Marker Of Outcome In Patients Research Articles

Clinical and Social Concerns in Treated Patients with Primary Hypothyroidism in Basrah: A Cross Sectional Study

Background: Despite available treatment for hypothyroidism, L-thyroxine replacement therapy in a biochemically appropriate dose does not necessarily relieve patients' symptoms and complaints. The aim of the study was to evaluate the concerns of patients treated with hypothyroidism and to correlate these concerns with different patient characteristics and thyroid biochemical control. Subjects and Methods: one hundred eighteen treated primary hypothyroid patients attending Al-Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Al-Basrah were entering a questionnaire designed to capture personal, anthropometric, biochemical and clinical data. Twenty-four concerns were questioned to the patients who score these concerns on a 4 point Likert scale. Results: The most scored patients' concerns were fatigue, neuropathic pain, lack of weight loss, cold intolerance, breathing problems, and swallowing problems. No statistically significant relations were existed between these concerns and thyroid stimulating hormone (TSH) control, except for a high TSH group which were highly likely to have concerns of feeling sick (OR: 0.27, 95%CI 0.54 to 2.0, p=0.001), neuropathic pain (OR: 0.4, 95%CI 0.17 to 1.6, p=0. 01), cold intolerance (OR: 0.35, 95%CI 0. 0.3 to 1.7, p=0.005), and hair problems (OR: 0.26, 95%CI 0.6 to 2.1, P<0.0001). A significant correlation existed between duration of the hypothyroidism and patients' concerns of swelling of the hands and feet (R=0.7 P<0.0001), memory problems (R=0.4 P<0.0001), hearing disturbance (R=0. 38 P<0.0001), and hair problems (R=0. 3 P=0.001). Age significantly affects patients' concerns of memory problems (R=0. 6 P<0.0001), swelling of the hands and feet (R=0.4 P<0.0001), and hearing disturbance (R=0.37 P<0.0001). Positive correlation was present between low density lipoprotein cholesterol level and patients' concerns of cold intolerance (R=0.3 P=0.001), hair problems (R=0. 28 P=0.003), feeling sick (R=0. 2 P=0. 02), and neuropathic pain (R=0.18 P=0.04). The total cholesterol level also showed a positive correlation with patients' concerns of cold intolerance (R=0.3 P=0.001), hair problems (R=0. 25 P=0.01), neuropathic pain (R=0. 22 P=0. 01), and fatigue (R=0. 2 P=0.04). Conclusion: We cannot rely on the TSH level alone as a marker of optimal treatment outcome in patients with primary hypothyroidism because it does not reflect the concern status of the patients.

Bevacizumab-induced hypertension is a predictive marker for improved outcomes in patients with recurrent glioblastoma treated with bevacizumab.

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor and is approved for the treatment of patients with recurrent glioblastoma (GBM). Previous authors have reported differential response to bevacizumab on an individual basis. Bevacizumab-induced hypertension is a well-documented side effect, and some reports have suggested this occurrence to be related to treatment outcome in other cancers. In the current study, the authors analyzed patients with recurrent GBM who were treated with bevacizumab based on whether the patients developed drug-induced hypertension. All patients with GBM treated within the Emory Healthcare system from 2007 through 2012 were reviewed. A total of 82 patients were identified who received bevacizumab for the treatment of recurrent GBM and were included in the current study. Patients were classified as normotensive or hypertensive depending on whether hypertension developed that was attributable to therapy. Progression-free survival (PFS) and overall survival (OS) were graphed by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards method. The median follow-up was 19.7 months. Of the 82 patients with recurrent GBM who were treated with bevacizumab, 30 developed drug-induced hypertension. The median time to the development of hypertension was 21 days. The median PFS for the normotensive and hypertensive groups were 2.5 months (95% confidence interval [95% CI], 1.6-3.0 months) and 6.7 months (95% CI, 4.6-10.0 months), respectively (P<.001). The median OS times for the normotensive and hypertensive groups were 4.9 months (95% CI, 4.4-6.8 months) and 11.7 months (95% CI, 9.0-20.5 months), respectively (P<.001). Patients with recurrent GBM who developed bevacizumab-induced hypertension demonstrated significantly better PFS and OS compared with normotensive individuals. Bevacizumab-induced hypertension may be a physiologic marker of outcome in patients with recurrent GBM.

Ultrasonography as a prognostic and objective parameter in Achilles tendinopathy: A prospective observational study

ObjectivesTo study prospectively whether structural changes determined by ultrasound scanning (US) can be used as prognostic markers for outcome in patients with symptomatic Achilles tendinopathy (AT) and to investigate whether there exists an association between US findings and pain measured by visual analog scale (VAS) and a general assessment score (GA). Methods92 consecutive patients with AT symptoms were recruited from two outpatient clinics in rheumatology. The patients underwent a conservative treatment protocol consisting of reduced activities, controlled rehabilitation including eccentric exercises of the calf muscles and if needed supplemented with corticosteroid injections. The patients were examined clinically and by US (tendon thickness, hyper- and hypoechogenicity, calcification, bursitis, calcaneusspure, tenosynovitis, gray scale and color Doppler focusing on increased flow intra- or peritendinous). The clinical and US examination were performed at entry, 1, 2, 3 and at 6 month. Results42 women and 50 men were included (mean age of 47 years). They had symptoms for more than 13 months and a symptomatic Achilles tendon mean thickness of 7.4±2.3mm. Heterogeneity at the initial examination was found to be a prognostic marker for the clinical outcome. Tendon thickness, hypoechogenicity and increased flow at any time point were significantly correlated to pain at function, palpatory pain and morning pain at the same time points. A reduction in tendon thickness was statistically associated with a decrease in palpatory pain. ConclusionHeterogeneity is a prognostic marker in AT. Tendon thickness, hypoechogenicity and increased Doppler activity can be used as objective outcome parameters for the treatment effect of AT.

Influence of human papillomavirus and p16INK4a on treatment outcome of patients with anal cancer

BackgroundThe purpose of this study was to evaluate HPV-DNA and p16INK4a (p16) expression as prognostic markers for outcome in patients with anal cancer. MethodsFrom January 2000 to December 2011 a cohort of 105 anal cancer patients was treated with definitive chemoradiation at our institution. Tumor biopsies from 90 patients were analyzed for HPV-DNA by polymerase chain reaction and for p16 expression by immunohistochemistry. ResultsMedian follow-up was 48.6months (range 2.8–169.1months). HPV-DNA or p16-expression was found in 75 anal cancers each (83.3%), concordance was detectable in 70 tumors (77.8%). Significantly improved overall survival (OS) [77.1% vs. 51.4%, p=0.005], progression-free survival (PFS) [64.0% vs. 35.0%, p<0.001] and improved local control [81.0% vs. 55.9%, p=0.023] was found for concomitant HPV- and p16-positive anal carcinomas (cHPPAC) in univariate analysis. Multivariate analysis showed better OS [p=0.015] and PFS [p=0.002] for cHPPAC. ConclusionThe combination of HPV-DNA and p16 can be used as an independent prognostic parameter in anal cancer patients.

Prognostic value of N-terminal pro C-type natriuretic peptide in heart failure patients with preserved and reduced ejection fraction.

A-type and B-type natriuretic peptides are established markers in chronic heart failure (HF). C-type natriuretic peptide (CNP) belongs to the same peptide family, but is predominantly localized in the endothelium. The prognostic role of CNP in heart failure has not been established. The aim of the study was to determine the prognostic power and clinical correlates of the N-terminal part of pro CNP (NT-proCNP) in patients with chronic HF. In 567 hospitalized heart failure patients, NT-proCNP levels were measured at hospital discharge. The primary endpoint was a combined endpoint of all-cause mortality and HF hospitalization after 18 months. Heart failure with a preserved ejection fraction (HFpEF) was pre-defined as an LVEF >40%. Mean (±SD) age was 71 ± 11 years, 62% were male, mean LVEF was 32 ± 14%, and 23% had HFpEF. In multivariate linear regression, NT-proCNP levels showed a positive correlation with NT-proBNP levels and parameters of renal function, whereas a negative correlation with female sex and vascular endothelial growth factor was observed. After 18 months follow-up, 240 patients reached the combined endpoint. We observed interaction between NT-proCNP and LVEF for outcome (P = 0.046). Multivariate analyses revealed NT-proCNP to be strongly predictive for the primary endpoint [hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.18-2.67, P = 0.006) in patients with HFpEF, but not in patients with a reduced ejection fraction (HFrEF) (HR 1.07, 95% CI 0.81-1.43, P = 0.616). Finally, reclassification showed significant additive value in patients with HFpEF (P < 0.001), but not in those with HFrEF (P = 0.453). NT-proCNP is a strong independent marker for outcome in patients with HFpEF, but not in those with HFrEF.

Sarcopenia as a marker of outcome in patients with metastatic non-small cell lung cancer: A retrospective review.

e14000 Background: Most patients with lung cancer at the time of diagnosis have stage IV or metastatic disease.Various prognostic markers like performance are associated with worse outcome. We want...

Acquired hypothyroidism as a predictive marker of outcome in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine-kinase inhibitors (TKIs): A literature-based meta-analysis.

Acquired hypothyroidism as a predictive marker of outcome in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine-kinase inhibitors (TKIs): A literature-based meta-analysis.

P0143 ASC amino acid transporter 2 (ASCT2) as a novel prognostic marker in non-small-cell lung cancer

Background ASC amino acid transporter-2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small-cell lung cancer (NSCLC) remains unclear. Methods One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry for ASCT2, Ki-67, phospho-mTOR, and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by immunohistochemistry from an independent cohort. Findings ASCT2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma. Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in patients with adenocarcinoma. Interpretation ASCT2 expression has a crucial role in the metastasis of pulmonary adenocarcinoma, and is a potential molecular marker for predicting poor prognosis after surgery.

Calcium, phosphate and calcium phosphate product are markers of outcome in patients with chronic heart failure

Serum calcium (Ca) and inorganic phosphate (Pi) concentrations and calcium-phosphate product (CPP) levels are positively associated with worse outcomes in patients with chronic kidney disease, but there are few data for Pi or Ca and none for CPP in patients with chronic heart failure (CHF). Unselected, consecutive patients with CHF (left ventricular ejection fraction, LVEF ≤45%) were enrolled in a prospective observational study for the occurrence of hospitalisation and mortality. Blood samples were collected at the time of recruitment and analysed immediately. Patients (n = 713) were on contemporary optimal treatment and mean (standard error, SE) follow-up was 765 (18.9) days. Mean (SE) Ca was 2.29 (0.004) mmol/l. Median (interquartile range, IQR) Pi was 1.11 (0.98-1.23) mmol/l and median CPP 2.53 (2.21-2.88) mmol(2)/l(2). LVEF correlated inversely with Ca, natural log-transformed (Ln)Pi, and LnCPP. There was no difference in CPP between classes of symptom severity or diabetes status. Ca and LnCPP (but not LnPi) were associated with total mortality. Ca was significantly associated with progressive HF and non-cardiovascular death but not with sudden death. Binary logistic regression analyses showed that LnPi and LnCPP were associated with risk of hospitalisation. Ca, Pi and CPP could be useful additional variables in determining risk in CHF patients. Further work is required to elucidate the mechanisms underlying the adverse influence and determine whether lowering phosphate levels per se in CHF patients is of benefit.

Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.

452 Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p &lt; 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p &lt; 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.

Impact of GATA-3 and FOXA1 expression in patients with hormone receptor-positive/HER2-negative breast cancer

Determining the indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/HER2-negative breast cancer are difficult. The transcription factors GATA-binding protein 3 (GATA-3) and Forkhead-box protein A1 (FOXA1) are crucial for the hormone responsive phenotype of breast cancer. This study evaluated whether the expression of GATA-3 and FOXA1 is a prognostic and predictive marker of outcomes in patients with HR-positive/HER2-negative breast cancer. The expression of GATA-3 and FOXA1 was analyzed immunohistochemically in 214 patients with invasive breast cancer to evaluate the association with the clinicopathological features and the prognosis. GATA-3 expression was positively correlated with FOXA1 expression (P<0.0001). Both GATA-3 and FOXA1 were positively correlated with ER (P<0.0001 each) and PR expression (P=0.0001 and P=0.0009, respectively), and inversely correlated with nuclear grade (P=0.0002 and P=0.0018, respectively) and Ki67 index (P=0.0052 and P=0.0049, respectively). Expression of GATA-3 and FOXA1 was associated with better prognosis. FOXA1 was an independent favorable prognostic marker in HR-positive/HER2-negative breast cancer. Disease-free survival rates were similar in patients with HR-positive/HER2-negative breast cancer and high FOXA1 expression given adjuvant hormone therapy (HT) alone and those given CT plus HT. GATA-3 and FOXA1 are associated with a less aggressive phenotype and a better prognosis in patients with HR-positive/HER2-negative breast cancer. FOXA1 may be useful in identifying those patients who may not require adjuvant CT.

Acquired hypothyroidism as a predictive marker of outcome in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine-kinase inhibitors (TKIs): A literature-based meta-analysis.

500 Background: The development of hypothyroidism in patients with mRCC during treatment with the tyrosine kinase inhibitors (TKIs) sunitinib and sorafenib is a well-established side effect. The potential role of hypothyroidism as predictive marker of outcome has been studied with conflicting results. The aim of the present meta-analysis was to assess the predictive value of hypothyroidism for both progression free (PFS) and overall survival (OS) in patients with mRCC treated with TKI. Methods: We searched PubMed as well as the electronic abstract databases of the major international congresses’ proceedings to identify all eligible studies which reported a correlation of the development of hypothyroidism during treatment with TKI and outcome in patients with mRCC. Hazard ratios (HRs) with 95% confidence intervals (CIs) for PFS and OS were obtained from these publications and pooled in a meta-analysis by using random-effects or fixed-effects models based on the heterogeneity of the included studies. Results: Eleven studies with a total of 500 patients fulfilled the inclusion criteria. We found no statistical significant difference in PFS between patients who developed hypothyroidism and patients without hypothyroidism during sunitinib therapy (HR: 0.82, 95% CI: 0.59-1.13, p-value = 0.22) (6 studies; 250 patients). For studies that included patients treated with either sunitinib or sorafenib, the development of hypothyroidism was found to be predictive for longer progression free survival (HR: 0.59, 95% CI: 0.42-0.84, p-value = 0.003) (3 studies; 205 patients). The HR for OS was 0.52 (95% CI: 0.31-0.87, p-value = 0.01) for patients who developed hypothyroidism during sunitinib therapy compared to patients without hypothyroidism (4 studies; 147 patients). Conclusions: The development of hypothyroidism during TKIs therapy is not clearly shown to be predictive in patients with mRCC. The observed advantage in overall survival for patients with treatment related hypothyroidism should be interpreted with caution due to the potential imbalance of treatments received after first line treatment in each group.

Screening of unfavorable outcome markers in patients with unstable angina pectoris

Aim: The work was initiated to comparatively assess clinical–instrumental parameters for the screening of possible risk factors in patients with unstable angina pectoris (UAP) and type 2 diabetes mellitus (DM). Materials and methods: We examined 141 patients, 68 and 73 without and with type 2 DM, respectively among them. Mean age was 52.3 ± 0.52 years, IHD and type 2 DM duration 5.69 ± 0.38 and 5.79 ± 0.63 years, respectively. IHD and type 2 DM diagnosis was verified in accordance with ESC (2007) and WHO (1999) recommendations (2007), respectively. Clinical parameters, ECG, echocardiogram, endothelial function (EF) as well as lipid and carbohydrate parameters were analyzed. The patients were divided into two groups by the character of outcome. Thus, 119 patients (84.3%) were included into the group of favorable outcome (FO), 22 patients (15.6%) comprising the one with unfavorable outcome (UO), such as, sudden death, fatal and non-fatal myocardium infarction within the period observed. Antocoagulants, antiaggregants, nitrates, beta-adrenoreceptor blockers, ACE inhibitors, atorvastatin and glibenclamide were the medications used for therapy. Statistical processing was performed by means of Statistica 6.0 program, Student’s criterion being used for analysis of inter-group differences and the paired Student’s criterion for analysis of the repeated measures. χ2 was used tor analysis of qualitative signs, Fisher’s method being used for small samples. Differences at P < 0.05 were considered confident. Results: In UO patients basal intima–media complex (IMC) thickness was 0.90 ± 0.06 versus 0.78 ± 0.02 in FO group, P < 0.05. No inter-group differences in most EF parameters were observed, only endothelium-dependent vasodilatation in UO group was 1.62 ± 1.60% versus 5.94 ± 1.04% in FO group, P < 0.05. As to lipid profile parameters, total cholesterol and LDL cholesterol in patients with IHD were 237.5 ± 4.71 versus 265.3 ± 16.5 mg/dl and 159.9 ± 4.39 versus 183.74 ± 12.22 mg/dl in FO patients, respectively (P = 0.03). Type 2 DM duration was higher in UO patients (5.7 ± 1.0 versus 2.84 ± 0.46 years; P < 0.05). The absence of T wave and ST segment depression was registered 2 times more frequently in FO patients with UAP than in UO group (47.1% versus 18.2%; χ2 = 4.065; Р = 0.022). ECG at discharge demonstrated preservation of ischemic ST segment depression observed at hospitalization in 36.4% of UO patients with IHD versus 8.4% of FO group, P < 0.001. End point observation demonstrated 7 (10.2%) and 15 (20.54%) cases in UAP patients and UAP patients with type 2 DM, respectively. Survival curve for the sample with dropout rate taken into account in groups with and without type 2 DM showed confident divergence (P = 0.000, logrank test of survival curves with Yates' correction to compensate z resolution — 3.468, P = 0.000). Conclusion: The findings from the study served as the basis for the development of risk stratification method for UAP patients without heart rate disorders and clinical manifestations of circulatory deficiency.

Prognostic value of NT-pro-C-type natriuretic peptide (NT-proCNP) in heart failure patients with preserved and reduced ejection fraction

Background: BNP and NT-pro-BNP are established markers in chronic heart failure (HF). C-type Natriuretic Peptide (CNP) belongs to the same peptide family. No data are available of CNP as marker in HF. Objective: To assess the prognostic power of the N-terminal part of pro-CNP (NT-proCNP) in HF. Methods: In 571 patients, NT-proCNP was measured at discharge. Primary endpoint was a composite endpoint of all-cause mortality and HF hospitalization after 18 months. Secondary endpoint was all-cause mortality after 3 years. Results: Mean age was 71±11 years, 62% was male and left ventricular ejection fraction (LVEF) was 32±14%. In a multivariate linear regression model, NT-proCNP showed a positive correlation with NT-proBNP and a negative correlation with renal function and female sex. 240 Patients reached the composite endpoint and 234 died. Interaction analysis revealed a strong interaction between NT-proCNP and LVEF for both endpoints (p-value for interaction: 0.003 respectively 0.008). Therefore further analysis was stratified into patients with a reduced (HFrEF) or preserved (HFpEF) LVEF. In multivariate analyses, each doubling of NT-proCNP was strongly predictive for both the primary (HR 1.72; 95% C1 1.28-2.32; P<0.001) and secondary endpoint (HR 1.72 (1.27-2.34; P=0.001) in patients with HFpEF, but not in patient with HFrEF. View this table: Hazard ratios for doubling of NT-proCNP Conclusion: NT-proCNP is a strong independent marker for outcome in patients with HFpEF.

Reduction in circulating pro‐angiogenic and pro‐inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega‐3 fish oil

BackgroundPancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well‐established link between pro‐inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. MethodsAs part of a single‐arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega‐3 rich lipid emulsion (n‐3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression‐free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. ResultsPlatelet‐derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)‐6 and ‐8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. DiscussionTreatment with gemcitabine plus i.v. n‐3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL‐6 and ‐8 may be surrogate markers for outcome in patients with APC treated with this regimen.

Expression of pAkt affects p53 codon 72 polymorphism-based prediction of response to radiotherapy in nasopharyngeal carcinoma

BackgroundCodon 72 (Arg/Pro), the most frequently studied single nucleotide polymorphism (SNP) of p53 to date, is associated with the ability of the gene to induce cell apoptosis. The PI3K/Akt pathway plays an essential role in the transcriptional activation function of p53, and is an important factor in radiotherapy resistance. The present study was designed to evaluate the prediction of response to radiotherapy based on p53 codon 72 SNP and pAkt expression in biopsy specimens of locoregional nasopharyngeal carcinoma (NPC) before treatment.Materials and methodsIn total, 75 consecutive patients with locoregional NPC were enrolled. The p53 codon 72 SNP was identified from retrospectively collected paraffin-embedded biopsy specimens using Sanger sequencing. Expression patterns of p53, p21, 14-3-3σ, and pAkt proteins were investigated using immunohistochemical analyses. The effects of genetic polymorphisms and protein expression on progression-free survival (PFS) were evaluated using the Cox proportional hazards model, Kaplan–Meier method, and log-rank test.ResultsThe p53 codon 72 Pro/Pro carriers showed lower risk of disease progression (local recurrence and distant metastases) (HR: 0.300; 95% CI: 0.092–0.983; p=0.047). However, this association between the p53 codon 72 polymorphism and PFS was not significant in the pAkt-positive subgroup. No association was observed between protein expression of p53, p21 or 14-3-3σ and p53 codon72 polymorphisms. Notably, positive expression of p53 protein appeared to be correlated with poorer PFS among patients diagnosed as local regional lymph node metastasis (N+) before treatment (p=0.032).ConclusionsThe p53 codon 72 Pro/Pro genotype may be an effective independent prognostic marker for better outcome in patients with locoregional NPC. Based on the current findings, we hypothesize that pAkt weakens the predictive value of p53 codon 72 SNP in NPC. A combination of positive p53 protein expression and local regional lymph node metastasis may additionally be predictive of high risk of disease progression.

Abstract LB-350: Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias.

Abstract In hematological malignancies, quiescent leukemic stem cells are responsible for persistence of minimal residual disease and relapse. Emerging evidence points to the involvement of the bone marrow microenvironment in survival and systemic retention of leukemic stem/progenitor cells. Integrins, particularly α4β1, which controls hematopoietic stem cell trafficking, were shown to be required for leukemic stem cells lodging to the bone marrow niche, and were shown to be crucial for the persistence of minimal residual disease. The molecular mechanism governing these processes is not known. We have just recently obtained evidence that newly identified α4 integrin-Abelson interactor 1 (Abi1) signaling cross-talk is involved in acquired drug resistance in Bcr-Abl positive leukemic cells. Our data also indicated that Abi1 and α4 integrin may be useful as prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia. Comparison of mRNA levels of Abi1 and α4 integrin in Bcr-Abl positive CD34+ progenitor cells isolated from blood or bone marrow of CML (chronic myelogenous leukemia) patients at diagnosis and at relapse revealed significant decrease in mRNA levels of Abi1 and increase in mRNA levels of α4 integrin in relapsing CD34+ progenitor cells. Subsequent analyses performed on various imatinib mesylate (IM) resistant cell lines including K562, LAMA-84 or Bcr-Abl supplemented Ba/F3 cells, confirmed abnormal expression of Abi1 and α4 integrin, both mRNA and protein levels. IM resistant cells also exhibited acquired anchorage-dependent phenotype and enhanced adhesive properties. Further detailed analyses of α4 integrin-dependent pathways revealed significant de-regulation of integrin α4 downstream signaling being due to the abnormal expression of Abi1, what resulted in elevated levels of phospho-Akt (Ser472), phospho-Erk (Thr202/Tyr204) and abnormal JNK/SAPK and p38MAPK phosphorylation signals. In summary, our results not only indicate that Abi1 and α4 integrin may serve as potentially useful prognostic markers of treatment outcome in patients with relapsing Bcr-Abl positive leukemia, but also suggest that newly identified α4 integrin-Abi1-Bcr-Abl cross-talk may play a significant role in the interactions between leukemic progenitor cells and the bone marrow microenvironment, and alterations in this signaling mediate acquisition of the drug resistant phenotype of leukemic cells and contribute to the mechanisms of acquired drug resistance. Citation Format: Anna D. Chorzalska, Ibrahem Salloum, Hammad Shafqat, Saad Khan, Philip Marjon, Vincent Falanga, Ting Zhao, John Reagan, Eric Winer, Samer Al-Homsi, Nicola Kouttab, Patrycja M. Dubielecka. Abelson interactor-1 (Abi1) expression levels as a prognostic and drug resistance marker in Bcr-Abl positive leukemias. [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 LB-350. doi:10.1158/1538-7445.AM2013-LB-350

PET-Based Primary Tumor Volumetric Parameters and Survival of Patients With Non—Small Cell Lung Carcinoma

The purpose of the study was to assess metabolic tumor volume and total glycolytic activity of the primary tumor as prognostic parameters for outcome in patients with non-small cell lung carcinoma (NSCLC). Thirty-nine patients who had undergone a baseline staging PET/CT examination at our institution for the diagnosis of NSCLC were retrospectively identified. The maximum standardized uptake value (SUV(max)), metabolic tumor volume, and total glycolytic activity were segmented from PET using the gradient method; 12-month survival and overall survival at the end of follow-up were used as outcome measures. Multivariate logistic regression, receiver operating characteristic curve analysis, and Kaplan-Meier curves for survival analysis were generated and compared using the Mantel-Cox log-rank test. The mean gradient-based metabolic tumor volume and gradient-based total glycolytic activity were significantly greater in the patients who died (93.3 mL and 597.5 g) than in those who survived (19.3 mL and 193.9 g, respectively) (p < 0.003 and p < 0.031). There was no statistically significant difference in the mean SUV(max) between the patients who survived (12.7) at 12 months and those who had died (13.1) (p = 0.85). On multivariate analysis, gradient-based metabolic tumor volume was the only variable associated with 12-month mortality when adjusted for all other factors.(.) The area under the curve (AUC) for gradient-based metabolic tumor volume was 0.77 (p < 0.006). A significant difference in the time to survival was observed between high and low gradient-based metabolic tumor volume (log-rank p < 0.05) cohorts using the median gradient-based metabolic tumor volume (9.7 mL) as the cut point. PET-based volumetric imaging parameters are potential prognostic markers of outcome in patients with NSCLC.

MTOR inhibitor therapy for metastatic sarcomatoid clear cell renal cell carcinoma (ccRCC).

450 Background: Sarcomatoid variant describes a histomorphologic pattern with presence of spindle-cell features that can be seen across all subtypes of RCC. It is associated with an aggressive phenotype and poor prognosis. Outcome to mTOR inhibitor therapy was accessed in patients (pts) with ccRCC with sarcomatoid features. Methods: Patients with metastatic sarcomatoid ccRCC treated with mTOR inhibitors at our center were retrospectively identified. Demographic characteristics and treatment outcome were assessed. Overall response rate (ORR) was determined by formal response criteria (RECIST 1.1). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 29 pts were treated with temsirolimus (18) or everolimus (11). Median age was 57 years (53 to 61) and there were 21 male pts (72%). Median number of metastatic sites was 3 (1 to 7) and 18 pts (62%) had ≥ 3 metastatic sites. Distribution between Memorial Sloan-Kettering Cancer Center risk groups was 14% favorable, 72% intermediate, and 14% poor-risk disease. Median number of prior therapies was 1 (0 to 5) and 79% of pts received mTOR inhibitor as ≥ 2nd-line of therapy. Three patients (10.3%) achieved a partial response (PR), 11 (38%) stable disease (SD), and 15 (51.7%) had progressive disease (PD). Tumor shrinkage was observed in 9 pts (31%) and the mean change in tumor burden was +24% (-45% to +100%). Median PFS and OS were 3.4 months (CI: 1.4-5.3) and 8.3 months (CI: 4.8- 17), respectively. Conclusions: OS was poor in this heterogeneous group of pts. Future studies to characterize this variant at a molecular level are warranted and might identify predictive markers for clinical outcome in patients treated with mTOR inhibitors. [Table: see text]

Abstract P3-06-24: Early activation of IFN/STAT signaling in tumor cells of patient-derived triple negative breast cancer xenografts predicts tumor sensitivity to chemotherapy

Abstract Triple negative breast cancer (TNBC) is a tumor subtype characterized by the absence of overexpressed estrogen receptor-alpha (ER), progesterone receptor (PR), and HER2 receptor, encoded by ERBB2, a known proto-oncogene. This type of tumors account for approximately 15–25% of breast cancers at diagnosis, and is one of the most aggressive subtypes, with 77% of patients that live free of disease 5 years post-diagnosis. One of the most reliable predictive markers of patient outcome is the pathological complete response (pCR), which indicates that the surgical specimen removed after neoadjuvant chemotherapy contains no viable tumor cells detectable at histopathological level. For patients with pCR, the probability of surviving the disease is very high, however, pCR is observed only in about 20–30% of TNBC. On the other hand, for patients with no pCR the probablity of developing recurrent disease at 5 years is 50%. As pCR is strongly correlated with treatment efficacy, it is mandatory to develop methods that allow to tell as quick as possible if the treatment chosen for a given patient is efficiently working or if it should be abandoned in favor of an alternative strategy that could prove more efficacious. XenTech collection of breast cancer patient-derived xenografts (PDXs) includes 25 models of TNBC that display heterogeneous response to different chemotherapy agents. We used our models to investigate if transcriptional changes could be detected in PDXs that responded well to genotoxic agents. To do this we analyzed the gene expression profile of laser-microdissected residual tumor nodules interspersed in the murine stroma upon very efficient response to Adriamycin/Cyclophosphamide (AC). When doing so, we identified several genes of the IFN/STAT1 pathway that were over-expressed when compared to untreated tumors. This activation seems to be a transient event, as it was lost in tumors relapsing after the residual tumor nodule stage. The finding that residual cells from tumors strongly responding to AC treatment over-expressed IFN/STAT1 pathway-related genes prompted us to investigate whether this effect could be detected as an early event upon tumor exposure to chemotherapy. All TNBC models tested that were good responders to AC treatment displayed over-expression of IFN/STAT1 pathway-related genes as early as 3 days post-treatment, most of them reaching a plateau of intensity at day 7 post-treatment. By contrast, TNBC insensitive or low responders to AC treatment failed to show over-expression of IFN/STAT1 pathway-related genes. To verify if the selective over-expression of these genes in TNBC models sensitive to AC was independent of the treatment administered, Irinotecan and Capecitabine were used to treat TNBC models with heterogeneous response to these drugs. Again, we found that overexpression of IFN/STAT1 pathway-related genes was specifically identified at early stages only in TNBC models that responded well to these drugs. These results suggest that genes of the IFN/STAT1 pathway could be early predictors of tumor response in patients receiving neoadjuvant chemotherapy. Prospective clinical validation studies are warranted to confirm the findings from this preclinical study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-24.