Citations

BACKGROUNDOxaliplatin in combination with either 5‐fluorouracil or capecitabine is commonly used as first‐line therapy for patients with small bowel adenocarcinoma. The addition of irinotecan improves survival in other gastrointestinal tumors but at the cost of hematologic toxicity. The authors performed a phase 2 cooperative group study (North Central Cancer Treatment Group N0543, Alliance) using genotype‐dosed capecitabine, irinotecan, and oxaliplatin (gCAPIRINOX), with dosing assigned based on UDP glucuronosyltransferase family 1 member A1 (UGT1A1) genotype to test: 1) whether the addition of irinotecan would improve outcomes; and 2) whether UGT1A1 genotype‐based dosing could optimize tolerability.METHODSPreviously untreated patients with advanced small bowel adenocarcinoma received irinotecan (day 1), oxaliplatin (day 1), and capecitabine (days 2‐15) in a 21‐day cycle and were dosed with gCAPIRINOX according to UGT1A1*28 genotypes (6/6, 6/7, and 7/7).RESULTSA total of 33 patients (17 with the 6/6 genotype, 10 with the 6/7 genotype, and 6 with the 7/7 genotype) were enrolled from October 2007 to November 2013; 73% were male, with a mean age of 64 years (range, 41‐77 years). Location of the primary tumor included the duodenum (58%), jejunum (30%), and ileum (9%). The regimen yielded a confirmed response rate of 37.5% (95% confidence interval, 21%‐56%), with a median progression‐free survival of 8.9 months and a median overall survival of 13.4 months. Neither hematologic toxicity (grade ≥3 in 52.9%, 30.0%, and 33.3%, respectively, of the 6/6, 6/7, and 7/7 genotype groups) nor tumor response rate (41.2%, 33%, and 33%, respectively) were found to differ significantly by UGT1A1 genotype.CONCLUSIONSUGT1A1 genotype‐directed dosing (gCAPIRINOX) appears to be feasible with favorable rates of hematologic toxicity compared with prior 3‐drug studies in unselected patients. Larger studies would be needed to determine the regimen's comparability to oxaliplatin and capecitabine (CapeOx) alone or if response/toxicity differs among patients with different UGT1A1 genotypes. Cancer 2017;123:3494‐501. © 2017 American Cancer Society.

Abstract A hallmark of glioblastoma (GBM) tumors is their highly invasive behavior. Tumor dissemination into surrounding brain tissue is responsible for incomplete surgical resection, and subsequent tumor recurrence. Identification of targets that control GBM cell dissemination is critical for developing effective therapies to treat GBM. A majority of GBM tumors have dysregulated EGFR signaling, due most frequently to EGFR amplification or the presence of a constitutively active EGFRvIII mutant. Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that can activate multiple MAPK pathways. In this study, evidence is provided that MLK3 is essential for GBM cell migration and invasion, and that an MLK inhibitor blocks EGF-induced migration and invasion. MLK3 silencing or MLK inhibition blocks EGF-induced JNK activation, suggesting that MLK3-JNK signaling promotes invasion of GBM cells. Mechanistically, it is demonstrated that DOCK180, a RAC1 guanine nucleotide exchange factor (GEF) overexpressed in invasive GBM cells, activates the MLK3-JNK signaling axis in a RAC1-dependent manner. In summary, this investigation identifies an EGFR–DOCK180–RAC1–MLK3–JNK signaling axis that drives glioblastoma cell migration and dissemination. Implications: On the basis of these findings, MLK3 emerges as a potential therapeutic target for the treatment of glioblastoma. Mol Cancer Res; 15(8); 1085–95. ©2017 AACR.

Objective: High GATA2 expression has been associated with an increased risk of poor clinical outcomes after radical prostatectomy; however, this has not been studied in relation to risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer after radical prostatectomy. Our aim was to evaluate the association between protein expression levels of GATA2 in primary prostate cancer tumour samples and the risk of BCR after SRT. Methods: 109 males who were treated with SRT were included. The percentage of cells with nuclear staining and GATA2 staining intensity were both measured. These two measures were multiplied together to obtain a GATA2 H-score (range 0–12) which was our primary GATA2 staining measure. Results: In unadjusted analysis, the risk of BCR was higher for patients with a GATA2 H-score >4 (hazard ratio = 2.04, p = 0.033). In multivariable analysis adjusting for SRT dose, pre-SRT PSA, pathological tumour stage and Gleason score, this association weakened substantially (hazard ratio = 1.45, p = 0.31). This lack of an independent association with BCR appears to be the result of correlations between GATA2 H-score >4 and higher pre-SRT PSA (p = 0.021), higher Gleason score (p = 0.044) and more severe pathological tumour stage (p = 0.068). Conclusion: Higher levels of GATA2 expression appear to be a marker of prostate cancer severity; however, these do not provide independent prognostic information regarding BCR beyond that of validated clinicopathological risk factors. Advances in knowledge: A higher GATA2 expression level appears to be correlated with known measures of prostate cancer severity and therefore is likely not an independent marker of outcome after SRT.

SummaryBackgroundThe impact of combination therapy on disease‐related morbidity in patients with established Crohn's disease (CD) or ulcerative colitis (UC) remains to be well‐defined.AimTo examine the effect of combination therapy on disease outcomes in CD and UC.MethodsUsing a multicenter prospective cohort, we classified CD and UC patients as being on monotherapy with anti‐TNF or on combination with an immunomodulator. The primary outcome was a composite of new IBD‐related surgery, hospitalisations, penetrating complications, need for corticosteroids or new biological at 1 year. Multivariable regression models adjusted for potential confounders.ResultsWe included 707 patients with CD (45% combination therapy) and 164 with UC (38% combination therapy). Combination therapy was not associated with reduction in the composite outcome in either CD (OR: 0.87, 95% CI: 0.63‐1.22) or UC (OR: 1.45, 95% CI: 0.63‐3.38). However, while no difference was noted in those with nonstricturing, nonpenetrating CD, a significant reduction in the likelihood of the outcome was seen in those with stricturing or penetrating CD (30% vs 39%, OR: 0.58, 95% CI: 0.37‐0.90). A stronger effect was also observed in those with disease duration <5 years (OR: 0.35, 95% CI: 0.14‐0.87) compared to those with a longer duration (OR: 0.75, 95% CI: 0.45‐1.27). A similar reduction in occurrence of composite outcome was noted with infliximab and with other anti‐TNF biologics.ConclusionThe benefit of combination immunomodulator‐biological therapy is stronger in those with complicated Crohn's disease, particularly early on in their disease course.

ABSTRACT Objectives: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. Methods: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age‐ and sex‐specific z scores for mannitol and lactulose recoveries and the L:M ratio. Results: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex‐specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. Conclusions: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M‐ z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

Purpose Major cardiovascular complications associated with noncardiac surgery represent a substantial population health problem for which there are no established efficacious and safe prophylactic interventions. Acetyl-salicylic acid (ASA) represents a promising intervention. The objective of this study was to determine surgeons' perioperative usage of ASA, and if they would enrol their patients in a perioperative ASA randomized controlled trial (RCT). Methods Cross-sectional survey of all practicing Canadian general, orthopedic, and vascular surgeons. Our mailed, self-administered survey asked surgeons to consider only their patients who were at risk of a major perioperative cardiovascular complication. Results The response rate was 906/1854 (49%). For patients taking ASA chronically, there was marked variability regarding ASA continuation prior to surgery amongst the general and orthopedic surgeons, whereas 76% of vascular surgeons continued ASA in 81-100% of their patients. For patients not taking ASA chronically, approaches to starting ASA prior to surgery were variable amongst the vascular surgeons, whereas 70% of general and 82% of orthopaedic surgeons did not start ASA. For patients taking ASA chronically, 73% of general surgeons, 70% of orthopaedic surgeons, and 36% of vascular surgeons would allow at least 40% of their patients to participate in a perioperative RCT comparing stopping versus continuing ASA. For patients not taking ASA chronically, most general (76%), orthopaedic (67%), and vascular (51%) surgeons would allow at least 40% of their patients to participate in a perioperative RCT comparing starting ASA versus placebo. Conclusion This national survey demonstrates that perioperative ASA usage as reported by surgeons is variable, identifying the need for, and community interest in, a large perioperative ASA trial.

Background: The purpose of this study was to determine the frequency with which postoperative radiographs resulted in a change in management following closed reduction and percutaneous pinning of displaced pediatric supracondylar humerus fractures. We hypothesize that only the initial postoperative radiograph will lead to changes in management of operative supracondylar humerus fractures. Methods: A retrospective review was performed at 2 level I pediatric trauma centers. Inclusion criteria were patients below 18 years of age who sustained supracondylar humerus fractures (Gartland type II, III, IV) who were operatively treated from 2008 to 2013 with adequate radiographic follow-up. Patients with flexion type, intra-articular, transphyseal, and open fractures were excluded from the study. Routine radiographs were taken at initial follow-up (1 wk postoperatively) and at pin removal (3 to 4 wk postoperatively). Results: The final analysis included 572 patients. Initial postoperative radiographs changed treatment in 9 patients (1.6%), including revision surgeries, 2 pin adjustments, and 2 early pin removals. At the time of pin removal, 20 (3.5%) patients required further immobilization. There were no changes to the initial plan for continued nonoperative treatment at final follow-up (6 to 8 wk postoperatively). Conclusions: In this large retrospective series of patients treated with closed reduction and percutaneous pinning of displaced supracondylar humerus fractures, radiographs at 3 weeks do not reveal a need to return to the operating room or other significant pathology. These findings suggest that radiographs should be obtained within 7 to 10 days postoperatively for type III fractures and may only need to be repeated if the clinical situation warrants it, such as severe fracture pattern, persistent pain, or clinical deformity. Level of Evidence: Level IV—case series.