Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide-Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma.

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the ß phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.

Complete Genome Characterization of Penicillimonavirus gammaplasmoparae, a Bipartite Member of the Family Mymonaviridae.

In this study, we identified Plasmopara-viticola-lesion-associated mononegaambi virus 3 (recently classified as Penicillimonavirus gammaplasmoparae), a fungi-associated mymonavirus, in grapevine plants showing an unusual upward curling symptomatology on the leaves and premature decline. Mymonaviridae is a family comprising nine genera of negative-sense single-stranded RNA viruses infecting filamentous fungi, although few of them have been associated with oomycetes, plants, and insects. Although the first mymonavirus genome description was reported a decade ago, the genome organization of several genera in the family, including the genus Penicillimonavirus, has remained unclear to date. We have determined the complete genome of P. gammaplasmoparae, which represents the first complete genomic sequence for this genus. Moreover, we provide strong evidence that P. gammaplasmoparae genome is bipartite and comprises two RNA molecules of around 6150 and 4560 nt. Our results indicate that the grapevine powdery mildew pathogen, Erysiphe necator, was also present in the analyzed plants and suggest P. gammaplasmoparae could be infecting this fungus. However, whether the fungus and/or the mycovirus are associated with the symptomatology that initially prompted these efforts remains to be determined.

[Assessment of knowledge in Transfusional Medicine in residents in Bajío]. / Evaluación de conocimientos en Medicina Transfusional en médicos residentes del Bajío.

Background: Despite the existence of national and international guidelines, multiple studies show that the clinical use of blood components is not based on scientific evidence; this situation replicates, therefore it was necessary to apply an assessment tool in our medical unit. Objective: Assessment the knowledge in transfusion medicine in medical residents who have high requirements of blood hemocomponentes in Unidad Médica de Alta Especialidad Hospital de Especialidades No.1 Centro Médico Nacional Bajío. Material and methods: A descriptive cross-sectional study was designed, and through a validated test the knowledge in transfusional medicine of residents of the unit was evaluated. Results: 100 residents participated in the research, most of them from the anesthesiology department; as a result, the evaluation tool showed a "Fair" performance in 75% of the participants. No specialty achieved a "Satisfactory" result. Conclusions: The application of this tool is the first step to develop and implement strategies to reduce unjustified transfusions of blood components and thus continue to provide excellent care to beneficiaries, minimizing risks and optimizing institutional resources.

Introducción: a pesar de la existencia de guías tanto nacionales como internacionales, múltiples estudios han puesto de manifiesto que el uso clínico de hemocomponentes no está basado en la evidencia científica; esta situación se replica y es necesario modificarla. Por ello, se planteó aplicar una herramienta de evaluación de conocimientos en medicina transfusional para tal fin en nuestra unidad. Objetivo: evaluar el conocimiento sobre medicina transfusional en médicos residentes de las especialidades con más demandas de hemocomponentes del Hospital de Especialidades No.1 del Centro Médico Nacional Bajío. Material y métodos: se diseñó un estudio transversal descriptivo y, por medio de un examen validado, se evaluó el conocimiento en medicina transfusional de médicos residentes de las especialidades que indican el mayor número de transfusiones en la unidad. Resultados: se contó con la participación de 100 residentes; la mayor participación fue de la especialidad de Anestesiología. El 75% de los participantes obtuvieron un desempeño "Regular" en la herramienta de evaluación. Ninguna especialidad alcanzó un resultado "Satisfactorio". Conclusiones: la aplicación de esta herramienta es el primer paso para desarrollar e implementar estrategias que permitan disminuir las transfusiones de hemocomponentes injustificadas y de esta manera seguir brindando una atención de excelencia a los derechohabientes, minimizando riesgos y optimizando recursos institucionales.

Development and Validation of a Duplex RT-qPCR for Detection of Peach Latent Mosaic Viroid and Comparison of Different Nucleic-Acid-Extraction Protocols.

Peach latent mosaic viroid (PLMVd) is an important pathogen that causes disease in peaches. Control of this viroid remains problematic because most PLMVd variants are symptomless, and although there are many detection tests in use, the reliability of PCR-based methods is compromised by the complex, branched secondary RNA structure of the viroid and its genetic diversity. In this study, a duplex RT-qPCR method was developed and validated against two previously published single RT-qPCRs, which were potentially able to detect all known PLMVd variants when used in tandem. In addition, in order to simplify the sample preparation, rapid-extraction protocols based on the use of crude sap or tissue printing were compared with commercially available RNA purification kits. The performance of the new procedure was evaluated in a test performance study involving five participant laboratories. The new method, in combination with rapid-sample-preparation approaches, was demonstrated to be feasible and reliable, with the advantage of detecting all different PLMVd isolates/variants assayed in a single reaction, reducing costs for routine diagnosis.

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development.

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g., optimal dose, frequency of administration, dose adjustments for special populations). This white paper is the output of an industry-government collaboration among scientists with broad experience in E-R modeling as part of regulatory submissions. The goal of this white paper is to provide guidance on what the preferred methods for E-R analysis in oncology clinical drug development are and what metrics of exposure should be considered.

A Novel and Highly Inclusive Quantitative Real-Time RT-PCR Method for the Broad and Efficient Detection of Grapevine Leafroll-Associated Virus 1.

Grapevine (Vitis vinifera L.) is one of the most important crops in the world due to its economic and social impact. Like many other crops, grapevine is susceptible to different types of diseases caused by pathogenic microorganisms. Grapevine leafroll-associated virus 1 (GLRaV-1) is a virus associated with grapevine leafroll disease and it is considered at the national and European level as a pathogen that must be absent in propagative plant material. For this reason, the availability of specific, sensitive and reliable detection techniques to ascertain the sanitary status of the plants is of great importance. The objective of this research was the development of a new GLRaV-1 detection method based on a TaqMan quantitative real-time RT-PCR targeted to the coat protein genomic region and including a host internal control in a duplex reaction. To this end, three new GLRaV-1 full genomes were recovered by HTS and aligned with all sequences available in the databases. The method has been validated following EPPO standards and applied for the diagnosis of field plant material and transmission vectors. The new protocol designed has turned out to be highly sensitive as well as much more specific than the current available methods for the detection and absolute quantitation of GLRaV-1 viral titer.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

High-Throughput Sequencing Discloses the Cucumber Mosaic Virus (CMV) Diversity in Slovakia and Reveals New Hosts of CMV from the Papaveraceae Family.

Cucumber mosaic virus (CMV; Cucumovirus, Bromoviridae) is an omnipresent virus characterized by a large host range and high genetic variability. Using high-throughput sequencing, we have characterized near complete genomes of 14 Slovak CMV variants from different plant hosts. Of these, three variants originated from the Papaveraceae species (oilseed poppy, common poppy and great celandine), previously poorly described as CMV natural hosts. Based on a BLAST search and phylogenetic analysis, the Slovak CMV isolates can be divided into two genetically different Groups, Ia and II, respectively. The SL50V variant, characterized by a divergent RNA2 sequence, potentially represents a reassortant variant. In four samples (T101, SL50V, CP2, MVU2-21), the presence of satellite CMV RNA was identified along with CMV. Although mechanically transmitted to experimental cucumber plants, the role of satellite RNA in the symptomatology observed could not be established due to a complex infection of original hosts with different viruses.

Pharmacometric modeling and machine learning analyses of prognostic and predictive factors in the JAVELIN Gastric 100 phase III trial of avelumab.

Avelumab (anti-PD-L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable-importance assessments) was used to build models to identify prognostic/predictive factors associated with long-term OS and tumor growth dynamics (TGDs). Baseline, re-baseline, and longitudinal variables were evaluated as covariates in a parametric time-to-event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log-logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma-glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil-lymphocyte ratio, lactate dehydrogenase, or C-reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time-varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re-baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.

Natural Infection of Pomegranate (Punica Granatum) by Apple Dimple Fruit Viroid.

The analysis by high throughput sequencing (HTS) and RT-PCR of Spanish pomegranate fruits showing yellow rings revealed the presence of viroid isolates closely related to fig isolates of apple dimple fruit viroid (ADFVd). The analysis of pomegranate public RNASeq data (Sequence Reads Archives, SRAs) from Israel provided evidence for the presence of similar ADFVd isolates in pomegranate trees in this country. In addition, reads or contigs of plum viroid I (PVd-I) isolates were also identified in two of the analyzed SRA datasets from Israel, suggesting the presence of this second viroid in pomegranate. Full length ADFVd genomic sequences have been recovered, increasing knowledge on the diversity of this viroid and on the pomegranate virome in which only four viruses and one viroid had previously been reported.

First Detection and Molecular Characterization of Apple Stem Grooving Virus, Apple Chlorotic Leaf Spot Virus, and Apple Hammerhead Viroid in Loquat in Spain.

Loquat (Eriobotrya japonica) is an important crop in Spain. To date, only one viral species, apple stem pitting virus (ASPV), has been detected in Spanish loquat orchards. In this study, the presence of additional viruses infecting this crop in Spain was investigated. RT-PCR and high-throughput sequencing (HTS) of symptomatic loquat plants led to first-time detection and characterization of apple stem grooving virus (ASGV), also known as citrus tatter leaf virus (CTLV), and apple chlorotic leaf spot virus (ACLSV) from Spain with description of nearly complete genomic sequences. The frequency of ACLSV infection was the highest, with over 30% of the samples testing positive and were also detected as coinfections with ASGV and ASPV, although most of the samples infected were symptomless. Studies on all the full-length sequences available in the databases were performed in order to establish the phylogenetic relationships of the Spanish isolates of these two viral species. Moreover, apple hammerhead viroid (AHVd) was also detected to infect loquat, the first host different from apple reported for this viroid to date.

Characterization of Spanish Olive Virome by High Throughput Sequencing Opens New Insights and Uncertainties.

The use of high throughput sequencing (HTS) for the analysis of Spanish olive trees showing leaf yellowing discoloration, defoliation, and/or decline has provided new insights into the olive viruses present in Spain and has opened discussions about the pros and cons of these technologies for diagnostic purposes. In this study, we report for the first time in Spanish orchards the presence of olive leaf yellowing-associated virus (OLYaV), for which the second full coding sequence has been determined. This virus has also been detected in a putative vector, the psyllid Euphyllura olivina. In addition, the presence in Spain of Olea europaea geminivirus (OEGV), recently reported in Italy, has been confirmed, and the full-length sequence of two isolates was obtained by HTS and Sanger sequencing. These results, as well as the detection of other viral sequences related to olive latent virus 3 (OLV-3) and olive viral satellite RNA, raises questions on the biological significance of the findings, about the requirement of standardization on the interpretation of HTS results, and the necessity of additional tests to confirm the relevance of the HTS detection of viral sequences.

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome.

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up-titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half-maximal effective concentration (EC50 ) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model-based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Lorlatinib Exposure-Response Analyses for Safety and Efficacy in a Phase I/II Trial to Support Benefit-Risk Assessment in Non-Small Cell Lung Cancer.

Lorlatinib is a small molecule inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinases and is approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). In the phase I/II study (NCT01970865), potential exposure-response (E-R) relationships between lorlatinib and selected safety and efficacy end points were evaluated in patients with NSCLC. E-R relationships were assessed for safety end points with incidence > 10% in all treated patients (n = 328). In total, 4 safety end points were assessed: hypercholesterolemia grade ≥ 3, hypertriglyceridemia grade ≥ 3, weight gain grade ≥ 2, and treatment-emergent adverse events (TEAEs) grade ≥ 3. Using logistic regression, significant relationships were identified between lorlatinib plasma exposure and risk of hypercholesterolemia grade ≥ 3 (odds ratio (OR) 5.256) and risk of TEAE grade ≥ 3 (OR 3.214). The covariates baseline cholesterol and time on study prior to the event (TE) were associated with the probability of hypercholesterolemia grade ≥ 3. Baseline cholesterol and TE were found to have a statistically significant correlation with TEAE grade ≥ 3. Exposure-efficacy relationships were assessed for objective response rate (ORR; n = 197) and intracranial objective response rate (IC-ORR; n = 132). Lorlatinib plasma exposure was not identified as a statistically significant factor related to either efficacy end point. The only significant E-R relationships identified for efficacy were between baseline alkaline phosphatase and baseline amylase with IC-ORR (ORs 0.363 and 1.015, respectively). These findings support the lorlatinib indicated dose and dose modification guidelines regarding the management of lorlatinib-related AEs.

Exposure-response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer.

PURPOSE: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. METHODS: A concentration-QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. RESULTS: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5-640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. CONCLUSIONS: The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.

Population pharmacokinetic model with time-varying clearance for lorlatinib using pooled data from patients with non-small cell lung cancer and healthy participants.

Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK-positive or ROS1-positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well-characterized by a two-compartment model with sequential zero-order and first-order absorption and a time-varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto-induction of lorlatinib reaches saturation in ~ 5 half-lives, clearance was estimated to approach a maximum of 14.5 L/h at steady-state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first-order absorption rate constant was estimated to be 3.1 h-1 . Baseline albumin and lorlatinib total daily dose were significant covariates on lorlatinib clearance. Use of proton pump inhibitors was found to be a significant covariate on the lorlatinib absorption rate constant. These factors were assessed to have no clinically meaningful impact on lorlatinib plasma exposure, and no dose adjustments are considered necessary based on the examined covariates.

Evaluation of the Relationship of Glasdegib Exposure and Safety End Points in Patients With Refractory Solid Tumors and Hematologic Malignancies.

Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposure-efficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Estimated pharmacokinetic parameters were used to derive glasdegib exposure metrics. Demographic characteristics, disease factors, and other variables of interest as potential moderators of safety signals were evaluated. Clinical trial data from patients who received single-agent glasdegib (N = 70; 5-640 mg once daily); or glasdegib (N = 202, 100-200 mg once daily) with low-dose cytarabine, decitabine, or daunorubicin and cytarabine were analyzed. Glasdegib exposure was statistically significantly associated with the cluster term safety end points dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged. The impact of age on muscle spasms and baseline body weight and creatinine clearance on renal toxicity helped explain the AE grade distribution. At the 100 mg once daily clinical dose, the predicted probabilities of the highest AE grade were 11.3%, 6.7%, 7.7%, and 2.5% for dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged, respectively. Overall, the predicted probability of developing an AE of any severity for these safety end points was low. Therefore, no starting dose adjustments are recommended for glasdegib based on the observed safety profile.

Characterization of the Relationship of Inotuzumab Ozogamicin Exposure With Efficacy and Safety End Points in Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia.

Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, is approved in Europe and the United States for treatment of adults with relapsed or refractory acute lymphoblastic leukemia (ALL). Population analyses were performed to evaluate the relationship between InO exposure and efficacy and safety end points in patients with ALL. The probability of achieving complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD)-negativity for InO relative to chemotherapy was also investigated. Data from study 1010 (NCT01363297) and INO-VATE (NCT01564784) were pooled for exposure-response (InO, n = 234) and treatment-response (InO, n = 234; chemotherapy, n = 143) analyses. The analyses demonstrated that InO exposure was significantly correlated with achieving CR/CRi and MRD-negativity, as well as with hepatic event adjudication board-reported veno-occlusive disease/sinusoidal obstruction. Patients with ALL treated with InO had significantly greater odds of achieving CR/CRi (7-times higher) and MRD-negativity (13-times higher) than those receiving chemotherapy.

Loquat (Eriobotrya japonica) is a New Natural Host of Apple Stem Pitting Virus.

Loquat (Eriobotrya japonica) is a minor but important woody crop cultivated in Asia and Europe. High-throughput sequencing (HTS) analysis of an asymptomatic loquat plant using RNAseq Illumina technology has allowed the detection for the first time of apple stem pitting virus (ASPV), the type species of the genus Foveavirus in the family Betaflexiviridae, infecting this crop. A nearly complete genome of 9303 nts (ASPV-SL61) reconstructed bioinformatically shows the typical genomic structure of this viral species and a highest nucleotide identity (85.9%) with the Chinese ASPV isolate YLX from pear. A close phylogenetic relationship between ASPV-SL61 and ASPV-YLX has been confirmed by the sequence analysis of full-length ASPV genomic sequences available in the databases. In fact, a phylogenetic study based on a partial CP N-terminal sequence previously proposed to be involved in host adaptation has shown that ASPV-SL61 loquat isolate is more closely related to ASPV pear isolates. The presence of ASPV in loquat has been further confirmed by RT-PCR and Sanger sequencing and DAS-ELISA. An incidence of 15% was determined in one of the loquat Spanish growing areas. The sequence analysis of the partial CP sequences amplified by RT-PCR has shown a high level of variability between loquat isolates. To our knowledge, this is the first record of loquat as a natural host of ASPV.