodology quality independently. Meta-analysis showed that compared with chemotherapy, both allo-HSCT and autologous hematopoietic cell transplantation (auto-HSCT) can reduce the relapse rate (p < 0.01) and improve both the OS (p < 0.01) and DFS (p < 0.01). But when compared allo-HSCT with auto-HSCT, the OS (p = 0.27) and DFS (p = 0.19) have no statistical significance, and only the relapse indicator has statistical significance, p < 0.01. Based on the results, we can conclude that allo-HSCT is an efficient therapy approach for patients with FLT3/ITD AML. Chemotherapy cannot change the poor prognosis. Auto-HSCT can improve OS and DFS, but it cannot reduce the relapse rate.

Regional Heterogeneity in 3D Myocardial Shortening in Hypertensive Left Ventricular Hypertrophy: A Cardiovascular CMR Tagging Substudy to the Life Study.

BackgroundIncreased relative wall thickness in hypertensive left ventricular hypertrophy (LVH) has been shown by echocardiography to allow preserved shortening at the endocardium despite depressed LV midwall circumferential shortening (MWCS). Depressed MWCS is an adverse prognostic indicator, but whether this finding reflects reduced global or regional LV myocardial function, as assessed by three-dimensional (3D) myocardial strain, is unknown.Methods and ResultsCardiac Magnetic Resonance (CMR) tissue tagging permits direct evaluation of regional 3D intramyocardial strain, independent of LV geometry. We evaluated 21 hypertensive patients with electrocardiographic LVH in the LIFE study and 8 normal controls using 3D MR tagging and echocardiography. Patients had higher MR LV mass than normals (116 ± 40 versus 63 ± 6 g/m2, P = 0.002). Neither echocardiographic fractional shortening (32 ± 6 versus 33% ± 3%), LVEF (63% versus 64%) or mean end-systolic stress (175 ± 27 versus 146 ± 28 g/cm2) were significantly different, yet global MWCS was decreased by both echocardiography (13.4 ± 2.8 versus 18.2% ± 1.5%, P < 0.001) and MR (16.8 ± 3.6 versus 21.6% ± 3.0%, P < 0.005). 3D MR MWCS was lower at the base versus apex (P = 0.002) in LVH and greater in lateral and anterior regions versus septal and posterior regions (P < 0.001), contributing to the higher mean global MWCS by MR than echo. MR longitudinal strain was severely depressed in LVH patients (11.0 ± 3.3 versus 16.5% ± 2.5%, P < 0.001) and apical twist was increased (17.5 ± 4.3 versus 13.7 ± 3.7, P < 0.05). Importantly, both circumferential and longitudinal shortening correlated with LV relative wall thickness (R > 0.60, P = 0.001 for both).ConclusionsIn patients with hypertensive LVH, despite normal LV function via echocardiography or CMR, CMR intramyocardial tagging show depressed global MWCS while 3D MR strain revealed marked underlying regional heterogeneity of LV dysfunction.