Reconsidering the absence of extrapancreatic extension in T staging for pancreatic adenocarcinoma in the AJCC (8th ed) Staging Manual using the National Cancer Database.

PURPOSE: Although the concept of extrapancreatic extension (EPEx) was removed in the eighth edition of the American Joint Committee on Cancer pancreatic cancer staging system, several studies have supported the prognostic significance of EPEx. This study aimed to investigate the significance of EPEx in pancreatic ductal adenocarcinoma (PDAC) using the National Cancer Database (NCDB). METHODS: Data of patients who underwent resection for PDAC between 2006 and 2016 were extracted and analyzed from the NCDB. Cases arising from premalignant lesions, those with metastases, and those treated with neoadjuvant therapy were excluded. RESULTS: Among 37,634 patients, the median overall survival was 23 months and the 5-year survival rate was 22.7%. The EPEx prevalence was the lowest for T1 stage (63.2%) and increased with each T-stage (T2:83.4%, T3:85.8%). The overall survival was better in EPEx-negative patients than in EPEx-positive patients (median 33.7 vs. 21.5 months; p<0.001). When the T-stages were stratified by EPEx, EPEx-positive patients showed worse survival in all T-stages than EPEx-negative patients. Survival was comparable between T1 EPEx-positive and T2 or T3 EPEx-negative patients (p=0.088 and p=0.178, respectively). Furthermore, T2 and T3 EPEx-negative patients had similar survival to each other (p=0.877), and distinctly superior survival compared to T2 and T3 EPEx-positive patients (p<0.001). CONCLUSIONS: EPEx was an important prognostic factor in the overall cohort and in differentiating between T stages. This study strongly suggests that staging systems should reinstate EPEx and apply it to all T-stages, especially in T1, where EPEx was absent in 36% of patients.

Features of T1 pancreatic cancer and validation of the eighth edition AJCC staging system definition using a Korean-Japanese joint cohort and the SEER database.

BACKGROUND/PURPOSE: Little is known about the features of T1 pancreatic ductal adenocarcinoma (PDAC) and its definition in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system needs validation. The aims were to analyze the clinicopathologic features of T1 PDAC and investigate the validity of its definition. METHOD: Data from 1506 patients with confirmed T1 PDAC between 2000 and 2019 were collected and analyzed. The results were validated using 3092 T1 PDAC patients from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The median survival duration of patients was 50 months, and the 5-year survival rate was 45.1%. R0 resection was unachievable in 10.0% of patients, the nodal metastasis rate was 40.0%, and recurrence occurred in 55.2%. The current T1 subcategorization was not feasible for PDAC, tumors with extrapancreatic extension (72.8%) had worse outcomes than those without extrapancreatic extension (median survival 107 vs. 39 months, p < .001). Extrapancreatic extension was an independent prognostic factor whereas the current T1 subcategorization was not. The results of this study were reproducible with data from the SEER database. CONCLUSION: Despite its small size, T1 PDAC displayed aggressive behavior warranting active local and systemic treatment. The subcategorization by the eighth edition of the AJCC staging system was not adequate for PDAC, and better subcategorization methods need to be explored. In addition, the role of extrapancreatic extension in the staging system should be reconsidered.

Is the New T1 Category as Defined in the Eighth Edition of the AJCC Pancreatic Cancer Staging System an Improvement?

BACKGROUND: The new T1 pancreatic cancer by the eighth edition of the AJCC staging system discards the concept of "extension beyond the pancreas" and focuses on size only. Furthermore, the new T1 is divided into T1a, T1b, and T1c based on size. The evidence pertaining to these changes has not been evaluated. This is to evaluate the feasibility of the new T1 definition in the pancreas head cancer cohort. METHODS: Data from 540 patients with T1 pancreatic ductal adenocarcinoma as defined by the eighth edition were collected from Korea, Japan, and the USA. Invasive IPMNs were excluded. Survival analyses were performed. RESULTS: Of the 540 patients, 181 patients were T1 according to the seventh edition and 359 were down-staged to T1 from the former T3 because the concept of "extension beyond the pancreas" was discarded. The 5-year survival rate and the median survival of T1 patients were 30.6% and 27 months, respectively. Comparing tumors that extend beyond the pancreas (new T1) and those confined within the pancreas (original T1), the latter showed significantly longer median survival (43 vs. 24 months, p < 0.001). In terms of T1a/b/c, there were no significant differences in survival. Using MaxStat, subdividing into two groups using 1.1 cm as the cut-off value, yielded significantly discrete prognostic groups (p < 0.001). CONCLUSION: The new T1 definition may be more practical, but the implications of the concept of "extension beyond the pancreas" should be re-investigated. Further, the subcategorization of T1a/b/c may not be adequate and may require revision or deletion.

Multinational validation of the American Joint Committee on Cancer 8th edition pancreatic cancer staging system in a pancreas head cancer cohort.

BACKGROUND: The aim of the present study was to compare the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system for pancreas head cancer and to validate the 8th edition using three multinational tertiary center data. METHODS: Data of 2,864 patients with pancreas head cancer were collected from Korea (571), Japan (824), and the USA (1,469). Survival analysis was performed to compare the 7th and 8th editions. Validation was performed by log-rank tests and test for trend repeated 1,000 times with random sets. RESULTS: In the 7th edition, 4.1%, 3.1%, 18.6%, 67.5%, 3.6%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV. In the 8th edition, 8.8%, 13.9%, 3.1%, 38.2%, 32.9%, and 3.1% were stage IA, IB, IIA, IIB, III, and IV, respectively. The change in T category downstaged 459 patients from IIA to the new IA and IB. The new N2 category upstaged 856 patients from the former IIB to III. The 7th edition reversely stratified IA and IB. The 8th edition corrected this mis-stratification of the 7th edition, but lacked discriminatory power between IB and IIA (P = 0.271). Validation using the log-rank showed that the 8th edition provided better discrimination in 6.387 test sets among 10 tests. The test for trend validated the 8th edition to stratify stages in correct order more often (7.815/10). CONCLUSION: The 8th edition provides more even distribution with more powerful discrimination compared to the 7th edition.

Alternative Carcinogenicity Screening Assay Using Colon Cancer Stem Cells: A Quantitative PCR (qPCR)-Based Prediction System for Colon Carcinogenesis.

The carcinogenicity of chemicals in the environment is a major concern. Recently, numerous studies have attempted to develop methods for predicting carcinogenicity, including rodent and cell-based approaches. However, rodent carcinogenicity tests for evaluating the carcinogenic potential of a chemical to humans are time-consuming and costly. This study focused on the development of an alternative method for predicting carcinogenicity using quantitative PCR (qPCR) and colon cancer stem cells. A toxicogenomic method, mRNA profiling, is useful for predicting carcinogenicity. Using microarray analysis, we optimized 16 predictive gene sets from five carcinogens (azoxymethane, 3,2'-dimethyl-4-aminobiphenyl, N-ethyl-n-nitrosourea, metronidazole, 4-(n-methyl-n-nitrosamino)-1-(3-pyridyl)-1-butanone) used to treat colon cancer stem cell samples. The 16 genes were evaluated by qPCR using 23 positive and negative carcinogens in colon cancer stem cells. Among them, six genes could differentiate between positive and negative carcinogens with a p-value of < or =0.05. Our qPCR-based prediction system for colon carcinogenesis using colon cancer stem cells is cost- and time-efficient. Thus, this qPCR-based prediction system is an alternative to in vivo carcinogenicity screening assays.

Proposed new staging system for ampulla of Vater cancer with greater discriminatory ability: multinational study from eastern and western centers.

BACKGROUND: We built a multinational retrospective database of patients with ampulla of Vater cancer to develop a reliable new staging system. METHOD: This study included 841 patients with ampulla of Vater cancer after curative surgery at Seoul National University Hospital (n = 440) and Johns Hopkins University medical institutions (n = 401) between 1985 and 2013. RESULTS: The 5-year overall survival (OS) rates of patients staged according to the 7th American Joint Committee on Cancer staging system were 80.3%, 60.9%, 58.1%, 36.6%, 17.9%, and 25.0% for Stages IA (n = 140), IB (n = 194), IIA (n = 115), IIB (n = 348), III (n = 33), and IV (n = 4), respectively. Five-year OS rates were similar in patients with Stage IB (T2N0M0) and IIA (T3N0M0) tumors (P = 0.556), but differed significantly between other pairs of groups. The number of positive lymph nodes (PLN) enhanced prognosis when stratified as 0, 1-2 and ≥3 (P < 0.001). The revised staging system consisted of Stages I (T1, PLN 0), IIA (T2-T3, PLN 0), IIB (T1-T3, PLN 1-2), III (PLN ≥3 or any T4), and IV (any M1), with 5-year OS rates differing significantly in each pair of groups, including Stages I and IIA (P < 0.001). CONCLUSION: This new staging system has better discriminatory ability in stratifying 5-year OS rates based on a large multinational database.

Proposed Nomogram Predicting the Individual Risk of Malignancy in the Patients With Branch Duct Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVES: This study evaluated individual risks of malignancy and proposed a nomogram for predicting malignancy of branch duct type intraductal papillary mucinous neoplasms (BD-IPMNs) using the large database for IPMN. BACKGROUND: Although consensus guidelines list several malignancy predicting factors in patients with BD-IPMN, those variables have different predictability and individual quantitative prediction of malignancy risk is limited. METHODS: Clinicopathological factors predictive of malignancy were retrospectively analyzed in 2525 patients with biopsy proven BD-IPMN at 22 tertiary hospitals in Korea and Japan. The patients with main duct dilatation >10 mm and inaccurate information were excluded. RESULTS: The study cohort consisted of 2258 patients. Malignant IPMNs were defined as those with high grade dysplasia and associated invasive carcinoma. Of 2258 patients, 986 (43.7%) had low, 443 (19.6%) had intermediate, 398 (17.6%) had high grade dysplasia, and 431 (19.1%) had invasive carcinoma. To construct and validate the nomogram, patients were randomly allocated into training and validation sets, with fixed ratios of benign and malignant lesions. Multiple logistic regression analysis resulted in five variables (cyst size, duct dilatation, mural nodule, serum CA19-9, and CEA) being selected to construct the nomogram. In the validation set, this nomogram showed excellent discrimination power through a 1000 times bootstrapped calibration test. CONCLUSION: A nomogram predicting malignancy in patients with BD-IPMN was constructed using a logistic regression model. This nomogram may be useful in identifying patients at risk of malignancy and for selecting optimal treatment methods. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

Analysis of multiple related phenotypes in genome-wide association studies.

Most genome-wide association studies (GWAS) have been conducted by focusing on one phenotype of interest for identifying genetic variants associated with common complex phenotypes. However, despite many successful results from GWAS, only a small number of genetic variants tend to be identified and replicated given a very stringent genome-wide significance criterion, and explain only a small fraction of phenotype heritability. In order to improve power by using more information from data, we propose an alternative multivariate approach, which considers multiple related phenotypes simultaneously. We demonstrate through computer simulation that the multivariate approach can improve power for detecting disease-predisposing genetic variants and pleiotropic variants that have simultaneous effects on multiple related phenotypes. We apply the multivariate approach to a GWA dataset of 8,842 Korean individuals genotyped for 327,872 SNPs, and detect novel genetic variants associated with metabolic syndrome related phenotypes. Considering several related phenotype simultaneously, the multivariate approach provides not only more powerful results than the conventional univariate approach but also clue to identify pleiotropic genes that are important to the pathogenesis of many related complex phenotypes.

Clinical implication of serum carcinoembryonic antigen and carbohydrate antigen 19-9 for the prediction of malignancy in intraductal papillary mucinous neoplasm of pancreas.

BACKGROUND: Little is known about the prognostic significance of serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) concentrations for predicting malignancy in patients with intraductal papillary mucinous neoplasm (IPMN) of pancreas. METHOD: The study cohort consisted of 367 patients with surgical biopsy proven IPMN at Seoul National University Hospital. Preoperative serum tumor markers were evaluated and compared with other clinical variables. RESULTS: Malignant pathology (high grade dysplasia [HGD] and invasive IPMN) was identified in 117 (31.9%) patients. Elevated serum CA19-9 was more frequent in patients with malignant (34.2%, P < 0.001; invasive IPMN vs. HGD 47.9% vs. 11.4%, P < 0.001) and main duct type (40.0%, P = 0.003) IPMN. Multivariate analysis showed main pancreatic duct (MPD) >5 mm (P < 0.001), mural nodules (P < 0.001), and elevated serum CA19-9 (P < 0.001) were independent predictors of malignancy. The sensitivity, specificity and accuracy were 34.2%, 92.4%, and 73.8%, respectively, for elevated serum CA19-9; 63.3%, 78.0%, and 73.3%, for MPD >5 mm; and 59.0%, 86.4%, and 77.7%, for mural nodules. CONCLUSION: Serum CA19-9 is significantly higher in patients with malignant IPMN, especially in patients with invasive and main duct type IPMN. The diagnostic power of serum CA19-9 in predicting malignancy is comparable to that of MPD >5 mm and mural nodules.

Adenovirus-mediated expression of human sodium-iodide symporter gene permits in vivo tracking of adipose tissue-derived stem cells in a canine myocardial infarction model.

INTRODUCTION: In vivo tracking of the transplanted stem cells is important in pre-clinical research of stem cell therapy for myocardial infarction. We examined the feasibility of adenovirus-mediated sodium iodide symporter (NIS) gene to cell tracking imaging of transplanted stem cells in a canine infarcted myocardium by clinical single photon emission computed tomography (SPECT). METHODS: Beagle dogs were injected intramyocardially with NIS-expressing adenovirus-transfected canine stem cells (Ad-hNIS-canine ADSCs) a week after myocardial infarction (MI) development. (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) and (99m)Tc-pertechnetate ((99m)TcO4(-)) SPECT imaging were performed for assessment of infarcted myocardium and viable stem cell tracking. Transthoracic echocardiography was performed to monitor any functional cardiac changes. RESULTS: Left ventricular ejection fraction (LVEF) was decreased after LAD ligation. There was no significant difference in EF between the groups with the stem cell or saline injection. (125)I uptake was higher in Ad-hNIS-canine ADSCs than in non-transfected ADSCs. Cell proliferation and differentiation were not affected by hNIS-carrying adenovirus transfection. (99m)Tc-MIBI myocardial SPECT imaging showed decreased radiotracer uptake in the infarcted apex and mid-anterolateral regions. Ad-hNIS-canine ADSCs were identified as a region of focally increased (99m)TcO4(-) uptake at the lateral wall and around the apex of the left ventricle, peaked at 2 days and was observed until day 9. CONCLUSIONS: Combination of adenovirus-mediated NIS gene transfection and clinical nuclear imaging modalities enables to trace the fate of transplanted stem cells in infarcted myocardium for translational in vivo cell tracking study for prolonged duration.

Clinicopathological Meaning of Size of Main-Duct Dilatation in Intraductal Papillary Mucinous Neoplasm of Pancreas: Proposal of a Simplified Morphological Classification Based on the Investigation on the Size of Main Pancreatic Duct.

BACKGROUND: The 2012 consensus guideline on intraductal papillary mucinous neoplasm of the pancreas (IPMN) described a three-stage criteria involving main pancreatic duct (MPD) size with definitions of malignancy relevant for treatment decisions. Re-evaluation and simplification of this classification for clinicians are warranted. METHODS: Data from the Seoul National University Hospital of 375 consecutive patients with pathology-confirmed IPMN after surgery were analyzed. The association between clinicopathologic characteristics of IPMN and MPD size was assessed. The cut-off value of MPD size for a current definition of malignancy prediction was calculated. RESULTS: Diagnostic accuracy for malignancy was highest when the cut-off value of MPD size was 7 mm (area under the curve=0.7126). Dichotomizing IPMN into MPD≤7 mm versus MPD> mm, patient age (p=0.039), sex (p=0.001), presence of mural nodule (p<0.001), and invasiveness risk (13.2 vs. 39.8%, p<0.001) resulted in significantly different results. Mural nodule-negative patients with MPD>7 mm had a significantly lower 5-year survival rate than those with MPD≤7 mm (78.4 vs. 91.4%, p=0.006). Among patients with MPD size≤7 mm, elevated serum CA 19-9 and mural nodule were independent risk factors of malignancy. Patients with MPD size≤7 mm without these risk factors had malignancy risk of 2.6%. CONCLUSION: Using the definition of malignancy provided in the 2012 guideline, the MPD size> mm criterion was statistically driven. The current morphologic classification of IPMN can be simplified as branch-duct-predominant IPMN (MPD≤7 mm)' and main-duct-predominant IPMN (MPD> mm). Patients who are determined to have main-duct-predominant IPMN and branch-duct-predominant IPMN with elevated serum CA 19-9 or mural nodule are recommended to undergo surgical treatment.

Log-linear model-based multifactor dimensionality reduction method to detect gene gene interactions.

MOTIVATION: The identification and characterization of susceptibility genes that influence the risk of common and complex diseases remains a statistical and computational challenge in genetic association studies. This is partly because the effect of any single genetic variant for a common and complex disease may be dependent on other genetic variants (gene-gene interaction) and environmental factors (gene-environment interaction). To address this problem, the multifactor dimensionality reduction (MDR) method has been proposed by Ritchie et al. to detect gene-gene interactions or gene-environment interactions. The MDR method identifies polymorphism combinations associated with the common and complex multifactorial diseases by collapsing high-dimensional genetic factors into a single dimension. That is, the MDR method classifies the combination of multilocus genotypes into high-risk and low-risk groups based on a comparison of the ratios of the numbers of cases and controls. When a high-order interaction model is considered with multi-dimensional factors, however, there may be many sparse or empty cells in the contingency tables. The MDR method cannot classify an empty cell as high risk or low risk and leaves it as undetermined. RESULTS: In this article, we propose the log-linear model-based multifactor dimensionality reduction (LM MDR) method to improve the MDR in classifying sparse or empty cells. The LM MDR method estimates frequencies for empty cells from a parsimonious log-linear model so that they can be assigned to high-and low-risk groups. In addition, LM MDR includes MDR as a special case when the saturated log-linear model is fitted. Simulation studies show that the LM MDR method has greater power and smaller error rates than the MDR method. The LM MDR method is also compared with the MDR method using as an example sporadic Alzheimer's disease.

Odds ratio based multifactor-dimensionality reduction method for detecting gene-gene interactions.

MOTIVATION: The identification and characterization of genes that increase the susceptibility to common complex multifactorial diseases is a challenging task in genetic association studies. The multifactor dimensionality reduction (MDR) method has been proposed and implemented by Ritchie et al. (2001) to identify the combinations of multilocus genotypes and discrete environmental factors that are associated with a particular disease. However, the original MDR method classifies the combination of multilocus genotypes into high-risk and low-risk groups in an ad hoc manner based on a simple comparison of the ratios of the number of cases and controls. Hence, the MDR approach is prone to false positive and negative errors when the ratio of the number of cases and controls in a combination of genotypes is similar to that in the entire data, or when both the number of cases and controls is small. Hence, we propose the odds ratio based multifactor dimensionality reduction (OR MDR) method that uses the odds ratio as a new quantitative measure of disease risk. RESULTS: While the original MDR method provides a simple binary measure of risk, the OR MDR method provides not only the odds ratio as a quantitative measure of risk but also the ordering of the multilocus combinations from the highest risk to lowest risk groups. Furthermore, the OR MDR method provides a confidence interval for the odds ratio for each multilocus combination, which is extremely informative in judging its importance as a risk factor. The proposed OR MDR method is illustrated using the dataset obtained from the CDC Chronic Fatigue Syndrome Research Group. AVAILABILITY: The program written in R is available.

An estimator of the survival function based on the semi-Markov model under dependent censorship.

Lee and Wolfe (Biometrics vol. 54 pp. 1176-1178, 1998) proposed the two-stage sampling design for testing the assumption of independent censoring, which involves further follow-up of a subset of lost-to-follow-up censored subjects. They also proposed an adjusted estimator for the survivor function for a proportional hazards model under the dependent censoring model. In this paper, a new estimator for the survivor function is proposed for the semi-Markov model under the dependent censorship on the basis of the two-stage sampling data. The consistency and the asymptotic distribution of the proposed estimator are derived. The estimation procedure is illustrated with an example of lung cancer clinical trial and simulation results are reported of the mean squared errors of estimators under a proportional hazards and two different nonproportional hazards models.

Statistical tests for identifying differentially expressed genes in time-course microarray experiments.

MOTIVATION: Microarray technology allows the monitoring of expression levels for thousands of genes simultaneously. In time-course experiments in which gene expression is monitored over time, we are interested in testing gene expression profiles for different experimental groups. However, no sophisticated analytic methods have yet been proposed to handle time-course experiment data. RESULTS: We propose a statistical test procedure based on the ANOVA model to identify genes that have different gene expression profiles among experimental groups in time-course experiments. Especially, we propose a permutation test which does not require the normality assumption. For this test, we use residuals from the ANOVA model only with time-effects. Using this test, we detect genes that have different gene expression profiles among experimental groups. The proposed model is illustrated using cDNA microarrays of 3840 genes obtained in an experiment to search for changes in gene expression profiles during neuronal differentiation of cortical stem cells.