bluuebunny/crossref_metadata_2025 huggingface dataset:
Can the human coronavirus epidemic also spread through solid waste?
Authors: Mol Marcos Paulo Gomes , Caldas Sérgio
Published: April 2020

Wastes generated in healthcare facilities have been discussed and the World Health Organization has proposed a guideline for controlling the spread of the virus that causes Coronavirus Disease 2019 (COVID-19). However, waste management outside the generating facility should be discussed in more detail, taking into account factors such as virus resistance, differences in waste management systems and the climatic conditions in each affected region. Patients infected by human coronavirus being treated at home are generating infected waste possibly discarded as domestic waste, which can pose risks to workers and the environment, depending on the conditions of transport and disposal. In particular, the spread of the coronavirus may be increased by inadequate waste management, highlighting poor handling conditions associated with inappropriate use of personal protective equipment and other unfavourable conditions presented mainly in developing countries.
Innovation in hemodialysis: Using the Biodesign process to identify unmet needs
Authors: Augustin Dimitri A , Chertow Glenn M , Azagury Dan E
Published: April 2020

There is renewed demand to accelerate innovation in nephrology; public and private sectors are creating programs to support its growth. The Stanford Biodesign innovation process, first developed in 2000, provides a roadmap for health technology and device innovation. There is insufficient published guidance on the application of the Biodesign process in the generation of novel devices to address nephrology- and/or dialysis-related clinical unmet needs. We present “needs finding,” the initial part of the identify phase in the Biodesign innovation process and how it may be utilized for nephrology- and/or dialysis-related innovation. We describe here how to apply the Biodesign process to identify unmet dialysis-related needs, with the use of specific case-based examples based on observations within a hemodialysis unit. We then explore how to develop these needs using background research, direct clinical observations, interviews, documentation of observations and interview findings, and development of multiple needs statements. We conclude that there is an opportunity for nephrology innovators to use this methodology broadly in order to identify areas for innovation and initiated the development on novel solutions to be introduced into patient care.
Human Herpesvirus-6 Meningitis in a Premature Infant with Fevers: A Case and Literature Review
Authors: Kim Faith , Reichman Victoria , Hooven Thomas A
Published: April 2020

Human herpesvirus-6 (HHV-6) is a common virus that can cause nearly universal infection in infancy and early childhood. It typically manifests as an acute febrile illness. We describe a case of a premature infant with congenital hydrocephalus secondary to aqueductal stenosis with a ventriculoperitoneal shunt in place who developed intermittent fevers while she was admitted to the neonatal intensive care unit. She was ultimately diagnosed with acute HHV-6 meningitis. In addition to this report, we present a literature review regarding this virus’s potential modes of transmission and forms of clinical presentation in the neonatal period.
A systematic review of lower extremity electrical stimulation for treatment of walking impairment in peripheral artery disease
Authors: Jéhannin Pierre , Craughwell Meghan , Omarjee Loukman , Donnelly Alan , Jaquinandi Vincent , Mahé Guillaume , Le Faucheur Alexis
Published: April 2020

Lower extremity peripheral artery disease (PAD) induces an ischemic pain in the lower limbs and leads to walking impairment. Electrical stimulation has been used in patients with PAD, but no systematic review has been proposed to address the efficacy of the technique as a treatment for walking impairment in PAD. A systematic search was performed to identify trials focused on electrical stimulation for the treatment of walking impairment in patients with PAD in the Cochrane Central Register, PubMed, Embase, and the Web of Science. Studies were included where the primary outcomes were pain-free walking distance and/or maximal walking distance. When appropriate, eligible studies were independently assessed for quality using the Cochrane Collaboration’s tool for assessing risk of bias. Five studies eligible for inclusion were identified, of which only two were randomized controlled studies. Trial heterogeneity prevented the use of the GRADE system and the implementation of a meta-analysis. Three types of electrical stimulation have been used: neuromuscular electrical stimulation (NMES, n = 3), transcutaneous electrical stimulation ( n = 1), and functional electrical stimulation ( n = 1). The two available randomized controlled studies reported a significant improvement in maximal walking distance (+40 m/+34% and +39 m/+35%, respectively) following a program of NMES. Owing to the low number of eligible studies, small sample size, and the risk of bias, no clear clinical indication can be drawn regarding the efficacy of electrical stimulation for the management of impaired walking function in patients with PAD. Future high-quality studies are required to define objectively the effect of electrical stimulation on walking capacity.
Prevalence and diagnostic value of nail fold capillary microscopy in hereditary hemorrhagic telangiectasia: A retrospective study
Authors: Kroon Steven , Vorselaars Veronique MM , Hosman Anna E , Post Martijn C , Snijder Repke J , Mager Johannes J
Published: April 2020

Abnormal vasculature is a key feature of hereditary hemorrhagic telangiectasia (HHT) and can also present in the nail fold capillary beds. However, the exact prevalence and the clinical diagnostic value in HHT are still largely unknown. The nail fold can be easily and noninvasively inspected with a capillary microscope. We therefore retrospectively assessed the prevalence and diagnostic value of abnormal nail fold capillaries in all patients who were screened between January 2000 and July 2017 for the presence of HHT and underwent capillary microscopy in St Antonius Hospital, The Netherlands. Capillary microscopy results and clinical characteristics were extracted from medical files and the prevalence of abnormal nail fold capillaries was calculated and the diagnostic value of the Curaçao criteria with and without capillary microscopy results was assessed. Of the 1761 individuals screened, 923 (52%) were diagnosed with a clinical and/or genetic HHT diagnosis. In these patients, capillary microscopy was normal in 23% ( n = 218), enlarged loops were seen in 11% ( n = 99), and giant loops in 66% ( n = 606). The sensitivity and specificity of the Curaçao criteria for the diagnosis of HHT without capillary microscopy results were 96% and 90%, respectively. The addition of the presence of giant loops to the Curaçao criteria led to a small increase in sensitivity to 97% without affecting the specificity. In conclusion, the prevalence of nail fold abnormalities in patients with HHT is high. Capillary microscopy can be a useful, easy, and noninvasive diagnostic tool in HHT.
Why do people call crisis helplines? Identifying taxonomies of presenting reasons and discovering associations between these reasons
Authors: Turkington Robin , Mulvenna Maurice D , Bond Raymond R , O’Neill Siobhan , Potts Courtney , Armour Cherie , Ennis Edel , Millman Catherine
Published: April 2020

The objective of this study is to identify the most common reasons for contacting a crisis helpline through analysing a large call log data set. Two taxonomies were identified within the call log data from a Northern Ireland telephone crisis helpline (Lifeline), categorising the cited reason for each call. One taxonomy categorised the reasons at a fine granular level; the other taxonomy used the relatively coarser International Classification of Diseases–10. Exploratory data analytic techniques were applied to discover insights into why individuals contact crisis helplines. Risk ratings of calls were also compared to assess the associations between presenting issue and of risk of suicide as assessed. Reasons for contacting the service were assessed across geolocations. Association rule mining was used to identify associations between the presenting reasons for client’s calls. Results demonstrate that both taxonomies show that calls with reasons relating to suicide are the most common reasons for contacting Lifeline and were a prominent feature of the discovered association rules. There were significant differences between reasons in both taxonomies concerning risk ratings. Reasons for calling helplines that are associated with higher risk ratings include those calling with a personality disorder, mental disorders, delusional disorders and drugs (legal). In conclusion, employing two differing taxonomy approaches to analyse call log data reveals the prevalence of main presenting reasons for contacting a crisis helpline. The association rule mining using each taxonomy provided insights into the associations between presenting reasons. Practical and research applications are discussed.
Key considerations when interviewing individuals with expressive language difficulties
Authors: Verseghy Judy , Atack Lynda , Maher Janet
Published: April 2020

Qualitative research comes with its fair share of challenges; however, those challenges are often amplified when interviewing individuals with intellectual and developmental disabilities. A research project, Friendly Housemates, was conducted where people with intellectual and developmental disabilities were matched with post-secondary students to live together as housemates. Drawing on experience gleaned from interviews conducted for the study and earlier research, recommendations are made for collecting, analyzing, and reporting data from participants who are quiet or have expressive language difficulties. These practices will help to ensure that the voices that are so often relegated to the fringes are brought to the disability research discourse.
Trauma, self-stigma, and visual narrative: participatory research in Shinchimachi, Fukushima, following Japan’s 2011 nuclear disaster
Authors: Kwesell Allison
Published: April 2020

This research employs visual narrative as a tool in processing past trauma and perceptions of an irradiated, contaminated and contagious stigma that created social barriers for residents of Fukushima Prefecture in a post-nuclear disaster context. Residents from Shinchimachi, a village 50km north of the Fukushima Daiichi Nuclear Power Plant, felt that the media’s limited portrayal of their village diminished their lived experiences and they began to be identified by the post-nuclear disaster narrative. This research seeks to determine if visual narration of their own story could empower trauma victims by allowing them to create the story they deem real, offering a space to converse in a small-group setting, and aiding their understanding of their shared experience. A gap exists in current participatory visual methods research, few delving into participants’ resulting internal changes. In the present study, participants’ visual narratives illustrated internal shifts: their memories of the disaster, concerns and hopes, and day-to-day realities of living with a stigma imposed by outsiders and their internalization of it. Findings argue for a new term, visual self-narrative, derived from photographs, captions and photo-elicitation interviews, in order to illustrate changes that occur from the reflective process of visually narrating one’s own story.
A review on the Surface-Piercing Propeller: Challenges and opportunities
Authors: Seyyedi Seyyed Mostafa , Shafaghat Rouzbeh
Published: April 2020

The application of surface-piercing propeller (SPP) has been widely used in high-speed crafts due to possessing many favorable features. Due to the information gaps in the design of SPP, researchers have made great efforts to conduct hydrodynamic analysis of these propulsion systems. Despite the previous studies, there is still a considerable shortage in literature. In this article, a comprehensive review has been carried out on the experimental, theoretical, and experimental–theoretical studies in the field of SPP to introduce the strengths, limitations, and gaps in the previous research. The results of previous studies have also been presented in the form of benchmarking tables and statistical figures. Investigations have proved the inability of the numerical methods to simulate SPP. In recent years, the most precise methods of analyzing complex flows around SPP have been the computational fluid dynamics methods. The most suitable computational fluid dynamics method is the Reynolds-averaged Navier–Stokes method. Moreover, despite the heavy costs of experiments, the experimental approach is still the most reliable way of understanding the flow phenomena, studying the time-dependent dynamic behavior of propellers, and determining the hydrodynamic coefficients of thrust and torque. It can also serve to develop the numerical methods for comparing the results and reducing the errors of semi-experimental equations. Therefore, one of the primary objectives of future studies will be the comprehensive experimental analysis of various propeller blade profiles considering the effect of the variations of the trailing edge angle and the effects of the parameters influencing SPP, especially the shaft inclination angle.
Social inequality in child educational development in China
Authors: Liu Airan , Li Wangyang , Xie Yu
Published: April 2020

Nearly all past studies on educational inequality have examined the relationship between family and children’s educational achievement in western countries. Very few have examined this question in other social contexts, such as China. This article investigates differences in factors that influence children’s development between China and western countries. Capitalizing on recent national representative data, we extend previous studies by using more recent data and considering different measurements of educational outcomes. Our findings show that structural forces, such as hukou and residence, are more important than family and individual characteristics in China for influencing children’s educational outcomes; and that family non-monetary resources such as expectations and parenting practices are more important than family monetary resources such as income, for children’s educational achievement.
Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.
Authors: Cortes Jorge , Talpaz Moshe , O’Brien Susan , Garcia-Manero Guillermo , Ravandi-Kashami Farhad , Giles Francis , Faderl Stefan , Wierda William , Shan Jianqin , Rios Mary Beth , Kantarjian Hagop
Published: April 2020

When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) <100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p < 0.0001), and major cytogenetic response was 48% and 13%, respectively (p <0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p<0.05) included time from diagnosis to treatment >36 mo, splenomegaly, Hgb <10 g/dl, plts <100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils >5%, blasts + promyelocytes >5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p<0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration >1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p<0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.
Outcome of Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia. A Comparison of Cyclophosphamide and Total Body Irradiation Versus VP16 and Total Body Irradiation Conditioning Regimens.
Authors: Gassas Adam , Sung Lillian , Saunders Fred , Doyle John
Published: April 2020

Stem cell transplantation (SCT) has become the standard therapy for children with relapsed acute lymphoblastic leukemia (ALL) or certain high-risk features at diagnosis. The authors report their experience with SCT for 108 children with ALL conditioned with 2 different regimens over 14 years period. Children (0–18y) who received fully matched-related (MRD) or fully matched-unrelated (MUD) for a diagnosis of ALL in the Hospital for Sick Children, Toronto between 1990–1998 were conditioned with a single dose of VP16 (60mg/kg infused over 4 hours) and fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (VP/TBI). Between 1998–2003, children with ALL were conditioned with cyclophosphamide 50mg/kg infused over 1 hour daily for 4 days followed by fractionated total body irradiation (TBI; 1200cGy) in six fractions over 3 days (CY/TBI). All children received cyclosporine A and a short course of methotrexate for graft versus host disease (GVHD) prophylaxis.

Results: Sixty-two children with ALL were conditioned with VP16/TBI, 36 MRD transplantation and 26 MUD transplantation. Median age at SCT was 9.4y (range 0.8–19.4). Remissions status at SCT were; complete remission (CR) 1 (n=17), CR 2 (n=32), and CR 3 (n=12) and one patient received SCT in relapse. Forty-six patients were conditioned with CY/TBI, 23 MRD transplantation and 23 MUD transplantation. Median age at SCT was 9.2y (range 1–17.5) Remissions status at SCT time were; CR 1 (n=11), CR 2 (n=29), and CR 3 (n=6). Neutrophils engraftment (defined as absolute neutrophil count (ANC) of > 0.5 x 109/l for 2 consecutive days) occurred at 19d (range 10–28d) and 17d (range 10–28d) for the VP16/TBI and the CY/TBI groups, respectively. Two patients failed to engraft in the VP16/TBI group, one required re- conditioning with cyclophosphamide and ATG and a second dose of stem cells from the same donor, the other patient sustained a fatal intracranial hemorrhage. There was no significant difference in three years event free survival (EFS) and overall survival (OS) between the groups with EFS and OS of 47 ± 7%, 55 ± 7% for the VP16/TBI and 51 ± 8%, 53 ± 8% for the CY/TBI group. There was no significant difference in the incidence of acute or chronic graft versus host disease (GVHD), transplant related mortality (TRM) between the 2 groups.

Conclusion: Both VP16/TBI and CY/TB regimen are equally effective preparative regimens for SCT in pediatric ALL.
Imatinib’s Potential Effects on Fertility, Immunity and Pulmonary Function: A Prospective Study in Patients with Previously Untreated CML.
Authors: Seymour John Francis , Grigg Andrew , Reynolds John , Matthews Jane , Schwarer Anthony P. , Herrmann Richard , Taylor Kerry McDonald , Hertzberg Mark S. , Mills Anthony , Guzzo-Pernell Nancy , Copeman Michael , Lynch Kevin , Hughes Timothy
Published: April 2020

Imatinib therapy was rapidly introduced for CML because of its efficacy and tolerability, so ongoing scrutiny is warranted to elucidate any effects not seen in registration trials. Imatinib strongly inhibits several tyrosine kinases (abl, arg, kit, and pdgfr’s) with functions in normal tissues. Mice lacking these genes have impaired male fertility (abl or kit knockouts), B- and T- cell lymphopenia (abl), emphysema (pdgf) and glomerular dysfunction (pdgf). Hence, we prospectively analysed chronic-phase CML patients on higher-dose imatinib (Hughes TP et al. Abstract #95 ASH 2003) for fertility, immunoglobulin levels, lymphocyte sub-sets and pulmonary function over 1 year. 39/103 patients participated in the safety sub-study, with median age 50 (range 28–75), on median daily imatinib doses of 558–575mg.

In 20 males tested, median serum testosterone (in nmol/L) changed little, from 12.8 at baseline to 14.7 at 6 months, to 11.4 at 1 year (Wilcoxon p=0.05). Serum LH, FSH and oestradiol were unchanged. Only 2 patients had repeat sperm counts: one recovered from azoospermia to have low counts; the other had normal counts at baseline and 6 months. In 20 females, there were no changes in median serum progesterone, oestradiol or LH. FSH (in U/L) fell from 25 to 5 at 6 months, but rose to 21 at 1 year (p=0.03). Median serum IgG levels (in g/L; n=34) fell from 10.5 to 9.8 at 6 months, to 8.6 at 1 year (p<0.0001). Serum IgM (in g/L) also fell from 1.4 to 0.8 at 6 months, to 0.9 at 1 year (p=0.0003). Serum IgA declined from 1.6 to 1.5g/L (p=0.002). There were no consistent changes in median B−, NK− or CD8+ T-cell counts (n=26). T-cell counts declined, with falls in CD4+ cells (x10^9/L) from 1.0 to 0.7 at 6 months, to 0.6 at 1 year (p=0.003). 3 of 39 patients had Grade 3–4 infections; in all 3, lower IgM’s were noted (with one below normal) at 6 months; in one case IgG and IgA also fell below normal. Pulmonary function tests (n=32) showed no consistent changes. Median FEV1 (in L) fell from 3.64 to 3.22 at 6 months (p=0.03), but rose to 3.52 at 1 year. Vital Capacity (in L) also fell from 4.89 to 4.12 at 6 months (p=0.02), but rose to 4.60 at 1 year. DLCO improved marginally. PEFR (in L/sec) trended down from 8.79 to 7.37 at 6 months, to 7.68 at 1 year. There was no evidence of glomerular dysfunction, measured by 24-hour urinary protein. In summary, in patients with chronic-phase CML treated with imatinib at a median dose of ~600mg/day for 1 year, changes in hormonal, immune and pulmonary parameters were recorded. Declines in serum IgG and IgM were highly significant, but were not associated with lower B-cell numbers. These data reveal novel and potentially clinically relevant effects in CML patients on imatinib.
Treosulfan/Fludarabine - a Low Toxicity but Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia.
Authors: Holowiecki Jerzy , Giebel Sebastian , Wojnar Jerzy , Krawczyk-Kulis Malgorzata , Wylezol Iwona , Kruzel Tomasz , Markiewicz Miroslaw
Published: April 2020

Although allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only treatment of proved long-term efficacy in chronic myeloid leukemia (CML), high procedure-related toxicity observed after oral busulfan- or TBI-based conditioning limits its applicability and deteriorates outcome.

In a series of 13 CML patients (age 35, range 16–52 years) we introduced a novel myeloablative conditioning regimen consisting of Treosulfan (alkylyting agent, soluble Busulfan-derivative) 14 g/m2/d. on days −6, −5, −4, Fludarabine 30 mg/m2/d on days −5, −4, −3, −2, −1, and, in case of unrelated donor transplants (URD-HSCT), anti-thymocyte globulin (Thymoglobulin) at a total dose of 6 mg/kg. Twelve patients were in the 1st chronic phase, one - in 2nd chronic phase. Median disease prior to alloHSCT equaled 10 (6–90) months. 8 patients were given transplant from an unrelated donor, 5 - from HLA identical sibling. GVHD prophylaxis consisted of cyclosporin A and short-course Methotrexate.

All patients engrafted after a period of absolute agranulocytosis. Median time to neutrophil recovery >0.5 G/L was 24 (13–42) days, and to PLT >50 G/L - 21 (13–38) days. 1/13 patient experienced grade 3 mucositis; no severe neutropenic infection nor hepatic toxicity was observed. None of the patients developed grade III–IV acute GVHD, 1/13 patient experienced grade II acute GVHD. One patient died of EBV-related lymphoproliferative disease; the cumulative incidence of transplant-related mortality at 1 year equaled 8% (1/13).

11/13 patients achieved complete molecular remission and complete donor chimerism within 100 days after alloHSCT. The remaining two patients required immunosuppression taper and additional interferone treatment. The probability of current disease-free survival at one year equaled 92%. We conclude that Treosulfan/Fludarabine +/− ATG myeloablative conditioning is characterized by reduced toxicity and low incidence of acute GVHD. This together with high anti-leukemic efficacy makes the regimen feasible in CML patients.
Experience with Epidural Anesthesia in Pregnant Women with Von Willebrand Disease.
Authors: Varughese Jay , Cohen Alice J.
Published: April 2020

Von Willebrand Disease (vWD) is an autosomal dominant inherited bleeding disorder that is characterized by epistaxis, mucosal and postoperative bleeding, menorrhagia and postpartum hemorrhage. In particular, there is a paucity of safety data for, and thus a reluctance to use, epidural anesthesia (EA) for delivery. We thus conducted a review of all women followed with vWD in a referral hemophilia clinic who had ≥ 1 pregnancy. Thirty-three subjects were screened; 31/33 (94%) had type 1 and 2/33 (6%) had type 2A vWD. There were 59 term pregnancies (range 1–3 per patient), and 5 fetal losses (in 4 patients). Of the term pregnancies, 16/59 (27%) were delivered by Caesarian Section (C-Section), complicated by postpartum hemorrhage in 3 (19%); 43/59 (73%) were delivered by normal spontaneous vaginal delivery (NSVD), complicated by hemorrhage in 21 (49%) (p=0.05). EA was administered during 14 (13 with type 1 vWD) of 59 (24%) of the deliveries, all without DDAVP, plama-derived factor VIII-von Willebrand factor containing concentrates or blood products, and in no patient were bleeding complications encountered at the site of EA nor were there any neurologic complications. Conclusion: Postpartum hemorrhage was a common complication in patients with vWD, more after NSVD than C-Section. In a selected subset, EA was safely administered without bleeding complications, possibly due to pregnancy induced increase in factor VIII:C and von Willebrand factor activity counteracting the tendency to bleed. Larger series and prospective studies should be performed to confirm the safety of EA and the relationship to coagulation factor levels in pregnant women with vWD.
Efficacy and Safety of the Gardos Channel Inhibitor, ICA-17043, in Patients with Sickle Cell Anemia.
Authors: Ataga Kenneth I. , DeCastro Laura M. , Swerdlow Paul , Saunthararajah Yogen , Smith Wally ,   The ICA-17043 Study Investigators6
Published: April 2020

The rate and extent of hemoglobin S (HbS) polymer formation in the circulating sickle erythrocyte (RBC) is strongly influenced by the intracellular concentration of HbS. ICA-17043 (bis(4-fluorophenyl)phenyl acetamide) is a novel Gardos channel inhibitor that specifically blocks Ca++-dependent K+ efflux from the human RBC. By limiting the loss of K+, Cl−, and water, this drug preserves the hydration status of the RBC, prevents increases in HbS concentration and thereby inhibits HbS-polymerization. We hypothesized that ICA-17043 could decrease both the hemolytic rate and vaso-occlusive complications of sickle cell anemia (SCA). In a recently completed multicenter, parallel-group, randomized, double-blind, dose-range-finding study, we examined the efficacy and safety of ICA-17043 in patients with SCA. In this 12-week study, 90 patients were randomized into 3 arms: placebo; low dose ICA-17043 (6 mg); and high dose ICA-17043 (10 mg). The primary outcome variable was the change in hemoglobin (Hb) from baseline to the end of the study. A total of 90 subjects were enrolled in this study, 80 of whom completed the 12-week treatment period. Using an intent-to-treat analysis, we found a significant increase from baseline of the total Hb when the subjects in the high dose arm (0.68 ± 0.11 g/dL, S.E.) were compared to those in the placebo arm (0.01 ± 0.12 g/dL), p < 0.001. Although an increase in Hb was also seen in the subjects in the low dose arm (0.28 ± 0.15 g/dL), this smaller change failed to reach statistical significance.

Figure Figure

In addition to the increase in Hb (as well as similar increases in hematocrit and RBC count), statistically significant decreases were noted after 12 weeks on 10 mg of ICA-17043 vs. placebo in the following variables: a) dense RBC (% with Hb >41 g/dL) [−2.41 vs. −0.08, p < 0.001]; b) reticulocyte count (%) [−4.12 vs. −0.46, p <0.001]; c) LDH (u/L) [−121 vs. −15, p = 0.002]; and d) indirect bilirubin (mg/dL) [−1.18 vs. 0.12, p < 0.001]. ICA-17043 was well tolerated by the subjects. The most common adverse experiences were diarrhea and nausea, both of which occurred more frequently in the subjects receiving active treatment than in those on placebo. No patients died during the study, and only 3 of the 10 patients who dropped out of the study did so because of adverse events. In summary, we found that 12 weeks of treatment with ICA-17043 at a dose of 10 mg/d produced a significant increase in Hb and significant decreases in the various markers of RBC destruction. Furthermore, we found this drug to be safe and well tolerated. Therefore, based on the beneficial, dose-dependent RBC effects, a Phase III study has now been designed that will examine the clinical effect of ICA-17043 on the frequency of vaso-occlusive events in patients with sickle cell disease.
Pharmacokinetics of C1 Esterase Inhibitor, Human (Pasteurized) in Subjects with Hereditary Angioedema.
Authors: Kreuz Wolfhart , Martinez-Saguer Inmarculada , Stoll Hildegard , Knaub Sigurd , Klingebiel Thomas
Published: April 2020

Hereditary and acquired deficiencies in C1 inhibitor (C1-INH) function can result in potentially life-threatening attacks of hereditary angioedema (HAE). A highly purified and pasteurized C1-INH concentrate has been used effectively as prophylaxis against and treatment for angioedema attacks in patients with hereditary C1-INH deficiencies, but relatively little is known about its pharmacokinetic properties.

Objective: To evaluate the pharmacokinetics and in vivo recovery (IVR) of C1-INH concentrate (Berinert®P) in two groups of patients with hereditary angioedema (HAE) receiving this preparation either as individual replacement therapy (IRT, regular, immediate treatment of first HAE symptoms in patients with frequent and severe attacks) or as on-demand treatment.

Methods: Forty subjects (15 under IRT, 25 under on-demand treatment) with HAE received intravenous injections of C1-INH (542–1,617 U) in an attack-free interval in a prospective, open, uncontrolled, single-center study. Blood was sampled for determination of C1-INH with a commercially available functional chromogenic assay for up to 72 hours after dosing. Pharmacokinetic parameters were calculated using a single-compartment model and IVR was determined using standard methods.

Results: The mean (± SD) time to maximum plasma concentration (Tmax) for C1-INH administered in patients under IRT was 1.3 ± 2.1 hours, the area under the time versus plasma concentration curve (AUC) was 20.5 ± 19.1 hour•U/mL, the elimination half-life (t½) was 33.3 ± 19.8 hours, mean residence time (MRT) was 48.0 ± 28.5 hours, total body clearance (Cl) was 1.1 ± 0.6 mL/kg/hour, and volume of distribution at steady state (Vss) was 39.5 ± 9.9 mL/kg. The respective values for patients treated on demand were 2.9 ± 6.5 hours, 20.0 ± 14.5 hour•U/mL, 43.9 ± 22.4 hours, 63.4 ± 32.3 hours, 1.2 ± 1.0 mL/kg•hour, and 51.4 ± 10.9 mL/kg. The mean IVRs for IRT and on-demand treatment were 108.2 ± 48.3% and 85.8 ± 28.3%, respectively. Children tended to have slightly lower half-life and a slightly higher Vss compared to adults.

Conclusions: C1-INH concentrate has a short Tmax and a long, t½ and MRT consistent with the rapid onset of clinical efficacy for this preparation in subjects suffering angioedema attacks and the ability to effectively carry out IRT with injections administered every 2–5 days. This analysis provides to our knowledge the most comprehensive pharmacokinetic evaluation in subjects with HAE.
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome) with Transfusion Requirement. Effect of Danazol in 18 Patients with Long Follow-Up.
Authors: Fernandez Jose , Riveros Dardo , Garay Guy , Campestri Reinaldo , Garate Gonzalo , Grand Beatriz , Dupont Juan , Cacchione Roberto
Published: April 2020

Hereditary hemorrhagic telangiectasia (HHT) is a relatively uncommon, autosomal dominant disorder characterized by telangiectases that develop in the skin, mucous membranes, and visceral organs. Mucous localization may seldom bleed profusely, especially epistaxis and upper gastrointestinal (GI) tract. Effective drug treatment is not well established, and multiple blood transfusions and endoscopic or surgical procedures may be the ultimate solution to the frequently bleeding HHT patient. Danazol (DZ) is a mild androgen that has been used in small series of HHT pts with ambiguous results. Its toxicity profile in long standing administration is now well known. Eighteen patients with HHT with transfusion requirements (TR) were treated with DZ at 400–600 mg/daily for the initial three months and 200–400 mg/daily thereafter as a maintenance treatment. At the time of initiation of DZ therapy, median age was 54 yr-old (32–73), nine were female and 9 male, and the median previous TR was 16 RBC units/yr. (2–46). All patients had epistaxis and oral cavity bleeding, with 2 additional upper gastrointestinal tract active bleeding that were detected in ten patients in which an upper GI endoscopy was performed. One patient had a cerebral angioma, surgically treated. None had pulmonary fistula. All patients had some kind of iron treatment. DZ was the first drug treatment intended to reduce the HHT bleeding in 10/18 pts. Median follow-up was 7 years (1.2–14) and two pts were lost to follow-up at 4 and 11 years respectively. At three months of DZ therapy, 12/18 pts (66.6%) showed a remarkable reduction of bleeding, and in 6 patients that showed no response, DZ treatment was stopped. In 7 pts (39%) TR dropped to none and in 5 pts median RT dropped from 22 RBC units/yr. to 10 units/yr. Two of responders had a relapse with upper GI tract bleeding and 1 pts with epistaxis within the first 2 years of DZ treatment. Attempts to reduce the maintenance dose below 200 mg/daily were related to new bleeding or worsening of the active sites. None of the long standing DZ therapy had any significant toxicity. DZ treatment have shown efficacy and safety in this cohort of HHT patients. Mecanism of action may involve the increase of synthesis or expression of ALK-1 dependent proteins and less likely of endoglin. We propose DZ as a first line treatment for the transfusion dependent HHT patients.
Hereditary Protein S Type III Deficiency Is Not a Risk Factor for Venous and Arterial Thrombosis, in Contrast to Protein S Deficiency Type I. Results from a Family Cohort Study To Assess the Clinical Impact of a Laboratory Based Classification.
Authors: Brouwer Jan-Leendert P. , Veeger Nic J.G.M. , van der Schaaf Wim , Kluin-Nelemans Hanneke C. , van der Meer Jan
Published: April 2020

A family cohort study was performed to assess the absolute risk of thromboembolism associated with inherited protein S (PS) deficiency type I and type III. Probands were consecutive patients with thromboembolism and either type I or type III deficiency. Of living first degree relatives (age>15 years), 156 (90%) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) were analyzed. Annual incidences of venous thromboembolism were 1.47 and 0.17 in deficient and non-deficient relatives in cohort 1 (RR 8.9; 95% CI 2.6–30.0), and 0.27 versus 0.24 in cohort 2 (RR 0.9; 95% CI 0.4–2.2). The cut off level of free PS to identify subjects at risk was 30%. Lower levels were found in 40% and 1% of relatives in cohort 1 and 2, respectively. We demonstrated that the cut-off level of free PS is considerably lower than the lower limit of its normal range in healthy volunteers, that is commonly used (in our study 30% in stead of 65%). If we had used only a total PS assay, 8 (2%) relatives at risk would have been missed, but 67% (346/517) of relatives would not be tested. Only testing for free PS deficiency (free PS levels <65%) would have increased the number of tested relatives, but 179 (35%) relatives would be wrongly classified as at risk. Neither type I nor type III deficiency were associated with arterial thromboembolism. In conclusion, inherited PS deficiency type I, but not type III showed to be a strong risk factor for venous thromboembolism. This difference was due to lower free PS levels in type I deficient subjects and a free PS cut-off level that was half of the lower limit of its normal range.
The Cell Expression of PML-RARa at Diagnosis Has a Marginal Correlation with Prognosis in Patients with Acute Promyelocytic Leukemia (APL).
Authors: Fernández Carina , Chillón Carmen , Blázquez Lorena , Ramos F. , Fernández-Calvo J. , Rayón C. , Balanzategui A. , Martín-jiménez P. , Alcoceba M. , Sarasquete M. E. , Armellini A. , García-Sanz R. , González M. , Miguel J.F. San
Published: April 2020

Acute promyelocytic leukaemia (APL) is characterised by the t(15;17) leading to the fusion of the PML gene with the retinoic acid receptor a (RARa) gene. APL is associated with favourable prognosis, however, approximately 15–20% of patients ultimately relapse. With regards to pre-treatment characteristics, is now clear that long-established prognostic factors such as age and leukocyte count have a major impact on outcome. However, none of these parameters is robust enough, in order to adjust treatments strategies according to the risk of relapse. The quantification of PML-RARa fusion gene transcripts (leukemia-specific chimeric mRNA) can add important prognostic information useful for risk group stratification. However, few clinical studies have been carried out and there are discrepancies concerning the prognostic significance of the quantification of fusion gene transcripts of newly diagnosed patients. In this study we tested the PML- RARa fusion gene transcripts level in 126 newly diagnosed patients with t (15;17) in order to determine their correlation with disease characteristics at presentation and to identify a subset of patients at high risk of relapse. The presence of the PML- RARa fusion gene transcripts was analysed from 1mg of RNA by real-time quantitative RT-PCR (RQ-PCR) based on TaqMan probes and the 7700 Sequence Detector, performed according to the “Europe Against Cancer Program” (Leukemia2003, 17:2323; 2318–2357).

Results: In 121 out of 126 patients, evaluable data were obtained: 73 (60,3%) cases had bcr-1, 4 (3,3%) cases had bcr-2 and 44 (36,4%) cases had bcr-3 fusion types. The expression of the fusion gene was reported as the PML- RARa normalized quantities (NQ, number of PML- RARa copies per 1x104 ABL copies as gene control). The median of NQ was 3030 and the expression was highly variable (range of 826 to 9605). The NQ was not significantly associated with disease characteristic at diagnosis, such as age, percentage of blasts cells, fusion types and platelet counts. Nevertheless, patients with NQ above 3000 had lower white cell counts (7,4±12,1 vs 24,2±39,3x109/L, p=0,03). Therefore, the fusion transcript copy number per leukemic cell was higher in patients with lower leukocyte count. Moreover, in survival analysis, the NQ did not correlate with disease free survival or overall survival.

Conclusions: Our data confirms the wide range of differences in expression activity between individual patients. The NQ did not correlate with the clinical and biological disease characteristics except for white cell counts. Neither did it correlate with principal prognostic parameters (response and survival).
Genetic Instability in Remission Hematopoiesis Is Different from That in AML Blasts: A New Diagnostic Tool to Study Biology of AML.
Authors: Reichle Albrecht , Panzer Birgit , Goetz Gerlinde , Raffer Michael , Zaiss Matthias , Andreesen Reinhard , Wild Peter , Hofstaedter Ferdinand , Dietmaier Wolfgang
Published: April 2020

Recently we have shown that aberrations, ie microsatellite instability (MSI) and allelic imbalance (AI) in positively selected CD34+ cells from leukapheresis products collected during first complete remission of de novo AML following double induction or consolidation according to AMLCG protocol may be predictive for relapse-free survival (RFS). Here we present data of an extended patient population treated on the same protocol. We compared MSI/AI pattern in CD34+ cells (n=60) with the corresponding pattern in AML blasts at diagnosis (n=60) or at relapse (n=12), and compared the AI/MSI pattern in CD34+ cells with those observed in the corresponding unselected bone marrow aspirates in first CR (n=50). The following loci were tested: D7S486, D7S525, D8S559, TP53, D11S1356, D2S123, APC, MfD5. Minimal residual disease (MRD) in the tested remission specimen (FACS analysis) was <0.1%. MSI and/or AI at diagnosis could be detected in few cases (10 of 60, 17%), whereas CD34+ cells were tested positive in 25 of 60 cases (42%), and in 5 of 12 relapses studied (42%). Analysis of AI and MSI in DNA of bone marrow aspirates could not adequately confirm MSI and/or AI detectable in the corresponding CD34+ cells (n=3 cases, 12%). In 15 cases MSI and/or AI was observed in CD34+ cells, but not in AML blasts at diagnosis, in 5 cases in blasts at diagnosis, but not in CD34+ cells, in 4 cases in AML blasts at diagnosis and in CD34+ cells. Identical AI/MSI pattern were found in CD34+ cells and in AML blasts at relapse (n=2), as well as in AML blasts at diagnosis and relapse (n=1). According to the definition of genetic instability (GIN: MSI or >2 AI at any locus, AI at APC locus), GIN in CD34+ cells was predictive for unfavorable RFS (p=0.001). In conclusion, detection of AI/MSI in CD34+ cells of remission hematopoiesis represents a new important diagnostic tool to study biology of AML besides the detection of MRD. For the first time we could demonstrate, that the same AIs or MSIs detectable in CD34+ cells, but not in AML blasts at diagnosis may occur in AML blasts at relapse.
High Levels of Soluble HLA-I in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: Relevance to Clinical Behavior and b2M Levels.
Authors: Albitar Maher , Johnson Marcy , Do Kim-Ann , Day Amanda , Jilani Iman , Pierce Sherry , Estey Elihu , Kantarjian Hagop , Keating Michael , Verstovsek Srdan , O’Brien Susan , Giles Francis J.
Published: April 2020

Human leukocyte antigen-class I (HLA-I) molecules are membrane-associated proteins that contain two separate polypeptide chains: an alpha heavy chain and a beta chain. The beta chain is the b-2 microglobulin (b2-M). Significant levels of free soluble HLA-I (sHLA-I) have been detected in serum and studied as a marker for immunomodulation in patients with infection and after transplant. Little is known about the role of sHLA-I as a tumor marker, despite the documentation of b2-M as a tumor marker. We measured the levels of sHLA-I and b2-M in the plasma of 205 patients with acute myeloid leukemia (AML) and 95 patients with myelodysplastic syndrome (MDS) and assessed the value of both markers in predicting clinical behavior. Both sHLA-I and b2-M were strong predictors of response to therapy (P = 0.03 and P = 0.001, respectively), overall survival (both P <0.0001), and remission duration (both P <0.001). The Multivariate Cox proportional hazards model incorporating cytogenetics, b2-M, and sHLA-I demonstrated that only b2-M was an independent predictor of survival. In patients with MDS, b2-M but not sHLA-I correlated with response to therapy, overall survival, and response duration. These data not only establish the role of sHLA-I as a tumor marker in AML, but also suggest that MDS disease is significantly different from AML. Because sHLA-I has been reported to be an immunomodulator that inhibits the cytotoxic effects of T-lymphocytes, its role as an immunomodulator in patients with MDS needs further investigation.

Figure Figure
Clinical Relevance of Circulating Myeloperoxidase (MPO) in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).
Authors: Jilani Iman , Vincenti Ted , Faraji Homan , Giles Francis J. , Estey Elihu , Kantarjian Hagop M. , Albitar Maher
Published: April 2020

MPO, a hemoprotein expressed in polymorphonuclear neutrophils and their precursors, is an important component of the antimicrobial activity of phagocytes and is associated with inflammatory response. Cellular expression levels of MPO, assessed by cytochemical staining, are used extensively for the diagnosis and subtyping of various leukemias. However, the association of circulating (plasma or serum) MPO levels with hematologic values and clinical outcomes of AML and MDS has not been reported. We investigated whether MPO, presumably released from leukemic cells, can be detected in the plasma of patients with AML and MDS. We further assessed the association of plasma MPO levels with hematologic characteristics and outcomes. 144 patients with AML, 28 patients with MDS, and 100 control subjects were included in the analysis. Patients with AML (median 19.3, range 1.0–9514.7 ng/mL) and MDS (median 13.6, range 1.0–3021.9 ng/mL) had significantly higher plasma MPO levels than control subjects (median, 4.9; range, 3.5–20.6 ng/mL). Because MPO levels and overall survival did not differ significantly between AML and MDS patients, the 2 groups were considered together in subsequent analyses. MPO levels were inversely correlated with overall survival (Cox regression analysis, P<0.001). In the multivariate model, the inverse correlation between MPO levels and survival was independent of cytogenetics, performance status, anticident hematologic disease (AHD), age, and diagnosis (AML vs MDS). Response to therapy in AML and MDS patients was not associated with plasma MPO levels. However, responders with high MPO levels had shorter remission duration (CRD), although this difference did not reach statistical significance (P = 0.07). As expected, MPO levels correlated with the level of differentiation of leukemic cells (FAB subclassification): patients with M0 and M6 had lower MPO levels than those with M2, M3, or M4 (P = 0.0001). MPO levels also correlated positively with white cell count, beta2-microglobulin, monocyte, LDH, BUN, and creatinine levels. These data indicate that plasma MPO levels are elevated in AML and MDS and may be useful as a prognostic factor. Our findings also raise the question of how the proinflammatory properties of MPO might affect the clinical course of these diseases.