- Pulmonary Disease
- Solitary Pulmonary Nodule
- Lung Cancer Screening
- Lung Cancer
- Intensive Care of the Medical Patient
Instructor, Medicine - Pulmonary & Critical Care Medicine
Assistant Director, Lung Cancer Screening Program, Stanford (2014 - Present)
Co-Director, Lung Stanford Nodule Assessment Program (Lung-SNAP) (2013 - Present)
Associate Member, Canary Center at Stanford for Cancer Early Detection (2013 - Present)
Honors & Awards
Corr. of High-Res Imaging of Regional Lung Vent. by Single Energy CT with SPECT Vent. Images, Stanford Bio-X IIP Seed Grant (2015)
Loan Repayment Program "In vivo and In vitro diagnostics to improve lung cancer care", NIH NCI (10/13-10/15)
In vivo and in vitro diagnostics for assessing the lung nodule, LUNGevity Foundation Career Development Award (07/12-07/15)
An analysis of early-stage NSCLC transcriptomics across varying FDG uptake levels on PET imaging, Lung Cancer Research Foundation (11/10-11/11)
PET-FDG uptake, gene expression and outcome in stage I resected lung adenocarcinoma, The CHEST Foundation, Clinical Research Award (07/09-07/10)
Fellowship:Stanford University Division of PCCM (2010) CA
Residency:Santa Clara Valley Medical Center (2007) CA
Medical Education:Ohio State University (2004) OH
Board Certification: Critical Care Medicine, American Board of Internal Medicine (2010)
Bachelor of Arts, University of Pennsylvania, Chemistry (1998)
Masters of Science, Stanford University, Clinical Epidemiology (2011)
Board Certification: Internal Medicine, American Board of Internal Medicine (2007)
Board Certification: Pulmonary Disease, American Board of Internal Medicine (2009)
Board Certification, Critical Care Medicine, American Board of Internal Medicine (2010)
Current Research and Scholarly Interests
I am clinician by trade interested in training pulmonary and critical care physicians and internal medicine residents in addition to tackling the clinical problem of the early detection of lung cancer by better translating new non-invasive technologies and integrating existing ones to improve care. My research focuses on integrating imaging and blood biomarker (in vivo and in vitro) diagnostics to improve clinical practice. Additionally, I am interested in understanding the current limitations of “omics” and biomarker studies in clinical practice, thereby facilitating improved diagnostic and prognostic tests for the lung cancer patient.
Integrating Tumor and Stromal Gene Expression Signatures With Clinical Indices for Survival Stratification of Early-Stage Non-Small Cell Lung Cancer.
Journal of the National Cancer Institute
2015; 107 (10)
Accurate survival stratification in early-stage non-small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables.Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided.The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK.The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.
View details for DOI 10.1093/jnci/djv211
View details for PubMedID 26286589
The prognostic landscape of genes and infiltrating immune cells across human cancers.
Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing data sets are fragmented and difficult to analyze systematically. Here we present a pan-cancer resource and meta-analysis of expression signatures from ∼18,000 human tumors with overall survival outcomes across 39 malignancies. By using this resource, we identified a forkhead box MI (FOXM1) regulatory network as a major predictor of adverse outcomes, and we found that expression of favorably prognostic genes, including KLRB1 (encoding CD161), largely reflect tumor-associated leukocytes. By applying CIBERSORT, a computational approach for inferring leukocyte representation in bulk tumor transcriptomes, we identified complex associations between 22 distinct leukocyte subsets and cancer survival. For example, tumor-associated neutrophil and plasma cell signatures emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. This resource and associated analytical tools (http://precog.stanford.edu) may help delineate prognostic genes and leukocyte subsets within and across cancers, shed light on the impact of tumor heterogeneity on cancer outcomes, and facilitate the discovery of biomarkers and therapeutic targets.
View details for DOI 10.1038/nm.3909
View details for PubMedID 26193342
Circulating Tumor Microemboli Diagnostics for Patients with Non-Small-Cell Lung Cancer
JOURNAL OF THORACIC ONCOLOGY
2014; 9 (8): 1111-1119
Circulating tumor microemboli (CTM) are potentially important cancer biomarkers, but using them for cancer detection in early-stage disease has been assay limited. We examined CTM test performance using a sensitive detection platform to identify stage I non-small-cell lung cancer (NSCLC) patients undergoing imaging evaluation.First, we prospectively enrolled patients during 18F-FDG PET-CT imaging evaluation for lung cancer that underwent routine phlebotomy where CTM and circulating tumor cells (CTCs) were identified in blood using nuclear (DAPI), cytokeratin (CK), and CD45 immune-fluorescent antibodies followed by morphologic identification. Second, CTM and CTC data were integrated with patient (age, gender, smoking, and cancer history) and imaging (tumor diameter, location in lung, and maximum standard uptake value [SUVmax]) data to develop and test multiple logistic regression models using a case-control design in a training and test cohort followed by cross-validation in the entire group.We examined 104 patients with NSCLC, and the subgroup of 80 with stage I disease, and compared them to 25 patients with benign disease. Clinical and imaging data alone were moderately discriminating for all comers (Area under the Curve [AUC] = 0.77) and by stage I disease only (AUC = 0.77). However, the presence of CTM combined with clinical and imaging data was significantly discriminating for diagnostic accuracy in all NSCLC patients (AUC = 0.88, p value = 0.001) and for stage I patients alone (AUC = 0.87, p value = 0.002).CTM may add utility for lung cancer diagnosis during imaging evaluation using a sensitive detection platform.
View details for Web of Science ID 000340138700012
View details for PubMedID 25157764
Design and Analysis for Studying microRNAs in Human Disease: A Primer on -Omic Technologies
AMERICAN JOURNAL OF EPIDEMIOLOGY
2014; 180 (2): 140-152
microRNAs (miRNAs) are fundamental to cellular biology. Although only approximately 22 bases long, miRNAs regulate complex processes in health and disease, including human cancer. Because miRNAs are highly stable in circulation when compared with several other classes of nucleic acids, they have generated intense interest as clinical biomarkers in diverse epidemiologic studies. As with other molecular biomarker fields, however, miRNA research has become beleaguered by pitfalls related to terminology and classification; procedural, assay, and study cohort heterogeneity; and methodological inconsistencies. Together, these issues have led to both false-positive and potentially false-negative miRNA associations. In this review, we summarize the biological rationale for studying miRNAs in human disease with a specific focus on circulating miRNAs, which highlight some of the most challenging topics in the field to date. Examples from lung cancer are used to illustrate the potential utility and some of the pitfalls in contemporary miRNA research. Although the field is in its infancy, several important lessons have been learned relating to cohort development, sample preparation, and statistical analysis that should be considered for future studies. The goal of this primer is to equip epidemiologists and clinical researchers with sound principles of study design and analysis when using miRNAs.
View details for DOI 10.1093/aje/kwu135
View details for Web of Science ID 000339808700003
View details for PubMedID 24966218
NF-kappa B protein expression associates with F-18-FDG PET tumor uptake in non-small cell lung cancer: A radiogenomics validation study to understand tumor metabolism
2014; 83 (2): 189-196
We previously demonstrated that NF-κB may be associated with (18)F-FDG PET uptake and patient prognosis using radiogenomics in patients with non-small cell lung cancer (NSCLC). To validate these results, we assessed NF-κB protein expression in an extended cohort of NSCLC patients.We examined NF-κBp65 by immunohistochemistry (IHC) using a Tissue Microarray. Staining intensity was assessed by qualitative ordinal scoring and compared to tumor FDG uptake (SUVmax and SUVmean), lactate dehydrogenase A (LDHA) expression (as a positive control) and outcome using ANOVA, Kaplan Meier (KM), and Cox-proportional hazards (CPH) analysis.365 tumors from 355 patients with long-term follow-up were analyzed. The average age for patients was 67±11 years, 46% were male and 67% were ever smokers. Stage I and II patients comprised 83% of the cohort and the majority had adenocarcinoma (73%). From 88 FDG PET scans available, average SUVmax and SUVmean were 8.3±6.6, and 3.7±2.4 respectively. Increasing NF-κBp65 expression, but not LDHA expression, was associated with higher SUVmax and SUVmean (p=0.03 and 0.02 respectively). Both NF-κBp65 and positive FDG uptake were significantly associated with more advanced stage, tumor histology and invasion. Higher NF-κBp65 expression was associated with death by KM analysis (p=0.06) while LDHA was strongly associated with recurrence (p=0.04). Increased levels of combined NF-κBp65 and LDHA expression were synergistic and associated with both recurrence (p=0.04) and death (p=0.03).NF-κB IHC was a modest biomarker of prognosis that associated with tumor glucose metabolism on FDG PET when compared to existing molecular correlates like LDHA, which was synergistic with NF-κB for outcome. These findings recapitulate radiogenomics profiles previously reported by our group and provide a methodology for studying tumor biology using computational approaches.
View details for DOI 10.1016/j.lungcan.2013.11.001
View details for Web of Science ID 000331495000011
A Dominant Adenocarcinoma With Multifocal Ground Glass Lesions Does Not Behave as Advanced Disease
ANNALS OF THORACIC SURGERY
2013; 96 (2): 411-418
Invasive lung adenocarcinomas increasingly present with synchronous, multifocal, in situ lesions that appear as ground glass opacities (GGOs). The optimal approach in this circumstance (often nonsmokers) remains unclear. We evaluated a general strategy of anatomic resection of the dominant tumor (DT) and wedge resection of accessible ipsilateral GGOs.This is a retrospective review of 39 patients with suspected multifocal in situ adenocarcinomas and 1 DT in a predominantly Caucasian population. Mean follow-up is 30.7 months.Forty-nine percent of patients had no or minimal smoking history; 21% were Asian. The resected DT was pathologically "bronchioloalveolar carcinoma" (26%), minimally invasive adenocarcinoma (5%), adenocarcinoma with bronchioloalveolar features (41%), or moderate well-differentiated adenocarcinoma (28%). The p stage of the DT was IA in 20, IB in 15, and IIA in 4, with mean diameter of 2.6 cm. Thirty-two patients (82%) underwent anatomic resection of the DT; 7 (18%) underwent wedge resection. The mean number of GGOs present initially was 2.7 (range, 1 to 7) with a 5.2-mm mean diameter. An unresected nodule increased in size during follow-up in only 9 patients (23%). The mean diameter growth among these was 3.2 mm, with mean doubling time of 49 months. New GGOs (range, 1 to 8) developed in 16 patients (41%), all of which remained at 7 mm or less. Distant metastasis developed in 2 patients (5.2%); only 1 patient has required intervention for progression of a GGO. The overall survival is 100%.Patients with limited, multifocal, in situ adenocarcinomas and a clinical N0 DT enjoy prolonged survival with generally anatomic resection of the DT and wedge resection of accessible GGOs. These patients should not be considered to harbor T4 or M1a disease.
View details for DOI 10.1016/j.athoracsur.2013.04.048
View details for Web of Science ID 000323177800015
View details for PubMedID 23806231
- An Observational Study of Circulating Tumor Cells and F-18-FDG PET Uptake in Patients with Treatment-Naive Non-Small Cell Lung Cancer PLOS ONE 2013; 8 (7)
- Circulating tumour cells in early breast cancer LANCET ONCOLOGY 2012; 13 (9): E370-E371
Prognostic PET F-18-FDG Uptake Imaging Features Are Associated with Major Oncogenomic Alterations in Patients with Resected Non-Small Cell Lung Cancer
2012; 72 (15): 3725-3734
Although 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake during positron emission tomography (PET) predicts post-surgical outcome in patients with non-small cell lung cancer (NSCLC), the biologic basis for this observation is not fully understood. Here, we analyzed 25 tumors from patients with NSCLCs to identify tumor PET-FDG uptake features associated with gene expression signatures and survival. Fourteen quantitative PET imaging features describing FDG uptake were correlated with gene expression for single genes and coexpressed gene clusters (metagenes). For each FDG uptake feature, an associated metagene signature was derived, and a prognostic model was identified in an external cohort and then tested in a validation cohort of patients with NSCLC. Four of eight single genes associated with FDG uptake (LY6E, RNF149, MCM6, and FAP) were also associated with survival. The most prognostic metagene signature was associated with a multivariate FDG uptake feature [maximum standard uptake value (SUV(max)), SUV(variance), and SUV(PCA2)], each highly associated with survival in the external [HR, 5.87; confidence interval (CI), 2.49-13.8] and validation (HR, 6.12; CI, 1.08-34.8) cohorts, respectively. Cell-cycle, proliferation, death, and self-recognition pathways were altered in this radiogenomic profile. Together, our findings suggest that leveraging tumor genomics with an expanded collection of PET-FDG imaging features may enhance our understanding of FDG uptake as an imaging biomarker beyond its association with glycolysis.
View details for DOI 10.1158/0008-5472.CAN-11-3943
View details for Web of Science ID 000307354100004
View details for PubMedID 22710433
Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
2012; 104 (7): 528-540
MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -
View details for DOI 10.1093/jnci/djs027
View details for Web of Science ID 000302293200008
View details for PubMedID 22395642
- Fluorodeoxyglucose-PET Scanning in the Diagnosis of Pleural Disease CHEST 2011; 139 (4): 966-967
PET Scan F-18-Fluorodeoxyglucose Uptake and Prognosis in Patients With Resected Clinical Stage IA Non-small Cell Lung Cancer
2010; 137 (5): 1150-1156
Our objective was to examine the association between (18)F-fluorodeoxyglucose (FDG) uptake on PET scan and prognosis in patients with surgically treated, clinical stage IA non-small cell lung cancer (NSCLC).We reviewed data collection forms and Veterans Affairs administrative records of 75 patients with surgically treated, stage IA NSCLC who were enrolled in a prospective study of PET imaging from 1999 to 2001. We used Cox proportional hazards analysis to examine the association between FDG uptake and survival 4 years following enrollment.Most patients were men (97%), and the mean age was 68 +/- 9 years. Almost half of the patients (44%) had adenocarcinoma, and 35% underwent a sublobar resection. The mean maximum standardized uptake value (SUVmax) was 4.9 +/- 2.5 in survivors and 7.1 +/- 3.9 in nonsurvivors (P = .045). Before and after adjustment for age, tumor size, histology, and type of resection, the hazard of death was significantly higher in patients with squamous cell histology (adjusted hazard ratio [HR], 4.54; 95% CI, 1.09-18.9) and those with higher degrees of FDG uptake (adjusted HR, 1.21 per 1 unit increment; 95% CI, 1.01-1.45). At a threshold value of 5 for SUVmax, 34 of 39 patients (87%) with low FDG uptake survived, compared with only 24 of 36 patients (67%) with high FDG uptake (P = .04). Visual assessment of FDG uptake was not associated with an increased hazard of death (HR 0.66; 95% CI, 0.19-2.29).High FDG uptake as measured by SUVmax identifies individuals with clinical stage IA NSCLC who are at increased risk of death following surgery. Such high-risk patients may be good candidates for participation in future trials of adjuvant therapy.
View details for DOI 10.1378/chest.09-2356
View details for Web of Science ID 000277542300023
View details for PubMedID 20038738
- Management of Lung Nodules Detected by Volume CT Scanning NEW ENGLAND JOURNAL OF MEDICINE 2010; 362 (8): 757-757
Positron Emission Tomography F-18-Fluorodeoxyglucose Uptake and Prognosis in Patients with Surgically Treated, Stage I Non-small Cell Lung Cancer: A Systematic Review
JOURNAL OF THORACIC ONCOLOGY
2009; 4 (12): 1473-1479
18F-fluorodeoxyglucose (FDG) uptake holds potential as a noninvasive biomarker in patients with non-small cell lung cancer (NSCLC). We aimed to investigate the association between tumor FDG uptake and survival in patients with surgically resected, stage I NSCLC.We used systematic methods to identify studies for inclusion, assess methodological quality, and abstract relevant data about study design and results.Our literature search identified 1578 citations, of which nine retrospective, cross-sectional studies met eligibility criteria. In all studies, higher degrees of FDG uptake in the primary tumor were associated with worse overall or disease free survival after 2 to 5 years of follow-up, but these differences were statistically significant in only five studies. Across studies, the median overall or disease free survival was 70% for patients with higher FDG uptake compared with 88% for patients with lower FDG uptake. In three studies that performed multivariable analysis, the adjusted hazard of death or recurrence was 1.9 to 8.6 times greater in patients with higher FDG uptake.Current evidence suggests that increasing tumor FDG uptake is associated with worse survival in patients with stage I NSCLC. FDG uptake has the potential to be used as a biomarker for identifying stage I patients who are at increased risk of death or recurrence and therefore could identify candidates for participation in future trials of adjuvant therapy.
View details for Web of Science ID 000272095500005
View details for PubMedID 19887967