Publications by authors named "Sarah A Taylor"

31 Publications

Mechanisms of liver injury in high fat sugar diet fed mice that lack hepatocyte X-box binding protein 1.

PLoS One 2022 14;17(1):e0261789. Epub 2022 Jan 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver diseases in the United States and can progress to cirrhosis, end-stage liver disease and need for liver transplantation. There are limited therapies for NAFLD, in part, due to incomplete understanding of the disease pathogenesis, which involves different cell populations in the liver. Endoplasmic reticulum stress and its adaptative unfolded protein response (UPR) signaling pathway have been implicated in the progression from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). We have previously shown that mice lacking the UPR protein X-box binding protein 1 (XBP1) in the liver demonstrated enhanced liver injury and fibrosis in a high fat sugar (HFS) dietary model of NAFLD. In this study, to better understand the role of liver XBP1 in the pathobiology of NAFLD, we fed hepatocyte XBP1 deficient mice a HFS diet or chow and investigated UPR and other cell signaling pathways in hepatocytes, hepatic stellate cells and immune cells. We demonstrate that loss of XBP1 in hepatocytes increased inflammatory pathway expression and altered expression of the UPR signaling in hepatocytes and was associated with enhanced hepatic stellate cell activation after HFS feeding. We believe that a better understanding of liver cell-specific signaling in the pathogenesis of NASH may allow us to identify new therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261789PLOS
January 2022

Organ-Specific Comorbidities Are Associated With Distinct Complications After Liver Transplantation for Biliary Atresia.

Liver Transpl 2021 Nov 25. Epub 2021 Nov 25.

Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO.

Although transplant outcomes for biliary atresia (BA) have improved, there are few data to predict the risk of specific posttransplant complications. We therefore defined the impact of comorbidities in BA on posttransplant outcomes. Patients enrolled in the Society of Pediatric Liver Transplantation registry from 2011 to 2019 (n = 1034) were grouped by comorbidities of >1.0% incidence: any supplemental feeding, dialysis, other abdominal surgery (not Kasai portoenterostomy [KPE]), hepatopulmonary syndrome, and cardiac disease requiring intervention. Demographic and outcome data were compared using the Kruskal-Wallis, chi-square, and log-rank tests. Cox proportional hazards models and binary logistic regression were performed for modeling. Patients with BA with comorbidities comprised 77% (n = 799) of our cohort and had evidence of greater medical acuity, including higher calculated Pediatric End-Stage Liver Disease scores and hospitalizations in the intensive care unit before transplant (P < 0.001 for both) versus those without comorbidities. After transplant, patients with BA with comorbidities had more graft loss (P = 0.02), longer initial hospitalization and intubation (P < 0.001 for both), and increased rates of reoperation (P = 0.001) and culture-proven infection (P < 0.001) within 30 days after transplant. Only patients with BA with comorbidities on supplemental feed had increased rates of patient death (P = 0.02). Multivariate analysis identified lower z weight and higher creatinine as risk factors for graft and patient loss in patients with BA with comorbidities. Prior KPE was protective against culture-proven infection and vascular complications within 30 and 90 days, respectively. Patients with BA with comorbidities have evidence of higher medical acuity at transplant and reduced graft survival; however, they overall did not experience greater incidence of patient death. Our data provide organ-system-specific data to risk-stratify patients with BA and posttransplant outcomes.
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http://dx.doi.org/10.1002/lt.26376DOI Listing
November 2021

Transcriptional Analysis of Liver Tissue Identifies Distinct Phenotypes of Indeterminate Pediatric Acute Liver Failure.

Hepatol Commun 2021 Aug 6;5(8):1373-1384. Epub 2021 May 6.

Department of Pediatrics Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children's Hospital of Chicago Chicago IL USA.

Many patients with indeterminate pediatric acute liver failure (PALF) have evidence of T-cell driven immune injury; however, the precise inflammatory pathways are not well defined. We have characterized the hepatic cytokine and transcriptional signatures of patients with PALF. A retrospective review was performed on 22 children presenting with indeterminate (IND-PALF; n = 17) or other known diagnoses (DX-PALF; n = 6) with available archived liver tissue. Specimens were stained for clusters of differentiation 8 (CD8) T cells and scored as dense, moderate, or minimal. Measurement of immune analytes and RNA sequencing (RNA-seq) was performed on whole-liver tissue. Immune analyte data were analyzed by principal component analysis, and RNA-seq was analyzed by unsupervised hierarchical clustering, differential gene expression, and gene-set enrichment analysis. Most patients with IND-PALF (94%) had dense/moderate CD8 staining and were characterized by Th1 immune analytes including tumor necrosis factor α, interferon γ (IFN-γ), interleukin (IL) 1β, IL-12, C-X-C motif chemokine ligand (CXCL) 9, and CXCL12. Transcriptional analyses identified two transcriptional PALF phenotypes. Most patients in group 1 (91%) had IND-PALF and dense/moderate CD8 staining. This group was characterized by increased expression of genes and cell subset-specific signatures related to innate inflammation, T-cell activation, and antigen stimulation. Group 1 expressed significantly higher levels of gene signatures for regulatory T cells, macrophages, Th1 cells, T effector memory cells, cytotoxic T cells, and activated dendritic cells (adjusted  < 0.05). In contrast, patients in group 2 exhibited increased expression for genes involved in metabolic processes. Patients with IND-PALF have evidence of a Th1-mediated inflammatory response driven by IFN-γ. Transcriptional analyses suggest that a complex immune network may regulate an immune-driven PALF phenotype with less evidence of metabolic processes. These findings provide insight into mechanisms of hepatic injury in PALF, areas for future research, and potential therapeutic targets.
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http://dx.doi.org/10.1002/hep4.1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369940PMC
August 2021

Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study.

J Pediatr Gastroenterol Nutr 2021 10;73(4):478-484

University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.

Objectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants.

Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age.

Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at < 37 weeks' gestational age), and low birth weight (25/89; 28% born at <2500 g) were frequent, with no significant differences between outcomes. Clinical outcomes included death (n = 1), liver transplant (n = 1), biochemical resolution (total bilirubin [TB] ≤1 mg/dL and ALT < 35 U/L; n = 51), partial resolution (TB > 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%).

Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study.
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http://dx.doi.org/10.1097/MPG.0000000000003248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448404PMC
October 2021

Bivalirudin for the prevention of hepatic artery thrombosis in pediatric liver transplantation.

Pediatr Transplant 2021 Nov 13;25(7):e14068. Epub 2021 Jul 13.

Division of Transplant Surgery, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Early hepatic artery thrombosis (HAT) after liver transplantation is a serious complication that frequently results in graft loss and the need for retransplantation. Although studies have reported on various operative and endovascular treatment approaches, pharmacologic strategies for the prevention or management of HAT are not well defined. Patients with blood clotting disorders, those with a contraindication to heparin, and those who have previously developed HAT represent unique challenges in management.

Methods: We present the case of a 9-month-old male with a hypercoagulable state who developed early HAT after two liver transplants, despite the use of postoperative therapeutic heparin infusion.

Results And Conclusion: The patient successfully underwent a third liver transplant using intraoperative and postoperative bivalirudin infusion, a direct thrombin inhibitor. Rotational thromboelastometry (ROTEM) was used to guide anticoagulation and blood product administration in the perioperative period. At 1.5 years post-transplant, the patient has good graft function with patent hepatic vasculature. This case demonstrates the innovative use of bivalirudin anticoagulant therapy and viscoelastic methodologies to improve outcomes in hypercoagulable liver transplant recipients.
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http://dx.doi.org/10.1111/petr.14068DOI Listing
November 2021

Applying an Age-specific Definition to Better Characterize Etiologies and Outcomes in Neonatal Acute Liver Failure.

J Pediatr Gastroenterol Nutr 2021 07;73(1):80-85

Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.

Objective: Neonatal acute liver failure (ALF) is a rare disease with high mortality for which no standard age-specific definition exists. To advance the understanding of neonatal ALF, we characterize the etiology, presenting features, treatment, and outcomes in infants within 1 month of life.

Methods: We performed a single-center 11-year retrospective chart review of neonates ≤30 days of life with ALF as defined by an INR of ≥2.0. Comparisons were made by etiology and survival with native liver (SNL). Estimated survival was performed using the Kaplan-Meier method.

Results: Forty-three patients met inclusion criteria for neonatal ALF. Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21-associated myelodysplasia (TAM) (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%). Infants with viral etiologies had the highest alanine aminotransferase (ALT) at presentation (1179 IU/L, interquartile range [IQR] 683-1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18-64 IU/L). Across all etiologies, only 33% were alive at 1 year. Overall median survival was 74 days; 17 days for viral infection and 74 days for GALD-NH. Among laboratory values at presentation, alpha-fetoprotein (AFP) was significantly higher in patients that survived with their native liver (P = 0.04).

Conclusions: Overall, outcome for neonatal ALF is poor. Although initial laboratory values can differentiate viral infection or GALD-NH, further studies are needed to identify laboratory parameters that predict SNL by etiology to ultimately improve patient outcomes.
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http://dx.doi.org/10.1097/MPG.0000000000003103DOI Listing
July 2021

Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.

PLoS One 2021 7;16(1):e0244743. Epub 2021 Jan 7.

Division of Rheumatology, Department of Medicine, Northwestern University, Chicago, Illinois, United States of America.

Background & Aims: Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease.

Methods: We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages.

Results: We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver.

Conclusions: We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790256PMC
May 2021

Feasibility of a behavioral intervention using mobile health applications to reduce cardiovascular risk factors in cancer survivors: a pilot randomized controlled trial.

J Cancer Surviv 2021 08 10;15(4):554-563. Epub 2020 Oct 10.

Fred Hutchinson Cancer Research Center, PO Box 19024, Mailstop M4-C308, Seattle, WA, 98109, USA.

Purpose: Determine the feasibility of a remotely delivered mobile health (mHealth)-supported intervention to improve diet and physical activity in hematologic malignancy survivors.

Methods: Pilot randomized controlled trial of a 16-week intervention for improving diet and physical activity: individualized goal-setting (daily steps, sodium, saturated fat, added sugar intake) per feedback from mHealth trackers (Fitbit for activity; Healthwatch360 for diet), supplemented by a Facebook peer support group. Controls accessed the trackers without goal-setting or peer support. Everyone received standardized survivorship counseling with tailored advice from a clinician. Actigraphy and food frequency questionnaires assessed activity and diet at baseline and follow-up.

Results: Forty-one participants (51.2% male; median age 45.1 years; 7.0 years from treatment) were randomized (24 intervention; 17 control). Fitbit and Healthwatch360 use were more common among intervention versus control participants (75.0% versus 70.6% and 50.0% versus 17.7% of eligible days, respectively). Most intervention participants (66.7%) engaged with Facebook; overall, 91.7% interacted with the study's mHealth applications. While no comparisons in activity or dietary outcomes between intervention versus control group met statistical significance, the intervention was associated with greater reductions in the targeted dietary factors and improvements in Healthy Eating Index-2015 score, moderate-vigorous physical activity time, and daily steps. Participant retention at 6 months was 90.2%.

Conclusions: An intervention for cardiovascular risk reduction based on individualized goal-setting enhanced by mHealth and social media peer support was feasible and acceptable among cancer survivors.

Implications For Cancer Survivors: Effective and easily disseminated strategies that improve diet and physical activity in this population are needed.

Trial Registration: Registered in ClinicalTrials.gov (NCT03574012) on June 29, 2018.
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http://dx.doi.org/10.1007/s11764-020-00949-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035343PMC
August 2021

Activated CD8 T-cell Hepatitis in Children With Indeterminate Acute Liver Failure: Results From a Multicenter Cohort.

J Pediatr Gastroenterol Nutr 2020 12;71(6):713-719

Department of Pediatrics, Northwestern University.

Objectives: In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis.

Methods: PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n = 18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRβ) sequencing.

Results: Dense hepatic CD8 staining was found in significantly more IND-PALF (n = 29, 78%) compared with DX-PALF subjects (n = 5, 28%) (P = 0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P = 0.03) and CD103 (82% vs 40%, P = 0.02) staining compared with DX-PALF subjects. TCRβ sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P = 0.002).

Conclusions: Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies.
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http://dx.doi.org/10.1097/MPG.0000000000002893DOI Listing
December 2020

A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury.

Physiol Rep 2020 05;8(10):e14446

Department of Surgery, Northwestern University, Chicago, IL, USA.

There are limited murine models of cholestatic liver diseases characterized by chronic biliary obstruction and resumption of bile flow. While murine bile duct ligation (BDL) is a well-established model of obstructive cholestasis, current models of BDL reversal (BDLR) alter biliary anatomy. We aimed to develop a more physiologic model of BDLR to evaluate the time course and mechanism for resolution of hepatic injury after biliary obstruction. In the present study, we restored bile flow into the duodenum without disruption of the gall bladder after murine BDL using biocompatible PE-50 tubing. After establishing the technique, overall survival for BDLR at 7 or 14 days after BDL was 88%. Sham laparotomy was performed in control mice. Laboratory data, liver histology, and hepatic gene expression were compared among BDL, BDLR, and controls. Laboratory evidence of cholestatic liver injury was observed at day 7 after BDL and rapid improvement occurred within 48 hr of BDLR. After BDLR there was also enhanced gene expression for the bile acid transporter Abcb11, however, bile duct proliferation persisted. Assessment of the immune response showed increased gene and protein expression for the general immune cell marker Cd45 in BDLR versus BDL mice suggesting a reparative immune response after BDLR. In summary, we have established a novel murine model of BDLR that allows for the investigation into bile acid and immune pathways responsible for hepatic repair following obstructive cholestasis. Future studies with our model may identify targets for new therapies to improve outcome in pediatric and adult cholestatic liver disease.
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http://dx.doi.org/10.14814/phy2.14446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243199PMC
May 2020

Improved Outcomes for Liver Transplantation in Patients with Biliary Atresia Since Pediatric End-Stage Liver Disease Implementation: Analysis of the Society of Pediatric Liver Transplantation Registry.

J Pediatr 2020 04 28;219:89-97. Epub 2020 Jan 28.

Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO.

Objective: To identify changes in demographics, outcomes, and risk factors for patient and graft loss in patients with biliary atresia undergoing liver transplantation since Pediatric End-Stage Liver Disease implementation (2002).

Study Design: Demographics and outcomes were compared between patients enrolled in the Society of Pediatric Liver Transplantation registry before (n = 547) and after (n = 1477) 2002. Kruskal-and χ Wallis tests identified significant differences between eras. Risk factors for patient and graft loss after 2002 were determined by Cox regression model analysis of time to event data.

Results: Significant patient differences after 2002 support increasing disease severity including more status 1 patients and those with a derived Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease score of greater than 30 awaiting transplant. Both patient and graft survival improved after 2002 from 90% to 97% and 81% to 90%, respectively (primary transplant; P < .0001). Significant differences in complications within 30 days included reduced relisting for transplant, rejection, culture-positive infection, repeat operation, hepatic artery thrombosis, portal vein thrombosis, and death/transplant before discharge. Multivariable analysis identified deceased technical variant vs whole graft and retransplantation predictive for patient death, hazard ratios of 4.041 and 8.308, respectively. Deceased technical variant vs whole graft (hazard ratio, 1.963) and donor age 0-5 months vs 1-17 years (hazard ratio, 5.525) were risk factors for graft loss.

Conclusions: The overall outcomes of patients receiving liver transplantation for patients with biliary atresia have improved since 2002 despite evidence of increased disease severity at the time of transplant. Risk factors impacting post-transplant morbidity and mortality in patients with biliary atresia are now mainly surgical including donor variables.
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http://dx.doi.org/10.1016/j.jpeds.2019.12.023DOI Listing
April 2020

Liver Diseases in the Perinatal Period: Interactions Between Mother and Infant.

Hepatology 2020 04 18;71(4):1474-1485. Epub 2020 Mar 18.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO.

Liver diseases affecting the mother and infant dyad may present in the perinatal period from 20 weeks of gestation to 28 days of life. This review will focus on the current approach to neonatal acute liver failure and the progress made in the diagnosis and management of gestational alloimmune liver disease. It will highlight mother-to-child transmission of viral hepatitis, both management and public health implications. Emerging concepts implicating maternal obesity and nutrition in the development of a rapidly progressive nonalcoholic steatohepatitis phenotype in the offspring will be discussed. Finally, the presentation and management of acute fatty liver of pregnancy and intrahepatic cholestasis of pregnancy, and their impact on the fetus, will be reviewed.
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http://dx.doi.org/10.1002/hep.31109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150638PMC
April 2020

The Contribution of B Cells in Autoimmune Liver Diseases.

Semin Liver Dis 2019 11 21;39(4):422-431. Epub 2019 Jun 21.

Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.

Autoreactive B cells can promote autoimmunity through antigen presentation to autoreactive T cells, production of autoantibodies, generation of cytokines promoting T cell activation and differentiation, and inhibition of regulatory T cells and B cells. Here, the authors highlight studies pertaining to B cell mechanisms associated with disease pathogenesis and outcomes in autoimmune hepatitis and the immune-mediated cholangiopathies (primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia). The vast majority of investigations focus on autoantibodies and future research endeavors should include deciphering the role of the B cell in T cell activation (through antigen presentation, cytokine/chemokine production, and inhibition of regulation). Targeting B cell mechanisms in the treatment of autoimmune liver diseases is also highlighted.
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http://dx.doi.org/10.1055/s-0039-1688751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800599PMC
November 2019

Oligoclonal immunoglobulin repertoire in biliary remnants of biliary atresia.

Sci Rep 2019 03 14;9(1):4508. Epub 2019 Mar 14.

Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States.

Biliary atresia (BA) is a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation, however, the mechanism of disease remains unknown. There are two major forms of BA: isolated BA (iBA) comprises the majority of cases and is thought to result from an aberrant immune response to an environmental trigger, whereas syndromic BA (BASM) has associated malformations and is thought to arise from a congenital insult. To determine whether B cells in BA biliary remnants are antigen driven, we examined the immunoglobulin (Ig) repertoire of diseased tissue from each BA group. Deep sequencing of the Ig chain DNA was performed on iBA and BASM biliary remnants and lymph nodes obtained from the Childhood Liver Disease Research Network (ChiLDReN) repository. Statistical analysis of the Ig repertoire provided measures of Ig clonality and the Ig phenotype. Our data demonstrate that B cells infiltrate diseased iBA and BASM biliary remnant tissue. The Ig repertoires of iBA and BASM disease groups were oligoclonal supporting a role for an antigen-driven immune response in both sub-types. These findings shift the current understanding of BA and suggest a role for antigen stimulation in early iBA and BASM disease pathogenesis.
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http://dx.doi.org/10.1038/s41598-019-41148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418100PMC
March 2019

Liver Biopsy Can Be Safely Performed in Pediatric Acute Liver Failure to Aid in Diagnosis and Management.

J Pediatr Gastroenterol Nutr 2018 10;67(4):441-445

Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Objectives: Liver biopsy can be a valuable tool to help determine the etiology of pediatric acute liver failure (PALF), but is often not performed due to safety concerns. The primary aim was to describe the incidence of major complications after liver biopsy performed in the setting of PALF.

Methods: Medical records from 2006 to 2016 were reviewed. Patients age 0 to 17 years, who met criteria for PALF, and had a liver biopsy performed while their international normalized ratio (INR) was ≥1.5 were included.

Results: A total of 26 cases of liver biopsy in the setting of PALF were identified. The majority (n = 22, 85%) of patients had primary liver disease. Most biopsies (n = 17, 65%) were performed by the transjugular route, with 5 (19%) performed percutaneously under ultrasound guidance and 4 (15%) during a surgical procedure. Median INR before biopsy was 2.1 (IQR = 1.73-2.9). Blood products were given before or during the procedure in 23 (88%) cases. One patient (3.8%) had a major complication of biopsy-associated bleeding requiring a blood transfusion. An additional 3 patients had a hemoglobin decrease of 2.1 to 2.9 g/dL post-biopsy that was attributed to the procedure but no interventions were necessary. Biopsy results contributed to establishing a diagnosis in 62% (n = 16) of cases, and influenced treatment decisions in 9 of those cases.

Conclusions: Liver biopsy is safe in the majority of patients with PALF and associated with infrequent major complications. Clinicians should consider performing liver biopsy in this setting, especially when the transjugular approach is feasible, since findings may guide diagnosis and therapy.
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http://dx.doi.org/10.1097/MPG.0000000000002096DOI Listing
October 2018

Simulated activities of daily living do not replicate functional upper limb movement or reduce movement variability.

J Biomech 2018 07 9;76:119-128. Epub 2018 Jun 9.

Centre for Biomedical Engineering, Department of Mechanical Engineering Sciences, University of Surrey, Staghill Campus, Guildford GU2 7XH, UK; Department of Life Sciences, Brunel University London, Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK. Electronic address:

Kinematic assessments of the upper limb during activities of daily living (ADLs) are used as an objective measure of upper limb function. The implementation of ADLs varies between studies; whilst some make use of props and define a functional target, others use simplified tasks to simulate the movements in ADLs. Simulated tasks have been used as an attempt to reduce the large movement variability associated with the upper limb. However, it is not known whether simulated tasks replicate the movements required to complete ADLs or reduce movement variability. The aim of this study is to evaluate the use of simulated tasks in upper limb assessments in comparison to functional movements. Therefore answering the following questions: Do simulated tasks replicate the movements required of the upper limb to perform functional activities? Do simulated tasks reduce intra- and inter-subject movement variability? Fourteen participants were asked to perform five functional tasks (eat, wash, retrieve from shelf, comb and perineal care) using two approaches: a functional and a simulated approach. Joint rotations were measured using an optoelectronic system. Differences in movement and movement variability between functional and simulated tasks were evaluated for the thorax, shoulder, elbow/forearm and wrist rotations. Simulated tasks did not accurately replicate the movements required for ADLs and there were minimal differences in movement variability between the two approaches. The study recommends the use of functional tasks with props for future assessments of the upper limb.
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http://dx.doi.org/10.1016/j.jbiomech.2018.05.040DOI Listing
July 2018

Bile Acids, Microbiota, and Metabolism.

Hepatology 2018 10;68(4):1229-1231

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1002/hep.30078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173626PMC
October 2018

The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality.

J Pediatr 2018 05 27;196:123-128.e1. Epub 2018 Feb 27.

Department of Pediatrics, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL.

Objectives: To evaluate pregnancy outcomes in pedigrees of neonatal hemochromatosis to determine the spectrum of gestational alloimmune liver disease (GALD) in a large cohort.

Study Design: We prospectively collected data from women with a prior offspring with proven neonatal hemochromatosis between 1997 and 2015 and analyzed pregnancy outcomes.

Results: The pedigrees from 150 women included 350 gestations with outcomes potentially related to GALD. There were 105 live-born infants without liver disease, 157 live-born infants with liver failure, and 88 fetal losses. Fetal loss occurred in 25% of total gestations. Ninety-seven pedigrees contained a single affected offspring, whereas 53 contained multiple affected offspring. Analysis of these 53 pedigrees yielded a per-pregnancy repeat occurrence rate of 95%. Notably, the first poor outcome occurred in the first pregnancy in 60% of pedigrees. Outcomes of the 157 live-born infants with liver failure were poor: 18% survived, 82% died. Of the 134 live-born infants with treatment data, 20 received intravenous immunoglobulin with or without double-volume exchange transfusion of which 9 (45%) survived; 14 infants (10%) received a liver transplant of which 6 (43%) survived.

Conclusions: GALD is a significant cause of both fetal loss and neonatal mortality with a high rate of disease recurrence in untreated pregnancies at risk. Poor outcomes related to GALD commonly occur in the first gestation, necessitating a high index of suspicion to diagnose this disorder at first presentation.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.054DOI Listing
May 2018

Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation.

Fetal Diagn Ther 2018 5;43(3):218-225. Epub 2017 Aug 5.

Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL , USA.

Background: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD).

Objective: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD.

Methods: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks.

Results: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded.

Conclusion: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.
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http://dx.doi.org/10.1159/000477616DOI Listing
September 2018

MYO5B mutations cause cholestasis with normal serum gamma-glutamyl transferase activity in children without microvillous inclusion disease.

Hepatology 2017 01 5;65(1):164-173. Epub 2016 Oct 5.

Pediatric Hepatology and Pediatric Liver Transplantation Unit and National Reference Centre for Rare Pediatric Liver Diseases, Bicêtre University Hospital, University of Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France.

Some patients with microvillus inclusion disease due to myosin 5B (MYO5B) mutations may develop cholestasis characterized by a progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity. So far MYO5B deficiency has not been reported in patients with such a cholestasis phenotype in the absence of intestinal disease. Using a new-generation sequencing approach, we identified MYO5B mutations in five patients with progressive familial intrahepatic cholestasis-like phenotype with normal serum gamma-glutamyl transferase activity without intestinal disease.

Conclusion: These data show that MYO5B deficiency may lead to isolated cholestasis and that MYO5B should be considered as an additional progressive familial intrahepatic cholestasis gene. (Hepatology 2017;65:164-173).
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http://dx.doi.org/10.1002/hep.28779DOI Listing
January 2017

Neonatal acute liver failure.

Liver Transpl 2016 05;22(5):677-85

Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Neonatal acute liver failure (NALF) is a rare disease about which there is little published data; however, NALF is an extremely important condition as it is distinct from acute liver failure seen in older children and adults. First, unlike acute liver failure in older patients, NALF can be diagnosed in an infant with cirrhosis. This is due to the fetal-neonatal continuum of liver disease, or the principle that neonatal liver failure may be the result of a liver disease that began in utero. Further differences exist in the mechanism of disease, diagnostic principles, and the common etiologies of NALF when compared with pediatric and adult acute liver failure. This review will address many of the distinguishing features of NALF and focus on the most common etiologies of NALF, including gestational alloimmune liver disease (GALD), the most common cause of NALF. Additionally, this review will provide insight into the pathogenesis, diagnosis, and treatment of this rare condition. Liver Transplantation 22 677-685 2016 AASLD.
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http://dx.doi.org/10.1002/lt.24433DOI Listing
May 2016

Impact Study: MK-0646 (Dalotuzumab), Insulin Growth Factor 1 Receptor Antibody Combined with Pemetrexed and Cisplatin in Stage IV Metastatic Non-squamous Lung Cancer.

Front Oncol 2015 13;5:301. Epub 2016 Jan 13.

University of California Davis Comprehensive Cancer Center , Sacramento, CA , USA.

Background: Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL.

Methods: Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500 mg/m(2) and C at 75 mg/m(2) IV were given every 3 weeks. D was given at 10 mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PC + D.

Results: From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC + D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PC + D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4.

Conclusion: PC + D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL.

Trial Registration: NCT00799240, clinicaltrials.gov.
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http://dx.doi.org/10.3389/fonc.2015.00301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4710681PMC
January 2016

Anakinra-Induced Acute Liver Failure in an Adolescent Patient with Still's Disease.

Pharmacotherapy 2016 Jan 9;36(1):e1-4. Epub 2016 Jan 9.

Columbia University Medical Center, New York, New York.

The interleukin-1 (IL-1) family consists of 11 cytokines that play key regulatory roles in many immune and inflammatory processes. Anakinra (Kineret, Amgen, Inc.) is an IL-1 receptor antagonist (IL-1ra). Increased levels of IL-1 are found in several disease states suggesting that anakinra may be beneficial in disorders associated with elevated IL-1 levels. Anakinra has been effectively used in the treatment of systemic juvenile idiopathic arthritis and adult-onset Still's disease (AOSD). Despite its therapeutic benefits, anakinra also has potential side effects, including hepatotoxicity. We present a case of AOSD in an adolescent male that was treated with anakinra. During treatment, the patient developed acute liver failure that resolved upon withdrawal of anakinra. Although anakinra-induced liver injury has been reported in adults, including one case of subacute liver failure, we believe our case is the first to show severe acute liver failure in an adolescent treated with anakinra. This case provides significant insight into a potentially serious complication associated with anakinra. It is important to further delineate these complications as the treatment indications for this drug expand.
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http://dx.doi.org/10.1002/phar.1677DOI Listing
January 2016

Inhibition of RalA signaling pathway in treatment of non-small cell lung cancer.

Lung Cancer 2012 Aug 10;77(2):252-9. Epub 2012 Apr 10.

The University of Kansas Medical Center, Department of Medicine - Divisions of Hematology/Oncology & Gastroenterology, Molecular Medicine Laboratory, Kansas City, KS, USA.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and relatively resistant to chemotherapy. The most prevalent molecular abnormality in NSCLC is the overactivation of K-Ras proto-oncogene; therefore, elucidating down-stream Ras signaling in NSCLC is significantly important in developing novel therapies against this malignancy. Our work indicates that RalA, an important effector of Ras, is activated in NSCLC cell lines. While RalA was also overactivated in fetal human broncho-epithelial cells, RalBP1 (Ral binding protein-1), an important down-stream effector of RalA, was expressed at higher levels in cancer cell lines. Aurora kinase-A (AKA), an upstream activator of RalA, was also found to be active only in malignant cells. The outcome of inhibition of RalA (by gene specific silencing using a lentivirus) on the malignant phenotype of A549 cells was also studied. While proliferation and invasiveness of A549 cells were reduced upon silencing RalA, apoptosis and necrosis were elevated in such conditions. Additionally, the in vivo tumorigenesis of A549 cells was reduced upon partial inhibition of RalA and AKA using pharmacological inhibitors. Finally, we were interested in evaluating the level of active RalA in the fraction of NSCLC cells expressing cancer stem cell markers. For this purpose cells with increased expression of CD44 were separated from A549 cells and compared with cells with low level of expression of this marker and an unsorted population. A significant enhancement of RalA activation in high CD44+ cells was found as potential evidence for involvement of RalA signaling in initiation of the neoplastic procedure and an important contributor for tumor maintenance in NSCLC. Further studies can reveal therapeutic, preventive and diagnostic value of RalA pathway in this deadly disease.
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http://dx.doi.org/10.1016/j.lungcan.2012.03.007DOI Listing
August 2012

Early intervention for substance abuse among youth and young adults with mental health conditions: an exploration of community mental health practices.

Adm Policy Ment Health 2011 May;38(3):131-41

School of Social Work, Arizona State University, Phoenix, AZ 85004-0689, USA.

This mixed method study examined current practices and barriers for screening and assessing substance use among youth/young adults in community mental health systems. Substance use rates remain high among youth/young adults in the general population and substance use disorders are prevalent among young people involved in public service systems such as mental health. In an effort to understand the dynamics for early intervention, 64 case managers and/or clinical directors from children's mental health systems in two states participated in an online survey or focus group in fall 2008. Quantitative survey questions and qualitative focus group questions explored attitudes and perspectives about screening and early intervention for substance use among youth/young adults involved in the mental health system and current agency practices. Mixed method results suggest a number of barriers to substance use screening and early intervention and point to innovations that could be more effectively supported.
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http://dx.doi.org/10.1007/s10488-010-0308-xDOI Listing
May 2011

Phase II trial of cisplatin/etoposide and concurrent radiotherapy followed by paclitaxel/carboplatin consolidation for limited small-cell lung cancer: Southwest Oncology Group 9713.

J Clin Oncol 2004 Jan;22(1):127-32

Southwest Oncology Group (S9713), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217, USA.

Purpose: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC.

Patients And Methods: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m(2) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m(2), both drugs administered on day 1 of a 21 day cycle for three cycles.

Results: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%.

Conclusion: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.
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http://dx.doi.org/10.1200/JCO.2004.06.070DOI Listing
January 2004

Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349).

J Clin Oncol 2003 Jul;21(13):2466-73

Wilshire Oncology Medical Group, Inc, Pasadena, CA, USA.

Purpose: To test the hypothesis that therapy of intermediate- and high-grade (excluding Burkitt lymphoblastic) lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) could be safely dose-intensified with routine filgrastim support.

Patients And Methods: Eligible patients were those who were previously untreated and who had either bulky stage II, or stage III or IV lymphoma with working formulation histology D, E, F, G, H, or J; performance status < or = 2; and acceptable end organ function. No upper age limit was specified. Therapy was dose-intensified CHOP (CHOP-DI) with filgrastim support. Each course was repeated every 14 days for six planned courses.

Results: Eighty-eight eligible patients were treated with CHOP-DI and had a median follow-up of 5.1 years on this phase II study, designated Southwest Oncology Group (SWOG) 9349. The progression-free survival was 51% at 2 years and 41% at 5 years. The overall survival was 60% at 5 years. Three fatal treatment-related events occurred. One patient with myelodysplastic syndrome was reported.

Conclusion: Treatment with CHOP-DI can be safely administered in the cooperative group setting and results in improved survival. Estimated overall survival at 5 years was 14% better than that of patients treated with standard-dose CHOP in an earlier SWOG study, although progression-free survival of 60% at 2 years-the prespecified end point-was not achieved. CHOP-DI, given every 2 weeks at escalated doses, is a strategy that should be tested in a future randomized clinical trial in lymphoma.
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http://dx.doi.org/10.1200/JCO.2003.06.137DOI Listing
July 2003

Phase II trial of single agent carboplatin followed by dose-intense paclitaxel, followed by maintenance paclitaxel therapy in stage IV ovarian, fallopian tube, and peritoneal cancers: a Southwest Oncology Group trial.

Gynecol Oncol 2003 Mar;88(3):282-8

Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Objective: To improve the survival of women with stage IV epithelial ovarian cancer the Southwest Oncology Group conducted a phase II trial examining two novel treatment strategies: (a) modification of the chemotherapy regimen (carboplatin/paclitaxel) based on evidence of response during treatment and (b) "maintenance therapy," with the monthly administration of single agent paclitaxel (maximum 2 years).

Methods: Individuals with histologically documented stage IV ovarian, fallopian tube, or peritoneal cancers initially received a maximum of 3 courses of single agent carboplatin (AUC 6), with the decision to administer a subsequent course based on specific response criteria (i.e., declines in serum CA-125 or shrinkage of measurable mass lesions). This was followed by single agent paclitaxel (150 mg/m(2)), delivered every 2 weeks for a maximum of 6 courses, again based on evidence of continued response to the treatment program. Finally, in the absence of disease progression or unacceptable toxicity, patients received single agent paclitaxel (175 mg/m2) for a maximum of 24 monthly courses. The primary study end point was 2-year overall survival, which was to be compared to the survival of a previously published historical control population [stage IV ovarian cancer patients treated with a "standard" cisplatin/paclitaxel regimen (GOG 111; McGuire WP, N Eng E J Med 1996; 334:1)]. This analysis was employed to determine if this novel strategy was worthy of further clinical investigation in a controlled clinical trial.

Results: There were 53 patients entered this multicenter study, of whom 50 were evaluable for toxicity and 51 for survival. There were 2 treatment-related deaths. Grades 2 and 3 neutrotoxicity were observed in 18 and 4% of patients, respectively. There were no major treatment-related protocol violations. The overall 2-year survival was 48% (95% CI, 34-62%), compared to 60% for the historical control group.

Conclusions: While this trial demonstrated the feasibility of delivering a treatment regimen requiring frequent alternations in therapy based on predetermined changes in objective parameters of response, further exploration of this specific management approach does not appear warranted in stage IV ovarian cancer, based on the survival outcome compared to a reasonably similar historical control population. As this trial demonstrates, the prospective determination of clinical end points in a phase II study (e.g., 2-year survival) that will lead to continued evaluation of a particular investigative strategy in a large-scale randomized trial can be an effective method to reduce the bias and uncertainty often associated with this complex decision process.
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http://dx.doi.org/10.1016/s0090-8258(02)00100-2DOI Listing
March 2003

Causes of non-compliance with drug regimens in glaucoma patients: a qualitative study.

J Ocul Pharmacol Ther 2002 Oct;18(5):401-9

Albers School of Business, Seattle University, Seattle, WA, USA.

The purpose of this study was to gain insights into why patients are not compliant with their glaucoma medications. Patients were recruited from lists provided by two ophthalmologists. Each patient had seen a minimum of two ophthalmologists for their glaucoma, and was taking at least two topical medications for glaucoma. Qualitative methodology was utilized, including two focus groups and eleven in-depth interviews in patients' homes. The results showed that forgetfulness was the number one reported reason for non-compliance. Patients did not claim to be non-compliant specifically because of side effects, but they did complain about them. Communication between physicians and patients is a key factor in compliance for glaucoma patients. Specifically, patients would like their physicians to teach them how to instill their eye drops, tell them about new/alternate medications and procedures as they become available, and offer new ways to make their regimen easier. Patients often do not tell their physician if they experience a side effect unless it is intolerable to them, yet they do realize the seriousness of glaucoma, and the consequences of not following their doctor's orders. Finally, while cost was not a reported deterrence to compliance, some patients would prefer less expensive alternatives.
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http://dx.doi.org/10.1089/10807680260362687DOI Listing
October 2002
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