HPHS Journal Watch: January/February 2023
American Journal of Gastroenterology
Application of the Latest Advances in Evidence-Based Medicine in Primary Biliary Cholangitis
Kowdley KV, Bowlus CL, Levy C, et al. Am J Gastroenterol. 2023 Feb 1;118(2):232-242.
In this updated expert consensus document, the authors provide updates on staging, the use of non-invasive prognostic tools, and a treatment algorithm to provide evidence-based and practical tools for clinicians who manage PBC, with the ultimate goal to improve the long-term outcomes for patients with this chronic liver disease.
American Journal of Surgical Pathology
SOX9 Expression is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma
Ruzinova M, Ma C, Brunt EM, et al. Am J Surg Pathol. 2023 Jan;47(1):1-11.
Prior studies have shown that expression of stem cell-related markers by gene expression profiling is related to poor clinical prognosis in hepatocellular carcinoma (HCC). The authors of this study first evaluated the three stem cell markers EpCAM, K19, and SOX9 by immunohistochemistry in a cohort of 216 HCC cases in adult patients. They found that SOX9 nuclear expression was associated with lymphovascular space invasion, advanced TNM stage, reduced disease-free survival, and decreased overall survival. The authors next used the TCGA dataset to interrogate gene expression of the stem cell markers in 360 available patients. 25 (7%) tumors had elevated mRNA expression of SOX9; again, this expression was associated with decreased disease-free survival. The authors conclude that overexpression of SOX9 is a poor prognostic marker for HCC and that SOX9 immunohistochemical staining is a marker of this overexpression.
Clinical Gastroenterology and Hepatology
Pregnancy Outcomes in Women With Autoimmune Hepatitis – A Nationwide Population-based Cohort Study With Histopathology
Sharma R, Simon TG, Stephansson O, et al. Clin Gastroenterol Hepatol. 2023 Jan;21(1):103-114.e10.
This nationwide population-based cohort study compared pregnancy risks in women with autoimmune hepatitis (AIH) with a matched reference group from the general population. The authors found an increased risk of preterm birth in women with AIH, as well as an increased risk of cesarean section, increased odds of pre-eclampsia, increased risk of low 5-minute Apgar score, and low birth weight. Cirrhosis at diagnosis did not add to the impact of AIH on preterm birth, and there were increased risks of preterm birth in both women with inflammation without fibrosis (OR, 11.18; 95% CI, 2.20–56.83) and with fibrosis (OR, 10.75; 95% CI, 3.78–30.61).
Hepatocyte Adenosine Kinase Promotes Excessive Fat Deposition and Liver Inflammation
Li H, Zheng J, Xu Q, et al. 2023 Jan;164(1):134-146.
Our understanding of how nonalcoholic fatty liver disease (NAFLD) can progress to steatohepatitis with potentially advanced liver fibrosis is evolving. The role of hepatocyte adenosine kinase (ADK) in the pathophysiology of NAFLD is unknown. The study authors explored whether hepatocyte ADK functions as an obesogenic gene/enzyme to promote excessive fat deposition and liver inflammation. The study used human liver tissues to examine the presence and distribution of ADK using immunohistochemistry. Mice with hepatocyte-specific ADK disruption or overexpression were examined for hepatic fat deposition and inflammation. Liver lipidomics, hepatocyte RNA sequencing (RNA-seq), and single-cell RNA-seq for liver nonparenchymal cells were performed to analyze ADK regulation of hepatocyte metabolic responses and hepatocyte-nonparenchymal cells crosstalk. The study showed that patients with NAFLD had increased hepatic ADK levels, while mice with hepatocyte-specific ADK disruption displayed decreased hepatic fat deposition on a chow diet and were protected from diet-induced excessive hepatic fat deposition and inflammation. In contrast, mice with hepatocyte-specific ADK overexpression displayed increased body weight and adiposity and elevated degrees of hepatic steatosis and inflammation compared with control mice. RNA-seq and epigenetic analyses indicated that ADK increased hepatic DNA methylation and decreased hepatic Ppara expression and fatty acid oxidation. Thus, hepatocyte ADK appears to trigger or exacerbate the pathogenesis of NAFLD by promoting excessive fat deposition and liver inflammation, which could make hepatocyte ADK a therapeutic target for managing obesity and NAFLD.
Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification
Montironi C, Castet F, Haber PK, et al. Gut. 2023 Jan;72(1):129-140.
In a previous study, these authors reported an immune-specific class characterization of the hepatocellular carcinoma (HCC) immune contexture in ~25% of patients and now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. However, the immune traits of the remaining ~75% of HCCs are ill-defined. Further, the association between response (15%–20% of HCC cases) or resistance to immune checkpoint inhibitors and the role of CTNNB1 mutations is unclear. The authors performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence, and immunohistochemistry in a novel cohort of 240 HCC patients and validated these results in other cohorts comprising 660 patients. This integrative analysis led to defining the Inflamed class of HCC (37%), the intermediate class (enriched for p53 mutations), and the excluded class (enriched in CTNNB1 mutations and PTK2 overexpression). A 20-gene signature was able to capture ~90% of the inflamed class of HCCs and is associated with response to immunotherapy. This revised immunogenomic classification of HCC unveils several novel mechanisms of immune response and evasion and may help to better predict the distinct patterns of outcome associated with immunotherapy in HCC.
Commentary – Immunogenomic classification of hepatocellular carcinoma patients for immune check-point inhibitors therapy: cui bono?
Hernaez R, Avila MA. Gut. 2023 Jan;72(1):7-9.
This commentary is regarding the above article:Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.
The authors opine that, if the methodology for assessing this gene signature can be standardized in clinical laboratories, its implementation could guide the stratification of HCC patients to be treated with available systemic treatments and explore novel therapeutic avenues. Biopsies are not recommended in cirrhotic patients with typical radiological features of HCC, however, imaging-based diagnosis has a degree of uncertainty (5%–10%). Ideally, this situation could be circumvented by a liquid biopsy approach. The authors provide preliminary evidence by devising a 13-protein signature in peripheral blood, composed mainly of proteins involved in immune response and angiogenesis, which can discriminate these patients with high accuracy and sensitivity.
Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002–2033: the ITA.LI.CA database
Vitale A, Svegliati- Baroni G, Ortolani A, et al. Gut 2023;72:141–152.
The newly coined term metabolic-associated fatty liver disease (MAFLD) has been introduced to include the entire spectrum of liver diseases associated with metabolic disorders. Vitale et al used this new definition to reanalyze patients with hepatocellular carcinoma (HCC) retrospectively, using the well-established Italian Liver Cancer (ITA.LI.CA) group. MAFLD cases were defined by the presence of at least one of the following characteristics: overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation. HCC cases were divided into three groups: 1) single etiology MAFLD (S-MAFLD) including patients with HCC with a diagnosis of either MAFLD or MAFLD-cirrhosis, 2) mixed etiology MAFLD (M-MAFLD) including patients with HCC with a diagnosis of either MAFLD or MAFLD-cirrhosis and with additional etiological factor(s), and 3) Non-MAFLD: including patients with HCC not associated with metabolic disorders. The majority of patients with HCC had MAFLD (68.4%). The proportion of S-MAFLD significantly increased over the study period from 3.6% (2002–2003) to 28.9% (2018–2019), and these are projected to exceed the incidence of HCV-HCC and HCC of mixed etiology (presumed M-MAFLD) in about 4 and 6 years, respectively. When the authors grouped patients according to the MAFLD definition, they found a lower median overall survival in non-MAFLD (23.8 months) than in S-MAFLD (28.1 months) and M-MAFLD (27.1 months). This study emphasizes the close association between metabolic factors and HCC as shown by the constant prevalence of M-MAFLD during the entire study period. At present, there are no approved drugs for MAFLD, and the surveillance of the immense population with diabetes and obesity is not feasible. In the future, only the integration of healthcare personnel of different specialties into a network model of care, as well as healthcare policies to reduce the burden of metabolic diseases might slow the skyrocketing incidence of the new HCC phenotype.
Accurate liquid biopsy for the diagnosis of nonalcoholic steatohepatitis and liver fibrosis
Angelini G, Panunzi S, Castagneto-Gissey L, et al. Gut. 2023 Feb;72(2):392-403.
The diagnosis of non-alcoholic steatohepatitis (NASH) currently relies on invasive liver biopsy. There is an urgent need to find non-invasive biomarkers for NASH diagnosis, disease progression, and intervention response monitoring. The study aimed to identify a biomarker and algorithm able to predict the presence of NASH as well as its severity. The authors identified two monocyte proteins, PLIN2 and RAB14, which can predict the presence and severity of NASH and liver fibrosis, respectively. This novel biomarker was superior to the currently used FIB4, non-alcoholic fatty liver disease fibrosis score, and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. The authors claimed that the biomarkers they identified are sensitive and specific in diagnosing the presence and severity of NASH and/or liver fibrosis and are more reliable than currently used biomarkers. A liquid biopsy is, therefore, feasible in making a diagnosis of NASH and/or liver fibrosis. Sensitive and specific biomarkers can help in identifying patients eligible for NASH pharmacotherapy or surgery in clinical trials and treatment efficacy monitoring.
A nationwide assessment of hepatocellular adenoma resection: Indications and pathological discordance
Haring MPD, Elfrink AKE, Oudmaijer CAJ, et al. Hepatol Commun. 2023 Jan;7(1):e2110.
This nationwide observational cohort study performed in the Netherlands included patients who underwent liver resection for presumed hepatocellular adenoma (HCA), and evaluated outcomes in patients operated for HCAs < 50 mm compared to HCAs ≥ 50 mm. The authors found that male sex, tumor size <50 mm, and lack of hepatobiliary CE‐MRI were independent risk factors for postoperative change in tumor diagnosis. Preoperative diagnosis was altered from HCA or (pre)malignancy to focal nodular hyperplasia (FNH) in six out of the nine male patients with tumors <50 mm. The authors recommend hepatobiliary CE‐MRI in all patients with (suspected) HCAs, and percutaneous biopsy for all (suspected) HCAs in male patients.
The nonalcoholic steatohepatitis extended hepatocyte ballooning score: histologic classification and clinical significance
Gill RM, Allende D, Belt PH, et al. Hepatol Commun. 2023 Feb 1;7(2):e0033.
This study from the NASH Clinical Research Network utilized a large multicenter database of patients with NASH or NAFL. The authors propose a subclassification of ballooned hepatocytes either as classic hepatocyte ballooning (cHB, defined as >1.5× the diameter of adjacent hepatocytes with irregularly clumped cytoplasm and rarefaction of cytoplasm) or as nonclassic hepatocyte ballooning (nHB, which did not show the degree of enlargement of cHB, but showed similar cytoplasmic changes, and lacked well-formed Mallory-Denk bodies). Fibrosis stage, as well as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, fasting insulin, homeostasis model assessment of insulin resistance, and HDL were significantly elevated in patients with nonclassic hepatocyte ballooning compared to cases without ballooned hepatocytes. Based on these findings the authors suggest that nonclassic hepatocyte ballooning represents early changes of NASH and propose the use of an extended hepatocyte ballooning (eB) which corresponds with both clinical features of NASH and fibrosis stage.
Immunohistochemistry for hepatitis E virus capsid protein cross-reacts with cytomegalovirus-infected cells: a potential diagnostic pitfall
Lenggenhager D, Grossmann J, Gouttenoire J, et al. Histopathology. 2023 Jan;82(2):354-358.
Immunohistochemistry for hepatitis E virus (HEV) ORF2 (capsid) protein is a powerful tool for tissue-based diagnosis of hepatitis E, particularly useful in evaluating abnormal liver values in immunocompromised patients. The authors analyzed 23 specimens (including liver, gastrointestinal, lung, brain, and placental biopsies) with confirmed CMV infection/reactivation. Immunoreactivity of CMV-infected cells with HEV ORF2 antibody was observed in 18 of 23 specimens. While the HEV ORF2 antibody showed cytoplasmic, nuclear, and canalicular positivity in hepatitis E cases, positivity in CMV-infected cells was limited to the nucleus. Awareness of this cross-reactivity and knowledge of the differences in staining patterns will prevent pathologists from misinterpreting positive HEV ORF2 immunohistochemistry in liver specimens.
Alternative lengthening of telomeres in primary hepatic neoplasms
Yasir S, Thompson S, Chen ZE, et al. 2023 Jan;131:79-86.
Prior studies have revealed an alternative lengthening of telomeres (ALT) phenotype characterized by ultra-bright telomeres on fluorescence in situ hybridization (FISH), that is unique to the telomere maintenance in tumors and is not observed in normal tissues. ALT has been described in hepatocellular carcinoma (5-10%) and primary hepatic angiosarcomas (75%). To explore the frequency of ALT in other primary hepatic tumors, the study authors evaluated a wide range of primary hepatic neoplasms including intrahepatic and hilar cholangiocarcinomas (N = 110), hepatic adenomas (N = 35), hepatocellular carcinomas (N = 30), fibrolamellar carcinomas (n = 11), combined cholangiocarcinoma-hepatocellular carcinomas (N = 8), carcinosarcomas (N = 10), hepatoblastomas (N = 5), hemangiomas (N = 4), angiosarcomas (N = 8), epithelioid hemangioendotheliomas (N = 10), calcified nested stromal epithelial tumors (N = 2), embryonal sarcomas (N = 2), rhabdoid tumor (N = 1), bile duct adenoma (N = 1), and angiomyolipoma (N = 1). For epithelial tumors, ALT-FISH was positive in one carcinosarcoma (10% of cases), one cholangiocarcinoma (1% of cases), and one combined hepatocellular carcinoma-cholangiocarcinoma (13% of cases). Overall, ALT-FISH is positive in rare carcinosarcomas, cholangiocarcinomas, combined cholangiocarcinoma-hepatocellular carcinoma, and a subset of primary hepatic angiosarcomas. ALT is not a significant mechanism of telomere maintenance in hepatocellular adenomas or fibrolamellar carcinomas.
Primary neuroendocrine tumors and primary neuroendocrine carcinomas of the liver: a proposal for a multidiscipline definition
Torbenson M, Venkatesh SK, Halfdanarson TR, et al. 2023 Feb;132:77-88.
Primary hepatic neuroendocrine tumors and primary hepatic neuroendocrine carcinomas are rare, and determining whether the tumor is primary to the liver versus metastatic disease is challenging. The lack of a uniform definition of primary hepatic neuroendocrine neoplasms further limits our understanding of tumor biology and treatment modalities. The authors of this article present a multi-disciplinary definition and proposed guidelines for diagnosing a neuroendocrine tumor/neuroendocrine carcinomas as being primary to the liver.
Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities
Zen Y. 2023 Feb;132:197-207.
This comprehensive review of intrahepatic cholangiocarcinoma (iCCA) discusses the clinical and molecular features of small and large duct types, the immunohistochemical stains useful in classification, diagnostic pitfalls, and what future studies would be most valuable. The author notes that despite significant advances in hepatobiliary pathology, there are still controversial premalignant entities that require large comprehensive studies.
The many faces and pathologic diagnostic challenges of autoimmune hepatitis
Zhang X, Jain D. 2023 Feb;132:114-125.
The diagnosis of autoimmune hepatitis (AIH) can be challenging given the multiple clinical and pathologic criteria that must be carefully assessed and synthesized. This review article summarizes the histopathologic features of AIH and the utility of each, as well as the histologic variations of AIH, and common clinical scenarios. The review also discusses the consensus criteria for the diagnosis of AIH by the International AIH Pathology Group.
Journal of Hepatology
Survival benefit of adequate lymphadenectomy in patients undergoing liver resection for clinically node-negative intrahepatic cholangiocarcinoma
Sposito C, Ratti F, Cucchetti A, et al. J Hepatol. 2023 Feb;78(2):356-363.
Lymph node status is an important prognostic factor in intrahepatic cholangiocarcinoma (iCCA), but the utility and benefit of lymphadenectomy in patients with clinically node-negative (cN0) iCCA is unclear. To evaluate whether adequate lymphadenectomy improves long-term outcomes in patients undergoing liver resection of cN0 iCCA, the authors retrospectively studied 706 consecutive patients from 5 tertiary referral centers. An “adequate” lymphadenectomy was defined as retrieval of 6 or more lymph nodes, as defined by the AJCC 8th edition, and 59% of the patients received adequate lymphadenectomy. The overall (OS) and recurrence-free survival (RFS) of patients receiving adequate (AD-LAD) and non-adequate lymphadenectomy (NAD-LAD) was compared using inverse probability of treatment weighting (IPTW). Median follow-up was 33 months. There was no difference in OS and RFS between the AD- and NAD-LAD groups. However, in patients found to have nodal metastasis by pathologic evaluation, those who had AD-LAD had better OS and RFS. Subgroup analysis showed that AD-LAD showed improved OS and RFS in patients without chronic liver disease and those with less advanced tumors (solitary, smaller than 5 cm, CA19.90 <200 U/mL). The authors conclude that these results support the routine practice of adequate lymphadenectomy in patients with cN0 iCCA.
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer
Okawa Y, Iwasaki Y, John TA, et al. J Hepatol. 2023 Feb;78(2):333-342.
Although associations between biliary tract cancers (BTCs) and germline variants in BRCA genes have been reported, homologous recombination deficiency (HRD) has not been investigated in BTCs. To evaluate the heritability and actionability of variants in HR-related genes in BTCs (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampulla of Vater carcinoma), the authors performed targeted sequencing of 27 cancer-predisposing genes in 1292 Japanese patients with BTC and 37583 controls (without a personal or family history of cancer) to identify any germline variants. 317 total pathogenic variants were identified in 5.5% of BTC cases (5.5%) and 1.4% of controls. Variants enriched in BTCs were identified in BRCA1, BRCA2, APC, MSH6, and PALB2; APC variants were predominantly found in ampulla of Vater carcinomas. Carriers of pathogenic variants were younger and had an increased history of breast cancer (personal and family). Whole genome sequencing of 45 BTCs showed that 3 cases with pathogenic germline variants in BRCA2 and PALB2, with loss of heterozygosity, demonstrated HRD and a more frequent family history of cancer. However, pathogenic germline variants without a second hit or variants of other HR-related genes (e.g., ATM, BRIP1) demonstrated HR-proficient phenotypes. While this study was limited to Japanese individuals and only a small number of cases could be evaluated for HRD status, given the potential therapeutic implications (e.g., treatment response to platinum drugs or PARPi), evaluation of HR-related genes may nevertheless be helpful in BTCs.
Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury
Chalasani N, Li Y-J, Dellinger A, et al. J Hepatol. 2023 Feb;78(2):293-300.
Nitrofurantoin (NTF) is an antibiotic that is widely used short-term (treatment) and long-term (prevention) in urinary tract infections and is a well-known cause of drug-induced liver injury (DILI). In this study, the authors report the clinical characteristics, phenotypes of liver injury, histologic features, outcomes, and HLA risk factors in a cohort of individuals with well-characterized NTF-associated liver injury (NTF-DILI) enrolled in observational studies of the US Drug Induced Liver Injury Network (DILIN). 78 individuals with definite, highly likely, or probable NTF-DILI were enrolled (September 2004-January 2021). All but one were women, primarily Caucasian, with a mean age of 63 years (range 39-88). 18 individuals had short-term exposure (7 days or less), 16 had intermediate-duration exposure (8-364 days), and 44 had long-term exposure (1 year and longer). Liver injury was hepatocellular in 69%, mixed in 22%, and cholestatic in 9%; 55% of patients were jaundiced at diagnosis. AST>ALT (55%), ANA (58%) or SMA (45%) positivity, and corticosteroid use (50%) were more common in those with long-term exposure than in those with intermediate or longer-term exposure. Patients with short-term exposure were younger and less likely to have jaundice. Four patients with advanced liver injury due to short-term exposure had a history of intermittent NTF use. Patients with long-term exposure often showed autoimmune hepatitis (AIH)-like features and evidence of advanced fibrosis or cirrhosis histologically or clinically/by imaging (38%); submassive necrosis was seen histologically in 20%. No one in the short-term exposure group died or underwent transplantation, but 7 (12%) patients from intermediate (2) and long-term (5) exposure groups died or underwent transplantation.
Centrally reviewed biopsies (25) showed patterns of injury including acute (panacinar) hepatitis (10); chronic (portal-based) hepatitis (9) with one case showing non-necrotizing granulomas and acute hepatitis; bridging/multiacinar necrosis (13); increased plasma cells suggestive of AIH (11); fibrosis (15), with bridging fibrosis in 5 cases and cirrhosis in 3 cases.
Finally, HLA alleles were compared between NTF-DILI (73) and controls (population, non-NTF DILI, idiopathic AIH), all female individuals. HLA-DRB1*11:04 was the most significant allele with increased risk of developing NTF-DILI.
Although periodic monitoring for changes in biochemical tests for liver injury is recommended, this recommendation is seldom followed and none of the patients with NTF-DILI in this study were detected by prospective monitoring. Given the results of this study, with significant risk of serious liver injury, the authors suggest regulators consider a strong caution/black-box warning in the label along with risk evaluation and mitigation strategies.
Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.
Verna EC, Phipps MM, Halazun KJ, et al. Liver Transplantation. 2023 Jan 1;29(1):34-47.
NAFLD will soon be the most common indication for liver transplantation (LT). Adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001), and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha-fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49).
Hepatic Sarcomatoid Carcinoma Is an Aggressive Hepatic Neoplasm Sharing Common Molecular Features With Its Conventional Carcinomatous Counterparts
Yoshuantari N, Jeng YM, Liau JY, et al. Mod Pathol. 2023 Jan;36(1):100042.
The authors analyzed 59 hepatic sarcomatoid carcinomas using targeted next-generation sequencing (a 14-gene panel comprised of commonly mutated targets in primary liver cancers) and immunohistochemistry. Aberrant p53 and TERT promoter mutations were seen in 74% and 72% of cases, respectively. PD-L1 was expressed in tumor-associated immune cells in 67% of cases, and 33% of cases showed PD-L1 expression in tumor cells. Notably, PD-L1 expression in immune cells was significantly associated with a more favorable prognosis. The authors suggest that hepatic sarcomatoid carcinoma displays molecular similarity with conventional primary liver carcinomas and that PD-L1 may represent a potential biomarker for immunotherapeutic treatment.
Lindsey Westbrook, MD (Editor); University of Colorado
Dana Balitzer, MD; University of California San Francisco
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Meredith Pittman, MD; Maimonides Medical Center
Daniel Roberts, MD; Cleveland Clinic
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Xuefeng Zhang, MD; Cleveland Clinic