Citations

Background and Aims Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5‐year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary‐to‐secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary‐to‐secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine‐learning model, PSC‐BA profile score (concordance statistic [C‐statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C‐statistic, 0.86). Conclusions Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.

Goals: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). Background: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. Materials and Methods: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. Results: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). Conclusion: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Background and Aims Early detection of perihilar cholangiocarcinoma (CCA) among patients with primary sclerosing cholangitis (PSC) is important to identify more people eligible for curative therapy. While many recommend CCA screening, there are divergent opinions and limited data regarding the use of ultrasound or magnetic resonance imaging (MRI) for early CCA detection, and it is unknown whether there is benefit in testing asymptomatic individuals. Our aims were to assess the diagnostic performances and prognostic implications of ultrasound and MRI‐based CCA detection. Approach and Results This is a multicenter review of 266 adults with PSC (CCA, n = 120) who underwent both an ultrasound and MRI within 3 months. Images were re‐examined by radiologists who were blinded to the clinical information. Respectively, MRI had a higher area under the curve compared with ultrasound for CCA detection: 0.87 versus 0.70 for the entire cohort; 0.81 versus 0.59 for asymptomatic individuals; and 0.88 versus 0.71 for those listed for CCA transplant protocol. The absence of symptoms at CCA diagnosis was associated with improved 5‐year outcomes including overall survival (82% vs. 46%, log‐rank P < 0.01) and recurrence‐free survival following liver transplant (89% vs. 65%, log‐rank P = 0.04). Among those with asymptomatic CCA, MRI detection (compared with ultrasound) was associated with reduction in both mortality (hazard ratio, 0.10; 95% confidence interval, 0.01‐0.96) and CCA progression after transplant listing (hazard ratio, 0.10; 95% confidence interval, 0.01‐0.90). These benefits continued among patients who had annual monitoring and PSC for more than 1 year before CCA was diagnosed. Conclusions MRI is superior to ultrasound for the detection of early‐stage CCA in patients with PSC. Identification of CCA before the onset of symptoms with MRI is associated with improved outcomes.

Abstract Osteosarcoma is a rare tumor that requires complex multidisciplinary management. This paper reviews the general management and standard radiotherapy guidelines for osteosarcoma in both North America and Europe in a joined effort between the Children's Oncology Group and International Society of Pediatric Oncology. Standard treatment involves multiagent induction chemotherapy followed by surgical resection for local tumor control and consolidation local control to metastatic sites. Radiotherapy is reserved for cases with a marginal or incomplete resection or for definitive treatment in the case of unresectable disease. We present supporting data for the role of chemotherapy, surgery, and radiation therapy.

Background There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC. Methods A retrospective case series describing the use of LEN/PEM as salvage therapy in patients with progressive/metastatic ACC. Results Eight patients were treated with the LEN/PEM combination therapy. Half were female, and the median age at time of diagnosis was 38 years (range 21–49). Three (37.5%) patients had hormonally active ACC. The median number of prior lines of systemic therapy was 4 (range 2–9). Six (75%) patients had had disease progression on prior CPIs and five (62.5%) patients had progressed on prior MKI therapy. The median progression-free survival was 5.5 months (95% CI 1.8–not reached) and median duration of therapy was 8.5 months (range 2–22). Two (25%) patients had a partial response, one (12.5%) patient had stable disease, and five (62.5%) patients had progressive disease. None of the eight patients stopped therapy because of adverse events. Conclusions In our small cohort of heavily pretreated patients with ACC, the combination of LEN/PEM was associated with objective responses in a subset of patients without significant toxicity. This combination should be formally investigated in phase II clinical trial with robust correlative studies to identify predictors for response.

e19214 Background: ARST1321(PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NCT02180867) was the first National Clinical Trials Network (NCTN) study co-developed by pediatric (COG) and adult (NRG Oncology) consortia anticipating enrollment of adolescent and young adult (AYA) cancer patients. ARST1321 had two treatment cohorts, enrolling patients ≥ 2 years of age to either chemotherapy (C) (chemoradiation ± pazopanib) or non-chemotherapy (NC) (radiation ± pazopanib) arms. It was anticipated adults would contribute the majority of enrollments on the NC arm based on prior enrollment patterns. While the C arm accrued as anticipated (with high enrollment of adults and children), the NC arm had low enrollment leading to premature closure. We report on AYA accrual (defined as 15-39 years) to the NC arm and a survey aiming to identify barriers to enrolling AYA patients onto ARST1321. Methods: Our survey was emailed to 161 adult, surgical, and radiation oncologists at large sarcoma centers. A link was sent to an online questionnaire via SurveyMonkey Inc. and responses were reviewed on their platform. Results: 33 patients enrolled on the ARST1321 NC arm, of which 24% were AYA. 25% of AYA enrollments were from non-COG adult cooperative groups. This trial arm was closed in October 2017 after 3.25 years of accrual below anticipated rates. The survey response rate was 31% with a 70% completion rate. Almost half of respondents were medical oncologists with most seeing 50-200 new sarcoma cases/year at an academic institution and 30% in a pediatric environment (divided equally between radiation and surgical oncologists). 70% of respondents have a joint collaboration with their pediatric oncology team with 23% having a joint clinic. 70% of respondents’ sites opened ARST1321 and anticipated 1-5 patients would be eligible for the NC cohort. However, 42% of respondents’ sites had zero patients enrolled on that arm. The most common reasons for not opening the study and/or not enrolling patients on the NC arm included: lack of interest, disagreement with the therapy, lack of a site investigator, premature study closure, patient/family decision, competing trials, insufficient reimbursement, and regulatory delays. Conclusions: Our survey highlights multiple barriers to enrollment of AYA onto cross-NCTN consortia clinical trials spanning the age spectrum. The information obtained will help inform investigators aiming to effectively design, enroll, and conduct similar trial efforts for AYA in the future.

Objectives: To understand from the perspective of patients who did, and did not attend ICU recovery programs, what were the most important components of successful programs and how should they be organized. Design: International, qualitative study. Setting: Fourteen hospitals in the United States, United Kingdom, and Australia. Patients: We conducted 66 semi-structured interviews with a diverse group of patients, 52 of whom had used an ICU recovery program and 14 whom had not. Interventions: None. Measurements and Main Results: Using content analysis, prevalent themes were documented to understand what improved their outcomes. Contrasting quotes from patients who had not received certain aspects of care were used to identify perceived differential effectiveness. Successful ICU recovery programs had five key components: 1) Continuity of care; 2) Improving symptom status; 3) Normalization and expectation management; 4) Internal and external validation of progress; and 5) Reducing feelings of guilt and helplessness. The delivery of care which achieved these goals was facilitated by early involvement (even before hospital discharge), direct involvement of ICU staff, and a focus on integration across traditional disease, symptom, and social welfare needs. Conclusions: In this multicenter study, conducted across three continents, patients identified specific and reproducible modes of benefit derived from ICU recovery programs, which could be the target of future intervention refinement.

Background/aims: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators’ lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. Methods: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. Results: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. Conclusion: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.