Higher American Joint Committee Research Articles

Population-based analysis of factors associated with survival in patients undergoing cytoreductive nephrectomy in the targeted therapy era

ObjectivesDespite level 1 evidence demonstrating a survival benefit of cytoreductive nephrectomy (CN) in well-selected patients with metastatic renal cell carcinoma (mRCC) in the cytokine era, its role in the contemporary period of targeted therapy remains understudied. To help facilitate improved patient selection for CN and clinical trial design in the targeted therapy era, this study sought to identify factors associated with RCC-specific survival in patients diagnosed with mRCC and undergoing CN between 2005 and 2010 using a large population-based cohort. Materials and methodsPatients diagnosed with mRCC and undergoing CN between 2005 and 2010 were identified from the Surveillance Epidemiology and End Results cancer database. Kaplan-Meier methods were used to calculate disease-specific survival. Stepwise multivariable Cox proportional hazards regression analysis was used to identify factors independently associated with risk of RCC-specific death. ResultsA total of 2,478 patients were identified who were eligible for analysis with a median disease-specific survival of 21 months (95% CI: 19, 22). Factors independently associated with an increased risk of RCC-specific death included age at diagnosis≥60 years, African American race, higher American Joint Committee on Cancer T stage (≥T3), high Fuhrman nuclear grade (3 or 4), primary tumor size≥7cm, regional lymphadenopathy, both distant lymph node and visceral metastases, and sarcomatoid histology. A higher number of adverse factors correlated with an increased risk of RCC-specific death (P<0.001). ConclusionsFactors associated with RCC-specific survival identified in this large population-based study can be used to better stratify patients suitable for CN and to help with future clinical trial design and interpretation.

Clinicopathologic features and prognosis of duodenal adenocarcinoma and comparison with ampullary and pancreatic ductal adenocarcinoma

Because of the rarity of duodenal adenocarcinoma (DAC), the clinicopathologic features and prognostication data for DAC are limited. There are no published studies directly comparing the prognosis of DAC to that of ampullary adenocarcinoma (AA) and of pancreatic ductal adenocarcinoma (PDA) after resection. In this study, we examined the clinicopathologic features of 68 patients with DAC, 92 patients with AA, and 126 patients with PDA who underwent resection. Patient clinicopathologic and survival information were extracted from medical records. Statistical analysis was performed using Statistical Package for the Social Sciences with 2-sided significance level of .05. Patients with DAC had higher American Joint Committee on Cancer (AJCC) stage than AA patients (P = .001). Lymph node metastasis (P = .013) and AJCC stage (P = .02) correlated with overall survival in DAC patients. Patients with DAC or AA had lower frequencies of lymph node metastasis and positive margin and better survival than those with PDA (P < .05). However, no differences in nodal metastasis, margin status, or survival were observed between DAC patients and those with AA. Our study showed that lymph node metastasis and AJCC stage are important prognostic factors for overall survival in DAC patients. Patients with DAC had less frequent nodal metastasis and better prognosis than those with PDA. There was no significant difference in prognosis between DAC and AA.

A Novel Risk-Adjusted Nomogram for Rectal Cancer Surgery Outcomes

The circumferential resection margin is the primary determinant of local recurrence and a major factor in survival in rectal cancer. Neither chemotherapy nor chemoradiation compensates for a margin positive for cancer. To identify treatment-related factors associated with hospital margin-positive resection and to develop a tool that could be used by individual hospitals to assess their outcomes based on their unique mix of patient and tumor characteristics. Retrospective review of the National Cancer Data Base, 1998-2007. Community and academic/research hospitals. Individuals with histologically confirmed localized rectal/rectosigmoid adenocarcinoma. All individuals underwent radical resection for rectal cancer with or without neoadjuvant therapy. Rate of margin positivity determined and adjusted for patient- and tumor-related factors to calculate expected margin positivity per hospital. An observed to expected ratio was calculated based on patient- and tumor-related factors to identify treatment-associated variation. The overall margin-positive resection rate was 5.2%. Patients with margins positive for cancer were more likely to be older, male, and African American; not have private insurance; and have their cancer diagnosed later in the study period. Associated tumor-related factors include rectal location, higher American Joint Committee on Cancer stage, signet/mucinous histology, and poor/undifferentiated grade. Among hospitals that were significantly low outliers, 47% were comprehensive community hospitals, and 43.9% were academic/research hospitals; of those that were significantly high outliers, 52.3% were comprehensive community hospitals, and 17.8% were academic/research hospitals. High-volume centers made up 80% of significantly low outlier hospitals and 17% of significantly high outlier hospitals. The rates of chemotherapy and radiation were similar, but low outlier hospitals gave more neoadjuvant radiation (26.3% vs 17%). After adjustment for patient- and tumor-related factors, we identified both low and high outlier hospitals for margin positivity at resection, as well as potentially modifiable risk factors. The nomogram created in this model allows for the evaluation of observed and expected event rates for individual hospitals, providing a hospital self-assessment tool for identifying targets for improvement.

Disease progression and patient survival are significantly influenced by BRAF protein expression in primary melanoma

Mutation of BRAF is a prevalent event in melanoma. Despite much attention to the role of BRAF mutation in melanoma, the status of BRAF protein expression and its significance in melanoma progression are unknown. We investigated the BRAF expression level in different stages of melanocytic lesions and evaluated its correlation with clinicopathological features and patient survival. Using tissue microarray, BRAF expression and its correlation with patient outcome was evaluated in 49 naevi samples and 370 patients with melanoma. We also evaluated the correlation of BRAF protein expression and V600E mutation using direct sequencing. Compared with naevi samples, BRAF expression was remarkably increased in primary melanomas and further increased in metastatic melanomas (P = 1·8 × 10(-11) ). High BRAF expression was significantly correlated with thicker tumours, ulceration and higher American Joint Committee on Cancer stages (P = 1·5 × 10(-7) , 1·5 × 10(-5) and 3·6 × 10(-13) , respectively). In cases of primary melanoma, patients with high BRAF expression had significantly worse overall (P = 0·009) and disease-specific 5-year survival (P = 0·007). While there was a trend for higher prevalence of BRAF V600E mutation in patients with high BRAF protein expression, no significant correlation was observed between protein expression and BRAF mutation. Furthermore, univariate Cox regression analysis confirmed high BRAF protein expression as a strong risk factor for poor patient survival in primary melanoma [hazard ratio (HR) 2·08 for overall survival; HR 2·39 for disease-specific survival]. Our data demonstrate that BRAF protein expression is significantly increased during melanoma progression. In addition, we revealed a novel prognostic value for BRAF protein expression in primary melanoma as it is significantly correlated with poor patient survival.

The Prognostic Significance of the Biomarker p16 in Oropharyngeal Squamous Cell Carcinoma

AimsThere is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. Materials and methodsFormalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. ResultsNinety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger (P < 0.0001), with lower alcohol (P = 0.0002) and tobacco (P = 0.0001) exposure. The tumours were less differentiated (P = 0.0069), had a lower T stage (P = 0.0027), higher nodal status (P = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group (P = 0.0036). AJCC prognostic group was significant for RFS (P = 0.0096) and CSS (P = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours (P = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin (P < 0.0001 and <0.0001), chemoradiotherapy (P = 0.005 and 0.03) and P16 status (P < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC (P < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43–7.08), (P < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57–10.61) and (P = 0.001, hazard ratio 3.74; confidence interval 1.76–7.95). ConclusionThis study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.

Clinicopathological analysis of colorectal cancer: a comparison between emergency and elective surgical cases

BackgroundApproximately 15 to 30% of colorectal cancers present as an emergency, most often as obstruction or perforation. Studies report poorer outcome for patients who undergo emergency compared with elective surgery, both for their initial hospital stay and their long-term survival. Advanced tumor pathology and tumors with unfavorable histologic features may provide the basis for the difference in outcome. The aim of this study was to compare the clinical and pathologic profiles of emergency and elective surgical cases for colorectal cancer, and relate these to gender, age group, tumor location, and family history of the disease. The main outcome measure was the difference in morphology between elective and emergency surgical cases.MethodsIn total, 976 tumors from patients treated surgically for colorectal cancer between 2004 and 2006 in Stockholm County, Sweden (8 hospitals) were analyzed in the study. Seventeen morphological features were examined and compared with type of operation (elective or emergency), gender, age, tumor location, and family history of colorectal cancer by re-evaluating the histopathologic features of the tumors.ResultsIn a univariate analysis, the following characteristics were found more frequently in emergency compared with elective cases: multiple tumors, higher American Joint Committee on Cancer (AJCC), tumor (T) and node (N) stage, peri-tumor lymphocytic reaction, high number of tumor-infiltrating lymphocytes, signet-ring cell mucinous carcinoma, desmoplastic stromal reaction, vascular and perineural invasion, and infiltrative tumor margin (P<0.0001 for AJCC stage III to IV, N stage 1 to 2/3, and vascular invasion). In a multivariate analysis, all these differences, with the exception of peri-tumor lymphocytic reaction, remained significant (P<0.0001 for multiple tumors, perineural invasion, infiltrative tumor margin, AJCC stage III, and N stage 1 to 2/3).ConclusionsColorectal cancers that need surgery as an emergency case generally show a more aggressive histopathologic profile and a more advanced stage than do elective cases. Essentially, no difference was seen in location, and therefore it is likely there would be no differences in macro-environment either. Our results could indicate that colorectal cancers needing emergency surgery belong to an inherently specific group with a different etiologic or genetic background.

Association of Positive Transection Margins with Gastric Cancer Survival and Local Recurrence

To examine the association between positive resection margins and survival and local recurrence in patients with gastric cancer undergoing resection with curative intent. Patients who underwent curative intent resection for gastric carcinoma from 1985 to 2010 were identified from a prospectively maintained database. Positive margins were defined as disease present at the line of luminal transection. Clinicopathological features and outcome of patients undergoing gastrectomy with negative and positive margins were compared. Among 2384 patients undergoing curative intent resection, 108 (4.5%) had positive margins. Positive margins were associated with higher American Joint Committee on Cancer (AJCC) stage, T stage, N stage, median number of positive nodes, diffuse Lauren type, and poorly differentiated tumors. Treatment of positive margins consisted of: observation (39%), chemoradiotherapy (26%), chemotherapy (20%), repeat resection (10%), radiotherapy (4%), and unknown (1%). Multivariate analysis of the entire cohort demonstrated margin status, T stage, N stage, grade, and perineural invasion to be independent predictors of survival. Margin status was an independent predictor of survival in patients with ≤3 positive nodes or T1-2 disease but was not in patients with >3 positive nodes or T3-4 disease. Local recurrence occurred in 16% of patients with a positive margin. We identified no factors predictive of local recurrence in patients with positive margins. Positive resection margin is associated with advanced AJCC stage and aggressive tumor biology but remains an independent predictor of worse survival. The significance of a positive margin in gastric cancer is confined to patients with nontransmural disease and/or limited nodal involvement.

Metadherin is a prognostic predictor of hepatocellular carcinoma after curative hepatectomy.

Background/AimsThe prognosis after surgical resection of hepatocellular carcinoma (HCC) remains poor because of a high rate of recurrence. Thus, it is crucial to identify patients with a high risk of recurrence after curative hepatectomy and to develop more effective and targeted treatment strategies to improve disease outcomes. In this study, we investigated the roles of metadherin (MTDH) in the prognosis of HCC.MethodsWe investigated MTDH expression using immunohistochemistry in tumor tissue microarrays of 288 primary HCC patients who underwent curative surgical resection.ResultsHigh MTDH expression was observed in 138 of the 288 HCC cases (47.9%). High MTDH expression was associated with a younger age (p<0.001), higher Edmondson grade (p<0.001), microvascular invasion (p<0.001), higher American Joint Committee on Cancer T stage (p=0.001), and higher α-fetoprotein level (p=0.003). Multivariate analyses revealed that high MTDH expression (p=0.014), higher Barcelona-Clinic Liver Cancer (BCLC) stage (p<0.001), and Edmondson grade III (p=0.042) were independent predictors of shorter disease-free survival (DFS). Higher BCLC stage (p<0.001) and Edmondson grade III (p=0.047) were also independent predictors of shorter disease-specific survival.ConclusionsHigh MTDH expression may be a prognostic predictor of shorter DFS in HCC patients after curative hepatectomy.

CHD1L Is a Marker for Poor Prognosis of Hepatocellular Carcinoma after Surgical Resection

BackgroundThe gene for chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) was recently identified as a target oncogene within the 1q21 amplicon, which occurs in 46% to 86% of primary hepatocellular carcinoma (HCC) cases. However, the prognostic significance of CHD1L in HCC remains uncertain. In this study, we investigated the roles of CHD1L in the prognosis of HCC.MethodsWe investigated the expressions of CHD1L in tumor tissue microarrays of 281 primary HCC patients who underwent surgical resection using immunohistochemistry. Prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 75.6 months.ResultsCHD1L expression was observed in 48 of the 281 HCCs (17.1%). CHD1L expression was associated with a younger age (p=0.033), higher Edmondson grade (p=0.019), microvascular invasion (p<0.001), major portal vein invasion (p=0.037), higher American Joint Committee on Cancer T stage (p=0.001), lower albumin level (p=0.047), and higher α-fetoprotein level (p=0.002). Multivariate analyses revealed that CHD1L expression (p=0.027), Edmondson grade III (p=0.034), and higher Barcelona Clinic Liver Cancer stage (p<0.001) were independent predictors of shorter disease-free survival.ConclusionsCHD1L expression might be a prognostic marker of shorter disease-free survival in HCC patients after surgical resection.

Serum 25-hydroxyvitamin D serum levels in a large German cohort of patients with melanoma

Observational studies have suggested that 25-hydroxyvitamin D [25(OH)D] is associated with better outcomes in patients with malignant melanoma (MM). To study the relationship between serum 25(OH)D levels and clinical parameters in a large German cohort of patients with MM. We prospectively investigated the 25(OH)D serum levels of 764 patients with MM using the direct competitive chemiluminescence LIAISON immunoassay. Patients with MM who were taking 25(OH)D supplements were not included. Median serum 25(OH)D baseline levels were 12·3 ng mL (lower quartile: 7·3 ng mL , upper quartile: 20·2 ng mL ). Of the 764 patients, 564 (73·8%) had 25(OH)D deficiency [25(OH)D < 20 ng mL ], 145 (18·8%) had 25(OH)D insufficiency [25(OH)D ≥ 20, < 30 ng mL ] and only 55 (7·2%) had serum 25(OH)D levels within the normal range (≥ 30 ng mL ). Using a multiple regression model, lower 25(OH)D levels were significantly associated with higher Breslow tumour thickness (class: < 1 mm; 1-4 mm; > 4 mm, regression coefficient -1·45, P = 0·028) and higher American Joint Committee on Cancer 2002 melanoma stage (regression coefficient: -0·79, P = 0·036). In patients with MM, decreased 25(OH)D serum levels are associated with increased tumour thickness and advanced tumour stage. Hence, evidence is accumulating that patients with MM might benefit from 25(OH)D supplements.

Features associated with locoregional spread of papillary carcinoma correlate with diagnostic category in the Bethesda System for reporting thyroid cytopathology

Most malignancies identified by thyroid fine-needle aspiration (FNA) are papillary thyroid carcinoma (PTC). This study sought to determine if clinically adverse features of PTC correlate with the preceding cytologic diagnosis. Thyroid FNA diagnoses were correlated with subsequent histopathologic findings. From 6175 thyroid FNAs, histologic follow-up confirmed PTC in 52 of 184 (28%) FNAs with atypia of undetermined significance (AUS), 52 of 190 (27%) FNAs suspicious for follicular neoplasm, 182 of 229 (79%) FNAs that were suspicious for malignancy, and 188 of 198 (95%) FNAs that were malignant (M). Sex, age, and disease multifocality did not differ among FNA diagnosis groups. However, PTCs following an M FNA were more likely to have a higher American Joint Committee on Cancer T and N stage, and have lymphovascular invasion and/or extrathyroidal extension. Two patients had distant metastasis at initial surgery, whereas 16 developed subsequent recurrence and/or metastasis; all had a preceding M FNA. High-risk histologic subtypes of PTC also stratify to the M category, accounting at least partly for the association of cytologic diagnosis with adverse pathological parameters. Conversely, follicular variants of PTC predominate in non-M categories. The Bethesda System for Reporting Thyroid Cytopathology conveys malignancy risk, but also predicts the presence of pathological risk factors and disease progression when the malignancy is PTC. M diagnoses identify higher risk PTCs, whereas AUS diagnoses identify low-risk PTCs, mostly follicular variants. These findings support the concept of conservative clinical management for some patients with AUS, while suggesting that a central neck dissection may be routinely justified in some patients with a M FNA.

Pure and mixed fibrolamellar hepatocellular carcinomas differ in natural history and prognosis after complete surgical resection

The purpose of the current study was to describe pure and mixed fibrolamellar hepatocellular carcinoma (FL-HCC). Consecutive patients with pure and mixed FL-HCC were identified from a central pathological review using Edmondson's criteria. Clinical, pathological, and epigenetic characteristics of patients who underwent curative surgery were evaluated. Overall and disease-free survival as well as patterns of disease recurrence were examined. Methylation levels of L1 retrotransposon (LINE-1) repetitive elements and Ras association domain family 1A gene (RASSF1) promoter were also assessed using pyrosequencing. Forty of 53 patients with a median age of 22 years (range, 9 years-;65 years) met the criteria for analysis. Central pathological review found that 30 patients (75%) had pure and 10 patients (25%) had mixed FL-HCC. Pure FL-HCC typically occurred in patients aged < 30 years. These patients often presented with lymph node metastasis at the time of diagnosis and frequently experienced extrahepatic recurrences (n = 16). Conversely, mixed FL-HCC appeared to resemble to classic HCC, occurring in patients aged > 40 years and frequently involving the liver as the primary site of disease recurrence. With a median follow-up of 7.8 years, the median overall survival from the time of diagnosis in all patients was 6.4 years (range, 3.2 years-12 years). Multivariate analysis found that the risk of death was increased in patients with higher American Joint Committee on Cancer disease stages (P = .003) and those with mixed FL-HCC (P = .03). Methylation analysis of LINE-1 repetitive elements and RASSF1 promoter revealed different methylation levels between pure and mixed FL-HCC, suggesting a different epigenetic background. Pure and mixed FL-HCC display distinct clinical presentations and epigenetic backgrounds leading to different prognoses and as such may be regarded as separate clinical entities.

The Role of Quantitative NPTX2 Hypermethylation as a Novel Serum Diagnostic Marker in Pancreatic Cancer

The majority of pancreatic cancers are found to be unresectable, and the only chance for cure lies on early detection and complete resection. Several genes have been discovered to be aberrantly methylated in primary pancreatic cancer tissue, and this cancer DNA can be detected in the plasma. The aims of this study were to develop a novel diagnostic marker based on epigenetic characteristics of pancreatic cancer. We enrolled 104 patients with pancreatic cancer, 60 with chronic pancreatitis, and 5 with benign biliary stone diseases. The blood samples were collected before surgery or any kinds of treatment modalities. DNA was extracted from the plasma of each patient, and NPTX2 (neuronal pentraxin II) CpG island hypermethylation was examined quantitatively by real-time polymerase chain reaction. NPTX2 hypermethylation levels were significantly higher compared with chronic pancreatitis (P = 0.016). The sensitivity and specificity were 80% and 76%, respectively (cutoff = 0.015). NPTX2 gene hypermethylation level was significantly elevated in correlation with higher American Joint Committee on Cancer stages. The aberrantly methylated NPTX2 gene may help to distinguish between chronic pancreatitis and pancreatic cancer with conventional diagnostic tools and could become a valuable diagnostic marker.

Up-Regulated Dicer Expression in Patients with Cutaneous Melanoma

BackgroundMicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.Methods and FindingsUsing an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow's depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.ConclusionsIncreased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.

Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis

Sentinel lymph node (SLN) metastasis is a major determinant for staging, prognostication and clinical management of patients with cutaneous melanoma. However, the role of lymphatic vs. vascular invasion (VI) for SLN spread remains unclear. We compared the frequency of lymphatic invasion (LI) vs. VI in melanoma sections from 94 patients with a mean three-year clinical follow up using immunostains for the lymphatic endothelial markers D2-40 (podoplanin) and LYVE-1 and the panvascular marker CD31. LI occurred more frequently than VI (16 vs. 3%, respectively, p = 0.001) and correlated with higher American Joint Committee on Cancer stage at diagnosis (p = 0.0004). In a univariate analysis, LI was strongly associated with SLN metastasis (p = 0.008), independent of tumor thickness. In a multivariate analysis, LI was not a significant risk factor for SLN metastasis. The presence of intratumoral lymphatics (ITLs) was associated with distant metastasis, whereas VI was rare and did not correlate with SLN or distant metastasis. A combination of LI and ITL had higher positive and negative predictive values for the risk of developing SLN metastasis compared with routine histology and VI. Detection of LI in the primary tumor may aid in identifying melanoma patients with the propensity to develop SLN metastasis.

Inactivation of O 6-methylguanine-DNA methyltransferase in soft tissue sarcomas: association with K-ras mutations

The DNA-repair protein O(6)-methylguanine-DNA methyltransferase removes alkyl adducts from the O(6)-position of guanine. The adducts can mispair with T during DNA replication, resulting in a G-to-A mutation. Epigenetic inactivation of O(6)-methylguanine-DNA methyltransferase has been found in human neoplasia and is considered one of the implicated factors in chemoresistance. Sixty-two patients with soft tissue sarcomas were analyzed with regard to the status of O(6)-methylguanine-DNA methyltransferase protein expression status using immunohistochemistry and promoter hypermethylation of the MGMT gene using methylation-specific PCR. G-to-A transitions in codons 12 and 13 of the K-ras oncogene were investigated using PCR and direct automated sequencing analysis. A loss of O(6)-methylguanine-DNA methyltransferase expression was noted in 20 (32.3%) cases of 62 total soft tissue sarcomas. The MGMT promoter hypermethylation rate was 33.9% (21/62 cases). Of the 54 sarcomas evaluated, K-ras mutations were found in only 2 (3.7%) cases. Loss of O(6)-methylguanine-DNA methyltransferase expression and MGMT promoter hypermethylation showed a significant association with high American Joint Committee on Cancer stage, high French Federation of Cancer Centers grade, and aggressive behavior. On multivariate analysis, these were not an independently significant prognostic factors. However, when the group receiving chemotherapy was analyzed (n = 27), loss of O(6)-methylguanine-DNA methyltransferase expression was correlated with worse survival on multivariate analysis (P = .024). MGMT promoter hypermethylation status had a strong correlation with loss of O(6)-methylguanine-DNA methyltransferase expression (P = .000). Our results suggest that MGMT promoter hypermethylation and loss of O(6)-methylguanine-DNA methyltransferase expression tend to be associated with poor prognosis and that the loss of O(6)-methylguanine-DNA methyltransferase protein expression frequently occurs via MGMT promoter hypermethylation. However, MGMT promoter hypermethylation was not significantly associated with point mutations of K-ras at codons 12 and 13 in sarcomas.

Fascin overexpression correlates with positive thrombospondin-1 and syndecan-1 expressions and a more aggressive clinical course in patients with gallbladder cancer

This study was conducted to evaluate the prognostic role of fascin expression in gallbladder (GB) cancer and to define the relationship of thrombospondin-1 (TSP-1) and syndecan-1 in fascin expression. We performed immunohistochemical detection of fascin, TSP-1, and syndecan-1 in 43 tissue samples from GB cancer patients who underwent macroscopic complete resection. There were 19 (44%) and 24 (56%) cases having low- and high-grade fascin expression, respectively. The tumors with high-grade fascin expression tended to more frequently show poorer differentiation, deeper invasion depth, lymph node metastasis, a higher American Joint Committee on Cancer stage, and recurrence (each P < 0.05). The patients with high-grade fascin expression had significantly shorter survival periods than those with low-grade fascin expression (P < 0.05). The frequency of positive TSP-1 or syndecan-1 expression in the cases with high-grade fascin expression was significantly higher than that in the cases with low-grade fascin expression (each P < 0.05). These results suggest that a subset of advanced GB cancers revealed a marked overexpression of fascin, which was associated with aggressive clinicopathologic findings and poor overall survival. Furthermore, fascin, TSP-1, and syndecan-1 may act in concert to mediate a more aggressive clinical course through enhanced tumor cell motility.

Reduced Expression of Apaf-1 in Colorectal Adenocarcinoma Correlates with Tumor Progression and Aggressive Phenotype

Apoptotic protease activating factor-1 (Apaf-1) is one of the key regulators in the mitochondrial apoptotic pathway, and the loss of Apaf-1 leads to cellular resistance against the apoptotic signals. We investigated the expression of Apaf-1 in colorectal tissues corresponding to the multistep carcinogenesis model to determine correlations between the clinicopathologic characteristics and the expression of this molecule and to evaluate the role of Apaf-1 in the development and progression of colorectal adenocarcinoma. Immunohistochemistry for Apaf-1 was performed on the tissue microarray of 38 normal mucosal tissues, 46 adenomatous polyps, 529 colorectal adenocarcinomas, and 76 metastatic tumors. Normal colonic mucosa tissues and adenomas were positive for Apaf-1 with no exceptions (100%). However, in colorectal adenocarcinomas, 119 of 529 cases (22.5%) were positive and 410 cases (77.5%) were negative. Moreover, 67 of 76 metastatic cases (88.2 %) were negative and only nine cases (11.8%) were positive for Apaf-1 expression. In the analyses between Apaf-1 expression and clinicopathologic parameters, reduced expression of Apaf-1 correlated with left colon location (p < 0.001), deeper tumor invasion (p < 0.001), frequent lymph node metastasis (p = 0.021), higher American Joint Committee on Cancer (AJCC) and Dukes' stage (p = 0.02 and p = 0.001, respectively) and poorer differentiation (p < 0.001). The patient survival was significantly associated with age, histological grade, AJCC stage, and lymphovascular invasion, but not Apaf-1 expression (p = 0.478). The results suggest that the loss of Apaf-1 expression is a relatively frequent late event and the loss of Apaf-1 expression may play an important role in tumorigenesis and tumor progression in colorectal adenocarcinoma.

Differential expression of α-methylacyl-coenzyme A racemase in colorectal carcinoma bears clinical and pathologic significance

alpha-methylacyl-coenzyme A racemase (AMACR) is a recently discovered biomarker that is shown to be overexpressed in some prostatic carcinomas and associated with prostatic cancer progression. Given that AMACR plays an important role in peroxisomal beta-oxidation of branched-chain fatty acids from red meat and dairy products, and that consumption of red meat may increase risk of developing colon cancer as suggested by epidemiological studies, it is plausible to explore the function of AMACR in colorectal carcinoma. A few previous studies have indeed observed overexpression of AMACR in 45% to 69% of the colorectal carcinomas. However, the clinical and pathologic characteristics of such AMACR expressers have not been investigated. In this study, the immunohistochemical expression pattern of AMACR of 163 patients with primary colorectal carcinoma treated primarily with surgical resection was analyzed and correlated with tumor pathologic features (tumor location, histologic type, grade, pathologic stage, lymph node and distant metastasis) and patient outcome (disease-specific survival). The results showed variable positive staining for AMACR in 123 (75%) of 163 tumors, and moderate to strong staining in 63 (39%) of 163. Lack of staining or low-intensity staining appeared to correlate significantly with mucinous histology (P < .001), poor tumor differentiation (P = .021), and presence of lymphovascular invasion (P = .032). Patients whose tumors showed lack of staining or low-intensity staining also had a significantly worse 5-year disease-specific survival (P < .012), as did patients whose tumors had lymphovascular invasion, or were of high American Joint Committee on Cancer (AJCC) stage. On multivariate analysis, AMACR staining and AJCC staging remained independent predictors for patient outcome. Thus, our data suggest that AMACR expression in colorectal carcinoma correlates with certain tumor pathologic characteristics (histologic type, differentiation, and lymphovascular invasion) and patient outcome. Additional confirmatory studies are needed to establish the significance of AMACR as a prognostic marker for colorectal carcinoma. Further investigation on interaction between AMACR and other known colorectal cancer development pathways may provide new insights on colorectal carcinogenesis.

Postoperative Radiotherapy for Stage II or III Non–Small-Cell Lung Cancer Using the Surveillance, Epidemiology, and End Results Database

To investigate the association between survival and postoperative radiotherapy (PORT) in patients with resected non-small-cell lung cancer (NSCLC). Within the Surveillance, Epidemiology, and End Results database, we selected patients with stage II or III NSCLC who underwent a lobectomy or pneumonectomy. Only those patients coded as receiving PORT or observation were included. To account for perioperative mortality, we excluded patients who survived less than 4 months. As a result of our inclusion criteria, we selected a total of 7,465 patients, with a median follow-up time of 3.5 years for patients still alive. Predictors for the use of PORT included age less than 50 years, higher American Joint Committee on Cancer stage, T3-4 tumor stage, larger tumor size, advanced node stage, greater number of lymph nodes involved, and a ratio of lymph nodes involved to lymph nodes sampled approaching 1.00. On multivariate analysis, older age, T3-4 tumor stage, N2 node stage, male sex, fewer sampled lymph nodes, and greater number of involved lymph nodes had a negative impact on survival. The use of PORT did not have a significant impact on survival. However, in subset analysis for patients with N2 nodal disease (hazard ratio [HR] = 0.855; 95% CI, 0.762 to 0.959; P = .0077), PORT was associated with a significant increase in survival. For patients with N0 (HR = 1.176; 95% CI, 1.005 to 1.376; P = .0435) and N1 (HR = 1.097; 95% CI, 1.015 to 1.186; P = .0196) nodal disease, PORT was associated with a significant decrease in survival. In a population-based cohort, PORT use is associated with an increase in survival in patients with N2 nodal disease but not in patients with N1 and N0 nodal disease.