Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia.

BACKGROUND: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points. METHODS: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model. RESULTS: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal (P < 0.025), anterior cingulate (P < 0.041), and striatal (P < 0.023) regions. Clinical measures showed benefit in quality of life (P < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group. DISCUSSION: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.

Transfusion practices at end of life for hematopoietic stem cell transplant patients.

PURPOSE: Limited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice. METHODS: This was a single-center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (n = 116) who enrolled or did not enroll in hospice. RESULTS: Sixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9 ± 66.7 vs. 14.6 ± 48.1 days, p < 0.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (p = 0.04). The last transfusion that occurred more than 96 h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24 h before death. CONCLUSIONS: Blood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24 h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients.

Advance Care Planning and Palliative Care Integration for Patients Undergoing Hematopoietic Stem-Cell Transplantation.

PURPOSE: Advance care planning (ACP) in hematopoietic stem-cell transplantation (HSCT) is challenging, given the potential for cure despite increased morbidity and mortality risk.The aim of this study was to evaluate ACP and palliative care (PC) integration for patients who underwent HSCT. METHODS: A retrospective analysis was conducted and data were extracted from electronic medical records of patients who underwent HSCT between January 2011 and December 2015. Patients who received more than one transplant and who were younger than 18 years of age were excluded. The primary objective was to determine the setting and specialty of the clinician who documented the initial and final code status. Secondary objectives included evaluation of advance directive and/or completion of the Physician Orders for Life-Sustaining Treatment form, PC consultation, hospice enrollment, and location of death. RESULTS: The study sample comprised 39% (n = 235) allogeneic and 61% (n = 367) autologous HSCTs. All patients except one (n = 601) had code status documentation, and 99.2% (n = 596) were initially documented as full code. Initial and final code status documentation in the outpatient setting was 3% (n = 17) and 24% (n = 143), respectively. PC consultation occurred for 19% (n = 114) of HSCT patients, with 83% (n = 95) occurring in the hospital. Allogeneic transplant type and age were significantly associated with greater rates of advance directive and/or Physician Orders for Life-Sustaining Treatment completion. Most patients (85%, n = 99) died in the hospital, and few were enrolled in hospice (15%, n = 17). CONCLUSION: To our knowledge, this is the largest single-center study of ACP and PC integration for patients who underwent HSCT. Code status documentation in the outpatient setting was low, as well as utilization of PC and hospice services.

Patient-Controlled Analgesia for Cancer-Related Pain: Clinical Predictors of Patient Outcomes.

Background: Patient-controlled analgesia (PCA) is an effective approach to treat pain. However, data regarding patterns of PCA use for cancer pain are limited. The purpose of this study was to define the patterns of PCA use and related outcomes in hospitalized patients with cancer. Methods: We identified 90 patients with cancer admitted to a single academic center who received PCA for nonsurgical, cancer-related pain and survived to discharge between January 2013 and January 2014. Data collected included patient demographics, cancer diagnosis, type of cancer-related pain, PCA use, opioid-specific adverse events, and 30-day readmission rates for pain. Univariable and multivariable linear regression models were used to analyze the association between patient and clinical variables with PCA duration. Logistic regression models were used to evaluate the relationship between patient and clinical variables and 30-day readmission rates. Results: The median length of hospitalization was 10.2 days with a median PCA duration of 4.4 days. Hematologic malignancies were associated with longer PCA use (P=.0001), as was younger age (P=.032). A trend was seen toward decreased 30-day readmission rates with longer PCA use (P=.054). No correlation was found between 30-day readmission and any covariate studied, including age, sex, cancer type (solid vs hematologic), pain type, palliative care consult, or time from PCA discontinuation to discharge. Conclusions: This study suggests that there is longer PCA use in younger patients and those with hematologic malignancies admitted with cancer-related pain, with a trend toward decreased 30-day readmission rates in those with longer PCA use.

Weight loss versus muscle loss: re-evaluating inclusion criteria for future cancer cachexia interventional trials.

PURPOSE: Participation in cancer cachexia clinical trials requires a defined weight loss (WL) over time. A loss in skeletal muscle mass, measured by cross-sectional computed tomography (CT) image analysis, represents a possible alternative. Our aim was to compare WL versus muscle loss in patients who were screened to participate in a cancer cachexia clinical trial. METHODS: This was a single-center, retrospective analysis in metastatic colorectal cancer patients screened for an interventional cancer cachexia trial requiring a ≥5 % WL over the preceding 6 months. Concurrent CT images obtained as part of standard oncology care were analyzed for changes in total muscle and fat (visceral, subcutaneous, and total). RESULTS: Of patients screened (n = 36), 3 (8 %) enrolled in the trial, 17 (47 %) were excluded due to insufficient WL (<5 %), 3 (8 %) were excluded due to excessive WL (>20 %), and 16 (44 %) met inclusion criteria for WL. Patients who met screening criteria for WL (5-20 %) had a mean ± SD of 7.7 ± 8.7 % muscle loss, 24.4 ± 37.5 % visceral adipose loss, 21.6 ± 22.3 % subcutaneous adipose loss, and 22.1 ± 24.7 % total adipose loss. Patients excluded due to insufficient WL had 2 ± 6.4 % muscle loss, but a gain of 8.5 ± 39.8 % visceral adipose, and 4.2 ± 28.2 % subcutaneous adipose loss and 0.8 ± 28.4 % total adipose loss. Of the patients excluded due to WL <5 % (n = 17), 7 (41 %) had a skeletal muscle loss >5 %. CONCLUSIONS: Defining cancer cachexia by WL over time may be limited as it does not capture skeletal muscle loss. Cross-sectional CT body composition analysis may improve early detection of muscle loss and patient participation in future cancer cachexia clinical trials.

Transmucosal Immediate-Release Fentanyl for Breakthrough Cancer Pain: Opportunities and Challenges for Use in Palliative Care.

Opioids are used to treat breakthrough cancer pain (BTCP) and can be classified by relative duration and onset of action. Regulatory approvals of numerous transmucosal immediate-release fentanyl (TIRF) formulations provide alternative options to palliative care-trained providers in the management of BTCP. TIRFs have been formulated as a sublingual tablet, sublingual spray, intranasal spray, pectin-based nasal spray, buccal tablet, and buccal soluble film. Differences exist between TIRFs regarding formulation design and dosing to treat BTCP. Opportunities for use include palliation of BTCP in head and neck cancer and/or radiation-induced mucositis. The purpose of this review is to discuss TIRF formulation and dosing, pharmacokinetics, clinical efficacy, patient acceptability, and safety/tolerability. In addition, barriers to TIRF utilization will be discussed.

Variable Patterns of Continuous Morphine Infusions at End of Life.

BACKGROUND: Continuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration. OBJECTIVE: The study objective was to evaluate CMI patterns at the EOL. METHODS: This single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death. RESULTS: Of the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24-hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0-1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0-5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4-30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4-70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0-5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0-27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05-126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r=-0.2, p=0.0062). CONCLUSIONS: Hospitalized patients at EOL had a much higher 24-hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered.

Lack of documentation of evidence-based prognostication in cancer patients by inpatient palliative care consultants.

BACKGROUND: Prognostication plays a key role in palliative care (PC). It is critical for advance care planning, determining hospice eligibility, and communication. In contrast to subjective clinical prognostication, evidence-based prognostication (EBP) uses existing validated data to quantify prognosis; however, the extent to which PC providers use EBP is limited. OBJECTIVE: The objective was to analyze documentation of EBP by PC providers in the absence of an inpatient consultation note template at a single academic medical center. METHODS: We retrospectively evaluated prognostic documentation of inpatient PC consultations on oncology patients at a single academic hospital. Ratings of Eastern Cooperative Oncology Group (ECOG) Scale, Karnofsky Performance Scale (KPS), Palliative Performance Scale, and/or activities of daily living (ADLs) were considered documentation of functional status. PC-specific documentation of EBP included the Palliative Prognostic Index and/or Palliative Prognostic Score. RESULTS: There were 412 inpatient PC consultations for oncology patients (2012-2013). Reasons for consultation included goals of care (n=108), symptom management (n=181), or both (n=123). In the absence of a note template, functional status was documented in 6% (n=24) of consultation notes, while no consultation notes contained EBP documentation of the Palliative Prognostic Index and Palliative Prognostic Score. CONCLUSION: This retrospective analysis conducted at a single academic medical center suggests poor documentation by PC providers of EBP in the absence of a consultation note template. Research and educational opportunities exist to evaluate barriers to EBP utilization and documentation by PC providers.

Novel investigational biologics for the treatment of cancer cachexia.

INTRODUCTION: Cancer cachexia is a complex multifactorial syndrome characterized by ongoing, irreversible skeletal muscle loss, leading to progressive functional impairment. Several investigational biologics targeting key inflammatory pathways and/or the myostatin/activin type II receptor pathway are in development. AREAS COVERED: Novel therapies include ALD518, MABp1, IP-1510, OHR/AVR118, bimagrumab and REGN1033 and are discussed. For each investigational therapy, the mechanism of action, preclinical data, cachexia definition, indication and clinical data are discussed. EXPERT OPINION: A critical look of the study protocols and two key challenges limiting the successful evaluation of these agents include: i) lack of a clinically meaningful cachexia definition; and ii) identification and treatment of cachexia in late stage. We describe our observations and clinical experience in an effort to redirect and promote successful strategies to evaluate these novel investigational biologics.

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.

Prediction of veno-occlusive disease using biomarkers of endothelial injury.

Predicting the development of veno-occlusive disease (VOD) of the liver remains challenging. We hypothesized that biomarkers of endothelial injury in myeloablative allogeneic transplantation recipients could predict VOD occurrence. We evaluated 4 biomarkers-von Willebrand Factor (vWF), thrombomodulin, E-selectin, and soluble intercellular adhesion molecule-1 (sICAM-1)-weekly in the peritransplantation period in an attempt to predict VOD. In the patients who received sirolimus, vWF, thrombomodulin, and sICAM-1 levels were significantly elevated in patients with VOD compared with those without VOD on day -1 (P or=1400 IU/mL and thrombomodulin >or=100 ng/mL on day +7 were both 100% sensitive and 100% specific in predicting VOD. These biomarkers were informative when adjusted for other risk factors for VOD in regression analysis. Among patients not receiving sirolimus, biomarkers of endothelial injury were not informative. We conclude that vWF, thrombomodulin, and sICAM-1 elevations before and early after transplantation may be useful in predicting VOD in patients receiving sirolimus.

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome.

The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI]=13.3%-14.1%). The mean incidence of VOD was significantly lower between 1979-1994 than between 1994-2007 (11.5% [95% CI, 10.9%-12.1%] vs 14.6% [95% CI, 14.0%-15.2%]; P <.05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%-88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.

Use of defibrotide in the treatment and prevention of veno-occlusive disease.

Hepatic veno-occlusive disease (VOD) is one of the most important complications of high-dose chemotherapy and stem cell transplantation. VOD is a clinical syndrome characterized by jaundice, hepatic enlargement and fluid retention typically seen by day +30 after transplantation. Severe VOD is complicated by multiorgan failure and a high mortality rate approaching 100%. Defibrotide (DF) is a novel agent with both antithrombotic and fibrinolytic properties that has emerged as an effective therapy for severe VOD. In Phase II studies, treatment of severe VOD has resulted in complete responses of 30-60% and survival past day 100 ranging between 32-50%. A Phase III, historically controlled study of DF for treatment of severe VOD has recently been completed and results are awaited with interest. In addition, DF may be effective prophylaxis for VOD in high-risk patients. This review will focus on a summary of the pharmacology of DF and the clinical evidence for its use in VOD.

Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation.

Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.