INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG).

BACKGROUND: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). METHODS/DESIGN: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator's choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. DISCUSSION: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. TRIAL REGISTRATION: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

VA-ECMO With Pericardiocentesis and Autologous Blood Transfusion - Stabilisation Strategy in Acute Cardiac Free Wall Rupture.

A 68-year old lady present with left ventricular free wall rupture and cardiac arrest post-myocardial infarction. This article illustrates a strategy combining pericardiocentesis with autologous transfusion together with VA-ECMO as a bridge to definitive surgical repair.

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment.

In prostate cancer, cancer-associated fibroblasts (CAF) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPF) and promote tumorigenesis. Resolving intercellular signaling pathways between CAF and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAF and NPF were characterized to identify discriminating proteomic signatures. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a hyper reaction monitoring data-independent acquisition (HRM-DIA) workflow. Proteins that exhibited a significant increase in CAF versus NPF were enriched for the functional categories "cell adhesion" and the "extracellular matrix." The CAF phosphoproteome exhibited enhanced phosphorylation of proteins associated with the "spliceosome" and "actin binding." STRING analysis of the CAF proteome revealed a prominent interaction hub associated with collagen synthesis, modification, and signaling. It contained multiple collagens, including the fibrillar types COL1A1/2 and COL5A1; the receptor tyrosine kinase discoidin domain-containing receptor 2 (DDR2), a receptor for fibrillar collagens; and lysyl oxidase-like 2 (LOXL2), an enzyme that promotes collagen crosslinking. Increased activity and/or expression of LOXL2 and DDR2 in CAF were confirmed by enzymatic assays and Western blotting analyses. Pharmacological inhibition of CAF-derived LOXL2 perturbed extracellular matrix (ECM) organization and decreased CAF migration in a wound healing assay. Further, it significantly impaired the motility of co-cultured RWPE-2 prostate tumor epithelial cells. These results indicate that CAF-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment and is a potential therapeutic target.

The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

BACKGROUND: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. METHODS: Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. RESULTS: Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. CONCLUSIONS: The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.

FGFR3 signaling and function in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) accounts for 16% of breast cancers and represents an aggressive subtype that lacks targeted therapeutic options. In this study, mass spectrometry (MS)-based tyrosine phosphorylation profiling identified aberrant FGFR3 activation in a subset of TNBC cell lines. This kinase was therefore evaluated as a potential therapeutic target. METHODS: MS-based tyrosine phosphorylation profiling was undertaken across a panel of 24 TNBC cell lines. Immunoprecipitation and Western blot were used to further characterize FGFR3 phosphorylation. Indirect immunofluorescence and confocal microscopy were used to determine FGFR3 localization. The selective FGFR1-3 inhibitor, PD173074 and siRNA knockdowns were used to characterize the functional role of FGFR3 in vitro. The TCGA and Metabric breast cancer datasets were interrogated to identify FGFR3 alterations and how they relate to breast cancer subtype and overall patient survival. RESULTS: High FGFR3 expression and phosphorylation were detected in SUM185PE cells, which harbor a FGFR3-TACC3 gene fusion. Low FGFR3 phosphorylation was detected in CAL51, MFM-223 and MDA-MB-231 cells. In SUM185PE cells, the FGFR3-TACC3 fusion protein contributed the majority of phosphorylated FGFR3, and largely localized to the cytoplasm and plasma membrane, with staining at the mitotic spindle in a small subset of cells. Knockdown of the FGFR3-TACC3 fusion and wildtype FGFR3 in SUM185PE cells decreased FRS2, AKT and ERK phosphorylation, and induced cell death. Knockdown of wildtype FGFR3 resulted in only a trend for decreased proliferation. PD173074 significantly decreased FRS2, AKT and ERK activation, and reduced SUM185PE cell proliferation. Cyclin A and pRb were also decreased in the presence of PD173074, while cleaved PARP was increased, indicating cell cycle arrest in G1 phase and apoptosis. Knockdown of FGFR3 in CAL51, MFM-223 and MDA-MB-231 cells had no significant effect on cell proliferation. Interrogation of public datasets revealed that increased FGFR3 expression in breast cancer was significantly associated with reduced overall survival, and that potentially oncogenic FGFR3 alterations (eg mutation and amplification) occur in the TNBC/basal, luminal A and luminal B subtypes, but are rare. CONCLUSIONS: These results indicate that targeting FGFR3 may represent a therapeutic option for TNBC, but only for patients with oncogenic FGFR3 alterations, such as the FGFR3-TACC3 fusion. Video abstract.

Identification of Novel Response and Predictive Biomarkers to Hsp90 Inhibitors Through Proteomic Profiling of Patient-derived Prostate Tumor Explants.

Inhibition of the heat shock protein 90 (Hsp90) chaperone is a promising therapeutic strategy to target expression of the androgen receptor (AR) and other oncogenic drivers in prostate cancer cells. However, identification of clinically-relevant responses and predictive biomarkers is essential to maximize efficacy and treatment personalization. Here, we combined mass spectrometry (MS)-based proteomic analyses with a unique patient-derived explant (PDE) model that retains the complex microenvironment of primary prostate tumors. Independent discovery and validation cohorts of PDEs (n = 16 and 30, respectively) were cultured in the absence or presence of Hsp90 inhibitors AUY922 or 17-AAG. PDEs were analyzed by LC-MS/MS with a hyper-reaction monitoring data independent acquisition (HRM-DIA) workflow, and differentially expressed proteins identified using repeated measure analysis of variance (ANOVA; raw p value <0.01). Using gene set enrichment, we found striking conservation of the most significantly AUY922-altered gene pathways between the discovery and validation cohorts, indicating that our experimental and analysis workflows were robust. Eight proteins were selectively altered across both cohorts by the most potent inhibitor, AUY922, including TIMP1, SERPINA3 and CYP51A (adjusted p < 0.01). The AUY922-mediated decrease in secretory TIMP1 was validated by ELISA of the PDE culture medium. We next exploited the heterogeneous response of PDEs to 17-AAG in order to detect predictive biomarkers of response and identified PCBP3 as a marker with increased expression in PDEs that had no response or increased in proliferation. Also, 17-AAG treatment led to increased expression of DNAJA1 in PDEs that exhibited a cytostatic response, revealing potential drug resistance mechanisms. This selective regulation of DNAJA1 was validated by Western blot analysis. Our study establishes "proof-of-principle" that proteomic profiling of drug-treated PDEs represents an effective and clinically-relevant strategy for identification of biomarkers that associate with certain tumor-specific responses.

Protocol for the P3BEP trial (ANZUP 1302): an international randomised phase 3 trial of accelerated versus standard BEP chemotherapy for adult and paediatric male and female patients with intermediate and poor-risk metastatic germ cell tumours.

BACKGROUND: Bleomycin, etoposide, and cisplatin (BEP) chemotherapy administered every 3 weeks for 4 cycles remains the standard first line treatment for patients with intermediate- and poor-risk metastatic germ cell tumours (GCTs). Administering standard chemotherapy 2-weekly rather than 3-weekly, so-called 'accelerating chemotherapy', has improved cure rates in other cancers. An Australian multicentre phase 2 trial demonstrated this regimen is feasible and tolerable with efficacy data that appears promising. The aim of this trial is to determine if accelerated BEP is superior to standard BEP as first line chemotherapy for adult and paediatric male and female participants with intermediate and poor risk metastatic GCTs. METHODS: This is an open label, randomised, stratified, 2-arm, international multicentre, 2 stage, phase 3 clinical trial. Participants are randomised 1:1 to receive accelerated BEP or standard BEP chemotherapy. Eligible male or female participants, aged between 11 and 45 years with intermediate or poor-risk metastatic GCTs for first line chemotherapy will be enrolled from Australia, the United Kingdom and the United States. Participants will have regular follow up for at least 5 years. The primary endpoint for stage 1 of the trial (n = 150) is complete response rate and for the entire trial (n = 500) is progression free survival. Secondary endpoints include response following treatment completion (by a protocol-specific response criteria), adverse events, health-related quality of life, treatment preference, delivered dose-intensity of chemotherapy (relative to standard BEP), overall survival and associations between biomarkers (to be specified) and their correlations with clinical outcomes. DISCUSSION: This is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and pediatric age groups open to both males and females. It is also the largest, current randomised trial for germ cell tumours in the world. Positive results for this affordable intervention could change the global standard of care for intermediate and poor risk germ cell tumours, improve cure rates, avoid the need for toxic and costly salvage treatment, and return young adults to long, healthy and productive lives. TRIAL REGISTRATION: ACTRN 12613000496718 on 3rd May 2013 and Clinicaltrials.gov NCT02582697 on 21st October 2015.

Homo- and Heterotypic Association Regulates Signaling by the SgK269/PEAK1 and SgK223 Pseudokinases.

SgK269/PEAK1 is a pseudokinase and scaffolding protein that plays a critical role in regulating growth factor receptor signal output and is implicated in the progression of several cancers, including those of the breast, colon, and pancreas. SgK269 is structurally related to SgK223, a human pseudokinase that also functions as a scaffold but recruits a distinct repertoire of signaling proteins compared with SgK269. Structural similarities between SgK269 and SgK223 include a predicted α-helical region (designated CH) immediately preceding the conserved C-terminal pseudokinase (PK) domain. Structure-function analyses of SgK269 in MCF-10A mammary epithelial cells demonstrated a critical role for the CH and PK regions in promoting cell migration and Stat3 activation. Characterization of the SgK269 "interactome" by mass spectrometry-based proteomics identified SgK223 as a novel binding partner, and association of SgK269 with SgK223 in cells was dependent on the presence of the CH and PK domains of both pseudokinases. Homotypic association of SgK269 and SgK223 was also demonstrated and exhibited the same structural requirements. Further analysis using pulldowns and size-exclusion chromatography underscored the critical role of the CH region in SgK269/SgK223 association. Importantly, although SgK269 bridged SgK223 to Grb2, it was unable to activate Stat3 or efficiently enhance migration in SgK223 knock-out cells generated by CRISPR/Cas9. These results reveal previously unrecognized interplay between two oncogenic scaffolds and demonstrate a novel signaling mechanism for pseudokinases whereby homotypic and heterotypic association is used to assemble scaffolding complexes with distinct binding properties and hence qualitatively regulate signal output.

Zn2+ mediates high affinity binding of heparin to the αC domain of fibrinogen.

The nonspecific binding of heparin to plasma proteins compromises its anticoagulant activity by reducing the amount of heparin available to bind antithrombin. In addition, interaction of heparin with fibrin promotes formation of a ternary heparin-thrombin-fibrin complex that protects fibrin-bound thrombin from inhibition by the heparin-antithrombin complex. Previous studies have shown that heparin binds the E domain of fibrinogen. The current investigation examines the role of Zn(2+) in this interaction because Zn(2+) is released locally by platelets and both heparin and fibrinogen bind the cation, resulting in greater protection from inhibition by antithrombin. Zn(2+) promotes heparin binding to fibrinogen, as determined by chromatography, fluorescence, and surface plasmon resonance. Compared with intact fibrinogen, there is reduced heparin binding to fragment X, a clottable plasmin degradation product of fibrinogen. A monoclonal antibody directed against a portion of the fibrinogen αC domain removed by plasmin attenuates binding of heparin to fibrinogen and a peptide analog of this region binds heparin in a Zn(2+)-dependent fashion. These results indicate that the αC domain of fibrinogen harbors a Zn(2+)-dependent heparin binding site. As a consequence, heparin-catalyzed inhibition of factor Xa by antithrombin is compromised by fibrinogen to a greater extent when Zn(2+) is present. These results reveal the mechanism by which Zn(2+) augments the capacity of fibrinogen to impair the anticoagulant activity of heparin.

Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways.

INTRODUCTION: Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets. METHODS: We applied an immunoaffinity/mass spectrometry workflow to three mouse models: murine stem cell virus-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus-polyoma virus middle T antigen (PyMT); and the p53-/- transplant model (p53). Pathways and protein-protein interaction networks were identified by bioinformatics analysis. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterised by Western blot analysis and array comparative genomic hybridisation. The functional role of mesenchymal-epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering RNA (siRNA)-mediated knockdown and cell proliferation assays. RESULTS: The three models could be distinguished on the basis of tyrosine phosphorylation signatures and signalling networks. HER2 tumours exhibited a protein-protein interaction network centred on avian erythroblastic leukaemia viral oncogene homologue 2 (Erbb2), epidermal growth factor receptor and platelet-derived growth factor receptor α, and they displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1. In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol 3-kinase signalling pathway, whereas p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton and shared signalling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, as well as Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were recapitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2. CONCLUSION: This study provides network-level insights into signalling in the breast cancer models utilised and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signalling pathways. The Met-amplified, p53-null tumours provide a new preclinical model for a subset of triple-negative breast cancers.

Selective D-dimer testing for diagnosis of a first suspected episode of deep venous thrombosis: a randomized trial.

BACKGROUND: D-Dimer testing is sensitive but not specific for diagnosing deep venous thrombosis (DVT). Changing the use of testing and the threshold level for a positive test result on the basis of risk for DVT might improve the tradeoff between sensitivity and specificity and reduce the need for testing. OBJECTIVE: To determine whether using a selective D-dimer testing strategy based on clinical pretest probability (C-PTP) for DVT is safe and reduces diagnostic testing compared with using a single D-dimer threshold for all patients. DESIGN: Randomized, multicenter, controlled trial. Patients were allocated using a central automated system. Ultrasonographers and study adjudicators but not other study personnel were blinded to trial allocation. (ClinicalTrials.gov: NCT00157677) SETTING: 5 Canadian hospitals. PATIENTS: Consecutive symptomatic patients with a first episode of suspected DVT. INTERVENTION: Selective testing (n = 860), defined as D-dimer testing for outpatients with low or moderate C-PTP (DVT excluded at D-dimer levels <1.0 µg/mL [low C-PTP] or <0.5 µg/mL [moderate C-PTP]) and venous ultrasonography without D-dimer testing for outpatients with high C-PTP and inpatients, or uniform testing (n = 863), defined as D-dimer testing for all participants (DVT excluded at D-dimer levels <0.5 µg/mL). MEASUREMENTS: The proportion of patients not diagnosed with DVT during initial testing who had symptomatic venous thromboembolism during 3-month follow-up and the proportion of patients undergoing D-dimer testing and ultrasonography. RESULTS: The incidence of symptomatic venous thromboembolism at 3 months was 0.5% in both study groups (difference, 0.0 percentage point [95% CI, -0.8 to 0.8 percentage points]). Selective testing reduced the proportion of patients who required D-dimer testing by 21.8 percentage points (CI, 19.1 to 24.8 percentage points). It reduced the proportion who required ultrasonography by 7.6 percentage points (CI, 2.9 to 12.2 percentage points) overall and by 21.0 percentage points (CI, 14.2 to 27.6 percentage points) in outpatients with low C-PTP. LIMITATION: Results may not be generalizable to all D-dimer assays or patients with previous DVT, study personnel were not blinded, and the trial was stopped prematurely. CONCLUSION: A selective D-dimer testing strategy seems as safe as and more efficient than having everyone undergo D-dimer testing when diagnosing a first episode of suspected DVT. PRIMARY FUNDING SOURCE: Heart and Stroke Foundation of Ontario.

Phenotype presentation for a novel mutation affecting a conserved cysteine residue in exon 63 of fibrillin-1 (Cys2633Arg).

Marfan syndrome is an autosomal dominant disease caused by mutations in the gene encoding for fibrillin-1 (FBN1). More than 1,000 FBN1 mutations have been identified, which may lead to multiple organ involvement, particularly of the ocular, skeletal, and cardiovascular systems. Mutations in exons 59-65 have been reported in the past to cause mild Marfan-like fibrillinopathies. We report a family with a mutation in exon 63 that manifests with significant cardiovascular system involvement such as aortic root dilatations, dissection of the aorta, and sudden death at a young age. Genetic analysis revealed that four related individuals are positive for a novel heterozygous Cys2633Arg mutation in exon 63. Their genotype-phenotype profile (based on the revised Ghent nosology) is described. We postulate that the Cys2633Arg mutation may manifest with significant and progressive enlargement of the aortic root, risk of aortic dissections, and minor skeletal abnormalities, without involving the ocular system (i.e., ectopia lentis).

A randomised controlled pilot study of a Nintendo Ring Fit Adventure™ balance and strengthening exercise program in community-dwelling older adults with a history of falls.

OBJECTIVES: This pilot study examined the feasibility, acceptability, and effects of a Nintendo Ring Fit Adventure™-based balance and muscle strengthening exercise program in community-dwelling older adults with a history of falls. METHODS: Older adults who have had at least one fall in the past year were randomly assigned to an experimental (n = 21) or control group (n = 21). The experimental group performed 16 exercise sessions in total, lasting 60 min each, twice a week for 8 weeks, whereas the control group received usual care. Feasibility was evaluated based on the scores of participants in the exercises. Acceptance was evaluated using a customised questionnaire examining participants' self-perceived enjoyment, feasibility and improvements. Clinical outcomes including balance (Mini-BESTest), lower limb muscle strength (Five-Time Sit-to-Stand test), mobility (Timed-Up and Go test), dual-task ability (Timed-Up and Go test-Dual Task), fear of falling (Icon-FES) and executive function (Color Trails Test) were evaluated at baseline and 8 weeks. RESULTS: Thirty-one participants (74%) finished the 8-week assessment. The experimental group significantly improved their scores in six out of eight exercises (all p < .031). The mean scores of the self-perceived enjoyment, feasibility and improvement domains of the acceptability questionnaire were 3.46 ± .53, 3.08 ± .59, and 3.47 ± .57 respectively. A significant improvement in the anticipatory subscore of the Mini-BESTest was found in the experimental group compared to the control group (p = .02; Partial eta squared = .14). CONCLUSIONS: The Nintendo Ring Fit Adventure™-based exercise program was feasible, acceptable, and potentially effective in community-dwelling older adults with a history of falls.

Feasibility, safety, and effects of a Nintendo Ring Fit Adventure™ balance and strengthening exercise program in community-dwelling older adults with a history of falls: A feasibility randomized controlled trial.

AIM: This pilot study examined the feasibility, safety, and effects of a Nintendo Ring Fit Adventure™-based exercise program to enhance balance and lower limb muscle strength in community-dwelling older adults with a history of falls. METHODS: In total, 42 older adults who experienced at least one fall in the past year were randomly assigned to an experimental or control group. Participants in the experimental group performed 60-min sessions of the exercise program twice per week for 8 weeks. The control group received usual care. We assessed the feasibility (retention and adherence to the exercise program), safety (number of adverse events), and clinical outcomes: (1) balance (Mini-BESTest); (2) functional lower limb muscle strength (Five-Time Sit-to-Stand test); (3) mobility (Timed-Up and Go test); (4) dual-task ability (Timed-Up and Go test - Dual Task); (5) fear of falling (Icon-FES); and (6) executive function (Color Trails Test). RESULTS: Thirty-one participants (74%) completed the 8-week assessment. No adverse event associated with the exercise program was reported. There was a significant interaction in the anticipatory domain score of the Mini-BESTest between the experimental and control groups over the 8 weeks (P = 0.019). CONCLUSIONS: The Nintendo Ring Fit Adventure™-based exercise program was feasible, safe, and potentially effective in improving anticipatory balance in community-dwelling older fallers. Geriatr Gerontol Int 2024; 24: 334-341.

Prothrombin Complex Concentrate vs Conservative Management in ICH Associated With Direct Oral Anticoagulants.

Importance: Intracerebral hemorrhage (ICH) associated with direct oral anticoagulant (DOAC) use carries extremely high morbidity and mortality. The clinical effectiveness of hemostatic therapy is unclear. Objective: To compare the clinical and radiological outcomes of DOAC-associated ICH treated with prothrombin complex concentrate (PCC) vs conservative management. Design, Setting, and Participants: In this population-based, propensity score-weighted retrospective cohort study, patients who developed DOAC-associated ICH from January 1, 2016, to December 31, 2021, in Hong Kong were identified. The outcomes of patients who received 25 to 50 IU/kg PCC with those who received no hemostatic agents were compared. Data were analyzed from May 1, 2022, to June 30, 2023. Main Outcomes and Measures: The primary outcome was modified Rankin scale of 0 to 3 or returning to baseline functional status at 3 months. Secondary outcomes were mortality at 90 days, in-hospital mortality, and hematoma expansion. Weighted logistic regression was performed to evaluate the association of PCC with study outcomes. In unweighted logistic regression models, factors associated with good neurological outcome and hematoma expansion in DOAC-associated ICH were identified. Results: A total of 232 patients with DOAC-associated ICH, with a mean (SD) age of 77.2 (9.3) years and 101 (44%) female patients, were included. Among these, 116 (50%) received conservative treatment and 102 (44%) received PCC. Overall, 74 patients (31%) patients had good neurological recovery and 92 (39%) died within 90 days. Median (IQR) baseline hematoma volume was 21.7 mL (3.6-66.1 mL). Compared with conservative management, PCC was not associated with improved neurological recovery (adjusted odds ratio [aOR], 0.62; 95% CI, 0.33-1.16; P = .14), mortality at 90 days (aOR, 1.03; 95% CI, 0.70-1.53; P = .88), in-hospital mortality (aOR, 1.11; 95% CI, 0.69-1.79; P = .66), or reduced hematoma expansion (aOR, 0.94; 95% CI, 0.38-2.31; P = .90). Higher baseline hematoma volume, lower Glasgow coma scale, and intraventricular hemorrhage were associated with lower odds of good neurological outcome but not hematoma expansion. Conclusions and Relevance: In this cohort study, Chinese patients with DOAC-associated ICH had large baseline hematoma volumes and high rates of mortality and functional disability. PCC treatment was not associated with improved functional outcome, hematoma expansion, or mortality. Further studies on novel hemostatic agents as well as neurosurgical and adjunctive medical therapies are needed to identify the best management algorithm for DOAC-associated ICH.

Association of Alternative Anticoagulation Strategies and Outcomes in Patients With Ischemic Stroke While Taking a Direct Oral Anticoagulant.

BACKGROUND AND OBJECTIVES: Ischemic stroke despite a direct oral anticoagulant (DOAC) is increasingly common and portends a high risk of subsequent ischemic stroke. The efficacy and safety of antithrombotic regimens after the condition are unclear. We aimed to compare the outcomes of patients with ischemic stroke despite DOACs with and without an alternative antithrombotic regimen and determine the risk factors of recurrent ischemic stroke while on anticoagulation. METHODS: In a population-based, propensity score-weighted, retrospective cohort study, we compared the clinical outcomes of DOAC-to-warfarin switch, DOAC-to-DOAC switch (DOACswitch), or addition of antiplatelet agents, with those of unchanged DOAC regimen (DOACsame) among patients with nonvalvular atrial fibrillation (NVAF) who developed the first ischemic stroke despite a DOAC from January 1, 2015, to December 31, 2020, in Hong Kong. The primary outcome was recurrent ischemic stroke. Secondary outcomes were intracranial hemorrhage, acute coronary syndrome, and death. We performed competing risk regression analyses to compare the clinical endpoints and determined the predictors of recurrent ischemic stroke in an unweighted multivariable logistic regression model. RESULTS: During the 6-year study period, among 45,946 patients with AF on a DOAC as stroke prophylaxis, 2,908 patients developed ischemic stroke despite a DOAC. A total of 2,337 patients with NVAF were included in the final analyses. Compared with DOACsame, warfarin (aHR 1.96, 95% CI 1.27-3.02, p = 0.002) and DOACswitch (aHR 1.62, 95% CI 1.25-2.11, p < 0.001) were associated with an increased risk of recurrent ischemic stroke. In the DOACsame group, adjunctive antiplatelet agent was not associated with a reduced risk of recurrent ischemic stroke. Diabetes mellitus, concurrent cytochrome P450/P-glycoprotein (CYP/P-gp) modulators, and large artery atherosclerotic disease (LAD) were predictors of recurrent ischemic stroke. DISCUSSION: In patients with NVAF with ischemic stroke despite a DOAC, the increased risk of recurrent ischemic stroke with switching to warfarin called for caution against such practice, while the increased ischemic stroke with DOAC-to-DOAC switch demands further studies. Adjunctive antiplatelet agent did not seem to reduce ischemic stroke relapse. Because diabetes mellitus, the use of CYP/P-gp modulators, and LAD were predictors of recurrent ischemic stroke, further investigations should evaluate whether strict glycemic control, DOAC level monitoring, and routine screening for carotid and intracranial atherosclerosis may reduce ischemic stroke recurrence in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with NVAF experiencing an ischemic stroke while being treated with a DOAC, continuing treatment with that DOAC is more effective at preventing recurrent ischemic stroke than switching to a different DOAC or to warfarin.

By increasing the affinity of heparin for fibrin, Zn(2+) promotes the formation of a ternary heparin-thrombin-fibrin complex that protects thrombin from inhibition by antithrombin.

Heparin binds fibrin and, by bridging thrombin onto fibrin, promotes the formation of a ternary heparin-thrombin-fibrin complex that protects thrombin from inhibition by antithrombin. Because thrombin binds γ(A)/γ'-fibrin, a variant with an extended γ-chain, with higher affinity than the bulk γ(A)/γ(A)-fibrin, γ(A)/γ'-fibrin affords bound thrombin more protection from inhibition by antithrombin-heparin. We examined the effect of Zn(2+) on heparin-thrombin-fibrin complex formation because Zn(2+) modulates heparin-protein interactions. Zn(2+) increased the affinity of heparin for γ(A)/γ(A)- and γ(A)/γ'-fibrin by 4.3- and 3.7-fold, respectively, but had no effect on the affinity of thrombin for either form of fibrin. In contrast, in the presence of heparin, Zn(2+) increased the affinity of thrombin for γ(A)/γ(A)-fibrin 4-fold (from a K(d) value of 0.8 to 0.2 µM) and slowed the rate of thrombin dissociation from γ(A)/γ(A)-fibrin clots. These findings suggest that Zn(2+) enhances the formation of ternary heparin-thrombin-fibrin complexes with γ(A)/γ(A)-fibrin but does not influence the already high affinity interaction of thrombin with γ(A)/γ'-fibrin. Consistent with this concept, in the presence of Zn(2+), γ(A)/γ(A)-fibrin protected thrombin from inhibition by antithrombin-heparin to a similar extent as γ(A)/γ'-fibrin. Therefore, by enhancing the binding of heparin to fibrin, physiological concentrations of Zn(2+) render fibrin-bound thrombin more protected from inhibition by antithrombin. Because fibrin-bound thrombin can trigger thrombus expansion, these findings help to explain why recurrent thrombosis can occur despite heparin treatment.

Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura.

Treatment options for patients with chronic refractory immune thrombocytopenic purpura (ITP) are limited. Because combination immunosuppressant therapy appeared to be effective in ITP and other disorders, we used this approach in patients with particularly severe and refractory ITP. In this retrospective, observational study, we determined the response (platelet count above 30 x 10(9)/L and doubling of baseline) among 19 refractory ITP patients. Treatment consisted of azathioprine, mycophenolate mofetil, and cyclosporine. The patients had failed a median of 6 prior treatments, including splenectomy (in all except 1). Of 19 patients, 14 (73.7%) achieved a response lasting a median of 24 months, after which time 8 (57.1%) relapsed. Of the 8 relapsing patients, 6 responded to additional treatments. Of the 14 patients who achieved an initial response, 2 (14.3%) remained in remission after eventually stopping all medications. Severe adverse events did not occur. Combination immunosuppressant therapy can produce a rise in the platelet count that is sometimes sustained in refractory ITP patients.

[Management of children after renal transplantation: highlights for general pediatricians].

The number of children undergoing successful renal transplantations has been increasing steadily and as a result, general pediatricians are now more likely to encounter children with a kidney allograft in their practice. Although the medical care immediately after transplantation is mostly provided by transplant teams, more and more outpatient care will eventually be performed at the patient's local community. Medical care from general pediatricians is particularly important, especially for children who are residing far from transplant centers. As these children require prolong immunosuppressive therapies and are susceptible to various specific clinical problems, it is imperative for their primary care providers and pediatricians to be knowledgeable about their specific needs and be competent in providing care. This article highlights the roles and common practice related issues that pertain to general pediatricians in the care of pediatric renal allograft recipients.

Thromboembolic Risks with Concurrent Direct Oral Anticoagulants and Antiseizure Medications: A Population-Based Analysis.

BACKGROUND AND OBJECTIVE: Drug-drug interactions between direct oral anticoagulants (DOAC) and antiseizure medications via the cytochrome P450 (CYP) or the P-glycoprotein (P-gp) systems may lead to under-anticoagulation. The clinical relevance of these interactions is unclear. We aimed to elucidate the risk of thromboembolism with concurrent DOAC and CYP/P-gp modulating antiseizure medications. METHODS: In this propensity score-weighted population-based retrospective cohort study, we used competing risk regression analyses to determine the risks of ischemic stroke, venous thromboembolism, and death in DOAC recipients taking CYP/P-gp-modulating antiseizure medications (phenytoin, valproate, levetiracetam, carbamazepine, or phenobarbital) versus those taking CYP/P-gp-neutral antiseizure medications (pregabalin, gabapentin, or clobazam). We also performed secondary analyses for the epilepsy and atrial fibrillation subgroups. RESULTS: Among DOAC users, CYP/P-gp-modulating antiseizure medications were collectively associated with an increased risk of ischemic stroke (adjusted hazard ratio 1.28, 95% confidence interval 1.05-1.57, p = 0.017). In addition, phenytoin (adjusted hazard ratio 1.34, 95% confidence interval 1.07-1.68, p = 0.011) and valproate (adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.74, p = 0.006) were associated with increased mortality. In the epilepsy subgroup, the risk of ischemic stroke and venous thromboembolism did not differ between CYP/P-gp-modulating and CYP/P-gp-neutral antiseizure medications. CONCLUSIONS: Although CYP/P-gp-modulating antiseizure medications were associated with an increased risk of ischemic stroke when paired with DOAC in the primary analysis, such a phenomenon was not found among patients with epilepsy who took phenytoin, valproate, or levetiracetam with DOAC. Therefore, these antiseizure medication options among patients with epilepsy with concurrent DOAC should not be restricted solely based on their potential drug-drug interactions. Yet, the increased mortality during concurrent use of DOAC with phenytoin or valproate might call for caution.