Severe transplantâ associated thrombotic microangiopathy in patients with hemoglobinopathies

Incidence and severity of transplantâ associated thrombotic microangiopathy (TAâ TMA) in patients with hemoglobinopathies receiving hematopoietic cell transplant is unknown. We report the outcomes for two patients with TAâ TMA who received eculizumab. A 2.5â yearâ old male with sickle cell disease developed TAâ TMAâ associated pericardial tamponade, severe hypertension, and acute kidney injury 2 months after transplant. A 7â yearâ old female with βâ thalassemia major developed TAâ TMAâ related acute kidney injury, severe hypertension, and seizures at 6 months after transplant. Both patients progressed to chronic kidney disease (CKD). In patients with hemoglobinopathies, preexisting endothelial dysfunction may place them at a greater risk for TAâ TMA and subsequent CKD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137747/1/pbc26503.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137747/2/pbc26503_am.pd

Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis.

Despite the marked improvement in the overall survival (OS) for patients diagnosed with Wilms' tumor (WT), the outcomes for those who experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and were reported to the Center for International Blood and Marrow Transplantation Research. The 5-year estimates for event-free survival (EFS) and OS were 36% (95% confidence interval (CI); 29-43%) and 45% (95 CI; 38-51%), respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. As attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus HDT followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. As disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy

Handbook on identification of Hispanic students for learning disabilities

The field of learning disabilities is plagued by disagreement among researchers and institutions on the definition and criteria for the identification of specific learning disabilities. Guidelines on the identification of specific learning disabilities vary from schooi to school, district to district, and state to state. There is a tremendous amount of research supporting the issue of misidentification of students in this field. Problems with the identification are particularly acute with students from diverse cultural and linguistic backgrounds, and there is an acknowledged lack of research in the area of learning disabilities occurring concomitantly with second language acquisition. Language acquisition may exhibit certain lea1ning patterns that mimic learning disabilities. With the lack of clear guidelines and identification criteria, students learning English as a second language are in an even more disadvantaged situation than their monolingual peers. Minority students are placed in disproportionate numbers in the category of specific learning disabilities. Some researchers estimate that approximately half of the students from diverse cultural and linguistic backgrounds placed in special education in the category of specific learning disabilities are misidentified. For the purpose of more accurate identification for learning disabilities, teachers need to be provided with clear identification criteria, since the amount of specific guidelines for the purpose of identification of Hispanic students for specific learning disabilities is limited. The identification requires a tremendous amount of observation and intuition on the part of general education teachers during the initial phase before referring a student for a professional assessment.Includes bibliographical references (leaves 86-96)California State University, Northridge. Department of Education

The Role of Complement in HSCT-TMA : Basic Science to Clinical Practice

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a common complication occurring post-HSCT and is associated with substantial morbidity and mortality if not promptly identified and treated. Emerging evidence suggests a central role for the complement system in the pathogenesis of HSCT-TMA. The complement system has also been shown to interact with other pathways and processes including coagulation and inflammation, all of which are activated following HSCT. Three endothelial cell-damaging "hits" are required for HSCT-TMA genesis: a genetic predisposition or existing damage, an endothelial cell-damaging conditioning regimen, and additional damaging insults. Numerous risk factors for the development of HSCT-TMA have been identified (including primary diagnosis, graft type, and conditioning regimen) and validated lists of relatively simple diagnostic signs and symptoms exist, many utilizing routine clinical and laboratory assessments. Despite the relative ease with which HSCT-TMA can be screened for, it is often overlooked or masked by other common post-transplant conditions. Recent evidence that patients with HSCT-TMA may also concurrently present with these differential diagnoses only serve to further confound its identification and treatment. HSCT-TMA may be treated, or even prevented, by removing or ameliorating triggering "hits", and recent studies have also shown substantial utility of complement-targeted therapies in this patient population. Further investigation into optimal management and treatment strategies is needed. Greater awareness of TMA post-HSCT is urgently needed to improve patient outcomes; the objective of this article is to clarify current understanding, explain underlying complement biology and provide simple tools to aid the early recognition, management, and monitoring of HSCT-TMA.Peer reviewe

Translating biomarker insights into practice: a path forward in TA-TMA management

Recent advances in the management of transplant-associated thrombotic microangiopathy (TA-TMA) include the harmonization of diagnostic criteria and the identification of high-risk disease features. Individual hematologic and complement biomarkers show moderate specificity when used alone in the detection of TA-TMA in hematopoietic stem cell transplant (HSCT) recipients, but the identification of endothelial injury due to microangiopathic process can be enhanced using longitudinal monitoring of biomarkers and clinical features. An increase in the sC5b-9 level reflects terminal complement activation, a hallmark of TA-TMA pathogenesis that guides therapeutic interventions. In addition, distinguishing physiologic from pathologic complement activation is essential for timely diagnosis of the disease and selection of targeted interventions. Eculizumab therapy, a biomarker-guided C5 blocker, significantly improves clinical outcomes in severe TA-TMA; however, there is a lack of knowledge on how to select second-line complement inhibitors or combination therapies for cases with a suboptimal response to eculizumab. This article proposes practical approaches to increasing the specificity and attributability of TA-TMA diagnostic biomarkers by integrating clinically available supportive diagnostic tests and provides insights into potential biomarkers for currently available novel complement inhibitors. These findings help ensure timely diagnosis, prevent irreversible organ injury, and improve outcomes in HSCT recipients with TA-TMA

Biotensegrity of the Extracellular Matrix: Physiology, Dynamic Mechanical Balance, and Implications in Oncology and Mechanotherapy

Cells have the capacity to convert mechanical stimuli into chemical changes. This process is based on the tensegrity principle, a mechanism of tensional integrity. To date, this principle has been demonstrated to act in physiological processes such as mechanotransduction and mechanosensing at different scales (from cell sensing through integrins to molecular mechanical interventions or even localized massage). The process involves intra- and extracellular components, including the participation of extracellular matrix (ECM) and microtubules that act as compression structures, and actin filaments which act as tension structures. The nucleus itself has its own tensegrity system which is implicated in cell proliferation, differentiation, and apoptosis. Despite present advances, only the tip of the iceberg has so far been uncovered regarding the role of ECM compounds in influencing biotensegrity in pathological processes. Groups of cells, together with the surrounding ground substance, are subject to different and specific forces that certainly influence biological processes. In this paper, we review the current knowledge on the role of ECM elements in determining biotensegrity in malignant processes and describe their implication in therapeutic response, resistance to chemo- and radiotherapy, and subsequent tumor progression. Original data based on the study of neuroblastic tumors will be provided

Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins-collectively termed lectins-bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway

Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms’ tumor: a CIBMTR retrospective analysis

Despite the dramatic improvement in the overall survival for patients diagnosed with Wilms’ tumor (WT), the outcomes for those that experience relapse have remained disappointing. We describe the outcomes of 253 patients with relapsed WT who received high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplant (HCT) between 1990 and 2013, and reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR). The 5-year estimates for event free survival (EFS) and overall survival (OS) were 36% (95% CI; 29 – 43%) and 45% (95% CI; 38 – 51%) respectively. Relapse of primary disease was the cause of death in 81% of the population. EFS, OS, relapse and transplant-related mortality (TRM) showed no significant differences when broken down by disease status at transplant, time from diagnosis to transplant, year of transplant or conditioning regimen. Our data suggest that HDT followed by autologous HCT for relapsed WT is well tolerated and outcomes are similar to those reported in the literature. Since attempts to conduct a randomized trial comparing maintenance chemotherapy with consolidation versus high-dose chemotherapy followed by stem cell transplant have failed, one should balance the potential benefits with the yet unknown long-term risks. Since disease recurrence continues to be the most common cause of death, future research should focus on the development of consolidation therapies for those patients achieving complete response to therapy

The Noninvasive Urinary Polyomavirus Haufen Test Predicts BK Virus Nephropathy in Children After Hematopoietic Cell Transplantation: A Pilot Study

After hematopoietic cell transplantation (HCT), polyoma-BK virus is associated with hemorrhagic cystitis and also with polyomavirus nephropathy (PVN). However, the true burden of post-HCT PVN is unknown because kidney biopsies are avoided due to their bleeding risk. The novel, non-invasive urinary PV-Haufen test detects PVN in kidney transplant recipients with >95% positive/negative predictive values. We hypothesized that the detection of PV-Haufen in voided urine samples–a positive PV-Haufen test–was also clinically significant after HCT