Prognostic Indicator Of Poor Outcome Research Articles

Abstract LB-68: MYCN-induced TRPM7 expression and channel activity occurs through a mechanism that involves ornithine decarboxylase

Abstract Neuroblastoma (NB) is an extra-cranial solid cancer in children. MYCN is a transcription factor that regulates the expression of genes that are involved in cell proliferation, growth, cell migration, etc. MYCN gene amplification is a prognostic indicator of poor outcome in NB. Recent studies have shown that intracellular free calcium regulates multiple steps involved in cell migration. Although significant advances have been made in understanding the role of calcium during migration, little has been achieved towards understanding its impact on the malignant progression of NB. Our results showed that MYCN gene amplification or over-expression of MYCN in NB cells increased TRPM7 expression, increased peak TRPM7 current, induced constitutive TRPM7 channel activity, enhanced calcium signaling, and promoted cell migration, implicating TRPM7 as a potential regulator of calcium signals that promote NB cell migration and invasion. Recent results suggest that MYCN may regulate TRPM7 expression through a process that involves ornithine decarboxylase (ODC), a rate limiting enzyme in the biosynthesis of polyamines, and a direct transcriptional target of MYCN. Treatment of NB cells with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, or transfection of ODC specific siRNA effectively decreased TRPM7 expression. This effect was attenuated by supplementing the culture media with spermidine, confirming that ODC may function downstream of MYCN to regulate TRPM7 expression. Interestingly, western blot analysis of NB cell lysates showed that MYCN induced the cleavage of the TRPM7 kinase domain, a post-translational modification that has been shown to increase TRPM7 currents and induce constitutive TRPM7 channel activity. Additionally, DFMO inhibited TRPM7 cleavage, an effect that was reversed by spermidine supplementation. Taken together, these results suggest that MYCN may regulate TRPM7 expression and channel activity through a mechanism that involves ODC-mediated polyamine biosynthesis. Citation Format: Dana-Lynn T. Koomoa, Ingo Lange. MYCN-induced TRPM7 expression and channel activity occurs through a mechanism that involves ornithine decarboxylase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-68. doi:10.1158/1538-7445.AM2014-LB-68

Lymphovascular Invasion as a Prognostic Indicator in Stage I Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Lymphovascular invasion (LVI) is considered a high-risk pathologic feature in resected non-small cell carcinoma (NSCLC). The ability to stratify stage I patients into risk groups may permit refinement of adjuvant treatment recommendations. We performed a systematic review and meta-analysis to evaluate whether the presence of LVI is associated with disease outcome in stage I NSCLC patients. A systematic search of the literature was performed (1990 to December 2012 in MEDLINE/EMBASE). Two reviewers independently assessed the quality of the articles and extracted data. Pooled hazard ratios (HRs) and 95% confidence intervals (CI) were estimated with a random effects model. Two end points were independently analyzed: recurrence-free survival (RFS) and overall survival (OS). We analyzed unadjusted and adjusted effect estimates, resulting in four separate meta-analyses. We identified 20 published studies that reported the comparative survival of stage I patients with and without LVI. The unadjusted pooled effect of LVI was significantly associated with worse RFS (HR, 3.63; 95% CI, 1.62 to 8.14) and OS (HR, 2.38; 95% CI, 1.72 to 3.30). Adjusting for potential confounders yielded similar results, with RFS (HR, 2.52; 95% CI, 1.73 to 3.65) and OS (HR, 1.81; 95% CI, 1.53 to 2.14) both significantly worse for patients exhibiting LVI. The present study indicates that LVI is a strong prognostic indicator for poor outcome for patients with surgically managed stage I lung cancer. Future prospective lung cancer trials with well-defined methods for evaluating LVI are necessary to validate these results.

MycN promotes TRPM7 expression and cell migration in neuroblastoma through a process that involves polyamines

Neuroblastoma is an extra-cranial solid cancer in children. MYCN gene amplification is a prognostic indicator of poor outcome in neuroblastoma. Recent studies have shown that the multiple steps involved in cell migration are dependent on the availability of intracellular calcium (Ca2+). Although significant advances have been made in understanding the role of Ca2+ during migration, little has been achieved towards understanding its impact on the progression of diseases such as cancer. Interestingly, previous studies showed that cancer cell migration is regulated by TRPM7, a calcium-permeable ion channel. The objective of the current study was to elucidate the mechanism by which MycN promotes NB cell migration and the mechanism regulating TRPM7 expression. The results showed that MycN increased TRPM7 expression, induced TRPM7 channel activity, increased intracellular Ca2+ signaling, and promoted cell migration in NB cells. The results also showed that inhibition or down-regulation of ornithine decarboxylase (ODC) inhibited TRPM7 expression, a process that was reversed by spermidine. Overall, this study provides evidence that MycN promotes TRPM7 expression and cell migration through a mechanism that involves ODC synthesis of polyamines.

Longitudinal Patterns of CRP Elevation and Crohnʼs Disease Severity

Purpose: C-reactive protein (CRP) is a biochemical marker that correlates with inflammation in Crohn's disease (CD). CRP confirms active inflammation and may function as a prognostic indicator of poor outcome. CD currently lacks a severity index, which stratifies groups of patients based on their burden of illness over time. We hypothesized that patterns of CRP elevation in CD patients followed longitudinally may correlate with disease-related complications and function as a biochemical marker of severity. Methods: Prospectively recruited CD patients from a longitudinal IBD natural history registry followed between 2009 and 2011, with annual visits and CRP evaluation, were analyzed. Short IBD questionnaire (SIBDQ) and Harvey-Bradshaw Index (HBI) scores completed at each visit, patterns of IBD-related hospitalization, and emergency department (ED) use were analyzed. Mean SIBDQ scores over 3 years > 50 were considered good quality of life. Results: A total of 153 CD patients were included in our study; 42.5% (65) were males, while 57.5% (88) were females. Patients had a mean age of 43.4 years (SD 14.2; range 21.4-81.2 years). Sixty-five of the 153 patients (42.5%) had no CRP elevation during the study period, while 57.5% of patients (88) had at least one CRP elevation. Among the patients with elevation in CRP, 23.55% (36) had CRP elevation in 1 year, 20.3% of patients (31) had CRP elevation in 2 of the 3 years, while 13.7% (21) had CRP elevation in all 3 years of the study. When comparing ED visits, 54% of patients with at least one CRP elevation over 3 years had an ED visit, as compared to 30% of patients with normal CRP over 3 years (p=0.026). 67.2% of patients (43) with normal CRP elevation over 3 years had a good quality of life, which was significantly higher than CD patients with CRP elevations over 1, 2, and 3 years (41.7%, 33.3%, and 30%, respectively); p=0.002. When comparing hospitalizations, 64% of patients with at least one CRP elevation in any of the 3 years of the study period required a CD-related hospitalization, as compared to 20% of patients with no CRP elevation in these 3 years (p<0.001). The HBI was significantly higher in patients with any CRP elevation compared to no CRP elevation (3.4 vs. 5.3, p<0.001). Conclusion: Prospective evaluation of CRP elevation in CD patients over a 3-year study period correlated with increased rates of ED use and hospitalization. Persistent elevation in CRP over multiple years correlated with worse quality of life in CD. CRP elevation carries important prognostic ramifications for CD-related complications, and persistent CRP elevation may define a sub-group of CD patients with severe and refractory disease.

The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

Abstract 3781: MYCN-induced TRPM7 mediates calcium influx and promotes neuroblastoma cell migration.

Abstract Neuroblastoma (NB) is the most common extra-cranial solid cancer in children. One of the genetic characteristics of advanced stage NB is MYCN gene amplification, a prognostic indicator of poor outcome. MYCN is a transcription factor from the myc proto-oncogene family that regulates fundamental processes by regulating the expression of genes that are involved in cell proliferation, growth, cell migration, etc. One of the hallmarks of the malignant progression of primary tumors is uncontrolled growth and spread of tumor cells, with the consequence of metastatic cells entering the blood stream or lymphatic system and nesting into secondary tissues and organs. Metastatic tumors affect the function of cells and/or organs at the secondary site, and compromise the health and survival of cancer patients. Recent studies have shown that the multiple steps involved in cell migration and invasion (such as lamellapodia formation, focal adhesion turnover, and cytoskeletal dynamics) are dependent on the availability of free intracellular calcium. Although significant advances have been made in understanding the role of calcium during migration and invasion itself, little has been achieved towards understanding its impact on the progression of diseases such as cancer where cell motility is critical for the spread of tumor cells. To address this deficiency, the objective of the current study was to elucidate the mechanism by which calcium signaling regulates NB migration and invasion. Our initial results showed that tetracycline-inducible over-expression of MYCN in NB cells increased TRPM7 expression, enhanced calcium signaling, and promoted cell migration, compared to control NB cells. In addition, increasing extracellular calcium augmented these processes. These results implicate TRPM7 as a potential regulator of calcium-dependent NB cell migration and invasion. In order to confirm the role of TRPM7 in these processes, we used pharmacological inhibitors of TRPM7 and TRPM7-specific siRNA to modulate TRPM7 activity in NB cells, and performed live-cell calcium measurements, electrophysiological patch-clamp recordings, and cell migration assays. The results showed that TRPM7 plays a role in regulating intracellular calcium signaling and NB cell migration. Overall, the results from this study suggest that MYCN over-expression and minute changes in extracellular calcium can promote NB cell migration and invasion through a process that involves TRPM7. Furthermore, this study identifies a new biomarker for NB (TRPM7) and novel target for the development of more effective chemotherapeutic drugs for the treatment of advanced stage NB. Citation Format: Ingo Lange, Dana-Lynn T. Koomoa. MYCN-induced TRPM7 mediates calcium influx and promotes neuroblastoma cell migration. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3781. doi:10.1158/1538-7445.AM2013-3781

Abstract 1210: Periostin expression in glioma correlates with genes related to mesenchymal transition and survival.

Abstract Background: Gliomas are the most common primary brain tumors and their prognosis is related to WHO histopathological grade. Glioblastoma (grade IV astrocytoma or GBM) is characterized by microscopic invasion into surrounding brain and universally poor prognosis despite treatment with surgery, radiation and chemotherapy . Recently, the matricellular protein periostin (POSTN) has been shown to be associated with increased parenchymal invasion (measured by edema on MRI) and poor prognosis in GBM. The specific aim of the present analysis was to determine the mechanistic impact of POSTN on glioma outcome. Methods: We used the gene expression of POSTN from 559 GBM patients (pts) included in the Cancer Genome Atlas (TCGA) to build a gene expression model of the expression of 12184 genes to predict POSTN expression using elastic net. This model was used to predict the POSTN expression in a testing set of 419 pts with gliomas included in Repository for Brain Neoplasia Data (REMBRANDT) (99 grade II, 71 grade III and 125 grade IV and 124 with no grade). Receiver-operating characteristic (ROC) and survival analysis were performed to measure the performance of the model, and gene-set enrichment analysis (GSEA) was used to reveal network topology perturbations. Results: The gene expression model discovered 721 genes highly correlated to POSTN expression that predict POSTN in the testing set with an area under the curve (AUC) of 0.96 on ROC curve. GSEA reveals genes involved in “mesenchymal transition,” transition of invasive ductal carcinoma (IDC) from ductal carcinoma in situ (DCIS) in breast cancer and stem cell signatures. Survival analysis of the TCGA GBM pts showed that the cohort with “high POSTN” had worse survival (median 12 months versus 15 months, log-rank p=0.0002). When applied to all pts in REMBRANDT, the model predicted classes also had significantly different survival (median 13.4 versus 38 months, log-rank p&amp;lt;0.0001). Interestingly, this classification of survival persists in the subset of pts with grade III (n=71, median survival 17.7 versus 42.4 months, p=0.0125) and grade II (n=99, median survival 17.9 versus 50.8, p=0.02) gliomas. Conclusions: We have developed a gene expression model related to POSTN, a gene linked to poor prognosis in GBM, to investigate the role correlated genes may play in the aggressive phenotype. Some of the genes found to be highly correlated to POSTN are related to mesenchymal transition, invasive behavior in breast cancer and stemness. We verify that high POSTN expression is a strong prognostic indicator for poor outcome in GBM, and reveal for the first time that pts with grade II and III glioma with a “high” POSTN signature have significantly worse survival. Given that low grade glioma pts often have less aggressive treatment at time of diagnosis, we propose studying the role of early chemoradiation in the subset of pts with poor POSTN signature to potentially improve their outcome. Citation Format: Andrew D. Trister, Andrei M. Mikheev, Jason K. Rockhill, Stephen H. Friend, Robert C. Rostomily. Periostin expression in glioma correlates with genes related to mesenchymal transition and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1210. doi:10.1158/1538-7445.AM2013-1210

Abstract 4037: HIF1α signaling contributes to an aggressive hypoxic phenotype in cervical cancer.

Abstract Tumor hypoxia is an adverse factor in cervical cancer that would be valuable to implement in the clinical decision-making. In a previous study, we identified a hypoxia gene signature associated with aggressiveness in locally advanced cervical cancer. It consisted of 31 genes, and was predictive of progression free survival in an independent cohort treated with chemoradiotherapy. The signature could be useful in the development of a prognostic test to select patients at risk of failure. The aim of the current study was to obtain a deeper understanding of the pathways reflected in the signature. This could provide an increased insight into the hypoxia-related aggressiveness of cervical cancer and be useful to fully exploit the clinical potential of the signature. The gene signature included a total of 12 genes which are known direct targets of HIF1, and 4 genes involved in the unfolded protein response (UPR), including 3 of the 12 HIF1-targets. To obtain a metric for comparison with other relevant factors, a score was calculated from the expression level of the 31 genes in 154 patients. This hypoxia score correlated significantly with HIF1α protein expression (p&amp;lt;0.001). Furthermore, 8 out of the 12 known HIF1α target genes in the signature showed an individual correlation to the expression of HIF1α (p&amp;lt;0.05), including the 3 UPR genes STC2, ERO1L, and AK2. Cox survival analysis of the hypoxia score was performed on the 154 patients. When stratifying the score on lymph node status, it was predictive of poor outcome only for the patients without metastases to the lymph nodes (89 patients) (p=0.001). When assessing the prognostic value of HIF1α protein expression in the whole patient group, it was not correlated with survival. However, in patients with no lymph node metastases, high levels of HIF1α were found to be a prognostic indicator of poor outcome (p=0.043). Multivariate cox survival analysis was performed on the lymph node negative patients, including the hypoxia score, HIF1α, and clinical parameters. Only the hypoxia score and FIGO stage were found to be independently related to patient survival. In conclusion, it appears that HIF1α is an important mediator of the aggressive phenotype associated with our hypoxia gene signature. However, since the hypoxia score emerged as a significantly better prognostic factor than HIF1α, other signaling pathways may also contribute. Furthermore, this hypoxic phenotype seems to be associated with aggressiveness particularly in patients with no metastases to the lymph nodes. Citation Format: Cathinka Halle, Eva-Katrine Aarnes, Ruth Holm, Gunnar B. Kristensen, Heidi Lyng. HIF1α signaling contributes to an aggressive hypoxic phenotype in cervical cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4037. doi:10.1158/1538-7445.AM2013-4037

Prognostic Impact of Mutant to Wild-Type Ratio and Insertion Site in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication

AbstractAbstract ▪785▪This icon denotes a clinically relevant abstract Background:FLT3 internal tandem duplications (FLT3-ITD) occur in about 25% of acute myeloid leukemia (AML), are associated with cooperating gene mutations (NPM1, DNMT3A), and confer an adverse prognosis. Several studies have indicated that the unfavorable impact of FLT3-ITD is influenced by a number of factors, such as the mutant to wild-type ratio (allelic ratio), insertion site of FLT3-ITD in the beta1 sheet of the tyrosine kinase domain 1, and the molecular background of cooperating mutations. Aims:To evaluate the relative impact of FLT3-ITD allelic ratio and insertion site, as well as cooperating genetic lesions on prognosis and treatment decision making in a large cohort of homogeneously treated younger adult patients. Methods:The basis of the study were 2377 younger adults (median age, 48 years; range, 16–62 years) with newly diagnosed AML enrolled on three prospective treatment trials of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. Patients with acute promyelocytic leukemia (n=99), core-binding factor AML (n=279) and AML with adverse-risk cytogenetics (n=436) according to the European LeukemiaNet recommendations were excluded. Based on material availability, the presence of FLT3-ITD could be analyzed in 1414 patients; NPM1 and DNMT3A mutational status was available in 97% and 84% of the patients, respectively. In FLT3-ITD positive AML (n=394), the allelic ratio, determined by Genescan-based fragment-length analysis, was available in 86% and the insertion site in 72%. Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission was performed in 41% and 29% of FLT3-ITD positive and negative patients, respectively. Results:We first evaluated the prognostic impact of the different FLT3-ITD characteristics within the subgroup of FLT3-ITD positive patients. The allelic ratio was categorized into quartiles ranging from low to high. For the endpoints event-free (EFS), relapse-free (RFS) and overall survival (OS), only the fourth quartile with the highest allelic ratio showed a prognostic impact for all endpoints, whereas no difference was identified between the other three quartiles. For further analyses, the allelic ratio was dichotomized comparing the fourth quartile versus the other three quartiles. FLT3-ITD insertion site in the beta1 sheet was significantly associated with an unfavorable outcome for all endpoints. Additionally, FLT3-ITD size was directly correlated with the insertion site: the more C-terminal the ITD inserted in the FLT3 gene the longer the FLT3-ITD size. There was no prognostic impact of FLT3-ITD size neither as continuous nor as quartile-categorized variable. Multiple FLT3-ITDs, present in 13% of AMLs, were associated with an unfavorable prognosis. The presence of either NPM1 and/or DNMT3A mutations in FLT3-ITD positive patients did not alter the original FLT3 prognosis. In multivariable models for the endpoint OS of the total cohort of intermediate-risk AML, an independent prognostic impact beyond the variable FLT3-ITD was shown for the allelic ratio (fourth quartile) [HR, 1.4; p=0.037] and in trend for insertion site in the beta1 sheet [HR, 1.33; p=0.06]. Survival of patients exhibiting a high allelic ratio (n=43) or insertion site in the beta1 sheet (n=60) was comparable, with a median of 10 and 13 months and 4-year survival of 19% and 24%, respectively. Of note, outcome of patients with both high allelic ratio and insertion site in the beta1 sheet (n=21) was very poor with a median OS of 10 months and 4-year OS of 5%, respectively. In patients with FLT3-ITD positive AML without these unfavorable factors (n=144), median and 4-year OS were 15 months and 42%, respectively. Of note, a clear benefit of allogeneic HSCT in first CR was only seen in FLT3-ITD positive patients without these two unfavorable factors, with a 4-year OS of 63%. In comparison, the 4-year OS of the same subgroup of patients achieving a CR after induction therapy without proceeding to allogeneic HSCT during first CR was 35%. In contrast, outcome in patients with high allelic ratio and/or insertion site in the beta1 sheet remained poor despite allogeneic HSCT in first CR. Conclusion:High FLT3-ITD allelic ratio and ITD insertion site in the beta1 sheet presented as prognostic indicators for poor outcome in patients with the presence of a FLT3-ITD. Only patients without these unfavorable FLT3-ITD features significantly benefitted from allogeneic HSCT. Disclosures:Schlenk:Roche: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Impact of severity of renal dysfunction on determinants of in‐hospital mortality among patients undergoing percutaneous coronary intervention

Chronic kidney disease (CKD) is a known prognostic indicator of poor outcomes following percutaneous coronary intervention (PCI) for coronary artery disease. However, it is unclear whether other predictors of mortality differ among patients with varying degrees of renal impairment. Thus, we aimed to identify determinants of in-hospital mortality which are specific to patients with preserved renal function, moderate CKD, or end stage renal disease (ESRD) on dialysis, undergoing PCI. The study population included 25,018 patients who underwent PCI between January 1, 2004, and December 31, 2007, at four New York State hospitals. The primary endpoint of the study was in-hospital mortality. A total of 474 (1.9%) patients had ESRD on dialysis, 6,596 (26.4%) had moderate CKD (GFR<60 ml/min/1.73 m(2) ), and 17,948 (71.7%) had preserved renal function (GFR>60 ml/min/1.73 m(2) ). Patients with ESRD and moderate CKD were older, more often male, and had higher rates of prior coronary revascularization, peripheral vascular disease, congestive heart failure, prior stroke, and diabetes than those with preserved function. All-cause in-hospital mortality rates were significantly higher in patients with ESRD and moderate CKD compared to patients with GFR >60 ml/min/1.73 m(2) (2.1% and 1.3%, respectively vs. 0.3%, p < 0.001). In multivariable analysis, ESRD (OR: 3.68, 95% CI 1.62-8.36) and moderate CKD (OR: 2.92, 95% CI 1.91-4.46) were independently associated with higher rates of in-hospital mortality. Independent predictors of mortality were markedly distinct in each group and included female gender and myocardial infarction within the past 72 hr in the ESRD group, versus left ventricular ejection fraction, peripheral vascular disease, congestive heart failure, emergency PCI, and absence of prior PCI in the moderate CKD group and age, prior bypass graft surgery, congestive heart failure, emergency PCI, and absence of prior myocardial infarction in patients with preserved renal function. Patients with moderate CKD or ESRD undergoing PCI have an approximately threefold increase in the risk of in-hospital mortality compared with patients with preserved renal function, with radically different mortality predictors existing for varying levels of renal function.

Association of overexpression of TIF1γ with colorectal carcinogenesis and advanced colorectal adenocarcinoma

To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ), Smad4 and transforming growth factor-beta (TGFβR) across a spectrum representing colorectal cancer (CRC) development. Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1γ, Smad4 and TGFβRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). Overexpression of TIF1γ was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFβRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1γ overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome.

Are prognostic indicators for poor outcome different for acute and chronic low back pain consulters in primary care?

Few studies have investigated whether prognostic indicators, which contribute to the transition from acute to chronic low back pain (LBP), are also those which contribute to continuing persistence of chronic LBP. We compared the contribution of physical, psychological and social indicators to predicting disability after one year between consulters with LBP of less than 3months duration and more than 3months duration. Data from two large prospective cohort studies of consecutive patients consulting with LBP in general practices were merged, providing complete data for 258 cases with acute/subacute LBP and 668 cases with chronic LBP at 12months follow-up. There were significant differences between the two LBP groups in baseline characteristics and clinical course of disability, assessed by Roland Morris Disability Questionnaire, during the year of follow-up. Adjusted associations between potential prognostic indicators and disability at 12months were carried out in the two LBP subgroups. The final multivariable regression models showed that being non-employed, having widespread pain, a high level of Chronic Pain Grade, and catastrophising were the strongest prognostic indicators for disability at 12months in both LBP groups. Fear of pain was significantly associated with disability in chronic LBP. Importantly, beyond baseline disability, the effect size of the other prognostic indicators for poor outcome was rather low. These findings must continue to challenge researchers to identify useful early predictors of outcome in persons with disabling back pain, as screening and targeted treatment approaches are dependent upon prognostic indicators with clinical significance.

Depression and Increased Short-Term Hospitalization Risk Among Geriatric Patients Receiving Home Health Care Services

Depression and Increased Short-Term Hospitalization Risk Among Geriatric Patients Receiving Home Health Care Services

Prognostic indicators of poor short‐term outcome of physiotherapy intervention in women with stress urinary incontinence

To identify prognostic indicators independently associated with poor outcome of physiotherapy intervention in women with primary or recurrent stress urinary incontinence (stress UI). A prospective cohort study was performed in physiotherapy practices in primary care to identify prognostic indicators 12 weeks after initiation of physiotherapy intervention. Patients were referred by general practitioners or urogynecologists. Risk factors for stress UI were examined as potential prognostic indicators of poor outcome. The primary outcomes were defined as poor outcome on the binary Leakage Severity scale (LS scale) and the binary global perceived effectiveness (GPE) score. Two hundred sixty-seven women, with a mean age of 47.7 (SD = 8.3), with stress UI for at least 6 months were included. At 12 weeks, 43% and 59% of the women were considered recovered on the binary LS scale and the binary GPE score, respectively. Prognostic indicators associated with poor outcome included 11 indicators based on the binary LS scale and 8 based on the binary GPE score. The prognostic indicators shared by both models show that poor recovery was associated with women with severe stress UI, POP-Q stage > II, poor outcome of physiotherapy intervention for a previous UI episode, prolonged second stage of labor, BMI > 30, high psychological distress, and poor physical health. This study provides robust evidence of clinically meaningful prognostic indicators of poor short-term outcome. These findings need to be confirmed by replication studies.

Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force.

Disseminating disease is a predictive and prognostic indicator of poor outcome in children with neuroblastoma. Its accurate and sensitive assessment can facilitate optimal treatment decisions. The International Neuroblastoma Risk Group (INRG) Task Force has defined standardised methods for the determination of minimal disease (MD) by immunocytology (IC) and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) using disialoganglioside GD2 and tyrosine hydroxylase mRNA respectively. The INRG standard operating procedures (SOPs) define methods for collecting, processing and evaluating bone marrow (BM), peripheral blood (PB) and peripheral blood stem cell harvest by IC and QRT-PCR. Sampling PB and BM is recommended at diagnosis, before and after myeloablative therapy and at the end of treatment. Peripheral blood stem cell products should be analysed at the time of harvest. Performing MD detection according to INRG SOPs will enable laboratories throughout the world to compare their results and thus facilitate quality-controlled multi-centre prospective trials to assess the clinical significance of MD and minimal residual disease in heterogeneous patient groups.

Does Obesity Confer an Increased Risk and/or More Severe Course of Post-ERCP Pancreatitis?

Pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). Recent studies have suggested that obesity may serve as a prognostic indicator of poor outcome in non-ERCP-induced acute pancreatitis. However, to our knowledge, no one has ever investigated the potential association of obesity and ERCP-induced pancreatitis. Thus, the purpose of our study was to determine whether obesity conferred an increased risk and/or more severe course of post-ERCP pancreatitis. A 160 variable database was prospectively collected by a defined protocol on patients undergoing diagnostic or therapeutic ERCP at 15 centers in the Midwest Pancreaticobiliary Group and participating in a randomized controlled study, evaluating whether prophylactic corticosteroids reduces the incidence of post-ERCP pancreatitis. Body mass indices (BMIs) were available on 964 of the 1115 patients from the original study. A BMI > or = 30 kg/m2 was defined as obese (World Health Organization) and used as a cutoff point in this study. BMIs were analyzed in a retrospective fashion to determine whether obesity confers an increased risk and/or more severe course of post-ERCP pancreatitis. Data were collected before the ERCP, at the time of procedure, and 24 to 72 hours after discharge. Standardized criteria were used to diagnose and grade the severity of postprocedure pancreatitis. Nine hundred sixty four patients were enrolled in the study. Pancreatitis occurred in 149 patients (15.5%) and was graded as mild in 101 (67.8%), moderate in 42 (28.2%), and severe in 6 (4.0%). The patients were categorized by BMI (kg/m2) using the following breakdowns: BMI < 20, 20 to < 25, 25 to < 30, and > or = 30, as well as BMI < 30 or > or = 30. The groups were similar with respect to the patient and procedure risk factors for post-ERCP pancreatitis except the group with BMI > or = 30 had a higher frequency of females, were younger, had less frequent chronic pancreatitis, a lower number of pancreatic duct injections, and fewer patients received more than 2 pancreatic duct injections. Of the patients with a BMI < 30, 119 (16.4%) developed post-ERCP pancreatitis compared with 30 (12.5%) of those with a BMI > or = 30 (P=0.14). There was no association between the presence of obesity and the severity of pancreatitis (P=0.74). Patients with a BMI < 20, 20 to < 25, 25 to < 30, and > or = 30 had a similar incidence of post-ERCP pancreatitis. Obesity did not seem to confer an increased risk for ERCP-induced pancreatitis. A statistically significant association between obesity and the severity of ERCP-induced pancreatitis was not apparent.

Long-Term Evaluation of Interdigital Neuroma Treated by Surgical Excision

We examined a large cohort of patients who had interdigital neurectomy and evaluated their clinical outcomes by using a previously developed scoring system as well as a visual analog scale (VAS). In addition, we wanted to identify risk factors that may lead to poorer outcomes. A retrospective review identified 232 patients who had neuroma excision between 1994 and 2004, after failure of conservative treatment. Each patient was contacted via mail and given a Neuroma Clinical Evaluation Score survey as well as a visual analog score. Each patient received a unique identification number, allowing the evaluation process to be single-blinded. Of the 232 patients contacted, 120 (52%) returned their completed surveys. The average Giannini neuroma score was 53: 61 feet (51%) had good or excellent results, 12 (10%) had fair results, and 48 (40%) had poor results. The average VAS score was 2.5. The only significant (p = 0.027) difference in outcome was the location of the neuroma: second webspace had worse outcomes than third webspace neuromas on both the VAS and neuroma score. This retrospective review identified location in the second webspace as a possible prognostic indicator of poor outcome, but the more important finding may be that outcomes of neuroma excision do not appear to be as successful at long-term followup as previously reported.

OC109: Prominence of the coronary circulation in the fetus: a prognostic indicator of poor outcome?

OC109: Prominence of the coronary circulation in the fetus: a prognostic indicator of poor outcome?

Modulation of the Glycemic Response Using Insulin Attenuates the Pulmonary Response in an Animal Trauma Model

Hyperglycemia has been shown to be an independent prognostic indicator of poor outcome in the traumatized patient. The role of insulin and the prevention of hyperglycemia in the trauma patient have as yet not been fully explored. We hypothesized that the systemic inflammatory response to trauma could be modified by modulating the glycemic response to trauma using insulin. A rodent model of end- organ (lung) injury in trauma was chosen. Two groups underwent bilateral femur fracture and 15% blood loss. The third group was anesthetized only. The treatment group immediately received subcutaneous insulin according to a sliding scale. The control groups received normal saline subcutaneously. The animals were maintained under anesthesia for 4 hours from injury. Blood samples were then taken. Bronchoalveolar lavage was performed for neutrophil content and total protein estimation. The left lower lobe was harvested for wet:dry lung weight ratios as a measure of end-organ tissue edema. Measures of end-organ injury, wet:dry lung weight ratios, and bronchoalveolar lavage neutrophil content were significantly reduced in the insulin-treated animals compared with in the controls (p < 0.05). Neutrophil respiratory burst activity was increased in insulin-treated animals compared with in controls (p < 0.05). Insulin reduces leukocyte lung sequestration and end-organ (lung) edema, indicating an endothelial protective effect in this injured-animal model without attenuating neutrophil function. This work confirms that modifying the glycemic response to trauma using insulin may have a role in reducing adult respiratory distress syndrome rates in injured patients and thereby lead to improved outcomes.

Does Obesity Increase the Incidence and Severity of Post-ERCP Pancreatitis?

Background: Pancreatitis is the most common major complication of endoscopic retrograde cholangiopancreatography (ERCP). Recent studies suggest that obesity may serve as a prognostic indicator of poor outcome in non-ERCP-induced acute pancreatitis. However, to our knowledge, no one has investigated the potential association of obesity and ERCP-induced pancreatitis. The purpose of our study was to determine whether obesity conferred an increased risk and/or more severe course of post-ERCP pancreatitis. Methods: A 160 variable database was prospectively collected by a defined protocol on patients undergoing diagnostic or therapeutic ERCP at 15 centers in the Midwest Pancreaticobiliary Group and participating in a randomized controlled study evaluating whether prophylactic corticosteroids reduces the incidence of post-ERCP pancreatitis. Data were collected prior to the ERCP, at the time of procedure, and 24-72 hours after discharge. Standardized criteria were used to diagnose and grade the severity of post-procedure pancreatitis. A body mass index (BMI) >30 kg/m2 was defined as obese and used as a cut-off point in this study. Results: 964 patients were enrolled in the study. Pancreatitis occurred in 149 patients (15.5%) and was graded as mild in 101 (67.8%), moderate in 42 (28.2%), and severe in 6 (4.0%). The patients were categorized by BMI using the following breakdowns: BMI <20, 20 - <25, 25 - <30, and >30, as well as BMI <30 or >30. The groups were similar with respect to patient and procedure risk factors for post-ERCP pancreatitis except the group with BMI >30 had a higher frequency of females, were younger, had less chronic pancreatitis, a lower number of pancreatic duct injections, and fewer patients receiving more than 2 pancreatic duct injections. Of the patients with a BMI <30, 119 (16.4%) developed post-ERCP pancreatitis compared to 30 (12.5%) of those with a BMI >30 (p = 0.14). There was no association between the presence of obesity and the severity of pancreatitis (p = 0.74). Patients with a BMI <20, 20 - <25, 25 - <30, and >30 had a similar incidence of post-ERCP pancreatitis. Conclusions: Obesity did not confer an increased risk for ERCP-induced pancreatitis. There was no statistically significant association between obesity and the severity of ERCP-induced pancreatitis.