The InSight HP3 Penetrator (Mole) on Mars: Soil Properties Derived from the Penetration Attempts and Related Activities.

The NASA InSight Lander on Mars includes the Heat Flow and Physical Properties Package HP3 to measure the surface heat flow of the planet. The package uses temperature sensors that would have been brought to the target depth of 3-5 m by a small penetrator, nicknamed the mole. The mole requiring friction on its hull to balance remaining recoil from its hammer mechanism did not penetrate to the targeted depth. Instead, by precessing about a point midway along its hull, it carved a 7 cm deep and 5-6 cm wide pit and reached a depth of initially 31 cm. The root cause of the failure - as was determined through an extensive, almost two years long campaign - was a lack of friction in an unexpectedly thick cohesive duricrust. During the campaign - described in detail in this paper - the mole penetrated further aided by friction applied using the scoop at the end of the robotic Instrument Deployment Arm and by direct support by the latter. The mole tip finally reached a depth of about 37 cm, bringing the mole back-end 1-2 cm below the surface. It reversed its downward motion twice during attempts to provide friction through pressure on the regolith instead of directly with the scoop to the mole hull. The penetration record of the mole was used to infer mechanical soil parameters such as the penetration resistance of the duricrust of 0.3-0.7 MPa and a penetration resistance of a deeper layer ( > 30 cm depth) of 4.9 ± 0.4 MPa . Using the mole's thermal sensors, thermal conductivity and diffusivity were measured. Applying cone penetration theory, the resistance of the duricrust was used to estimate a cohesion of the latter of 2-15 kPa depending on the internal friction angle of the duricrust. Pushing the scoop with its blade into the surface and chopping off a piece of duricrust provided another estimate of the cohesion of 5.8 kPa. The hammerings of the mole were recorded by the seismometer SEIS and the signals were used to derive P-wave and S-wave velocities representative of the topmost tens of cm of the regolith. Together with the density provided by a thermal conductivity and diffusivity measurement using the mole's thermal sensors, the elastic moduli were calculated from the seismic velocities. Using empirical correlations from terrestrial soil studies between the shear modulus and cohesion, the previous cohesion estimates were found to be consistent with the elastic moduli. The combined data were used to derive a model of the regolith that has an about 20 cm thick duricrust underneath a 1 cm thick unconsolidated layer of sand mixed with dust and above another 10 cm of unconsolidated sand. Underneath the latter, a layer more resistant to penetration and possibly containing debris from a small impact crater is inferred. The thermal conductivity increases from 14 mW/m K to 34 mW/m K through the 1 cm sand/dust layer, keeps the latter value in the duricrust and the sand layer underneath and then increases to 64 mW/m K in the sand/gravel layer below. Supplementary Information: The online version contains supplementary material available at 10.1007/s11214-022-00941-z.

Spacecraft sample collection and subsurface excavation of asteroid (101955) Bennu.

Carbonaceous asteroids, such as (101955) Bennu, preserve material from the early Solar System, including volatile compounds and organic molecules. We report spacecraft imaging and spectral data collected during and after retrieval of a sample from Bennu's surface. The sampling event mobilized rocks and dust into a debris plume, excavating a 9-meter-long elliptical crater. This exposed material is darker, spectrally redder, and more abundant in fine particulates than the original surface. The bulk density of the displaced subsurface material was 500 to 700 kilograms per cubic meter, which is about half that of the whole asteroid. Particulates that landed on instrument optics spectrally resemble aqueously altered carbonaceous meteorites. The spacecraft stored 250 ± 101 grams of material, which will be delivered to Earth in 2023.

Ganymede Observations by JunoCam on Juno Perijove 34.

During the Juno Mission's encounter with Ganymede on 7 June 2021, the Juno camera (JunoCam) acquired four images of Ganymede in color. These images covered one-sixth of Ganymede at scales from 840 m to ∼4 km/pixel. Most of this area was only previously imaged by Voyager 1 in 1979, at lower spatial resolution and poorer image quality. No changes were observed over this area of Ganymede in the 42 years since Voyager. JunoCam provided overlapping coverage, from which we developed a digital elevation model of the best-resolved area. A 3 km high dome at the subjovian point was confirmed, 450 km by 750 km. We used the JunoCam images to refine the geologic map of Ganymede in eastern Perrine Regio.

Geology of the InSight landing site on Mars.

The Interior Exploration using Seismic Investigations, Geodesy and Heat Transport (InSight) spacecraft landed successfully on Mars and imaged the surface to characterize the surficial geology. Here we report on the geology and subsurface structure of the landing site to aid in situ geophysical investigations. InSight landed in a degraded impact crater in Elysium Planitia on a smooth sandy, granule- and pebble-rich surface with few rocks. Superposed impact craters are common and eolian bedforms are sparse. During landing, pulsed retrorockets modified the surface to reveal a near surface stratigraphy of surficial dust, over thin unconsolidated sand, underlain by a variable thickness duricrust, with poorly sorted, unconsolidated sand with rocks beneath. Impact, eolian, and mass wasting processes have dominantly modified the surface. Surface observations are consistent with expectations made from remote sensing data prior to landing indicating a surface composed of an impact-fragmented regolith overlying basaltic lava flows.

Variation in lung function and nutritional decline in cystic fibrosis by genotype: An analysis of the Canadian cystic fibrosis registry.

BACKGROUND: This study aimed to improve our understanding of the natural history of cystic fibrosis (CF) by comparing lung function and body mass index z-score (zBMI) between patients with different genotypes and identify a genotype with outcomes most comparable to homozygous ΔF508 patients. METHODS: Data was obtained from the Canadian CF Registry between January 1st 2007-January 1st 2016. Patients were categorized into one of five groups based on their genotype. A mixed-effects model was conducted with adjustments for age, sex, age of diagnosis, and baseline clinical measures. RESULTS: Among 2612 patients, those with non-mild forms of CF, and particularly adult patients with the same functional allele classification were found to have a lung function trajectory comparable to individuals with the homozygous ∆F508 genotype (annual change in percent predicted forced expiratory volume in 1 s of -0.83, 95% CI: -0.93, -0.73). The rates of zBMI change over the study period were not significantly different between the genotype groups. CONCLUSION: This population-based study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. The finding that there are different genotypes with comparable rates of lung function decline to patients of the homozygous ∆F508 group supports the use of multiple comparison groups to assess the long-term efficacy of emerging CF therapies.

Mapping the preclinical to clinical evidence and development trajectory of the oncolytic virus talimogene laherparepvec (T-VEC): a systematic review.

OBJECTIVE: This study aimed to conduct a systematic review of preclinical and clinical evidence to chart the successful trajectory of talimogene laherparepvec (T-VEC) from the bench to the clinic. DESIGN: This study was a systematic review. The primary outcome of interest was the efficacy of treatment, determined by complete response. Abstract and full-text selection as well as data extraction were done by two independent reviewers. The Cochrane risk of bias tool was used to assess the risk of bias in studies. SETTING: Embase, Embase Classic and OvidMedline were searched from inception until May 2016 to assess its development trajectory to approval in 2015. PARTICIPANTS: Preclinical and clinical controlled comparison studies, as well as observational studies. INTERVENTIONS: T-VEC for the treatment of any malignancy. RESULTS: 8852 records were screened and five preclinical (n=150 animals) and seven clinical studies (n=589 patients) were included. We saw large decreases in T-VEC's efficacy as studies moved from the laboratory to patients, and as studies became more methodologically rigorous. Preclinical studies reported complete regression rates up to 100% for injected tumours and 80% for contralateral tumours, while the highest degree of efficacy seen in the clinical setting was a 24% complete response rate, with one study experiencing a complete response rate of 0%. We were unable to reliably assess safety due to the lack of reporting, as well as the heterogeneity seen in adverse event definitions. All preclinical studies had high or unclear risk of bias, and all clinical studies were at a high risk of bias in at least one domain. CONCLUSIONS: Our findings illustrate that even successful biotherapeutics may not demonstrate a clear translational road map. This emphasises the need to consider increasing rigour and transparency along the translational pathway. PROSPERO REGISTRATION NUMBER: CRD42016043541.

Assessing the Completeness of Reporting in Preclinical Oncolytic Virus Therapy Studies.

Irreproducibility of preclinical findings could be a significant barrier to the "bench-to-bedside" development of oncolytic viruses (OVs). A contributing factor is the incomplete and non-transparent reporting of study methodology and design. Using the NIH Principles and Guidelines for Reporting Preclinical Research, a core set of seven recommendations, we evaluated the completeness of reporting of preclinical OV studies. We also developed an evidence map identifying the current trends in OV research. A systematic search of MEDLINE and Embase identified all relevant articles published over an 18 month period. We screened 1,554 articles, and 236 met our a priori-defined inclusion criteria. Adenovirus (43%) was the most commonly used viral platform. Frequently investigated cancers included colorectal (14%), skin (12%), and breast (11%). Xenograft implantation (61%) in mice (96%) was the most common animal model. The use of preclinical reporting guidelines was listed in 0.4% of articles. Biological and technical replicates were completely reported in 1% of studies, statistics in 49%, randomization in 1%, blinding in 2%, sample size estimation in 0%, and inclusion/exclusion criteria in 0%. Overall, completeness of reporting in the preclinical OV therapy literature is poor. This may hinder efforts to interpret, replicate, and ultimately translate promising preclinical OV findings.

Monitoring and Modeling the Rapid Evolution of Earth's Newest Volcanic Island: Hunga Tonga Hunga Ha'apai (Tonga) Using High Spatial Resolution Satellite Observations.

We have monitored a newly erupted volcanic island in the Kingdom of Tonga, unofficially known as Hunga Tonga Hunga Ha'apai, by means of relatively frequent high spatial resolution (~50 cm) satellite observations. The new ~1.8 km2 island formed as a tuff cone over the course of a month-long hydromagmatic eruption in early 2015 in the Tonga-Kermadec volcanic arc. Such ash-dominated eruptions usually produce fragile subaerial landscapes that wash away rapidly due to marine erosion, as occurred nearby in 2009. Our measured rates of erosion are ~0.00256 km3/year from derived digital topographic models. Preliminary measurements of the topographic expression of the primary tuff cone over ~30 months suggest a lifetime of ~19 years (and potentially up to 42 years). The ability to measure details of a young island's landscape evolution using satellite remote sensing has not previously been possible at these spatial and temporal resolutions.

Comparing Twitter data to routine data sources in public health surveillance for the 2015 Pan/Parapan American Games: an ecological study.

OBJECTIVES: This study examined Twitter for public health surveillance during a mass gathering in Canada with two objectives: to explore the feasibility of acquiring, categorizing and using geolocated Twitter data and to compare Twitter data against other data sources used for Pan Parapan American Games (P/PAG) surveillance. METHODS: Syndrome definitions were created using keyword categorization to extract posts from Twitter. Categories were developed iteratively for four relevant syndromes: respiratory, gastrointestinal, heat-related illness, and influenza-like illness (ILI). All data sources corresponded to the location of Toronto, Canada. Twitter data were acquired from a publicly available stream representing a 1% random sample of tweets from June 26 to September 10, 2015. Cross-correlation analyses of time series data were conducted between Twitter and comparator surveillance data sources: emergency department visits, telephone helpline calls, laboratory testing positivity rate, reportable disease data, and temperature. RESULTS: The frequency of daily tweets that were classified into syndromes was low, with the highest mean number of daily tweets being for ILI and respiratory syndromes (22.0 and 21.6, respectively) and the lowest, for the heat syndrome (4.1). Cross-correlation analyses of Twitter data demonstrated significant correlations for heat syndrome with two data sources: telephone helpline calls (r = 0.4) and temperature data (r = 0.5). CONCLUSION: Using simple syndromes based on keyword classification of geolocated tweets, we found a correlation between tweets and two routine data sources for heat alerts, the only public health event detected during P/PAG. Further research is needed to understand the role for Twitter in surveillance.

Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series.

BACKGROUND: Central nervous system (CNS) germ cell tumors account for 3 % of all pediatric brain tumors in the USA. Presenting symptoms are typically location based with pineal tumors presenting with obstructive hydrocephalus and suprasellar tumors with hypothalamic/pituitary dysfunction and ophthalmologic abnormalities. Psychiatric manifestations such as psychosis and behavioral changes are atypical presentations of CNS germ cell tumors, with only 11 previously reported cases. METHODS: This is a retrospective case series describing patients with CNS germ cell tumors with an atypical presentation including psychiatric manifestations. Information regarding clinical presentation, treatment course, and outcome were obtained. RESULTS: We report seven patients who presented with psychiatric symptoms consisting of psychomotor delay as well as behavioral and mood changes. Six of the seven patients were diagnosed ≥6 months after onset of psychiatric symptoms. All of the seven are alive but five continue to have neurologic and psychiatric issues post treatment. CONCLUSIONS: Atypical presentations of CNS germ cell tumors can delay diagnosis and treatment and may be secondary to atypical locations as well as endocrine dysfunction manifesting as psychiatric symptoms. Delayed diagnosis did not appear to affect survival but earlier diagnosis may potentially be associated with better neurologic and psychiatric outcome. Patients who present with these symptoms and atypical neuroimaging should have a thorough evaluation for CNS germ cell tumors including serum and CSF markers. Clinicians should be aware of these less common presentations to aid in prompt diagnosis and treatment.

TRPV4 mediates flow-induced increases in intracellular Ca in medullary thick ascending limbs.

UNLABELLED: Medullary thick ascending limbs (mTAL) regulate Na balance and therefore blood pressure. We previously showed that cell swelling and luminal flow activates the mechanosensitive channel TRPV4 in mTAL. AIM: We hypothesized that TRPV4 mediates flow-induced increases in intracellular Ca (Cai) in rat mTALs. METHODS: We performed ratiometric measurements of Cai in perfused mTALs. RESULTS: Increasing luminal flow from 0 to 20 nL min(-1) caused Cai to peak 231 ± 29 nmol L(-1) above basal concentrations (n = 18). The general TRPV inhibitor ruthenium red at 15 and 50 µmol L(-1) reduced peak Cai by 41 ± 9 (P < 0.01; n = 5) and 77 ± 10% (P < 0.02; n = 6). The selective TRPV4 inhibitor RN1734 at 10 and 50 µmol L(-1) reduced peak Cai by 46 ± 11 (P < 0.01; n = 7) and 76 ± 5% (P < 0.02; n = 5) respectively. To specifically target TRPV4, mTALs were transduced with adenoviruses expressing TRPV4 small hairpin (sh) RNA. In non-transduced control mTALs, luminal flow generated a peak increase in Cai of 111 ± 21 nmol L(-1) (n = 8). In TRPV4shRNA-transduced mTALs, the Cai peak was reduced to 56 ± 8 nmol L(-1) (P < 0.03, n = 9). Removing extracellular Ca completely abolished flow-induced increases in Cai. Increasing luminal flow in the presence of hexokinase 20 (U mL(-1) ) to scavenge extracellular ATP did not modify significantly the increases in Cai induced by luminal flow. Finally, we studied the effect of the TRPV4 selective agonist GSK1016790A on Cai. In the absence of luminal flow, GSK1016790A (10 nmol L(-1) ) increased Cai from 60 ± 11 nmol L(-1) to 262 ± 71 nmol L(-1) (P < 0.05; n = 7). CONCLUSION: We conclude that flow-induced increases in Cai are mediated primarily by TRPV4 in the rat mTAL.

Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma.

The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases.

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease.

BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with ~85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m(2), alemtuzumab 54 mg/m(2) (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.

Osteoarthritis of the hand I: aetiology and pathogenesis, risk factors, investigation and diagnosis.

OBJECTIVE: Osteoarthritis (OA) of the hand can be a debilitating condition that hinders an individual's quality of life. With multiple joints within the hand that are commonly affected OA, an individual's ability to use their hand in everyday movements become more limited. The article aims to review literature on the aetiology and pathogenesis of OA, risk factors, characteristics of hand OA and the steps of diagnosis. KEY FINDINGS: The aetiology and pathogenesis of OA, in particular hand OA, is not fully understood. However, it is known that several factors play a role. Environmental factors, such as stress from mechanical loading, especially to vulnerable joints predispose individuals to developing OA. Extracellular matrix changes in protein levels have also been noted in individuals with OA. Linked to hand OA development are boney enlargements (Herbeden's and Bouchard's nodes). Several risk factors for OA include: age, obesity, gender, smoking, genetics, diet and occupation. Various diagnostic methods include a combination of using radiographic methods, clinical presentation, a number of developed measurements and scales. SUMMARY: With OA having several risk factors and various causes and contributing elements, it is important to elucidate the pathogenesis of OA and determine exactly how risk factors play a role in its development. Because of the contributions from several elements, diagnosis is best when it uses multiple methods. In turn, understanding OA and making better diagnoses could lead to improved management of the condition through both pharmacological and non-pharmacological interventions.

Osteoarthritis of the hand II: chemistry, pharmacokinetics and pharmacodynamics of naproxen, and clinical outcome studies.

OBJECTIVE: This article aims to review osteoarthritis of the hand and the role of the non-steroidal anti-inflammatory drug (NSAID) naproxen on its management. We discuss the chemical and pharmacological properties of naproxen and the NSAID class, with an emphasis on its mechanism and adverse reactions. In the context of part I of this paper in characterizing hand osteoarthritis (OA), we review clinical trials that have been conducted involving hand OA and naproxen. KEY FINDINGS: The therapeutic effect of NSAIDs stems from its role on inhibiting cyclo-oxygenase (COX)-1 or COX-2 enzyme activity in the body. These enzymes play a major role in maintaining several functions in the body and due NSAIDs' inhibitory effects; many principle adverse reactions occur with the use of NSAIDs such as: gastrointestinal tract issues, cardiovascular risks, renal, hepatic, central nervous system and cutaneous. Review of clinical trials involving naproxen and hand OA show that it is significantly more efficacious when compared with placebo. SUMMARY: These studies, along with the finding that naproxen is of least cardiovascular risk in the NSAID class, may show that it can be part of one of the approaches in managing the condition. It is important to note that the optimal NSAID to use varies for each individual. The finding that the use of naproxen leads to the smallest increase in cardiovascular risk appeals to those at-risk individuals who suffer from OA and require pharmacological treatment for relief.

Pediatric allo-SCT for malignant and non-malignant diseases: impact on health-related quality of life outcomes.

The objective of this study was prospectively to investigate the health-related quality of life (HRQOL) of 80 pediatric recipients of allo-SCT for malignant and non-malignant diseases. The PedsQL 4.0 was used to assess self-reported physical, emotional and social functioning of children 5 years old once, pre-allo-SCT and on days +100, +180, +365 and +730. Emotional and social functioning was stable pre-to-post-allo-SCT and comparable to the normative sample (P>0.05), and physical functioning was 17 points lower pre-allo-SCT (P0.01) with improved scores equivalent to the norms by day +730. Lower physical scores were reflected by 50-54% of children reporting difficulties with movement, strength, pain and fatigue. At baseline, children ages 5-7 reported lower social functioning (P<0.05) and patients with non-malignant disease reported better physical functioning (P<0.05). Emotional functioning in ages 8-12 improved over time (P<0.05). More than 50% of the participants were minority and their HRQOL was similar to non-minority participants. Physical functioning significantly improved for recipients of reduced-toxicity conditioning (P0.01), significantly worsened for patients with chronic GVHD (cGVHD; P<0.05), and significantly decreased in recipients of matched-unrelated donor transplant who developed cGVHD (P<0.05). Multidisciplinary efforts are necessary to identify and support pediatric patients' physical needs to improve functional outcomes.

A case of duodenal rupture secondary to massive inguino-scrotal hernia.

INTRODUCTION: Surgical intervention for giant inguino-scrotal herniae in the acute setting is high risk with significantly increased incidence of morbidity and mortality. While uncommon in modern practise, there are several surgical issues and approaches that need to be considered when this problem presents. CASE REPORT AND DISCUSSION: We describe the unusual occurrence of acute duodenal rupture as a direct result of a giant inguino-scrotal hernia. The literature on the operative management of giant inguino-scrotal hernia is also reviewed. CONCLUSION: Giant inguino-scrotal herniae are best managed electively with full preoperative work up and assessment. Surgery in the acute patient is fraught with difficulty leading to increased morbidity.

The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients.

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65-0.73 L/kg; t(1/2): 122-147 min; weight-normalized clearance (CL(n)): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628-746 ng/mL. Comparison between recipients ≤4 vs >4 years old revealed significant differences in t(1/2) (mean: 115 vs 146 min, P=0.008) and CL(n) (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.

Pediatric considerations for pineal tumor management.

Pineal tumors are relatively rare central nervous system lesions with a predilection for the pediatric population. For the vast majority of these lesions, surgical resection is a critical step in effective treatment. This article discusses current strategies for preoperative evaluation, operative management, and postoperative care of the pediatric patient with a newly diagnosed pineal region tumor.

A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents.

We report the results of a pilot study of a BU-fludarabine-alemtuzumab (BFA)-reduced toxicity conditioning (RTC) followed by allogeneic hematopoietic SCT (AlloHSCT) in 12 children and adolescents (<21 years) with malignant and non-malignant diseases. Stem cell sources were: two unrelated cord blood, one unrelated BM, two related and seven unrelated PBSC. Positive CD34 selection was performed in five unrelated PBSC grafts. RCT was carried out with BFA, and GVHD prophylaxis was FK506 and mycophenolate mofetil. The median time for neutrophil and platelet engraftment was 16 and 31 days, respectively. The P of developing ≥ grade II, ≥ grade III aGVHD and cGVHD was 41.6, 25 and 9%, respectively. Only 1 out of 12 developed ≥ grade III toxicity. There was one primary and no secondary graft failure. Mixed donor chimerism on day 100 and 1 year was median 99 and 96%, respectively; ≥ 90% of recipients achieved ≥ 80% donor chimerism. The 3-year overall survival (OS) in all patients was 91.7 ± 8% (100% for malignant vs. 80% for non-malignant diseases, ns). In all, 11 (91%) patients remain alive at median 2.8 (0.3-6.8) years. RTC followed by AlloHSCT, based on BFA conditioning, is feasible and tolerable in children and adolescents, and results in prompt achievement of durable mixed donor chimerism and excellent OS.