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innate immunity are less well-recognized in ulcerative co-litis (Curr Opin Gastroenterol 2011;27:328–334).

A vaccination against HZ, Zostavax, was introduced inMayof 2006, which has been shown to decrease the incidence ofHZ by 51.3% and postherpetic neuralgia by 66.5% in adults>60 years old (N Engl J Med 2005;352:2271–2284). In 2011,the US Food and Drug Administration approved its use inadults�50 years old. However, it remains to be seenwhethervaccination would provide full immunity and prevent infec-tion in patients with IBD compared with the general popu-lation. Fiorino et al previously demonstrated an impairedresponse to the pneumococcal vaccination in IBD patients onanti-TNF therapy, but not among those on thiopurines, whencompared with patients on mesalamine (Inflamm Bowel Dis2012;18:1042–1047). Furthermore, because Zostavax is alive vaccine, there is also appropriate concern over the safetyof administration to immunosuppressed individuals. In arecent study, Zhang et al found that patients being treatedwith anti-TNF medications did not have an increased risk ofprimary varicella or HZ within 42 days of HZ vaccination.Moreover, they demonstrated a decreased risk of HZ amongthese patients at 2 years, compared with unvaccinatedpatients (JAMA 2012;308:43–49).

In this study by Long et al, patients being treated with 5-aminosalicylate compounds did not have an increased riskof HZ. Given these data, the safest time to vaccinate patientswith IBD is likely early in a patient’s disease course,including those who present with presumably mild acuteflares while being treated with 5-ASA compounds. Earlyvaccination may also offer greater antibody titer levelscompared with vaccination while on increased immuno-suppressants. The European Crohn’s and Colitis Organiza-tion guidelines recommended immunization with the VZVvaccine �3 weeks before starting immunomodulator ther-apy and even suggest considering immunization at the timeof diagnosis (J Crohns Colitis 2009;3:47–91).

One of themany strengths of this article includes the largesample size used to determine the risks of acquiring HZ.Another strength was the use of previously validated Inter-national Classification of Diseases, 9th edition (ICD-9)for the definition of HZ infection (Mayo Clin Proc2011;86:1146–1153). Although the authors did not usevalidated ICD-9 codes for IBD for this specific dataset, theyused a previously published definition for IBD exposure,based on multiple health contacts and IBD prescriptions. Theauthors required�3 visits with an applicable ICD-9 code or 1visit with an ICD-9 code and 1 pharmacy visit for an ICD-9code. Although ICD-9 codes have some limitations, they arecommonly used in administrative datasets after validatingtheir sensitivity and specificity. An additional limitation,which the authors acknowledged, was the study populationonly included patients <64 years, particularly given that therisk of HZ infection increases with age. Furthermore, thestudy did not assess the impact of factors such as race,administration of HZ vaccination, and the dosing or intervalof immunosuppressants on risk of HZ infection.

Overall, this study by Long et al confirms an increased riskof HZ among IBD patients, and quantifies this risk based onspecific medication classes. Patients on both thiopurines and

anti-TNF agents seem to be at a particularly high risk for HZand may be ideal candidates for vaccination. Whether vacci-nation in these patients with IBD is safe and effective, as wellas optimal timing of vaccination, continues to be an area ofdiscussion. However, recent guidelines from the InfectiousDiseases Society of America state that the HZ vaccine can besafely administered in patients 60 years old and above withlow-level immunosuppressive therapy (prednisone <20 mgper day for less than 14 days; methotrexate less than or equalto 0.4 mg/kg/week; azathioprine less than or equal to 3 mg/kg/day; or 6-mercaptopurine less than or equal to 1.5 mg/kg/day). It is currently debated if this recommendationshould be extended to those 50–59 years old who are un-dergoing low-level immunosuppression. All patients who areanticipated to undergo high-level immunosuppression(prednisone greater than or equal to 20 mg per day for 14 ormore days or a tumor necrosis factor-a blocker) shouldreceive the HZ vaccine at least 4 weeks prior to therapy tominimize the theoretical risk of reactivation (Clin Infect Dis2013, doi: 10.1093/cid/cit684). In our practice, we typicallydo not administer the HZ vaccine in patients who havealready started anti-TNF therapy. We believe this study byLong et al highlights the risk of HZ in the IBD population andshould bring a sense of urgency to the debate.

ANAND PATELJOSHUA B. MAXDepartment of Internal MedicineUniversity of Michigan Medical CenterAnn Arbor, Michigan

AMIT G. SINGALDepartment of Internal MedicineUT SouthwesternDallas, Texas

AKBAR K. WALJEEDivision of Gastroenterology and HepatologyDepartment of Internal MedicineUniversity of Michigan Medical Center andInflammatory Bowel Disease ProgramAnn Arbor VA Healthcare SystemAnn Arbor, Michigan

DEDICATED OUTREACH ISEFFECTIVE IN INCREASINGUPTAKE OF COLORECTAL CANCERSCREENING IN AN UNDERSERVEDPOPULATION

Gupta S, Halm EA, Rockey DC, et al. Comparative effec-tiveness of fecal immunochemical test outreach, colonoscopyoutreach, and usual care for boosting colorectal cancerscreening among the underserved: a randomized clinical trial.JAMA Intern Med 2013;173:1725–1732.

In this single-center, randomized, controlled trial, Guptaet al examined the effectiveness of mailed outreach in

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improving colorectal cancer (CRC) screening uptake in anunderserved population. Prior studies have demonstratedthat CRC screening is often underused, particularly inuninsured and minority patients (Cancer Epidemiol Bio-markers Prev 2011;20:1611–1621). Mailed outreach withfecal occult blood testing and invitations to attend colo-noscopy have shown some success (J Natl Cancer Inst2004;96:770–780; Arch Intern Med 2011;171:906–912).However, we know little about the comparative effective-ness of mailed outreach for stool-based testing versuscolonoscopy. Furthermore, 1-sample fecal immunochemicaltesting (FIT), which is more convenient than 3-sampleguaiac-based testing, has not been studied in this context.

The study population consisted of uninsured individualsenrolled in a medical assistance program provided by asingle health system in Texas. Individuals were eligible ifthey were between ages 54 and 64 and were due for CRCscreening according to current guidelines. Individuals whowere at increased risk for CRC or did not speak English orSpanish were excluded. Additionally, individuals wereexcluded if they had not had �1 health system visit in theprior 8-month period. Eligible patients were randomized to1 of 3 arms: (1) FIT outreach (intervention), (2) colonos-copy outreach (intervention), or (3) usual care (control). FIToutreach consisted of a mailed 1-sample FIT kit with testinstructions and a return envelope. Colonoscopy outreachconsisted of an invitation letter and phone number forscheduling a screening colonoscopy. Usual care consisted oftypical office-based screening (no mailed intervention orclinical reminders). Both intervention arms also received 2automated telephone calls, and nonresponders also receivedup to 2 “live” telephone calls. The primary outcome wascompletion of a CRC screening test within 1 year ofrandomization (“screening participation”), measured usingadministrative data. Patients were analyzed according to thegroup to which they were randomized (intention-to-treat).Informed consent was not required for study participation.

The authors randomized 5994 patients; 24 patients laterwere found to not meet age inclusion criteria, yielding asample size of 5970 patients. The mean age was 59 years,64% were women, and 41% were white. Spanish was theprimary language for 17% of study participants. The rate ofscreening participation was 41% for FIT outreach, 25% forcolonoscopy outreach, and 12% for usual care, and thesedifferences were significant. Furthermore, these differenceswere maintained within gender and race/ethnicity groups.Additionally, screening participation was slightly higher inblacks and Hispanics compared with whites for both thecontrol arm and the intervention arms (although these dif-ferences were not statistically significant). To screen 1additional person compared with usual care, 8 patientswould have to be invited for colonoscopy and 3.5 patientswould have to be invited for FIT (number needed to treat).Notably, FIT outreach was significantly more effective thancolonoscopy outreach. However, 11 of 60 individuals withpositive FIT did not complete colonoscopy.

Comment. CRC screening is an evidence-based, widelyrecommended preventive service that has traditionally been

underused (Ann Intern Med 2008;149:627–637). Althoughsome large, integrated healthcare systems have achievedhigh rates of CRC screening, uptake remains low on averagein the United States, particularly in underserved pop-ulations, who may have limited access to care. The reasonsfor low uptake in underserved populations are complex, butour health system’s haphazard, opportunistic approach toscreening is a key barrier. Opportunistic screening refers toscreening that is ordered by a healthcare provider in thecourse of an office visit. This approach should be contrastedwith systematic screening, which systematically invitespatients to attend a screening test without necessarilyinvolving a provider. In this elegant study, Gupta et aldemonstrate that a systematic, outreach-based screeningintervention is highly effective in an underserved population.Although prior studies have examined direct patientoutreach, the comparison of FIT with colonoscopy is novel, asis the examination of FIT rather than guaiac-based testing.In addition to increasing screening uptake, the authors alsodemonstrated that outreach led to higher yield of colorectalneoplasia (although the numbers were small). Increasingscreening participation from 12% to 40%would therefore beexpected to have a profound effect on morbidity and mor-tality attributable to CRC. It is important to note that studyauthors obtained a waiver of informed consent for studyparticipants from the institutional review board, makingthis a true “real-world” comparative effectiveness studyrather than an efficacy study in a highly selected population.

Although the study was well-designed, several limita-tions should also be highlighted. First, it is important to notethat the outreach groups received not only mailed FIT orcolonoscopy invitations but also multiple phone calls and,for the colonoscopy group, specific assistance with colo-noscopy scheduling and instructions for bowel preparation.The comprehensiveness of the intervention likely enhancedits effectiveness but also creates challenges in sustainabilityand scalability. Second, the authors separately examinedoutreach for FIT and outreach for colonoscopy but did notexamine combined outreach for FIT or colonoscopy. Priorwork has demonstrated that offering patients a “menu” ofoptions can increase screening uptake in underservedpopulations (Arch Intern Med 2012;172:575–582). Finally,the Affordable Care Act will likely improve the affordabilityof care for uninsured patients across the United States andwill have special provisions for United States PreventiveServices Task Force-endorsed preventive services (such asCRC screening). Although access to care is more complexthan affordability alone, it is likely that improving theaffordability of care will increase screening uptake andpotentially attenuate the benefit of (and need for) outreachin underserved populations.

So, how should we utilize these data in our practice toimprove CRC screening uptake in underserved populations?The results of this and other studies provide compellingevidence for the effectiveness of fecal occult blood testingand FIT outreach. Taken with data suggesting that providing>1 screening option can increase uptake, the ideal approachmay be to perform outreach that offers both FIT and colo-noscopy. Naturally, such a combined approach warrants

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further study, but until such work can be performed, it maybe reasonable to employ a combined outreach approach inclinical settings that care for underserved populations.

SAMEER D. SAINIVA Center for Clinical Management ResearchVA Ann Arbor Healthcare System andDivision of Gastroenterology and HepatologyUniversity of Michigan Medical SchoolAnn Arbor, Michigan

CHARACTERISTICS OFHEPATOCELLULAR CARCINOMAWITH STEM/PROGENITOR CELLPHENOTYPES

Yong KJ, Gao C, Lim JS, et al. Oncofetal gene SALL4 inaggressive hepatocellular carcinoma. N Engl J Med 2013;368:2266–2276.

Liver cancers are the third leading cause of cancer mor-tality worldwide. Among primary liver cancers, hepatocel-lular carcinoma (HCC) is the most common histologicsubtype, accounting for 70%–85% of the total liver cancerglobally. The molecular mechanisms underlying hep-atocarcinogenesis, however, remain unclear. Radiofrequencyablation, surgical resection, and liver transplantation couldbe curative for qualified patients with early HCC, but theprognosis is poor for patients with advanced HCC. Furtherstudies of the mechanisms underlying hepatocarcinogenesisand the development of more effective therapies are neededto improve the prognosis.

In their study published in The New England Journal ofMedicine, Yong et al investigated the role of the oncofetalgene SALL4 in HCC based on the following previous find-ings: (1) SALL4 is a key factor for maintaining pluripotencyand self-renewal in embryonic stem cells; (2) in mice, SALL4is expressed in fetal liver, but disappears by adulthood(Gastroenterology 2009;108:2726–2735); (3) SALL4 ex-pression is detectable in various human tumors; and (4) aprogenitor-like subtype of HCC is reported to be associatedwith poor prognosis. The authors thus hypothesized thatSALL4 could be a marker of an HCC subtype withprogenitor-like properties and thus a worse prognosis.

First, they examined SALL4 expression in human livertissues, and confirmed that SALL4 was expressed in fetalliver, but not in adult liver, and reexpressed in a subgroup ofHCC specimens. Immunohistochemical analysis confirmedSALL4 expression in 55.6% of HCC specimens analyzed butnot in matched non-neoplastic liver specimens. Patientswith high SALL4 expression levels in their HCC tissues had apoorer prognosis than patients with low SALL4 expressionlevels, independent of baseline liver function. A global geneexpression analysis revealed that high SALL4-expressingHCCs clustered tightly with fetal liver, and that lowSALL4-expressing HCCs clustered with normal hepatocytes.Based on these results, Yong et al concluded that HCCsubtypes expressing SALL4 have a progenitor-like gene

signature, resulting in poor differentiation, aggressiveness,and poor prognosis.

A genetic loss-of-function experiment using short hairpinRNA to examine the role of SALL4 in hepatocarcinogenesisindicated that SALL4 knockdown decreased cell viability,increased apoptosis, and decreased the tumorigenicity ofHCC cells in vitro. A previous report indicated that SALL4associates with an epigenetic modulator (nucleosomeremodeling and histone deacetylase; NuRD) as a transcrip-tional factor to its downstream target genes. Among thetarget genes, the tumor suppressor phosphatase and tensinhomologue (PTEN) is repressed by SALL4. The SALL4 loss-of-function microarray analysis by Yong et al revealed that thePTEN–AKT pathway is involved in SALL4-induced hep-atocarcinogenesis. In a previous study, the authors demon-strated that a SALL4, 12 amino-acid peptide competitivelyinhibits the interaction between SALL4 and NuRD, thusblocking the NuRD-mediated SALL4-repression function.In the present study, in vitro functional assays revealedthat treatment with the SALL4 peptide reduced the numberof viable cells with increased levels of PTEN in a SALL4-positive HCC cell line but had no effect in a cell line withundetectable endogenous SALL4 expression. The authorsthus concluded that the SALL4 peptide specifically inhibitsSALL4-overexpressing HCC cells but has minimal toxicityon SALL4-negative normal cells. In a mouse xenograftmodel, the tumor loads at 18 days were significantlysmaller in mice that received the SALL4 peptide than inthose that did not.

Yong et al thus concluded that SALL4 plays an importantrole in the extensive network of heterogeneous cellularpathways underlying hepatocarcinogenesis, and that theSALL4 peptide has therapeutic potential.

Comment. In this study, Yong et al focused on SALL4 as amarker of a progenitor subtype of human HCC and investi-gated the clinical features and biologic significance of SALL4expression profiles in HCC tissues. SALL4 is a member of theSALL gene family (SALL1– SALL4) initially identified as ahomologue of the Drosophila homeotic gene spalt. SALL4comprises 4 exons and encodes a transcription factor withseveral C2H2 zinc finger domains that bind DNA and some-times RNA and proteins (Hum Mol Genet 2002;11:2979–2987). SALL4 is located on chromosome 20q13.3 inhumans, and has 3 splicing variant forms: SALL4A, SALL4B,and SALL4C. SALL4 is highly expressed in embryonic stemcells and acts as a transcription repressor to maintain plu-ripotency through its interactions with OCT3/4, SOX2, andNANOG (J Med Genet 2004;41:e113; Nat Cell Biol2006;8:1114–1123; J Biol Chem 2006;281:24090–24094).Recent studies revealed that SALL4 regulates the expressionof Sox2, Oct 4, c-myc, and Klf4, which are involved in thereprogramming of somatic cells into inducible pluripotentcells (Genes Cells 2009;14:683–694; PLoS One 2008;3:e10766). SALL4-null mice die during peri-implantation, andheterozygous mutant mice exhibit anorectal anomalies andexencephaly (Development 2006;133:3005–3013; GenesCells 2009;14:683–694; Genesis 2007;45,51–58). In humans,