Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance. METHODS: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection, and cryopreserved. Immunoablation using busulfan, cyclophosphamide, and rabbit antithymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic, and clinical evidence of rejection while off immunosuppression at 2 y post-aHSCT. RESULTS: Two of the 5 patients achieved operational tolerance with no clinical or histologic evidence of PSC progression or allorejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now >3 y after aHSCT. A fourth patient was weaned off immunosuppression but died 212 d after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T-cell clones, loss of autoantibodies, and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors. CONCLUSIONS: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed render this specific protocol unsuitable for clinical adoption.

CLIC-01: Manufacture and distribution of non-cryopreserved CAR-T cells for patients with CD19 positive hematologic malignancies.

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin's lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 106 CAR-T cells/kg (range 0.13-3.6 × 106/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.

Examining the Feasibility of Early Mobilization With Virtual Reality Gaming Using Head-Mounted Display and Adaptive Software With Adolescents in the Pediatric Intensive Care Unit: Case Report.

BACKGROUND: Early rehabilitative mobilization for adolescents is safe and feasible. However, there is a lack of published rehabilitation strategies and treatments that can maximize engagement and outcomes among adolescents in the pediatric intensive care unit (PICU). Virtual reality (VR) gaming using a head-mounted display (HMD) and adaptive software can allow active and nonactive gameplay at the bedside for people with limited arm mobility, making it a potentially inclusive and enjoyable treatment modality for adolescents in the PICU. OBJECTIVE: The purpose of this brief case study is to report on the preliminary feasibility of incorporating adaptive VR gaming using an HMD with 2 adolescents who received early mobility treatment within the PICU. METHODS: This study was a mini-ethnographic investigation of 2 adolescents (a 15-year-old male and a 13-year old male) in the PICU who underwent VR gaming sessions as part of their early mobilization care, using an Oculus Rift HMD and adaptive software (WalkinVR) that promoted full gameplay in bed. The Rift was plugged into a gaming laptop that was set up on a table within the patient's room before each session. The intervention was delivered by an adapted exercise professional and supervised by a physical therapist. Patients had access to a variety of active games (eg, boxing, rhythmic movement to music, and exploratory adventure) and nonactive games (eg, racing and narrative adventure). Gaming sessions were scheduled between usual care, when tolerable and requested by the participant. The interventionist and therapists took audio-recorded and written notes after completing each gaming session. These data were analyzed and presented in a narrative format from the perspective of the research team. RESULTS: Case 1 participated in 4 gaming sessions, with an average of 18 minutes (SD 11) per session. Case 2 participated in 2 sessions, with an average of 35 minutes (SD 7) per session. Both cases were capable of performing active gaming at a moderate level of exercise intensity, as indicated by their heart rate. However, their health and symptoms fluctuated on a daily basis, which prompted the gameplay of adventure or nonactive games. Gameplay appeared to improve participants' affect and alertness and motivate them to be more engaged in early mobilization therapy. Gameplay without the WalkinVR software caused several usability issues. There were no serious adverse events, but both cases experienced symptoms based on their condition. CONCLUSIONS: The findings of this study suggest that VR gaming with HMDs and adaptive software is likely a feasible supplement to usual care for adolescents within the PICU, and these findings warrant further investigation. Recommendations for future studies aimed at incorporating VR gaming during early mobilization are presented herein.

Transition in acquired brain injury youth (TrABI-Y): a systematic literature review protocol.

INTRODUCTION: Acquired brain injury (ABI) in paediatrics refers to children born with a neurological deficit, which will lead to a chronic neurological disorder. As advances in medical paediatric health progress, we are seeing these ABI youth transitioning into adult healthcare services while also going through different life events. Despite the growing number of young adult patients, access to transition programmes to facilitate the transition process is still limited and evidence on the effectiveness of these programmes is inconclusive. The purpose of this paper is to provide the protocol for an upcoming systematic literature review on this important issue. METHODS AND ANALYSIS: The start of this systematic literature review is planned for 1 October 2019 and will end on 31 December 2021. According to the PICO framework developed, the Population and the Problem of interest (P) will include children, adolescents and young adults (0-18 years) diagnosed with ABI. The selected articles will have to involve an Intervention (I) relating to the healthcare of this population or life transitions from paediatric to adult-oriented care. Studies will be included if a Comparator (C) intervention was used. The expected Outcomes (O) will have to report quantitative or qualitative health-related outcomes post-transition. This comprehensive search of peer-reviewed literature will include articles published between 2010 and 2020. The databases to be searched include Medline, All EBM Reviews, Embase, PsycINFO and CINAHL. The selected articles will be appraised using the Mixed Methods Appraisal Tool. A synthesis of the findings will be drafted to identify the effectiveness of available transition programmes as well as predictors, factors and determinants involved in the transition process. ETHICS AND DISSEMINATION: This project is not associated with direct individuals. The dissemination plan includes strategies such as using this systematic literature review to develop a research project on transition that will be published.

Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial.

BACKGROUND: Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. METHODS: In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight <10th percentile), pregnancy loss, or venous thromboembolism. We did intention-to-treat and on-treatment analyses. This trial is registered with ClinicalTrials.gov, number NCT00967382, and with Current Controlled Trials, number ISRCTN87441504. FINDINGS: Between Feb 28, 2000, and Sept 14, 2012, 292 women consented to participate and were randomly assigned to the two groups. Three women were excluded after randomisation because of ineligibility (two in the antepartum dalteparin group and one in the control group), leaving 146 women assigned to antepartum dalteparin and 143 assigned to no antepartum dalteparin. Some patients crossed over to the other group during treatment, and therefore for on-treatment and safety analysis there were 143 patients in the dalteparin group and 141 in the no dalteparin group. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis (dalteparin 25/146 [17·1%; 95% CI 11·4-24·2%] vs no dalteparin 27/143 [18·9%; 95% CI 12·8-26·3%]; risk difference -1·8% [95% CI -10·6% to 7·1%)) and on-treatment analysis (dalteparin 28/143 [19·6%] vs no dalteparin 24/141 [17·0%]; risk difference +2·6% [95% CI -6·4 to 11·6%]). In safety analysis, the occurrence of major bleeding did not differ between the two groups. However, minor bleeding was more common in the dalteparin group (28/143 [19·6%]) than in the no dalteparin group (13/141 [9·2%]; risk difference 10·4%, 95% CI 2·3-18·4; p=0·01). INTERPRETATION: Antepartum prophylactic dalteparin does not reduce the occurrence of venous thromboembolism, pregnancy loss, or placenta-mediated pregnancy complications in pregnant women with thrombophilia at high risk of these complications and is associated with an increased risk of minor bleeding. FUNDING: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Pharmacia and UpJohn.

Multi-center evaluation of the hepatitis B surface antigen (HBsAg) assay and HbsAg confirmatory assay for the family of Access immunoassay systems.

BACKGROUND: Accurate detection of Hepatitis B Surface Antigen (HBsAg) is an important aid in the diagnosis of patients infected with the hepatitis B virus (HBV). A multi-center study was conducted to characterize the performance of the HBsAg assay on the family of Access immunoassay systems from Beckman Coulter. METHODS: The Access HBsAg assay was characterized in a multi-center study and compared to the Abbott AxSYM* and PRISM* HBsAg assays. The bioMérieux VIDAS* assay was used to resolve discrepant results. Reproducibility studies (intra-assay, inter-assay and inter-lot) were performed with pooled serum samples (negative sample, close to cut off, low, medium and high positive samples). Analytical sensitivity, subtype and genotype detection were studied with various commercial panels (SFTS panel, WHO 80/549, WHO 00/588, Teragenix HBV Genotype panel). A panel of recombinant HBsAg mutant proteins was tested to investigate reactivity towards genetic mutations. Clinical sensitivity was verified with seroconversion panels and samples from subjects with known HBV infection. Analytical specificity was studied with samples from patients with potential cross-reactive infections. Clinical specificity was validated among blood donors and a hospitalized population. RESULTS: The imprecision was < 10%. Analytical sensitivity was < or = 0.1 ng/mL (SFTS panel), 0.020 PEI Units/mL (ad panel), 0.024 PEI Units/mL (ay panel), 0.092 IU/mL with WHO 80/549 and 0.056 IU/mL with WHO 00/588. All genotype samples and HBsAg mutants were reactive with the Access HBsAg assay. Seroconversion panels tested showed no significant difference with the reference method. Sensitivity for subjects with known HBV infection was 100%. No interference with potentially cross-reactive infections was observed after confirmatory testing. Specificity was 99.96% (100% after confirmatory testing) in a blood donor population and 99.5% (100% after confirmatory testing) in a hospitalized population. Excellent separation of positive and negative populations was observed. CONCLUSIONS: The Access HBsAg and HBsAg Confirmatory assays meet all clinical and analytical performance requirements of assays for the detection of HBsAg.

The effect of dalteparin on coagulation activation during pregnancy in women with thrombophilia. A randomized trial.

Low-molecular-weight heparin (LMWH) is increasingly being used for prophylaxis of venous thromboembolism (VTE) and prevention of pregnancy associated morbidity in pregnant women with thrombophilia. We sought to determine if the administration of prophylactic doses of LMWH downregulates coagulation activation in high risk pregnant women with thrombophilia. This sub-study was planned as part of a randomized open label controlled trial (Thrombophilia in Pregnancy Prophylaxis Study [TIPPS]) in which patients at high risk of pregnancy complications with confirmed thrombophilia are randomized to receive either dalteparin (5,000 units/day until 20 weeks then 5,000 units q12h until 37 weeks or onset of labor) or no treatment. Blood samples were collected at baseline, day 7-9 (after starting study drug), week 20 (before increasing study drug), week 36 (prior to stopping study drug) and at the time of admission to the labor and delivery unit. Samples were not drawn at fixed times in relation to drug injection. These samples were analyzed for levels of thrombin-antithrombin complexes (TAT), prothrombin fragments 1 + 2 (F1.2), D-dimer and anti-Xa activity. Generalized linear mixed models were used for statistical analysis and model results were controlled for age, smoking status, type of thrombophilia and predisposing risk factors. The effect of dalteparin on TAT levels was defined as the primary outcome. Of 198 patients eligible, 114 were enrolled in TIPPS. Ninety-one were eligible for the TIPPS coagulation activation sub-study and randomized. Thirty-nine patients were analyzed in the treatment group (dalteparin) and 46 patients in the control group (no intervention). Levels of coagulation activation factors F1.2, TAT and D-dimer increased significantly throughout pregnancy in both groups (p < 0.0001). Dalteparin prophylaxis resulted in a significant increase in anti-Xa activity through pregnancy (p < 0.0001) compared to controls. Dalteparin had no significant effects on the levels of TAT, F1.2 and D-dimer throughout pregnancy in thrombophilic women. A post-hoc Monte Carlo power analysis revealed that our study had 100% and 88% power to detect reductions in TAT values on treatment of 50% and 25%, respectively. Prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation in high risk thrombophilic women during pregnancy.

The bedside investigation of pulmonary embolism diagnosis study: a double-blind randomized controlled trial comparing combinations of 3 bedside tests vs ventilation-perfusion scan for the initial investigation of suspected pulmonary embolism.

BACKGROUND: We sought to determine whether using combinations of 3 bedside tests (7-variable clinical model, non-enzyme-linked immunosorbent assay D-dimer test, and alveolar dead-space fraction) to exclude pulmonary embolism (PE) before diagnostic imaging was as safe as a standard strategy of starting with ventilation-perfusion (V/Q) scan. METHODS: In this double-blind, randomized, controlled equivalency trial, patients were randomized to initial bedside tests or to initial V/Q scan without bedside tests. Patients assigned to the bedside test group had a sham V/Q scan performed if at least 2 of 3 bedside test results were negative; otherwise, they underwent an actual V/Q scan. Further diagnostic management was determined by a blinded physician after V/Q scan. The primary outcome measure was recurrent venous thromboembolic events during 3 months among patients who were not taking anticoagulant agents after the initial investigations were completed. RESULTS: Four hundred fifty-eight consecutive adults with suspected PE were eligible for the study; 398 of 399 consenting and randomized patients completed the study. The follow-up venous thromboembolic event rate was 2.4% in the bedside test group vs 3.0% in the V/Q scan group (P = .76). Pulmonary embolism was excluded in 34% (67/199) of the bedside test group patients with at least 2 negative results on 3 bedside tests vs 18% (35/199) excluded using only the 7-variable clinical model and the D-dimer test. CONCLUSION: Excluding PE with at least 2 negative results on 3 bedside tests safely eliminates the need for diagnostic imaging in 34% of patients with suspected PE.

[Follow-up of a cohort of 2604 colorectal adenomas treated in 1991 and 1992. Search for parameters related to adenomatous recurrence]. / Suivi d'une cohorte de 2 604 cas d'adénomes recto-coliques traités en 1991 et 1992. Recherche de paramètres liés à la récidive adénomateuse.

AIM: To evaluate the recurrence of colorectal neoplasia after endoscopic resection of adenomas. METHODS: The establishment of a register of colorectal cancers and pre-cancerous lesions for Loire-Atlantique (a French administrative division) led to the recording of files for all subjects with colorectal adenomas. The files for the cohort followed up for the years 1991 and 1992 were re-examined at the end of 1998 to determine the risk factors for recurrence. Data from control colonoscopies were recorded. RESULTS: The files of 2 208 (84.9%) of the 2 604 subjects included in the study were examined in 1998. One thousand and four hundred fifty- two subjects had at least one control colonoscopy after a mean period of 28 months: 743 (28.5%) had colorectal neoplasia recurrence, including 18 with a cancer and 50 (2%) with high-grade dysplasia adenomas. The parameters related to recurrence risk were: polyp size, number and topographic distribution of adenomas, pedunculated type, histopathological classification, especially the degree of dysplasia. CONCLUSION: Recurrence of neoplasic lesions (cancer, high grade dysplasia adenomas) may be observed after adenoma resection.