Light transmission aggregometry (LTA) is the most common method used to assess platelet function. However, there is no universal standard for its performance. The Platelet Physiology Subcommittee of ...the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis formed a working party of experts with the aim of producing a series of consensus recommendations for standardizing LTA. Due to a lack of investigations that directly compared different methodologies to perform LTA studies, there were insufficient data to develop evidence-based guidelines. Therefore, the RAND method was used, which obtains a formal consensus among experts about the appropriateness of health care interventions, particularly when scientific evidence is absent, scarce and/or heterogeneous. Using this approach, each expert scored as "appropriate", "uncertain" or "inappropriate" a series of statements about the practice of LTA, which included pre-analytical variables, blood collection, blood processing, methodological details, choice of agonists and the evaluation and reporting of results. After presentation and public discussion at SSC meetings, the assessments were further refined to produce final consensus recommendations. Before delivering the recommendations, a formal literature review was performed using a series of defined search terms about LTA. Of the 1830 potentially relevant studies identified, only 14 publications were considered to be actually relevant for review. Based upon the additional information, 6 consensus statements were slightly modified. The final statements were presented and discussed at the SSC Meeting in Cairo (2010) and formed the basis of a consensus document, which is the subject of the present report. This article is protected by copyright. All rights reserved.
Background: Light transmission aggregometry (LTA) is the most common method used in clinical and research laboratories to assess platelet function. However, the method has never been standardized. ...Objectives: As the first step towards development of methodological guidelines, the Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH) undertook a large, detailed, global survey of LTA practices. Methods: Members of ISTH and of External Quality Assurance in Thrombosis and Haemostasis organizations were invited to complete a 129 item, online questionnaire. Results were analyzed anonymously to participant identities. Results: The online supplement for this article (http://www.isth.org/Publications/OfficialCommunications/PlateletPhysiology/LightTransmissionAggregometry/tabid/201/Default.aspx) contains the full details of the study findings. 359 (244 clinical, 115 research) laboratories from 48 countries participated in the survey. LTA was widely used to assess inherited or acquired bleeding disorders. Common practices were identified in sample collection, processing and analysis and although some are generally considered acceptable, others are not ideal. The agonist concentrations used for LTA varied, and many laboratories used ADP, collagen, epinephrine and Ristocetin, at more than one concentration, in addition to arachidonic acid. The parameters commonly used to assess LTA responses were maximal amplitude or % aggregation, which was considered particularly important, in addition to the presence of a ‘secondary wave’, deaggregation, shape change and a measure of the lag phase. However, many laboratories did not have appropriate reference intervals. Conclusions: This is the largest and most detailed survey of LTA practices ever undertaken. It shows a very high variability in LTA practices worldwide, and, as a consequence, methodological standardization is necessary. The information gathered in this survey will be helpful in the development of ISTH methodological guidelines for LTA.
Background:
Daratumumab is a human anti‐CD38 monoclonal antibody approved for the treatment of relapsed or refractory multiple myeloma (MM). Due to the physiological presence of the antigen CD38 on ...the red blood cell (RBC) membrane, Daratumumab (DARA) inteferes with the classical pre‐transfusion tests, impairing the identification of potential auto‐ or alloantibodies whenever present. The duration of this interference has been reported to be of 2‐6 months after the last DARA administration Oostendorp M, Transfusion 2015.
Aims:
The present analysis aims at evaluating the duration of DARA‐related pre‐transfusion testing interference after the end of treatment at our Center, in order to better define an optimal strategy to assign compatible packed RBCs for transfusion therapy.
Methods:
According to our policy, all patients were typed for AB0, full Rh phenotype, K/k, direct/indirect antiglobulin tests and extended sierological RBCs typing before starting with DARA 2016 SIMTI recommendations; the identification of compatible packed RBCs was obtained after crossmatching using dithiothreitol‐treated patient's blood sample.
Results:
From October 2017, a total of n = 7 MM patients received DARA at a median age of 68y (range: 50‐79); median number of previous therapeutic lines was 3 (range: 1‐7) and the median number of weekly administrations was 7 per patient (range: 1‐12). Two patients are still receiving DARA (1 and 12 administrations respectively). As expected, both direct and indirect antiglobulin tests were positive for all patients; moreover, one patient had also a well‐identified allo anti‐D antibody. Among the n = 5 ongoing patients, n = 4 are evaluable because they underwent the subsequent pre‐transfusion tests after the end of DARA treatment: n = 1 still presents interference 50 days after the end of DARA whereas interference disappeared in n = 3 patients at 48, 65 and 111 days after the last treatment.
Summary/Conclusion:
Our preliminary data confirm the persistence of DARA‐related pre‐transfusion testing interference after the end of treatment for a median period of 2 months in this cohort of MM patients treated at our Institution. Futher follow‐up and the analysis of additional patients in the next future will allow to better determine the duration of interference; we believe these data are worthy of note due to increasing use of DARA, even for other clinical situations Chapuy CI, NEJM 2018; Kwun JEB, Am J Transplant 2017
The integration of Global Navigation Satellite Systems (GNSS) with Inertial Navigation Systems (INS) has been very actively researched for many years due to the complementary nature of the two ...systems. In particular, during the last few years the integration with micro-electromechanical system (MEMS) inertial measurement units (IMUs) has been investigated. In fact, recent advances in MEMS technology have made possible the development of a new generation of low cost inertial sensors characterized by small size and light weight, which represents an attractive option for mass-market applications such as vehicular and pedestrian navigation. However, whereas there has been much interest in the integration of GPS with a MEMS-based INS, few research studies have been conducted on expanding this application to the revitalized GLONASS system. This paper looks at the benefits of adding GLONASS to existing GPS/INS(MEMS) systems using loose and tight integration strategies. The relative benefits of various constraints are also assessed. Results show that when satellite visibility is poor (approximately 50% solution availability) the benefits of GLONASS are only seen with tight integration algorithms. For more benign environments, a loosely coupled GPS/GLONASS/INS system offers performance comparable to that of a tightly coupled GPS/INS system, but with reduced complexity and development time.
Human epidermal growth factor receptor 2 (HER2) overexpression is detected in approximately 15% to 20% of all breast cancers (BCs). A revolutionary change in the prognosis of this subgroup of ...patients has occurred since trastuzumab therapy was introduced into daily clinical practice. However, because trastuzumab resistance is common, new molecules with complementary and/or synergistic mechanisms of action have been developed. Pertuzumab is a new anti-HER2 humanized monoclonal antibody that prevents the formation of HER2 dimers.
A computer-based literature search was carried out using PubMed (keywords: breast neoplasm, dimerization, HER-2, pertuzumab); data reported at international meetings are included.
This paper describes pertuzumab's mechanism of action, safety, and role in HER2-positive BCs. It also explores the role of pertuzumab as a single agent or combined with trastuzumab by reviewing data from preclinical research to ongoing clinical trials. Recently published trials, particularly the CLEOPATRA study, highlight the efficacy, tolerability, and increase in disease-free survival associated with this novel agent when combined with trastuzumab.
The pertuzumab and trastuzumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder caused by mutations in the FOXP3 gene, required for generation of regulatory T (Treg) cells. ...Loss of Treg cells leads to immune dysregulation characterized by multi-organ autoimmunity and early mortality. Hematopoietic stem cell (HSC) transplantation can be curative, but success is limited by autoimmune complications, donor availability and/or graft-vs.-host disease. Correction of FOXP3 in autologous HSC utilizing a homology-directed repair (HDR)-based platform may provide a safer alternative therapy. Here, we demonstrate efficient editing of FOXP3 utilizing co-delivery of Cas9 ribonucleoprotein complexes and adeno-associated viral vectors to achieve HDR rates of >40% in vitro using mobilized CD34+ cells from multiple donors. Using this approach to deliver either a GFP or a FOXP3 cDNA donor cassette, we demonstrate sustained bone marrow engraftment of approximately 10% of HDR-edited cells in immune-deficient recipient mice at 16 weeks post-transplant. Further, we show targeted integration of FOXP3 cDNA in CD34+ cells from an IPEX patient and expression of the introduced FOXP3 transcript in gene-edited primary T cells from both healthy individuals and IPEX patients. Our combined findings suggest that refinement of this approach is likely to provide future clinical benefit in IPEX.
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Singh and colleagues describe a CRISPR-Cas9-based gene editing strategy to treat IPEX syndrome, a monogenic immune disorder caused by mutations in the FOXP3 gene. The authors demonstrate long-term in vivo engraftment of edited HSCs and efficient editing of IPEX patient cells.
The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival ...(PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC.
Eligible trials accrued HER2+ MBC patients in 1992–2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy.
We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months 95% confidence interval (CI) 21–23 months and the median PFS was 5.7 months (95% CI 5.5–6.1 months). At the individual level, the Spearman correlation was equal to ρ = 0.67 (95% CI 0.66–0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R2 = 0.51 (95% CI 0.22–0.81).
In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting.
There is a paucity of literature describing family planning challenges faced by Mohs fellows.
To characterize perceptions about and experiences with family planning, fertility, lactation, and ...parental leave and identify ways to support parental health and family planning for Mohs fellows.
A voluntary, anonymous survey was distributed to Mohs surgeons who recently completed fellowship.
In total, 116 Mohs surgeons completed the survey. Their mean age was 34.5 years old, and more were female ( n = 81, 69.8%) than male ( n = 35, 30.2%). Most had children before completion of their Mohs training ( n = 73, 62.9%). The most significant barrier to having children during fellowship was "loss of education or training time." Over 20% ( n = 23) of respondents or their partner had experienced infertility. Half of the 20 respondents ( n = 10) who breastfed or pumped did not have a convenient place to do so.
This study elucidates trainee perceptions and gaps in parental support for Mohs fellowship trainees. In addition, barriers to implementing a universal family planning policy in Mohs surgery are discussed.
Skin cancer is the most common malignancy after solid organ transplant and can lead to significant morbidity. The likelihood of developing squamous cell carcinomas and melanomas is 100 and 2.4 times ...more likely, respectively, in kidney transplant recipients when compared with the general population. There are few data regarding the assessment and influence of solid organ transplant recipient (SOTR) knowledge of skin cancer and its effect on short- and long-term awareness and behavior.
The purpose of this study was to assess the baseline knowledge of SOTR immediately after transplantation, and then to reassess their knowledge following a 5-minute educational video. We also wanted to determine whether lifestyle modifications had been implemented 4 to 8 months after the intervention.
Forty patients were enrolled within 2 months of transplantation. Eighty-seven percent of patients were renal transplant recipients, and 75% of patients were available for long-term follow-up. There was a significant increase in knowledge in the immediate postintervention period, which was sustained at 4- to 8-month follow-up, as assessed by patient questionnaire. Patients appeared to be applying this knowledge by participating in lifestyle risk modification and positive sun-protective behavior.
Our study suggests that incorporating additional skin cancer education into the early transplant timeline (perhaps in the first one or two outpatient follow-up visits) with an easy to administer educational video and question and answer form increases patient knowledge and influences positive sun-protective behavior.
•Skin cancer is the most common malignancy after solid organ transplant.•There are limited data assessing knowledge of skin cancer in transplant recipients.•Incorporation of an educational video increases transplant recipient knowledge.•Knowledge gained appears to positively influence risk modification and behavior.•This simple intervention offers a practical approach to help transplant patients.
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