Showing papers by "Daniel C. Chung published in 2019"

Genetic/Familial high-risk assessment: Colorectal, version 2.2019 featured updates to the NCCN guidelines

Abstract: Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

Abstract: Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'1-3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and β-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.

Cancer risk in microscopic colitis: a retrospective cohort study.

Abstract: The long-term natural history of microscopic colitis (MC) (collagenous colitis (CC), lymphocytic colitis (LC)), traditionally considered relapsing but non-progressive diseases, is poorly defined. Whether persistent histologic inflammation in such diseases is associated with an increased risk of colorectal neoplasia (CRN) or extracolonic cancers has not been robustly established. This retrospective cohort included diagnosed with MC at a referral center. Rates of CRN and extracolonic cancer were compared to patients undergoing screening colonoscopy (n = 306) and to the United States population using data from the Surveillance, Epidemiology, and End-Results (SEER) program. Standardized incidence ratios (SIR) and 95% confidence intervals were calculated and multivariable regression models used to identify the effect of MC diagnosis and severity on cancer risk. Our study included 221 patients with microscopic colitis (112 CC, 109 LC) among whom 77% were women. Compared to the colonoscopy control population, MC was associated with similar odds of tubular adenoma (Odds ratio (OR) 1.07, 95% CI 0.69–1.66) or villous adenoma (OR 1.26, 95% CI 0.17–9.42). Compared to patients with a single episode of MC, those with 2 or more episodes had similar risk of colon cancer (OR 0.83, 95% CI 0.20–3.39) or tubular adenoma (OR 1.49 95% CI 0.83–2.67). We also identified no statistical increase in the rates of cancer in the MC population compared to US-SEER data. Microscopic colitis was not associated with increased risk of CRN and extracolonic cancers when compared to controls undergoing colonoscopy or the US SEER population.

Cost‐effectiveness of immune checkpoint inhibitors for microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer

Abstract: Background Patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) show a significant response to checkpoint inhibitor therapies, but the economic impact of these therapies is unknown. A decision analytic model was used to explore the effectiveness and cost burden of MSI-H/dMMR mCRC treatment. Methods The treatment of hypothetical patients with MSI-H/dMMR mCRC was simulated in 2 treatment scenarios: a third-line treatment and an exploratory first-line treatment. The treatments compared were nivolumab, ipilimumab and nivolumab, trifluridine and tipiracil (third-line treatment), and mFOLFOX6 and cetuximab (first-line treatment). Disease progression, drug toxicity, and survival rates were based on the CheckMate 142, study of TAS-102 in patients with metastatic colorectal cancer refractory to standard chemotherapies (RECOURSE), and Cancer and Leukemia Group B/Southwest Oncology Group 80405 trials. The analyzed outcomes included survival (life-years), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results Ipilimumab with nivolumab was the most effective strategy (10.69 life-years and 9.25 QALYs for the third line; 10.69 life-years and 9.44 QALYs for the first line) in comparison with nivolumab (8.21 life-years and 6.76 QALYs for the third line; 8.21 life-years and 7.00 QALYs for the first line), trifluridine and tipiracil (0.74 life-years and 0.07 QALYs), and mFOLFOX6 and cetuximab (2.72 life-years and 1.63 QALYs). However, neither checkpoint inhibitor therapy was cost-effective in comparison with trifluridine and tipiracil (nivolumab ICER, $153,000; ipilimumab and nivolumab ICER, $162,700) or mFOLFOX6 and cetuximab (nivolumab ICER, $150,700; ipilimumab and nivolumab ICER, $158,700). Conclusions This modeling analysis found that both single and dual checkpoint blockade could be significantly more effective for MSI-H/dMMR mCRC than chemotherapy, but they were not cost-effective, largely because of drug costs. Decreases in drug pricing and/or the duration of maintenance nivolumab could make ipilimumab and nivolumab cost-effective. Prospective clinical trials should be performed to explore the optimal duration of maintenance nivolumab.

Screening high‐risk populations for esophageal and gastric cancer

Abstract: Cancers of the esophagus and stomach remain important causes of mortality worldwide, in large part because they are most often diagnosed at advanced stages. Thus, it is imperative that we identify and treat these cancers in earlier stages. Due to significant heterogeneity in incidence and risk factors for these cancers, it has been challenging to develop standardized screening recommendations. This review summarizes the current recommendations for screening populations at high risk of developing esophagogastric cancers.

Gastric cancer in Lynch syndrome is associated with underlying immune gastritis

Abstract: Lynch syndrome is the most common cause of hereditary colon cancer but is also associated with gastric cancer.1 Interestingly, gastric cancer was a distinguishing feature of the original Lynch pedigree described in 1913.2 Currently, the standardised incidence ratio (SIR) for gastric cancer in Lynch syndrome is estimated to be 3.4.3 Among 255 gene-positive patients with Lynch followed prospectively in our Hereditary Gastrointestinal Cancer programme, 7 (2.7%, 95% CI 1.3% to 5.7%) were diagnosed with gastric cancer at a median age of 55 years. Six carried an MSH2 mutation, five were women and five exhibited underlying chronic immune-mediated gastritis. Patients with Lynch syndrome, defined by a germline mutation in a DNA mismatch repair gene, were first identified in a REDCap-based Hereditary GI Cancer registry of individuals followed longitudinally at an academic centre, and clinical and endoscopic features were reviewed in those with a new diagnosis of gastric cancer. SIRs were calculated using age and an age-adjusted and gender-adjusted rate from the Surveillance Epidemiology and End Result (SEER) database.4 Among the 255 individuals (102 men and 153 women) identified with Lynch syndrome, the following was the distribution of germline mutations: MSH2 (n=93, 36.5%) , MSH6 (n=63, 24.7%) , MLH1 (n=58, 22.8%) , PMS2 (n=33, 12.9%) and EPCAM (n=8, 3.1%). Overall, there were more than 13 000 person-years of observation, with an average age …

Publisher Correction: Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors.

Abstract: In the version of this article initially published, a numbering error mistakenly associated author Paloma Cejas with affiliation 15, Hebrew University; the affiliation footnote has been removed. Affiliations 10 (published as Massachusetts General Hospital and Harvard Medical School) and 11 (published as UMC Utrecht Cancer Center) were incorrectly transposed, affecting authors Menno R. Vriens, and Carlos Fernandez-del Castillo and Christina R. Ferrone, respectively. In Figure 2a, the image was misoriented by 90°, resulting in incorrect orientation of the dendrogram. The errors have been corrected in the HTML and PDF versions of the article.