Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer

BACKGROUND:

Notch signaling plays a key role in embryonic vascular development and angiogenesis. The authors aimed to study the prognostic role of the angiogenesis‐related Notch ligands and receptors and investigate the prognostic impact of the coexpression of vascular endothelial growth factor‐A (VEGF‐A) and Notch signaling.

METHODS:

Tumor tissue samples from 335 resected patients with stage I to IIIA nonsmall cell lung cancer (NSCLC) were obtained, and tissue microarrays were constructed from duplicate cores of tumor cells and tumor‐related stroma from each specimen. Immunohistochemistry was used to evaluate the expression of the molecular markers Notch‐1, Notch‐4, Delta‐like ligand 4 (DLL4), and Jagged‐1.

RESULTS:

There were 191 squamous cell carcinomas (SCCs), 113 adenocarcinomas (ACs), and 31 large cell carcinomas. In AC, low tumor cell Delta‐like ligand 4 expression was an independent negative prognostic factor (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.4‐6.3 [P = .006]), whereas high tumor cell Notch‐1 expression was an independent negative prognostic factor (HR, 2.2; 95% CI, 1.2‐4.1 [P<.001]). In SCC, low stromal Delta‐like ligand 4 expression was an independent indicator of poor prognosis (HR, 3.3; 95% CI, 1.8‐6.1 [P<.001]). The coexpression of Notch‐1 and VEGF‐A had a significant prognostic impact (P<.001). For Notch‐1 and VEGF‐A, low/low (n = 142) versus high/high (n = 35) expression resulted in 5‐year survival rates of 69% and 32%, respectively.

CONCLUSIONS:

Delta‐like ligand 4 and Notch‐1 are independent prognostic factors in NSCLC, but have diverse impacts in SCC and AC. The coexpression of tumor cell Notch‐1/VEGF‐A has a major impact on survival. Cancer 2010. © 2010 American Cancer Society.     

Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first‐line palliative chemotherapy

BACKGROUND:

Advanced biliary tract adenocarcinoma (BTA) has been a rare but fatal cancer. If unresectable, palliative chemotherapy improved the quality and length of life, but to the authors' knowledge, prognostic factors in such patients have not been well established to date. In the current study, prognostic factors were investigated in patients with advanced BTA receiving first‐line palliative chemotherapy.

METHODS:

Data from 213 patients with advanced BTA who were in prospective phase 2 or retrospective studies from September 2000 through October 2007 were used.

RESULTS:

With a median follow‐up duration of 29.7 months, the median overall survival (OS) was 7.3 months (95% confidence interval [95% CI], 6.3 months‐8.3 months). A Cox proportional hazards model indicated that metastatic disease (hazards ratio [HR], 1.521; P = .011), intrahepatic cholangiocellular carcinoma (HR, 1.368; P = .045), liver metastasis (HR, 1.845; P < .001), Eastern Cooperative Oncology Group performance status (HR, 1.707; P < .001), and alkaline phosphatase level (IU/L) (HR, 1.001; P < .001) were statistically significant independent predictors of poor prognosis. Patients were classified into 3 risk groups based on the prognostic index (PI), which was constructed using the regression coefficients of each variable. The median OS was 11.5 months (95% CI, 9.6 months‐13.5 months) for the low‐risk group (PI ≤ 1.5; n = 67), 7.3 months (95% CI, 5.7 months‐8.9 months) for the intermediate‐risk group (PI > 1.5 but ≤ 2.2; n = 75), and 3.6 months (95% CI, 2.9 months‐4.1 months) for the high‐risk group (PI > 2.2; n = 70 [P < .001]).

CONCLUSIONS:

Five prognostic factors in patients with advanced BTA were identified. The predictive model based on PI appears to be promising and may be used for the management of individual patients and to guide the design of future clinical trials, although external validation is needed. Cancer 2009. © 2009 American Cancer Society.     

Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival

BACKGROUND:

Lung adenocarcinoma invasion and metastasis arises from autocrine and paracrine signaling events between tumor epithelial cells and the stromal microenvironment that is mediated in part by transforming growth factor‐β (TGF‐β) signaling. The copper‐dependent amine oxidase lysyl oxidase (LOX) plays a role in extracellular matrix structure and is up‐regulated in invasive type II TGF‐β receptor‐deficient cells. The authors hypothesized that LOX expression is associated with extent of invasion and survival in patients with lung adenocarcinoma.

METHODS:

LOX immunohistochemical staining was examined in 166 surgically resected lung adenocarcinomas and results were correlated with clinicopathological features and survival.

RESULTS:

High‐intensity LOX staining was found to be associated with the linear extent of invasion (Spearman correlation coefficient = 0.2; P = .01). There was an association between high LOX staining and decreased 5‐year survival observed within the entire cohort (log‐rank P < .001) and among the patients with stage I disease (n = 119; P < .001). Cox proportional hazards regression analysis confirmed that LOX was a significant prognostic indicator of increased risk of 5‐year mortality for all patients (hazard ratio [HR], 2.55; 95% confidence interval [95% CI], 1.51‐4.30 [P < .001]) and for patients with Stage I disease (HR, 3.51; 95% CI, 1.77‐6.99 [P < .001]). LOX expression was found to be independently associated with risk of death after adjustment for relevant covariates (HR, 2.29; 95% CI, 1.33‐3.94 [P = .003]).

CONCLUSIONS:

Higher expression of LOX is associated with invasion and is an independent predictor of poor prognosis in patients with early stage lung adenocarcinoma. Cancer 2011. © 2010 American Cancer Society.     

Utilization and expense of adjuvant cancer therapies following radical prostatectomy

BACKGROUND:

We sought to identify the costs of adjuvant therapies following radical prostatectomy (RP) and factors associated with their receipt.

METHODS:

We used SEER‐Medicare data from 2004‐2006 to identify 4247 men who underwent RP, of whom 600 subsequently received adjuvant therapies. We used Cox regression to identify factors associated with receipt of adjuvant therapies. Health care expenditures within 12 months of diagnosis were compared for RP alone versus RP with adjuvant therapies.

RESULTS:

Biopsy Gleason score, prostate‐specific antigen, risk group, and SEER region were significantly associated with receipt of adjuvant treatments (all P<.001). Higher surgeon volume was associated with lower odds of receiving adjuvant therapies (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46‐0.78 [P<.001]). Factors associated with increased receipt of adjuvant therapies were positive surgical margins (HR, 3.02; 95% CI, 2.55‐3.57 [P<.001]), high‐risk group versus low‐risk group (HR, 7.65; 95% CI, 5.64‐10.37 [P<.001]), lymph node–positive disease (HR, 5.36; 95% CI, 3.71‐7.75 [P<.001]), and treatment in Iowa (HR, 1.93; 95% CI, 1.12‐3.32 [P = .019]) and New Mexico/Georgia/Hawaii (HR, 1.92; 95% CI, 1.09‐3.39 [P = .025]) versus San Francisco SEER regions (baseline). Age, race, comorbidities, and surgical approach were not associated with use of adjuvant therapies. The median expenditures attributable to postprostatectomy hormonal therapy, radiation therapy, and radiation with hormonal therapy versus were $1361, $12,040, and $23,487.

CONCLUSIONS:

Men treated by high‐volume surgeons were less likely to receive adjuvant therapies. Regional variation and high‐risk disease characteristics were associated with increased receipt of adjuvant therapies, which increased health care expenditures by 2‐ to 3‐fold when radiotherapy was administered. Cancer 2011. © 2011 American Cancer Society.     

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma

BACKGROUND:

This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM‐MM).

METHODS:

In a retrospective survey in 9 cancer centers of the German Cancer Society, 692 patients were identified with BM‐MM during the period 1986 through 2007. Overall survival was analyzed using a Kaplan‐Meier estimator and compared with log‐rank analysis. Cox proportional hazards models were used to identify prognostic factors significant for survival.

RESULTS:

The median overall survival of the entire cohort was 5.0 months (95% confidence interval [95% CI], 4 months‐5 months). Significant prognostic factors in the univariate Kaplan‐Meier analysis were Karnofsky performance status (≥70% vs <70%; P < .001), number of BM‐MM (single vs multiple; P < .001), pretreatment levels of lactate dehydrogenase (LDH) (normal vs elevated; P < .001) and S‐100 (normal vs elevated; P < .001), prognostic groups according to Radiation Therapy Oncology Group (class I vs class II vs class III; P = .0485), and treatment choice (for the cohort with single BM‐MM only) (stereotactic radiotherapy or neurosurgical metastasectomy vs others; P = .036). Cox proportional hazards models revealed pretreatment elevated level of serum LDH (hazard ratio [HR], 1.6; 95% CI, 1.3‐2.0 [P = .00013]) and number of BM‐MM (HR, 1.6; 95% CI, 1.3‐2.0 [P = .00011]) to be independent prognostic variables in the entire cohort, whereas in patients with a single BM‐MM, treatment choice (HR, 1.5; 95% CI, 1.1‐1.9 [P = .0061]) was identified as a unique prognostic factor.

CONCLUSIONS:

The overall survival of patients with BM‐MM primarily depends on the number of metastases and pretreatment level of LDH. In the case of a single brain metastasis, stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival. Cancer 2011. © 2010 American Cancer Society.     

Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer

BACKGROUND:

The role of the interaction between tumor cells and inflammatory cells in nonsmall cell lung carcinoma (NSCLC) is unclear. In this study, the authors assessed the prognostic impact of intratumoral cluster of differentiation 66b (carcinoembryonic antigen‐related cell adhesion molecule 8 [CD66b])‐positive neutrophils and of the intratumoral CD66b‐positive neutrophil‐to‐cluster of differentiation 8 (cell surface antigen T8 [CD8])‐positive lymphocytes (the CD66b‐positive neutrophil‐to‐CD8‐positive lymphocyte ratio [iNTR]) in patients with resectable NSCLC.

METHODS:

Expression levels of CD66b and CD8 were evaluated by immunohistochemistry on tissue microarrays consisting of 632 NSCLC specimens from patients who underwent curative surgery. The relation between clinicopathologic variables and patient outcome was assessed.

RESULTS:

Intratumoral CD66b‐positive neutrophils were elevated in 318 patients (50%). In univariate analysis, an increase in CD66b‐positive cells was associated with a high cumulative incidence of relapse (CIR) (median CIR, 51 months for low CD66b‐positive cell density; 36 months for high CD66b‐positive cell density; P = .002) and trended toward worse overall survival (OS) (median OS, 57 months for low CD66b‐positive cell density; 54 months for high CD66b‐positive cell density; P = .088). The iNTR was elevated in 190 patients (30%). An increased iNTR was strongly associated with both a high CIR (median CIR: 43 months for an iNTR ≤1; 34 months for an iNTR >1; P < .0001) and poor OS (median OS: 60 months for an iNTR ≤1; 46 months for an iNTR >1; P < .0001). In multivariate analysis, independent prognostic factors for a higher CIR were high iNTR (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.56‐0.90; P = .005) and tumor stage >I, (HR, 0.39; 95% CI, 0.30‐0.52; P < .0001). Independent prognostic factors for worse OS were a high iNTR (HR, 0.70; 95% CI, 0.54‐0.91; P = .007) and tumor stage >I (HR, 0.35; 95% CI, 0.26‐0.47; P < .0001).

CONCLUSIONS:

The current results indicated that the iNTR is a novel, independent prognostic factor for a high rate of disease recurrence and poor OS in patients with resectable NSCLC. Cancer 2011;. © 2011 American Cancer Society.     

Stathmin expression and its relationship to microtubule-associated protein tau and outcome in breast cancer

BACKGROUND:

Microtubule‐associated proteins (MAPs) endogenously regulate microtubule stability. Here, the prognostic value of stathmin, a destabilizing protein, was assessed in combination with MAP‐tau, a stabilizing protein, in order to evaluate microtubule stabilization as a potential biomarker.

METHODS:

Stathmin and MAP‐tau expression levels were measured in a breast cancer cohort (n = 651) using the tissue microarray format and quantitative immunofluorescence (AQUA) technology, then correlated with clinical and pathological characteristics and disease‐free survival.

RESULTS:

Univariate Cox proportional hazard models indicated that high stathmin expression predicts worse overall survival (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.119‐1.966; P = .0061). Survival analysis showed 10‐year survival of 53.1% for patients with high stathmin expression versus 67% for low expressers (log‐rank, P < .003). Cox multivariate analysis showed high stathmin expression was independent of age, menopausal status, nodal status, nuclear grade, tumor size, and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression (HR = 1.19; 95% CI = 1.03‐1.37; P = .01). The ratio of MAP‐tau to stathmin expression showed a positive correlation to disease‐free survival (HR = 0.679; 95% CI = 0.517‐0.891; P = .0053) with a 10‐year survival of 65.4% for patients who had a high ratio of MAP‐tau to stathmin versus 52.5% 10‐year survival rate for those with a low ratio (log‐rank, P = .0009). Cox multivariate analysis showed the ratio of MAP‐tau to stathmin was an independent predictor of overall survival (HR = 0.609; 95% CI = 0.422‐0.879; P = .008).

CONCLUSIONS:

Low stathmin and high MAP‐tau are associated with increased microtubule stability and better prognosis in breast cancer. Cancer 2012. © 2012 American Cancer Society.     

Post-treatment (not interim) positron emission tomography-computed tomography scan status is highly predictive of outcome in mantle cell lymphoma patients treated with R-HyperCVAD

BACKGROUND:

Although convincing data exist regarding the prognostic utility of positron emission tomographic (PET)‐computed tomographic (CT) imaging in Hodgkin lymphoma and diffuse large B‐cell lymphoma, its prognostic utility both during treatment and immediately after treatment have not been systematically evaluated in a large mantle cell lymphoma (MCL) patient cohort to support its use in clinical practice.

METHODS:

The authors conducted a retrospective cohort study to examine the prognostic utility of PET‐CT imaging in a uniform MCL patient cohort undergoing dose‐intensive chemotherapy (R‐HyCVAD) in the frontline setting. The primary study endpoints were progression‐free survival (PFS) and overall survival (OS). PET‐CT images were centrally reviewed for the purposes of this study using standardized response criteria.

RESULTS:

Fifty‐three patients with advanced stage MCL with PET‐CT data were identified. With median follow‐up of 32 months, 3‐year PFS and OS estimates were 76% (95% confidence interval [CI], 64%‐84%) and 84% (95% CI, 72%‐90%), respectively. Interim PET‐CT status was not associated with PFS (hazard ratio [HR], 0.9; 95% CI, 0.3‐2.7; P = .8) or OS (HR, 0.6; 95% CI, 0.1‐2.9; P = .5). Post‐treatment PET‐CT status was statistically significantly associated with PFS (HR, 5.2; 95% CI, 2.0‐13.6; P = .001) and trended toward significant for OS (HR, 2.8; 95% CI, 0.8‐9.6; P = .07).

CONCLUSIONS:

These data do not support the prognostic utility of PET‐CT in pretreatment and interim treatment settings. A positive PET‐CT after the completion of therapy identifies a patient subset with an inferior PFS and a trend toward inferior OS. Cancer 2012;3565–3570. © 2011 American Cancer Society.     

Ultra‐early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer

BACKGROUND:

The authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed.

METHODS:

Sixty‐two cervical cancer patients underwent dynamic contrast‐enhanced (DCE) MRI before and during early radiation/chemotherapy (2‐2.5 weeks into treatment). Heterogeneous tumor perfusion was analyzed by signal intensity (SI) of each tumor voxel. Poorly perfused tumor regions were quantified as lower 10th percentile of SI (SI[10%]). DCE‐MRI and 3‐dimensional (3D) tumor volumetry MRI parameters were assessed as predictors of recurrence and cancer death (median follow‐up, 4.1 years). Their discriminating capacity was compared with clinical prognostic factors (stage, lymph node status, histology) using sensitivity/specificity and Cox regression analysis.

RESULTS:

SI(10%) and 3D volume 2‐2.5 weeks into therapy independently predicted disease recurrence (hazard ratio [HR], 2.6; 95% confidence interval [95% CI], 1.0‐6.5 [P = .04] and HR, 1.9; 95% CI, 1.1‐3.5 [P = .03], respectively) and death (HR, 1.9; 95% CI, 1.0‐3.5 [P = .03] and HR, 1.9; 95% CI, 1.2‐2.9 [P = .01], respectively), and were superior to clinical prognostic factors. The addition of MRI parameters to clinical prognostic factors increased sensitivity and specificity of clinical prognostic factors from 71% and 51%, respectively, to 100% and 71%, respectively, for predicting recurrence, and from 79% and 54%, respectively, to 93% and 60%, respectively, for predicting death.

CONCLUSIONS:

MRI parameters reflecting heterogeneous tumor perfusion and subtle tumor volume change early during radiation/chemotherapy are independent and better predictors of tumor recurrence and death than clinical prognostic factors. The combination of clinical prognostic factors and MRI parameters further improves early prediction of treatment failure and may enable a window of opportunity to alter treatment strategy. Cancer 2010. © 2010 American Cancer Society.     

Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups

BACKGROUND:

The objective of identifying protein biomarkers for patients with stage III and IV colorectal cancer is to improve risk stratification and, thus, to identify patients in the postoperative setting who may benefit from more targeted treatment. The objective of the current study was to determine the prognostic value of 19 protein markers assessed in primary tumors and matched lymph node (LN) metastases from patients with stage III and IV colorectal cancer.

METHODS:

Matched primary tumors and LN metastases from 82 patients with stage III and IV colorectal cancer were mounted onto a multiple‐punch tissue microarray and were stained for 19 protein markers involved in tumor progression (β‐catenin, E‐cadherin, epidermal growth factor receptor, phosphorylated extracellular signal‐regulated kinase [pERK], receptor for hyaluronic acid‐mediated motility, phosphorylated protein kinase B, p21, p16, B‐cell lymphoma 2, Ki67, apoptotic protease activating factor 1, mammalian sterile 20‐like kinase 1, Raf kinase inhibitor protein, vascular endothelial growth factor, ephrin type‐B receptor 2, matrix metalloproteinase 7, laminin5γ2, mucin 1 [MUC1], and caudal‐related homeobox 2). The prognostic effects of biomarkers in both primary tumor and positive LNs were assessed.

RESULTS:

MUC1, pERK and p16 in LN (P = .002, P = .014, and P = .002, respectively) had independent prognostic value. In patients with stage III disease who received adjuvant treatment, negative p16 expression was associated with highly unfavorable outcomes overall (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.1‐0.6; P = .005) when the analysis was stratified by pathologic tumor classification (HR, 0.25; 95% CI, 0.1‐0.7; P = .005), age (HR, 0.23; 95% CI, 0.1‐0.6; P = .004), and LN ratio (HR, 0.26; 95% CI, 0.1‐0.7; P = .007); and, in multivariate analysis, it was associated with performance status and the receipt of folic acid treatment (HR, 0.29; 95% CI, 0.09‐0.89; P = .03).

CONCLUSIONS:

The loss of p16 in LN metastases contributed to adverse outcomes in adjuvantly treated patients with stage III colorectal cancer independent of pathologic tumor classification, age, LN ratio, performance status, or folic acid treatment. The current results support the investigation of p16 as a prognostic and potential predictive biomarker for future randomized trials of patients with stage III colorectal cancer. Cancer 2010. © 2010 American Cancer Society.     

The influence of high body mass index on the prognosis of patients with esophageal cancer after surgery as primary therapy

BACKGROUND:

High body mass index (BMI), a prevalent condition in the United States, is associated with esophageal adenocarcinoma (EAC). Its influence on a patient's outcome remains unclear. In the current study, the authors examined the impact of BMI on survival and complications in patients with esophageal cancer (EC) who underwent surgery as their primary therapy.

METHODS:

The authors retrospectively reviewed 301 consecutive EC patients who underwent surgery but received no adjunctive therapy. Patients were segregated into 2 subgroups based on their baseline BMI: normal/low (<25 kg/m²) and high (≥25 kg/m²).

RESULTS:

Seventy‐six (25%) patients had a BMI <25 kg/m² and 225 (75%) patients had a BMI ≥25 kg/m². In the high BMI group, there were more men (P < .001), fewer upper ECs (P = .021), a lower baseline clinical stage (P = .006), and frequent EAC (P < .001). Postoperative morbidity was similar in both groups, with the exception of gastrointestinal complications (P = .016). The 5‐year overall survival (OS) rates were 44% in the normal/low BMI group and 60% in the high BMI group (P = .017). The 5‐year disease‐free survival (DFS) rates were 41% in the normal/low BMI group and 60% in the high BMI group (P = .005). On multivariable analysis, age, weight loss, peripheral vascular disease (PVD), and both clinical and pathological stage of disease were found to be independent prognosticators for OS. Older age (hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.009‐1.049 [P = .004]), weight loss (HR, 1.525; 95% CI, 1.034‐2.248 [P = .033]), and PVD (HR, 2.325; 95% CI, 1.039‐5.204 [P = .040]) were found to be associated with poor OS.

CONCLUSIONS:

High BMI is common in EC patients and the better OS/DFS noted in patients with a high BMI is because of the diagnosis of a low baseline clinical stage. Confirmation of these findings is warranted. Cancer 2010. © 2010 American Cancer Society.     

Body mass index at diagnosis and survival among colon cancer patients enrolled in clinical trials of adjuvant chemotherapy

BACKGROUND:

Although obesity is an established risk factor for developing colon cancer, its prognostic impact and relation to patient sex in colon cancer survivors remains unclear.

METHODS:

The authors examined the prognostic and predictive impact of the body mass index (BMI) in patients with stage II and III colon carcinoma (N = 25,291) within the Adjuvant Colon Cancer Endpoints (ACCENT) database. BMI was measured at enrollment in randomized trials of 5‐fluorouracil–based adjuvant chemotherapy. Association of BMI with the time to recurrence (TTR), disease‐free survival (DFS), and overall survival (OS) were determined using Cox regression models. Statistical tests were 2‐sided.

RESULTS:

During a median follow‐up of 7.8 years, obese and underweight patients had significantly poorer survival compared with overweight and normal‐weight patients. In a multivariable analysis, the adverse prognostic impact of BMI was observed among men but not among women (P_interaction = .0129). Men with class 2 and 3 obesity (BMI ≥35.0 kg/m²) had a statistically significant reduction in DFS (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.01‐1.33; P = .0297) compared with normal‐weight patients. Underweight patients had a significantly shorter TTR and reduced DFS (HR, 1.18; 95% CI, 1.09‐1.28; P < .0001) that was more significant among men (HR, 1.31; 95% CI, 1.15‐1.50; P < .0001) than among women (HR, 1.11; 95% CI, 1.01‐1.23; P = .0362; P_interaction = .0340). BMI was not predictive of a benefit from adjuvant treatment.

CONCLUSIONS:

Obesity and underweight status were associated independently with inferior outcomes in patients with colon cancer who received treatment in adjuvant chemotherapy trials. Cancer 2013. © 2013 American Cancer Society.     

The long‐term outcome of treated high‐risk nonmuscle‐invasive bladder cancer

BACKGROUND:

The treatment of high‐risk nonmuscle‐invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single‐center series.

METHODS:

The authors reviewed all patients with primary, high‐risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow‐up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log‐rank analysis (2‐sided; P < .05).

RESULTS:

In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%‐18.3%) at a median of 17.2 months (interquartile range, 8.9‐35.8 months), including 26.5% (95% CI, 22.2%‐31.3%) of the 366 patients who had >5 years follow‐up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P < .001). Disease‐specific mortality occurred in 134 patients (18.8%; 95% CI, 16.1%‐21.9%) at a median of 28 months (interquartile range, 15‐45 months), including 28.7% (95% CI, 24.5%‐33.3%) of those who had 5 years of follow‐up. Disease‐specific mortality was associated with age (HR, 1.1; P < .001), stage (HR, 1.7; P = .003), dysplasia (HR, 1.3; P = .05), and progression (HR, 5.2; P < .001). Neither progression nor disease‐specific mortality were associated with the receipt of bacillus Calmette‐Guerin (P > .6).

CONCLUSIONS:

Within a program of conservative treatment, progression of high‐risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette‐Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease. Cancer 2012. © 2012 American Cancer Society.     

Microsatellite instability and DNA ploidy in colorectal cancer

BACKGROUND:

Appropriate stratification tools for targeted surveillance after resection for colorectal cancer (CRC) are lacking. The objective of the current study was to investigate the effect of microsatellite instability (MSI) and DNA ploidy on surveillance after surgery.

METHODS:

The authors evaluated 186 consecutive, population‐based patients with stage I through III CRC who underwent surgery with curative intent and who entered a systematic surveillance program. MSI was analyzed with polymerase chain reaction for 5 known quasimonomorphic markers (BAT‐26, BAT‐25, NR‐21, NR‐24, and NR‐27), and DNA ploidy was analyzed with automated cytometry. Recurrence, recurrence‐free survival (RFS), and disease‐specific survival (DSS) were evaluated by univariate and multivariate statistical tests.

RESULTS:

Patients with MSI (20%) were significantly younger than patients without MSI (median age, 61 years vs 67 years; P = .016). Proximal location (adjusted odds ratio [AOR], 5.4; 95% confidence interval [95% CI], 2.1‐14.1 [P = .001]), large tumor size (≥5 cm: AOR, 3.5; 95% CI, 1.3–9.6 [P = .015]), and poor tumor differentiation (AOR, 6.6; 95% CI, 2–21.8 [P = .002]) were associated with MSI. MSI conveyed an increased risk for locoregional recurrence (OR, 2.9; 95% CI, 1.2–7 [P = .016]), with a trend toward a shorter time to recurrence (P = .060). Neither MSI status nor DNA ploidy predicted distant metastasis, RFS, or DSS. Lymph node status was the best predictor of distant spread (AOR, 3.9; 95% CI, 2–7.9 [P < .001]) and DSS (hazard ratio, 4.9; 95% CI, 2.6–9 [P < .001]).

CONCLUSIONS:

Patients who had microsatellite instable tumors were at increased risk for locoregional recurrence, whereas lymph node status was the best predictor of distant metastasis. Clinical surveillance and choice of modality (ie, endoscopy vs radiologic imaging) may be improved when patients are stratified according to these cancer features. Cancer 2009. © 2009 American Cancer Society.     

Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival

BACKGROUND:

Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor‐A (VEGF‐A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR‐126 has been related to tumor angiogenesis and in the regulation of VEGF‐A. The authors aimed to investigate the prognostic impact of miR‐126 and its co‐expression with VEGF‐A in nonsmall cell lung cancer (NSCLC) patients.

METHODS:

Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF‐A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR‐126.

RESULTS:

In the total material, miR‐126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2‐2.8, P = .01). Stratified by histology, miR‐126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7‐5.6, P<.001). Stratified by lymph node status, miR‐126 was significant only in the lymph node‐positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0‐8.4, P < .001). High miR‐126 expression correlated significantly with high VEGF‐A expression (P = .037). The co‐expression of miR‐126 and VEGF‐A had a significant prognostic impact (P = .002), with 5‐year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively.

CONCLUSIONS:

miR‐126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status. Cancer 2011. © 2011 American Cancer Society.     

A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03)

Background

EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib, an oral tyrosine kinase inhibitor (TKI), administered in patients with advanced non-small cell lung cancer (NSCLC), not progressing following standard 1st-line chemotherapy.

Methods

Patients with advanced NSCLC, not-progressing after four cycles of platinum-based chemotherapy, were randomised to receive either gefitinib 250 mg/d or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival (OS). Secondary end-points were progression-free survival (PFS) and toxicity. The study was powered to detect a 28% increase in OS from a median of 11–14.1 months (HR = 0.78) and planned to randomise 598 patients to observe 514 deaths.

Results

After inclusion of 173 patients, the trial was prematurely closed due to low accrual. Baseline characteristics for gefitinib (n = 86) and placebo (n = 87) arms were well balanced. After a median follow up of 41 months, the difference in median OS in the gefitinib and placebo arms was not statistically significant (10.9 and 9.4 months, HR 0.83 [95% confidence interval (95% CI) 0.60–1.15]; p = 0.2). The difference in median PFS significantly favoured gefitinib (4.1 and 2.9 months, HR = 0.61, [95% CI 0.45, 0.83]), p = 0.0015). Adverse events reported in more than 10% of patients were rash (47% with gefitinib versus 13% with placebo) and diarrhoea (34% with gefitinib versus13% with placebo).

Conclusions

Despite its premature closure, this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS. However, no difference in OS was observed in this study (NCT00091156).     

Genetic variants in one‐carbon metabolism‐related genes contribute to NSCLC prognosis in a Chinese population

BACKGROUND:

One‐carbon metabolism plays a critical role in DNA methylation and DNA synthesis. Variants of genes involved in one‐carbon metabolism may result in aberrant methylation and/or DNA synthesis inhibition, and ultimately modulate the initiation and progression of tumors. In this study, the authors hypothesized that polymorphisms in one‐carbon metabolism‐related genes may contribute to the prognosis of nonsmall cell lung cancer (NSCLC).

METHODS:

The authors screened 57 potentially functional single nucleotide polymorphisms (SNPs) from 11 candidate genes involved in one‐carbon metabolism and genotyped them in a cohort of 568 NSCLC patients by using Illumina Golden Gate platform. The Kaplan‐Meier method with log‐rank test and Cox proportional hazards model were used for survival analyses.

RESULTS:

Variant alleles were significantly associated with favorable survivals of NSCLC for MTR rs3768160 A>G (allelic hazards ratio [HR], 0.78; 95% confidence interval [CI], 0.62‐0.98), MTRR rs2966952 G>A (allelic HR, 0.84; 95% CI, 0.71‐0.99) and DHFR rs1650697 G>A (allelic HR, 0.83; 95% CI, 0.70‐0.99) and with unfavorable prognosis for MTHFD1 rs1950902 G>A with borderline significance (allelic HR, 1.18; 95% CI, 0.99‐1.40). In addition, the combined genotypes of these four SNPs showed a locus‐dosage effect on NSCLC survival (P_trend = 6.9 × 10^?5). In the final multivariate Cox regression model, combined genotypes based on 3 categories may be an independent prognostic factor for NSCLC with adjusted trend HR of 0.78 (95% CI, 0.66‐0.92).

CONCLUSION:

Genetic variants in one‐carbon metabolism pathway may be candidate biomarkers for NSCLC prognosis. Cancer 2010. © 2010 American Cancer Society.     

Number of primary melanomas is an independent predictor of survival in patients with metastatic melanoma

BACKGROUND:

A history of multiple primary melanomas (PMs) has been associated with improved survival in patients with early stage melanoma, but whether it also is correlated with survival in patients with metastatic melanoma is unknown. The authors sought to address the latter question in the current study.

METHODS:

Patients with metastatic melanoma diagnosed at the Melanoma Institute Australia between 1983 and 2008 were identified. Overall survival (OS) was calculated from date of first distant metastasis. Survival analysis was performed using the Kaplan‐Meier method, log‐rank tests, and multivariate Cox proportional hazards models.

RESULTS:

Of 2942 patients with metastatic melanoma, 2634 (89.5%) had 1 PM and 308 (10.5%) had >1 PM. Factors that were associated independently with shorter OS were site of metastasis, including the brain (hazard ratio [HR], 2.41; 95% confidence interval [CI], 2.07‐2.81; P < .001) and nonlung viscera (HR, 1.92; 95% CI, 1.67‐2.22; P < .001, vs lymph node/subcutaneous/soft tissue), age >60 years (HR, 1.23; 95% CI, 1.12‐1.36; P < .001), shorter disease‐free interval from PM to first distant metastasis (≤12 months vs >36 months: HR, 1.62; 95% CI, 1.39‐1.89; P < .001), and fewer PMs (1 vs >1; HR, 1.26; 95% CI, 1.08‐1.47; P = .004).

CONCLUSIONS:

A history of multiple PM was an independent predictor of improved survival for patients with metastatic melanoma. The results indicate that a history of multiple PMs should be incorporated into multivariate analyses of prognostic factors and treatment outcomes. Cancer 2012. © 2012 American Cancer Society.     

Nodal yield and survival in oral squamous cancer: Defining the standard of care

BACKGROUND:

Elective neck dissection (END) is commonly used as a staging and therapeutic procedure for oral squamous cell carcinoma (SCC) at high risk of nodal metastases. The authors aimed to determine whether the extent of lymphadenectomy, as defined by nodal yield, is a prognostic factor in this setting.

METHODS:

A retrospective database review identified 225 patients undergoing END with curative intent for oral SCC between 1987 and 2009. Nodal yield was studied as a categorical variable for association with overall, disease‐specific, and disease‐free survival in univariate and multivariate analyses.

RESULTS:

Nodal yield <18 was associated with 5‐year overall survival of 51% compared with 74% in those with nodal yield ≥18 (P = .009). Five‐year disease‐specific survival rates were 69% in those with <18 nodes and 87% in patients with ≥18 nodes (P = .022). Similar results were obtained for disease‐free survival, with 5‐year rates of 44% with <18 nodes versus 71% with ≥18 nodes (P = .043). After adjusting for the effect of age, nodal status, T stage, and adjuvant radiotherapy on multivariate analysis, nodal yield <18 was associated with reduced overall (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1‐3.6; P = .020), disease‐specific (HR, 2.2; 95% CI, 1.1‐4.5; P = .043), and disease‐free survival (HR, 1.7; 95% CI, 1.1‐2.8; P = .040). In the pathologically lymph node‐negative subgroup (n = 148), similar results were obtained.

CONCLUSIONS:

Nodal yield is an independent prognostic factor in patients undergoing END for oral SCC. These results suggest that an adequate lymphadenectomy in this setting should include at least 18 nodes. Cancer 2011. © 2011 American Cancer Society.     

Expression patterns of Bmi-1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma

BACKGROUND:

The objective of this study was to link expression patterns of B‐cell–specific Moloney murine leukemia virus integration site 1 (Bmi‐1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC).

METHODS:

Expression levels of Bmi‐1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease‐specific, and recurrence‐free survival.

RESULTS:

The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi‐1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi‐1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167‐2.838); this correlation was also observed for atypical cytoplasmic Bmi‐1 expression (P = .001; HR, 2.164; 95% CI, 1.389‐3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178‐0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237‐16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146‐2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869‐13.635) were correlated with overall survival, disease‐specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477‐5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850‐15.679), and the combined markers also were correlated with recurrence‐free survival (P = .001; HR, 8.943; 95% CI, 2.562‐31.220).

CONCLUSIONS:

Cytoplasmic Bmi‐1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease‐specific and recurrence‐free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow‐up. Cancer 2011;. © 2011 American Cancer Society.