Citations

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

BACKGROUNDEarly treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high‐risk group of patients with an expected 5‐year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated.METHODSThis study compared autologous hematopoietic stem cell transplantation (auto‐HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo‐HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto‐HCT or allo‐HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression‐free survival, relapse, and nonrelapse mortality (NRM).RESULTSFour hundred forty FL patients had ETF (auto‐HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow‐up of 69 to 73 months, the adjusted probability of 5‐year OS was significantly higher after auto‐HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5‐year adjusted probability of NRM was significantly lower for auto‐HCT (5%) versus MSD (17%) or MUD HCT (33%; P < .0001). The 5‐year adjusted probability of disease relapse was lower with MSD (31%) or MUD HCT (23%) versus auto‐HCT (58%; P < .0001).CONCLUSIONSPatients with high‐risk FL, as defined by ETF, undergoing auto‐HCT for FL have low NRM and a promising 5‐year OS rate (70%). MSD HCT has lower relapse rates than auto‐HCT but similar OS. Cancer 2018;124:2541‐51. © 2018 American Cancer Society.

BACKGROUNDThe Centers for Medicare & Medicaid Services rewards hospitals that have low 30‐day risk‐standardized mortality rates (RSMR) for heart failure (HF).OBJECTIVETo describe the use of early comfort care for patients with HF, and whether hospitals that more commonly initiate comfort care have higher 30‐day mortality rates.DESIGNA retrospective, observational study.SETTINGAcute care hospitals in the United States.PATIENTSA total of 93,920 fee‐for‐service Medicare beneficiaries admitted with HF from January 2008 to December 2014 to 272 hospitals participating in the Get With The Guidelines‐Heart Failure registry.EXPOSUREEarly comfort care (defined as comfort care within 48 hours of hospitalization) rate.MEASUREMENTSA 30‐day RSMR.RESULTSHospitals' early comfort care rates were low for patients admitted for H F, with no change over time (2.5% to 2.6%, from 2008 to 2014, P = .56). Rates varied widely (0% to 40%), with 14.3% of hospitals not initiating comfort care for any patients during the first 2 days of hospitalization. Risk‐standardized early comfort care rates were not correlated with RSMR (median RSMR = 10.9%, 25th to 75th percentile = 10.1% to 12.0%; Spearman's rank correlation = 0.13; P = .66).CONCLUSIONSHospital use of early comfort care for HF varies, has not increased over time, and on average, is not correlated with 30‐day RSMR. This suggests that current efforts to lower mortality rates have not had unintended consequences for hospitals that institute early comfort care more commonly than their peers.

Objective Little is known about long‐term metabolic (energy expenditure) adaptation after bariatric surgery. Methods Resting metabolic rate under basal conditions (RMR), total daily energy expenditure (TDEE), and body composition were measured in 25 participants in the Longitudinal Assessment of Bariatric Surgery‐2. Results Six months after surgery, BMI (±SD) decreased (47 ± 6 kg/m 2 to 37 ± 5 kg/m 2 ), body fat went from 48% ± 6% to 40% ± 6% fat, and fat‐free mass went from 67 ± 9 kg to 60 ± 9 kg. In absolute terms, RMR and TDEE both decreased significantly (1,730 ± 278 kcal/d vs. 1,430 ± 200 kcal/d and 2,879 ± 544 kcal/d vs. 2,369 ± 304 kcal/d), and the achieved energy balance was −1,293 ± 355 kcal/d. Sixteen of these participants underwent repeated measures at ∼24 months; TDEE decreased 6 months postoperatively (2,957 ± 540 kcal/d to 2,423 ± 324 kcal/d; P = 0.0003), but at ∼24 months, TDEE (2,602 ± 471 kcal/d) was not significantly different compared with month 6. The average negative energy balance from baseline to month 24 was −379 ± 131 kcal/d. Conclusions RMR and TDEE fall precipitously in the first 6 months after bariatric surgery, but these adaptive changes were no longer significant after 2 years.

Abstract Patients who undergo surgical resection of brain metastases are at significant risk of cavity local recurrence without additional radiation therapy. Postoperative stereotactic radiosurgery (SRS) is a method of focal treatment to the cavity to maximize local control while minimizing the risk of neurocognitive detriment associated with whole brain radiation therapy. Recently published randomized trials have demonstrated the benefit of postoperative SRS in terms of cavity tumor control and preserving neurocognition. However, there are several potential drawbacks with postoperative SRS including a possible increase in symptomatic radiation necrosis because of the need for cavity margin expansion due to target delineation uncertainty, the variable postoperative clinical course and potential delay in administering postoperative SRS, and the theoretical risk of tumor spillage into cerebrospinal fluid at the time of surgery. Preoperative SRS is an alternative paradigm wherein SRS is delivered prior to surgical resection, which may effectively address some of these potential drawbacks. The goal of this review is to examine the rationale, technique, outcomes, evidence, and future directions for the use of SRS as an adjunct to surgical resection. This can be delivered as either preoperative or postoperative SRS with potential advantages and disadvantages to both approaches that will be discussed.

Key Points Biomarker scores generated after 1 week of steroid treatment of GVHD are prognostic. Biomarkers reflect prognosis better than early clinical response to GVHD treatment.

Abstract The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (P &lt; 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P &lt; 0.0001). Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805–12. ©2018 AACR.

Abstract Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in &gt;1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-10.

Background and Purpose: Management of carotid stenosis remains controversial despite several trials evaluating carotid endarterectomy (CEA) and carotid angioplasty/stenting (CAS). We compared attitudes in the management of carotid stenosis between selected experts within Europe and North America. Methods: A 3-phase Delphi survey was e-mailed to select stroke experts from Europe (n = 390) and North America (n = 289). Those completing the initial survey were shown all responses after each survey round. Consensus was defined as ≥80% agreement. Results: For phases 1, 2, and 3, response rates were 32%, 62%, and 73%, respectively. Overall, 100 (15%) of 679 participated in all 3 phases, 19% Europeans versus 9% North Americans ( P = .0007). The European group reached consensus in 6 of 15 statements; The North American group reached consensus in 4 of 15. Ninety percentage of Europeans versus 70% of North Americans ( P = .017) stated CEA is superior to CAS for symptomatic carotid stenosis. This difference was not significant in the final model (adjusted odds ratio: 3.72 [95% confidence interval: 0.95-14.5]). Sixty-nine percentage of North Americans agreed there is a stronger indication for CAS over CEA in patients younger than 65 years for symptomatic carotid stenosis, whereas 55% of Europeans ( P = .023) disagreed. For asymptomatic carotid stenosis, when asked how likely they would recommend CAS, 62% North Americans said “sometimes” versus 60% of Europeans said “never” ( P = .06). Conclusion: The majority of North American and European respondents did not consider the 2 procedures equivalent and seemed to indicate that CEA was preferred for the management of carotid stenosis. These findings need to be further explored to help establish evidence-based guidelines.