Citations

Objectives: Decreased urine output and/or increased serum creatinine may herald the development of acute kidney injury or reflect normal physiology. In this secondary analysis of the Sapphire study, we examined biomarkers of cell cycle arrest in the settings of oliguria and/or azotemia to improve risk assessment when used with conventional indices in predicting severe acute kidney injury (Kidney Disease: Improving Global Outcomes 3 defined by the need for renal replacement therapy or changes in urine output, serum creatinine or both) or death. Design: Prospective, international, Sapphire study. Setting: Academic Medical Center. Patients: Patients without acute kidney injury Kidney Disease: Improving Global Outcomes stage 2 or 3. Interventions: None. Measurements and Main Results: The primary endpoint being development of severe acute kidney injury or death within 1 week. Secondary analysis examined the relationship between tissue inhibitor of metalloproteinases-2 ([TIMP-2]) and insulin growth factor binding protein 7 ([IGFBP7]) and 9-month death or dialysis conditioned on progression to stage 2–3 acute kidney injury within 1 week. Seventy-nine patients reached the primary endpoint and were more likely to be surgical, with higher nonrenal Acute Physiology and Chronic Health Evaluation III scores and more chronic kidney disease. Stage 1 urine output, serum creatinine, and urinary [TIMP-2]•[IGFBP7] greater than 2.0 were all predictive of progression to the primary endpoint independent from nonrenal Acute Physiology and Chronic Health Evaluation III score. Combinations of predictors increased the hazard ratios considerably (from 2.17 to 4.14 to 10.05, respectively). In the presence of acute kidney injury (stage 1), [TIMP-2]•[IGFBP7] greater than 2.0 leads to an increased risk of death or dialysis at 9 months even in the absence of progression of acute kidney injury (stage 2–3) within 7 days. Conclusions: Cell cycle arrest biomarkers, TIMP-2 and IGFBP7, improve risk stratification for severe outcomes in patients with stage 1 acute kidney injury by urine output, serum creatinine or both, with risk increasing with each acute kidney injury indicator. Longer term outcomes demonstrate that the associated risks of a [TIMP-2]•[IGFBP7] greater than 2.0 is equivalent to acute kidney injury progression even where no progression from stage 1 acute kidney injury is observed.

Importance: Evidence has demonstrated that shoulder pain constitutes a functional impairment for patients with amyotrophic lateral sclerosis (ALS). No studies have yet examined the efficacy of scapular mobilization of the painful shoulder among patients with ALS. Objective: Our retrospective case series evaluated the effects of scapular mobilization on pain and shoulder motion among patients with ALS. Design: Retrospective case series over 2 yr. Setting: A multidisciplinary outpatient clinic at an academic medical institution. Participants: Twenty-eight patients with ALS who had shoulder pain and range of motion (ROM) limitations. Patients were excluded if information on visual analog scale (VAS) score for pain and shoulder ROM was not available. Intervention: Scapular mobilization, ROM, and caregiver education. All patients also received standard occupational therapy treatment for this patient population. Outcomes and Measures: The primary outcome was VAS shoulder pain scores; the secondary outcome was shoulder flexion ROM. Results: The median VAS pain score was 2 before treatment and 0 after treatment, with a significant median reduction of 2. Median shoulder flexion ROM was 100° before mobilization treatment and 130° after treatment, with a significant median increase of 25°. Conclusion and Relevance: The results provide strong evidence that both VAS pain score and shoulder ROM noticeably improve after mobilization treatment. What This Article Adds: Occupational therapists can effectively promote shoulder care techniques such as scapular mobilization to both patients and care providers to reduce pain and improve quality of life for patients with ALS.

AKI is a global concern with a high incidence among patients across acute care settings. AKI is associated with significant clinical consequences and increased health care costs. Preventive measures, as well as rapid identification of AKI, have been shown to improve outcomes in small studies. Providing high-quality care for patients with AKI or those at risk of AKI occurs across a continuum that starts at the community level and continues in the emergency department, hospital setting, and after discharge from inpatient care. Improving the quality of care provided to these patients, plausibly mitigating the cost of care and improving short- and long-term outcomes, are goals that have not been universally achieved. Therefore, understanding how the management of AKI may be amenable to quality improvement programs is needed. Recognizing this gap in knowledge, the 22nd Acute Disease Quality Initiative meeting was convened to discuss the evidence, provide recommendations, and highlight future directions for AKI-related quality measures and care processes. Using a modified Delphi process, an international group of experts including physicians, a nurse practitioner, and pharmacists provided a framework for current and future quality improvement projects in the area of AKI. Where possible, best practices in the prevention, identification, and care of the patient with AKI were identified and highlighted. This article provides a summary of the key messages and recommendations of the group, with an aim to equip and encourage health care providers to establish quality care delivery for patients with AKI and to measure key quality indicators.

Abstract Background: Pre-clinical data and results from early phase clinical trials point to synergistic antitumor activity and potential efficacy of palbociclib when given in combination with anti-HER2 therapy (tx). The aim of PATINA is to determine the effect of adding palbociclib to anti-HER2 and ET maintenance after induction tx in the 1st line setting for HR+/HER2+ MBC. Trial Design: The PATINA trial (AFT-38/NCT02947685) is a pivotal, open-label, international, phase III study. Following 6-8 cycles of chemotherapy (taxane or vinorelbine) with anti-HER2 tx for MBC participants will be randomized 1:1 to standard anti-HER2 tx (trastuzumab +/- pertuzumab) in combination with ET with or without palbociclib until disease progression. ET options are either an aromatase inhibitor or fulvestrant. Premenopausal patients (pts) must receive ovarian suppression. The trial is open to men or women with histologically confirmed HR+/HER2+ MBC provided they are without evidence of disease progression by local assessment after induction tx. Total planned accrual is 496 pts. Primary objective is to demonstrate that the combination of palbociclib with anti-HER2 tx plus ET is superior to anti-HER2 tx plus ET alone in prolonging progression-free survival (PFS). Key secondary objectives are measures of tumor control, overall survival, safety and Quality of Life. The main translational science objective is to compare PFS estimates according to PIK3CA mutation status. The study has a 90% power to detect a hazard ratio of 0.667 in favor of the palbociclib arm. All pts approached to participate in PATINA will be asked to share remaining biospecimens and clinical data with the Mastering Breast Cancer Initiative. This initiative was created in order to understand the natural history of MBC and how it envolves over time with the aim to develop new treatments for this patient population. Recruitment has started in 07/2017 and is planned for approximately 22 months in 140 sites in Australia, Germany, Italy, France, New Zealand, Spain, and the US. 69 pts have been recruited so far. The study is sponsored by Alliance Foundation Trials (AFT) and financially supported by Pfizer Citation Format: Metzger O, Mandrekar S, Loibl S, Mundhenke C, Seiler S, Valagussa P, Lim E, Tripathy D, Winer EP, Huang C, Carey L, Francis P, Miller K, Goetz MP, Prat A, Loi S, Krop I, Gianni L, Delalogue S, Vaz-Luis I, Dockter T, Lanzillotti J, Ciruelos E, DeMichele AM. PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-07.

AbstractIntroductionWe sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish dementia with Lewy bodies (DLB) from Parkinson's disease (PD).MethodsStored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols.ResultsIn the first step, the proteomic profile distinguished the DLB‐PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88.DiscussionThese data provide evidence of the potential utility of a multitiered blood‐based proteomic screening method for detecting DLB and distinguishing DLB from PD.

Abstract Aims We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). Methods and results We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. Conclusions Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

PURPOSE The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA. METHODS We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease. RESULTS Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs. CONCLUSION This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.

AbstractIntroductionOur primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy‐confirmed cohort of Alzheimer's disease cases.MethodsA retrospective study was conducted in the Florida Autopsied Multi‐Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self‐reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).ResultsHispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.DiscussionDespite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.

Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.