[Show abstract][Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a poor prognosis, limited treatment options, and a worldwide incidence that is expected to increase in the next decade. We evaluated Wnt7A expression in 50 surgically resected tumor specimens using quantitative PCR. The expression values, were assessed by clinicopathological factors and K-M and Cox's regression with OS. The mean level of Wnt7A expression had a significant correlation with International Mesothelioma Interest Group (IMIG) stage (P<0.034), gender, smoking history and ethnicity, respectively (P=0.020, P=0.014, P=0.039). In the univariate analysis, low Wnt7A expression was a significant negative factor for overall survival (P=0.043, HR=2.30). However, multivariate Cox's regression revealed no significant factors for overall survival (low Wnt7A: P=0.051, HR=2.283; non-epithelioid subtype: P=0.050, HR=2.898). In patients with epithelioid tumors, those with low Wnt7A expression had significantly worse prognosis (P=0.019, HR=2.98). In patients with epithelioid tumors, females had significantly better prognosis than males (P=0.035). In patients who did not have neoadjuvant chemotherapy, prognosis was significantly more favorable for patients with high Wnt7A expression than for those with low Wnt7A expression (P=0.031). Among the patients with low Wnt7A-expressing tumors, those who received neoadjuvant chemotherapy had better prognosis than those who did not (P=0.024). The results of our study suggest that Wnt7A expression is a putative prognostic factor and a predictor of chemosensitivity.
[Show abstract][Hide abstract] ABSTRACT: Background
A minority of liver transplant (LT) candidates pursue listing at multiple centers in order to achieve transplant. The purpose of this study was to assess the characteristics and outcomes of the “migrated” liver transplant (LT) candidates – those who travel to secondary centers seeking LT.
Single center retrospective study from January 1, 2005 to January 1, 2013 at a tertiary care center within UNOS Region 1. Adult recipients who were listed at the primary center of interest, but subsequently achieved transplant at a secondary center (MGH-migrated; n=44) were compared to recipients who achieved LT at the primary center (MGH-transplanted; n=279).
MGH-migrated recipients most frequently traveled to UNOS Region 3 (70.5%), with a mean (SD) distance traveled of 1134 (+/-392) miles. MGH-migrated patients, when compared to MGH-transplanted recipients, spent more time on the waitlist (907.6 +/- 930.1 vs 354.9 +/- 533.2 days, p<0.00001), were more likely to have cholestatic liver disease (22.7% vs 6.8%, p=0.0006) and private insurance (80.0% vs 51.6%, p=0.0005), but were less likely to have alcoholic liver disease (2.3% vs 18.6%, p=0.006) and MELD exception points (6.8% vs 50.9%, p<0.00001). On multivariable analysis, candidates with private insurance who lacked both alcoholic liver disease and MELD exception point listing, were significantly associated with the odds of pursuing migration. Despite achieving LT, MGH-migrated patients had inferior 5 year patient survival (63% versus 80%; p=0.03).
A small and distinctive cohort of LT recipients pursue migration to achieve transplant. Travel patterns of migrated LT recipients appear to reflect the ongoing geographic disparities in liver distribution, and further underscore the need for alterations in policy to allow for equitable distribution.
Journal of the American College of Surgeons 06/2014; 218(6). DOI:10.1016/j.jamcollsurg.2013.12.056 · 5.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is widespread agreement amongst clinical oncologists that more refined risk-stratification in early-stage lung cancer patients beyond conventional TNM staging is needed. Over the past decade, a number of molecular prognostic signatures have been designed to meet this need by correlating patterns in the differences in gene expression or modification to patient prognosis. Unfortunately, the majority of proposed signatures are not amenable to practical widespread implementation or have not yet undergone large-scale, rigorous clinical validation. A practical 14-gene prognostic signature that has undergone large-scale blinded independent validation is now ready for widespread clinical use. An international clinical trial is underway that has been designed to document the precise degree of benefit derived from adjuvant therapy in high-risk stage I patients identified by the 14-gene prognostic assay.
[Show abstract][Hide abstract] ABSTRACT: A molecular assay prognostic of survival in resected nonsquamous non-small cell lung cancer designed to meet the need for improved risk stratification in early-stage disease has recently been described. This assay measures the expression levels of 14 genes using RNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissues. The assay underwent blinded clinical validation in 2 large international cohorts involving approximately 1500 patients; the analytical precision and reproducibility of this assay, however, have not yet been reported. For each of the 14 TaqMan quantitative polymerase chain reaction (PCR) primer and probe sets used in the molecular prognostic assay, the linear range, PCR efficiency, limits of blank, limits of quantitation, and quantitative bias were determined using serial dilutions of pooled RNA extracted from FFPE samples. The reproducibility of the entire molecular assay was determined by performing repeat testing of FFPE samples over multiple days. The linear range of individual quantitative TaqMan PCR primer and probe sets was between 2- and 2-fold input RNA. The median CT of the quantitative PCR primer and probe sets at 10 ng of input RNA was 24.3; the median efficiency was 91.2%. The median quantitative bias across all quantitative PCR primer and probe sets was 0.75% (range, 0.32% to 1.32%). In repeat testing, the mean SD of the risk score (scaled from 1 to 100) was 2.18, with a mean coefficient of variation of 0.08. The molecular prognostic assay presented in this study demonstrates high precision and reproducibility, validating its clinical utility as a reliable prognostic tool that can contribute to the management of patients with early-stage disease.
Diagnostic molecular pathology: the American journal of surgical pathology, part B 04/2013; 22(2). DOI:10.1097/PDM.0b013e318273fb61 · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis. Much of this research has focused on the use of the airway-repair model to study response to injury. In this review, we discuss the primary evidence of the role that cancer stem cells play in lung cancer development. The implications of a stem cell origin of lung cancer are reviewed, and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.
Chinese journal of cancer 11/2012; 32(2). DOI:10.5732/cjc.012.10097 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mortality after initial diagnosis of lung cancer is higher than from any other cancer. Although mutations in several genes, such as EGFR and K-ras, have been associated with clinical outcome, technical complexity, cost and time have rendered routine screening prohibitive for most lung cancer patients prior to treatment. In this study, using both novel and established technologies, we developed a clinically practical assay to survey the status of three frequently mutated genes in lung cancer (EGFR, K-ras and TP53) and two genes (BRAF and β-catenin) with known hotspot mutations in many other cancers. A single 96-well plate was designed targeting a total of 14 fragments (16 exons) from EGFR, K-ras, TP53, BRAF and β-catenin. In 96 lung adenocarcinoma patients, the mutation frequencies of three major genes (EGFR, K-ras and TP53) were between 21-24%. Fifty-six out of 96 (58%) patients had a mutation in at least one of the five genes. K-ras mutations positively correlated with smoking pack-years (p=0.035). EGFR mutations were frequent in never-smokers (p=0.0007), Asians (p=0.0204) and non-stage I lung cancer (p=0.016). There was also a trend towards an association between the presence of any mutation and improved recurrence-free survival (p=0.070). We demonstrate that our novel multigene mutation assay technology can rapidly and cost-effectively screen for mutations in lung adenocarcinoma. This screening assay can be used in the clinical setting for the large-scale validation of prognosis and/or predicting therapeutic response so that the majority of lung cancer patients can benefit from leveraging up-to-date knowledge on how mutation profiles may influence treatment options.
International Journal of Oncology 03/2012; 40(6):1900-6. DOI:10.3892/ijo.2012.1396 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging.
A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC).
Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages.
Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection.
UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.
The Lancet 03/2012; 379(9818):823-32. DOI:10.1016/S0140-6736(11)61941-7 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While most often transient, brachial plexus birth injury can cause permanent neurologic injury. The major risk factors for brachial plexus birth injury are fetal macrosomia and shoulder dystocia. The degree of injury to the brachial plexus should be determined in the neonatal nursery, as those infants with the most severe injury--root avulsion--should be referred early for surgical evaluation so that microsurgical repair of the plexus can occur by 3 months of life. Microsurgical repair options include nerve grafts and nerve transfers. All children with brachial plexus birth injury require ongoing physical and occupational therapy and close follow-up to monitor progress.
[Show abstract][Hide abstract] ABSTRACT: The 5-year survival rate for stage I non-small-cell lung cancer (NSCLC) of 50% to 70% indicates that our current staging methods do not adequately predict outcome. Empty spiracles homeobox 2 (EMX2) is a homeo-domain-containing transcription factor that regulates a key developmental pathway known to promote lung tumorigenesis. This study assessed the significance of EMX2 as a prognostic biomarker in lung adenocarcinoma including bronchioloalveolar carcinoma (BAC).
144 patients with lung adenocarcinoma undergoing surgical resection were studied. Quantitative real-time reverse transcriptase polymerase chain reaction and Immunohistochemistry were used to analyze EMX2 mRNA and protein expression, respectively. Association of EMX2 mRNA expression levels with clinical outcomes was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model.
EMX2 mRNA expression was significantly downregulated in lung adenocarcinoma compared with matched adjacent normal tissue (P < .001). EMX2 protein expression was similarly found to be downregulated in lung adenocarcinoma. The EMX2-high mRNA expressing group had statistically significant better overall survival (OS) than the EMX2-low mRNA expressing group (P = .005). Subgroup analysis also demonstrated improved survival in stage I patients (P = .01) and patients with BAC (P = .03). Lastly, the EMX2-high mRNA expressing group had statistically significant better recurrence-free survival (RFS) than the EMX2-low mRNA expression group in patients with adenocarcinoma (P < .001).
EMX2 expression is downregulated in lung adenocarcinoma. Low EMX2 mRNA expression is significantly associated with decreased OS and RFS in patients with lung adenocarcinoma, particularly with stage I disease and BAC.
Clinical Lung Cancer 07/2011; 12(4):237-44. DOI:10.1016/j.cllc.2011.03.025 · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although stem cells were discovered more than 50 years ago, we have only recently begun to understand their potential importance in cancer biology. Recent advances in our ability to describe, isolate, and study lung stem cell populations has led to a growing recognition of the central importance cells with stem cell-like properties may have in lung tumorigenesis. This article reviews the major studies supporting the existence and importance of cancer stem cells in lung tumorigenesis. Continued research in the field of lung cancer stem cell biology is vital, as ongoing efforts promise to yield new prognostic and therapeutic targets.
The Annals of thoracic surgery 06/2010; 89(6):S2090-5. DOI:10.1016/j.athoracsur.2010.03.038 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with early-stage lung cancer demonstrate significant recurrence rates and lower-than-expected survival rates after surgical resection, indicating that our current staging methods do not adequately predict outcome. Since the last revision of the TNM staging system, a number of genomic models have been proposed which more accurately predict prognosis in patients with early-stage lung cancer. A variety of prognostic genomic models based on gene-expression profiling and quantitative polymerase chain reaction (PCR) are able to stratify patients with early-stage lung cancer into high- and low-risk groups with respect to disease-free and overall survival. In the future, clinical application of these models may ultimately dictate both the use of adjuvant therapy as well as the choice of surgical procedure in patients with early-stage lung cancer. An effort to develop a robust genomic model for use in the clinical setting should be prompted by encouraging results obtained by the use of a quantitative PCR-based genomic signature in the field of breast oncology.
Clinical Lung Cancer 06/2009; 10(3):151-7. DOI:10.3816/CLC.2009.n.021 · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anal canal duplications are rare congenital malformations, with fewer than 50 reported cases in the literature. Anal canal duplications are noncommunicating second anal orifices located posterior to the true anus without other associated hindgut duplications. Typically, these are asymptomatic, tubular malformations that present in females before the age of 6 years. Here, we report on a 16-year-old girl with a symptomatic anal canal duplication associated with a presacral cystic component. This is an unusual presentation of an already rare entity. An overview of the clinical presentation, radiologic workup, surgical treatment, and histologic features of anal canal duplications is provided.
Journal of Pediatric Surgery 10/2008; 43(9):1749-52. DOI:10.1016/j.jpedsurg.2008.05.026 · 1.39 Impact Factor