Zhao, Wei

ImportanceThe fecal immunochemical test (FIT) is widely used for colorectal cancer (CRC) screening, but evidence of its effectiveness is limited.ObjectiveTo evaluate whether FIT screening is associated with a lower risk of dying from CRC overall, according to cancer location, and within demographic groups.Design, Setting, and ParticipantsThis nested case-control study in a cohort of screening-eligible people was conducted in 2 large, integrated health systems of racially, ethnically, and socioeconomically diverse members with long-term programs of mailed FIT screening outreach. Eligible participants included people aged 52 to 85 years who died from colorectal adenocarcinoma between 2011 and 2017 (cases); cases were matched in a 1:8 ratio based on age, sex, health-plan membership duration, and geographic area to randomly selected persons who were alive and CRC-free on case’s diagnosis date (controls). Data analysis was conducted from January 2002 to December 2017.ExposuresCompleting 1 or more FIT screenings in the 5-year period prior to the CRC diagnosis date among cases or the corresponding date among controls; in secondary analyses, 2- to 10-year intervals were evaluated.Main Outcomes and MeasuresThe primary study outcome was CRC death overall and by tumor location. Secondary analyses were performed to assess CRC death by race and ethnicity.ResultsFrom a cohort of 2 127 128 people, a total of 10 711 participants (3529 aged 60-69 years [32.9%]; 5587 male [52.1%] and 5124 female [47.8%]; 1254 non-Hispanic Asian [11.7%]; 973 non-Hispanic Black [9.1%]; 1929 Hispanic or Latino [18.0%]; 6345 non-Hispanic White [59.2%]) was identified, including 1103 cases and 9608 controls. Among controls during the 10-year period prior to the reference date, 6101 (63.5%) completed 1 or more FITs with a cumulative 12.6% positivity rate (768 controls), of whom 610 (79.4%) had a colonoscopy within 1 year. During the 5-year period, 494 cases (44.8%) and 5345 controls (55.6%) completed 1 or more FITs. In regression analysis, completing 1 or more FIT screening was associated with a 33% lower risk of death from CRC (adjusted odds ratio [aOR], 0.67; 95% CI, 0.59-0.76) and 42% lower risk in the left colon and rectum (aOR, 0.58; 95% CI, 0.48-0.71). There was no association with right colon cancers (aOR, 0.83; 95% CI, 0.69-1.01) but the difference in the estimates between the right colon and left colon or rectum was statistically significant (P = .01). FIT screening was associated with lower CRC mortality risk among non-Hispanic Asian (aOR, 0.37; 95% CI, 0.23-0.59), non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.85) and non-Hispanic White individuals (aOR, 0.70; 95% CI, 0.57-0.86) (P for homogeneity = .04 for homogeneity).Conclusions and RelevanceIn this nested case-control study, completing FIT was associated with a lower risk of overall death from CRC, particularly in the left colon, and the associations were observed across racial and ethnic groups. These findings support the use of FIT in population-based screening strategies.

AbstractExtranodal marginal zone lymphoma (EMZL) is a heterogeneous disease with a subset of patients exhibiting a more aggressive course. We previously reported that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival. To better recognize patients with different patterns of progression‐free survival (PFS) we developed and validated a new prognostic index primarily based on patient's disease characteristics. We derived the “Revised mucosa‐associated lymphoid tissue International Prognostic Index” (Revised MALT‐IPI) in a large data set (n = 397) by identifying candidate variables that showed highest prognostic association with PFS. The revised MALT‐IPI was validated in two independent cohorts, from the University of Iowa/Mayo Clinic (n = 297) and from IELSG‐19 study (n = 400). A stepwise Cox regression analysis yielded a model including four independent predictors of shorter PFS. Revised MALT‐IPI has scores ranging from 0 to 5, calculated as a sum of one point for each of the following‐ age >60 years, elevated LDH, and stage III–IV; and two points for MMS. In the training cohort, the Revised MALT‐IPI defined four risk groups: low risk (score 0, reference group), low‐medium risk (score 1, HR = 1.85, p = .008), medium‐high risk (score 2, HR = 3.84, p < .0001), and high risk (score 3+, HR = 8.48, p < .0001). Performance of the Revised MALT‐IPI was similar in external validation cohorts. Revised MALT‐IPI is a new index centered on disease characteristics that provides robust risk‐stratification identifying a group of patients characterized by earlier progression of disease. Revised MALT‐IPI can allow a more disease‐adjusted management of patients with EMZL in clinical trials and practice.

Objective To examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer. Methods We used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date. Results Of the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only ( n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test ( n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test. Conclusions Our results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

INTRODUCTION: EMZL is a heterogeneous disease with variable risk for relapse and progression. Based on age ≥70 years, stage III-IV and elevated LDH, Thieblemont et al (Blood. 2017) developed the MALT-IPI to identify high-risk patients. In this index, disease characteristics (stage and LDH) account for 66% while a disease nonspecific characteristic (age) for 33% of the index score. We reported (Am J Hematol. 2019) that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival and increased incidence of higher grade transformation. To better recognize disease-attributable high-risk patients, we developed a new EMZL prognosis score chiefly based on patient's disease characteristics. METHODS: The revised (R)-MALT-IPI was developed using a retrospective data set of 405 EMZL patients treated at the University of Miami (UM) from 1995 to 2017. Cox proportional hazards regression analysis was conducted to evaluate the effect of the potential prognostic variables on progression-free survival (PFS) and overall survival (OS) and to develop the new index R-MALTI-IPI based on PFS. Model validation was performed in two independent cohorts of EMZL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) database (n=297) and the IELSG-19 study (n=400) used for the development of MALT-IPI. Performance of various prognostic indices was compared using AIC statistics, and concordance c-statistics by Harrell (CH) and by Gonen and Heller (CGH). RESULTS: Among the candidate variables tested in univariable analysis, the following were statistically significant predictors of shorter PFS: age >60, age ≥70, anemia (Hb<12g/dL), stage III-IV, ECOG PS ≥2, elevated serum LDH, number of extranodal sites >1, number of nodal sites >4, and presence of MMS at diagnosis, defined as EMZL with ≥2 different extranodal sites excluding spleen and bone marrow. A stepwise Cox regression analysis yielded a multivariable model with four independent predictors of shorter PFS: age >60 (HR=1.53, p=0.010), elevated LDH (HR=1.73, p=0.004), stage III-IV (HR=2.03, p=0.0003) and presence of MMS (HR=2.78, p<0.0001). Based on this, a new index R-MALT-IPI was developed with scores ranging from 0 to 5, calculated as a sum of 1 point for age >60, elevated LDH, stage III-IV, and 2 points for MMS. The R-MALT-IPI defined 4 risk groups: low-risk (score 0 (35%), reference group), low-medium risk (score 1 (39%), HR=1.91, p=0.005), medium-high risk (score 2 (13%), HR=3.77, p<0.0001), and high-risk (score 3+ (13%), HR=8.54, p<0.0001). When compared with MALT-IPI, R-MALT-IPI better stratifies and separates high risk patients (26%) into medium-high risk and high-risk patients with a median PFS of 5.8 years (2.9-9.1) and 1.8 years (1.3-2.6) respectively, compared to 2.6 years (1.8-4.7) in the high-risk MALT-IPI patients (16.8%). The R-MALT-IPI index also distinguished patients with different OS. For validation, we analyzed R-MALT-IPI index performance in independent Iowa/Mayo Clinic MER and IELSG-19 cohorts. Both R-MALT-IPI and MALT-IPI were useful in distinguishing PFS and OS in all the cohorts. In the UM training cohort, the concordance c-statistics' values for the two indices were similar: for PFS, CH=0.6893 and CGH=0.6611 for R-MALT-IPI, and CH=0.6551 and CGH=0.6367 for MALT-IPI; for OS, CH=0.7017 and CGH=0.6813 for R-MALT-IPI, and CH=0.7029 and CGH=0.67715 for MALT-IPI. In the validation cohorts, the concordance c-statistics' values for the two indices were also similar, but slightly lower than in the UM cohort for PFS. When comparing medium-high to high-risk R-MALT-IPI groups, there was a reduction of 4 years in median PFS in the UM cohort, and reduction in median EFS of 5.6 years in the MER cohort, an important difference between these risk groups identified by the R-MALT-IPI index. CONCLUSIONS: R-MALT-IPI is a new index for EMZL centered principally on disease characteristics. Overall, there is a similar prediction of PFS (EFS) by R-MALT-IPI and MALT-IPI indexes; however, R-MALT-IPI better recognizes a high-risk group accounting for 13% of EMZL patients with short median PFS and thus obviates the waiting period needed to recognize patients with shorter EFS24. Collaborative studies addressing best treatment approach for these high-risk EMZL patients are eagerly needed. Disclosures Alderuccio: Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; OncLive: Consultancy; Targeted Oncology: Honoraria; Puma Biotechnology: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member. Thieblemont:Cellectis: Membership on an entity's Board of Directors or advisory committees; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Zucca:Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.