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Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small cell lung cancer, a far more common G3 neuroendocrine neoplasm, although emerging molecular and clinical data increasingly question this approach. In this article, we will briefly summarize epidemiology and prognosis of gastroenteropancreatic neuroendocrine carcinomas to emphasize the very low incidence, aggressive nature, and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background compared with small cell lung cancer, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors), and additional treatment strategies targeting other tumor vulnerabilities (ie, Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis.

Introduction: The SARS-CoV-2 pandemic generated the need to keep immunosuppressed patients away from hospital institutions for as long as possible. This in turn stimulated the implementation of a home hospitalization model for autologous hematopoietic stem-cell transplantation (HSCT). Purpose: To analyze whether there are significant differences in post-transplantation complications related to catheters observed in patients treated in the home-transplant care modality compared to patients treated in the hospital. Methodology: Observational, analytical, longitudinal, and retrospective study of cases and controls. A convenience sample was chosen, in which the cases comprised 20 patients included in the home HSCT care model. For each patient, it was considered suitable to propose two controls among those who received autologous transplantation in the last five years with a baseline demographic and pathological profile similar to the case for whom they were control. Results: The home patients achieved an average of 22.4 ± 2.6 days of evolution with an average of 16.4 ± 2.08 days post-transplant, compared to the hospital process with an average of 21.21 ± 4.18 days of evolution and 15.51 ± 3.96 days post-transplant (evolution days p = 0.022; post-transplant days p = 0.002). A higher percentage of use of parenteral nutrition (p = 0.036) and transfusions (p = 0.003) was observed during the post-transplant phase in the hospital. The rest of the therapeutic measures did not show significant differences. When analyzing the frequency of adverse effects in the post-transplant phase, a significant increase in neutropenic fever (OR = 8.55) and positive blood cultures (OR = 6.65) was observed in hospital patients. Any other significant differences in other variables related to PICC were found (presence and days of neutropenic fever, catheter infection, complications, pathogens, admission to the ICU, or death). Concerning local complications (pain, DVT, Medical adhesive-related Skin Injury, and erythema), there was more erythema in the hospital (p = 0.056). Conclusions: The results obtained indicate that regarding the appearance of complications associated with PICCs in home hospitalization HSCT patients, there are no significant differences compared to hospitalization, so that home care can be a safe context for people with these lines

The exceptional versatility of sulfones has been extensively exploited in organic synthesis across several decades. Since the first demonstration in 2005 that sulfones can participate in Pd-catalysed Suzuki-Miyaura type reactions, tremendous advances in catalytic desulfitative functionalizations have opened a new area of research with burgeoning activity in recent years. This emerging field is displaying sulfone derivatives as a new class of substrates enabling catalytic C-C and C-X bond construction. In this review, we will discuss new facets of sulfone reactivity toward further expanding the flexibility of C-S bonds, with an emphasis on key mechanistic features. The inherent challenges confronting the development of these strategies will be presented, along with the potential application of this chemistry for the synthesis of natural products. Taken together, this knowledge should stimulate impactful improvements on the use of sulfones in catalytic desulfitative C-C and C-X bond formation. A main goal of this article is to bring this technology to the mainstream catalysis practice and to serve as inspiration for new perspectives in catalytic transformations.

Sirolimus has emerged as an alternative to calcineurin inhibitors-based (CNI) graft-versus-host disease (GVHD) prophylaxis. This retrospective study compares the outcome of 133 consecutive adult patients with haematological malignancies undergoing haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCy) and mycophenolate mofetil (MMF), combined with cyclosporine A (PTCy-CsA-MMF

Highlights • Rapid detection methods used as first diagnostic test for CARVs may delayed the start of antiviral therapy in a significant number of influenza and RSV cases. • Syndromic multiplex RT-PCR-based prospective clinical CARV survey in allo-HCT recipients translates into a lower mortality rate as compared to standard clinical practice based on RSV and influenza virus rapid detection test. • We found that donor/recipient HLA mismatch, CARV LRTD and high-risk ISI were also associated with higher mortality., Background There is a lack of studies comparing clinical outcomes among retrospective versus prospective cohorts of allogeneic stem cell transplant (allo-HCT) recipients with community acquired respiratory virus (CARV) infections. Methods We compare outcomes in two consecutive cohorts of allo-HCT recipients with CARV infections. The retrospective cohort included 63 allo-HCT recipients with 108 CARV infections from January 2013 to April 2016 who were screened and managed following standard clinical practice based on influenza and respiratory syncytial virus rapid antigen detection methods. The prospective cohort was comprised of 144 consecutive recipients with 297 CARV episodes included in a prospective interventional clinical surveillance program (ProClinCarvSur-P) based on syndromic multiplex PCR as first-line test from May 2016 to December 2018 at a single transplant center. Results CARV infections in the retrospective cohort showed more severe clinical features at the time of diagnosis compared to the prospective cohort (fever 83% vs. 57%, hospital admission 69% vs. 28% and lower respiratory tract 58% vs. 31%, respectively, p ≤ 0.002 for all comparisons). Antiviral therapy was more commonly prescribed in the prospective cohort (69 vs. 43 treated CARV episodes), particularly at the upper respiratory tract disease stage (34 vs. 12 treated CARV episodes). Three-month all-cause mortality was significantly higher in the retrospective cohort (n = 23, 37% vs. n = 10, 7%, p

We analyzed the outcomes of 26 consecutive patients with acquired severe aplastic anemia (SAA) undergoing peripheral blood stem cell transplantation (PBSCT) with partial ex vivo T cell depletion with a targeted T cell dose from HLA-identical sibling donors. The median patient age was 37 years (range, 3 to 63 years). Four patients with uncontrolled pneumonia at the time of transplantation died, on days +1, +2, +21, and +26. All evaluable patients engrafted, with a median time to neutrophil recovery of 11 days (range, 10 to 14 days) and a median time to platelet recovery of 19 days (range, 8 to 53 days). Two patients had transient grade I acute graft-versus-host disease (GVHD) with skin involvement, but no patients developed grade II-IV acute GVHD. Two patients had mild skin chronic GVHD, and 1 patient had moderate chronic GVHD with ocular involvement. No relapse was observed after a median follow-up of 114 months (range, 4 to 233 months). The overall cumulative incidence of TRM at 10 years was 19%, whereas it was 5% for those with a Karnofsky Performance Status (MPS) score >60 at the time of transplantation. Disease-free survival, overall survival, and GVHD and relapse-free survival at 10 years were 81%, 81%, and 80%, respectively, for all patients and 95%, 95%, and 90%, respectively, for patients with a MPS score >60 at transplantation. Our data indicate that PBSCT with partial ex vivo T cell-depleted targeted cell dose grafts from an HLA-identical sibling donor is a feasible, safe, and effective approach to reduce GVHD and cure patients with SAA. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

The last few years have witnessed the emergence of personalized precision medicine (PPM), a novel approach to improve clinical decisions, integrating individual multi-omic profiles, and heterogeneo...

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be associated with neurologic complications, data on noninfectious etiologies are scanty. Therefore, we analyzed the incidence, clinical characteristics, risk factors, and influence on outcomes of noninfectious neurologic complications (NCs) in 971 consecutive patients with hematologic malignancies undergoing allo-HSCT at our center between January 2000 and December 2016. We evaluated NCs affecting the central nervous system (CNS) and peripheral nervous system (PNS). The median duration of follow-up of survivors was 71 months (range, 11 to 213 months). A total of 467 patients received a matched sibling donor (MSD) transplant, 381 received umbilical cord blood (UCB), 74 received a haploidentical transplant, and 49 received a matched unrelated donor (MUD) transplant. One hundred forty-nine (15.3%) NCs were documented at a median of 78 days after transplantation (range, 5 days before to 3722 days after). The cumulative incidence risk of developing NC was 7.5% (95% confidence interval, 6% to 8.2%) at day +90 and 13% at 5 years. The 5 -year cumulative incidence of NCs was 10.8% after MSD alto-HSCT and 15.3% after alternative donor (UCB, MUD, haploidentical) allo-HSCT (P=.004). There were 101 (68%) CNS complications, including encephalopathy, n = 46 (31%); headache, n = 20 (13%); stroke, n = 15 (10%); seizures, n = 9 (6%), posterior reversible encephalopathy syndrome, n = 6 (4%), and myelopathy, n = 5 (3%). PNS complications (32%) included neuropathies, n = 25 (17%), and myopathies and neuromuscular junction disorders, n = 23 (17%), with 17% of the total PNS complications being immune-related. In multivariable analysis, donor type other than MSD, age >= 40 years, development of acute graft-versus-host disease (GVHD) grade II-IV (hazard ratio [HR], 3.3; P < .00001), and extensive chronic GVHD (HR, 3.2; P=.0002) were independently associated with increased risk of NCs. The 5 -year overall survival (OS) was 21% in patients who developed NCs and 41% for those who did not (P < .0001). This difference in OS was observed in patients developing CNS NCs, but not in those developing PNS complications. In conclusion, our study reveals NCs as a frequent and heterogeneous complication that, when affecting CNS, is associated with poor prognosis following allo-HSCT. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Objectives Umbilical cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) modalities have been developed to offset the lack of matched donors. In this study, we compare the transfusion requirements of patients undergoing UCBT and haplo-HSCT in a single institution with the aim of providing additional information for clinicians to choose the most adequate alternative graft for HSCT. Methods The study reviewed 67 and 46 patients undergoing UCBT and haplo-HSCT, respectively. Results There were no significant differences for RBC and PLT requirements according to the transplantation modality. Median time to RBC transfusion independence was 35 and 25.5 days in patients who received an UCBT and haplo-HSCT, respectively (P = 0.38), while median time to platelet transfusion independence was 31 days for UCBT patients and 23 for haplo-HSCT patients (P < 0.001). Days until neutrophils > 0.5 x 10(9)/L were the only variable that significantly influenced RBC and PLT requirements for both transplantation modalities. Cumulative incidence of RBC and PLT transfusion independence at 90 days after transplantation was similar for both UCBT and haplo-HSCT. Conclusions Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy.

Highlights • CMV DNA is frequently detected in BAL fluid specimens from allo-HSCT. • CMV DNA detection in BAL fluids is comparable across pneumonia etiologies. • CMV DNA loads in BAL fluids are comparable across pneumonia etiologies. • CMV DNA load in BAL may predict attributable-pneumonia mortality., Summary Objectives To date no definitive cut-off value for cytomegalovirus (CMV) DNA load in bronchoalveolar lavage (BAL) fluid specimens has been established to discriminate between CMV pneumonia and pulmonary CMV DNA shedding in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Methods The current retrospective study is aimed at assessing the range of CMV DNA loads quantified in BAL fluid specimens from allo-HSCT patients with pneumonia in which different microorganisms were causally involved. Results A total of 144 BAL specimens from 123 patients were included. CMV DNA was detected in 56 out of 144 BAL fluid specimens and the median CMV DNA load from patients in whom CMV pneumonia was unlikely or could be tentatively ruled out was 1210 (31–68, 920) IU/ml. The frequency of CMV DNA detection and median CMV DNA loads were comparable, irrespective of the attributable cause of pneumonia. Detection of CMV DNA loads in BAL fluid specimens >500 IU/ml was independently associated with pneumonia-attributable mortality. Conclusions The current study highlights the difficulty in establishing universal CMV DNA load thresholds in BAL fluid specimens for distinguishing between CMV pneumonia and pulmonary CMV DNA shedding, and suggests that the presence of CMV DNA in BAL fluid specimens beyond a certain level may have a deleterious impact on patient outcome.

OBJECTIVE Characteristics and risk factors (RFs) of invasive fungal disease (IFD) have been little studied in the setting of umbilical cord blood transplantation (UCBT). METHOD We retrospectively included 205 single-unit myeloablative UCBT recipients with a median follow-up of 64 months. RESULTS Fifty-six episodes of IFD were observed in 48 patients (23%) at a median time of 123 days after stem cell infusion. Invasive mold disease (IMD) occurred in 42 cases, 38 of them (90%) caused by invasive aspergillosis whereas invasive yeast disease (IYD) occurred in 14 cases, most of them due to candidemia (n = 12, 86%). The 5-year cumulative incidence of IFD, IMDs, and IYDs was 24% 19%, and 7%, respectively. In multivariate analysis, three RFs for IMDs were identified: age >30 years (HR 3.5, P = 0.017), acute grade II-IV graft-versus-host disease (HR 2.3, P = 0.011), and ≥1 previous transplant (HR 3.1, P = 0.012). The probability of IMDs was 2.5%, 14%, and 33% for recipients with none, 1, or 2-3 RFs, respectively (P

Oncogenic mutations in B-type Raf Kinase (BRAF) (particularly V600E) are present in 7-10% of metastatic colorectal cancer (mCRC), conferring resistance to conventional therapies and a poor prognosis. Src Family Kinases (SFKs) play a relevant role in CRC, where Src activation is associated with an aggressive phenotype and a worse prognosis; and could be involved in chemoresistance mechanisms. Dasatinib is a potent Src inhibitor with demonstrated anti-proliferative activity, although deeper knowledge is needed. Thus, we aimed to explore the role of Src in BRAF V600E CRC and to investigate this tumor subgroup in response to Dasatinib. SRC activation was evaluated by Western Blot. We generated Knock-Out (KO) Src cell lines by CRISPR/Cas9 system and stable Src overexpression (OE) by lentivirus. Cell viability was analysed by crystal violet and MTS assay. Phospho-kinase proteins screening was performed using the Proteome Profiler Human Phospho-Kinase Array kit. Expression levels of Src and phospho-Src (p-Src) displayed an inverse correlation with IC50 values for Dasatinib in a panel of 7 CRC cell lines including BRAF V600E (HT29, COLO201, RKO, LS411N) and BRAF WT (DIFI, HCA7 and LIM1215), and these doses were able to inhibit Src activation in all cell lines. Focusing on HT29 cells, inhibition of p-Src occurs in a dose-dependent manner and in shortened periods of treatment. Dasatinib showed a significant inhibition of proliferation and migration on HT29. Moreover, stable Src-OE HT29 cells showed higher clonogenicity, migration and proliferation capacities, as well as higher resistance to Dasatinib. Conversely, HT29 Src KO cells were more sensitive. In line with those results, silencing Src in other BRAF V600E cells (RKO and LS411N) also resulted in a remarkable reduction in clonogenicity and migration abilities. Xenograft mouse model of SRC depletion showed that the growth of SRC KO tumors was significantly slower than WT tumors. Phospho-kinase array quantification in basal and Src-OE HT29 cells showed up- and downregulated proteins related to classical tumorigenic signaling pathways such as MAPK (JNK1/2, MSK), PI3K/Akt (Akt, TOR, GSK3), and others. Further studies to explore resistance mechanisms mediated by Src/SFKs are required. To conclude, lower p-Src expression at baseline is related to a higher resistance to Dasatinib in all CRC cell lines. Dasatinib showed a significant anti-proliferative activity in a subset of CRC cell lines and regulates the activity of Src in a time and dose-dependent manner. Modified expression of Src (OE and KO) in BRAF V600E CRC cells significantly regulates clonogenicity, proliferation and migration abilities in vitro. Src overexpression is responsible of the acquired resistance to Dasatinib and regulates several pathways that could be involved in the tumorigenesis of BRAF V600E CRC, although further studies to explore resistance mechanisms mediated by Src/SFKs are required. Citation Format: Beatriz Rubio Cuesta, Beatriz Gil Calderón, Patricia LLamas Granda, Jacinto Sarmentero, Carlos Carretero Puche, María del Carmen Riesco, Rocío García Carbonero, Beatriz Soldevilla. Molecular characterization of BRAF V600E CRC in response to Src-targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 355.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with a wide anatomical distribution and different clinical behaviors that share common “neuro” and “endocrine” properties. They are classified in well differentiated G1, G2 and G3 neuroendocrine tumors (NETs), or poorly differentiated neuroendocrine carcinomas (NECs) which are all G3. Some studies have assessed the NET molecular landscape of certain primary sites, but no cross-sites molecular assessment has been performed to date. Thus, we aimed to perform a comprehensive transcriptomic and methylomic characterization of large series of NENs of different anatomical origins in order to identify molecular subgroups, unravel genes and/or pathways involved, and explore their potential clinical relevance. Transcriptomic and methylation data were obtained from tumor samples of 181 and 99 patients with NENs (37.02%G1; 54.7%G2 and 8.29%G3) using Clariom S Human microarrays and EPIC methylation arrays, respectively. Most common primary tumor site was the lung (43.1%), followed by the small intestine (35.4%), large intestine (8.8%), stomach (4.4%), pancreas (1.7%), other localizations (3.9%), and unknown primary (2.8%). Tumors were clustered using transcriptomic and methylation data by NMF and hierarchical clustering algorithms respectively, and differential expression (limma analysis) and gene set enrichment analysis (GSEA) was applied to transcriptomic data clusters NENs were classified into three different clusters. Two of them (C1 and C3) showed an inverse transcriptomic profile, while C2 presented a mixed profile. We identified that C3 had the highest expression levels of neuroendocrine-related genes (somatostatin receptor SSTR5 LFC: 0.77 ; FDR: 1.52x10e-25 ; serotonin receptor HTR1A LFC: 0.79 ; FDR: 1.20X10e-20 ; VIP LFC: 0.64 ; FDR= 1.41x10e-10 etc), in lung primary tumor samples (50%) and methylation cluster 1 (82.14%). On the other hand, C1 was enriched in some important cancer-related pathways ( MYC targets NES -6.37 FDR < 10-3; MTORC1 NES -3.78 FDR < 10-3) and oxidative phosphorylation (NES -4.87 FDR < 10-3) ; and showed a higher proportion of small intestine primary tumors (46.34%), Grade 2 tumors (73.17%) and methylation cluster 2 (75%). NENs of different primary sites can be stratified into two major transcriptomic clusters, with a third cluster having a mixed expression profile. The groups with extreme transcriptomic signatures were enriched in neuroendocrine-related genes or principal cancer pathways. These results suggest a dedifferentiation from a more indolent neuroendocrine phenotype to more aggressive proliferative tumor types that could be driven partially with the methylation profile. Citation Format: Carlos Carretero Puche, Beatriz Soldevilla, Beatriz Gil, Anna La Salvia, Alberto Lens-Pardo, Paula Espinosa, Beatriz Anton-Pascual, Gonzalo Gómez-López, Fátima Al-Shahrour, Rocío García-Carbonero. Comprehensive multiomic analysis reveals different subtypes in neuroendocrine tumors from multiple origins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2289.

Simple Summary Metabolic flexibility is one of the key hallmarks of cancer and metabolites are the final products of this adaptation, reflecting the aberrant changes of tumors. However, the metabolic plasticity of each cancer type is still unknown, and specifically to date, there are no data on metabolic profile in neuroendocrine tumors. The aim of our retrospective study was to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. We provided, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use, selecting a reduced set of metabolites of high diagnostic accuracy. We have identified 32 novel enriched metabolic pathways in NETs related with the TCA cycle, and with arginine, pyruvate or glutathione metabolism, which have distinct implications in oncogenesis and may open innovative avenues of clinical research. Abstract Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

We present Beyondcell (https://gitlab.com/bu_cnio/beyondcell/), a computational methodology for identifying tumour cell subpopulations with distinct drug responses in single-cell RNA-seq data and proposing cancer-specific treatments. Our method calculates an enrichment score in a collection of drug signatures, delineating therapeutic clusters (TCs) within cellular populations. Additionally, Beyondcell determines therapeutic differences among cell populations, and generates a prioritised ranking of the differential sensitivity drugs between chosen conditions to guide drug selection. We performed Beyondcell analysis in four single-cell datasets to validate our score and to demonstrate that TCs can be exploited to target malignant cells both in cancer cell lines and tumour patients.

Motivation Drug immunomodulation modifies the response of the immune system and can be therapeutically exploited in pathologies such as cancer and autoimmune diseases. Results DREIMT is a new hypothesis-generation web tool, which performs drug prioritization analysis for immunomodulation. DREIMT provides significant immunomodulatory drugs targeting up to 70 immune cells subtypes through a curated database that integrates 4960 drug profiles and ∼2600 immune gene expression signatures. The tool also suggests potential immunomodulatory drugs targeting user-supplied gene expression signatures. Final output includes drug–signature association scores, FDRs and downloadable plots and results tables. Availabilityand implementation http://www.dreimt.org. Supplementary information Supplementary data are available at Bioinformatics online.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P=.04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P=.02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P=.8), 9% versus 9% (P=1), 66% versus 43% (P=.04), and 41% versus 23% (P=.2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P=.06) and 17% versus 23% (P=.5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P=.2), 35% versus 59% (P=.1), and 17% versus 40% (P=.04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT., This study was supported by an unrestricted grant from Adienne.

Following the success of posttransplant cyclophosphamide (PT-CY) as graft-versus-host disease (GVHD) prophylaxis in haploidentical transplantation, this prevention strategy has progressively been used for allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched sibling (MSD) and unrelated donor (MUD). We have introduced PT-CY plus sirolimus and micophenolate mofetil (PT-CY-Sir-MMF) as GVHD prophylaxis in allo-HSCT, irrespective of donor type. This study reports on the safety and efficacy of PT-CY-Sir-MMF in 158 consecutive allo-HSCT from MSD (n = 52), MUD (n = 64), and haploidentical (n = 42) donor. Median age was 53 years and 66% had acute leukemia or myelodysplastic syndrome. Cumulative incidences of acute GHVD grade II–IV, III–IV and moderate to severe cGVHD were 27%, 9% and 27%, respectively. The incidence of hepatic sinusoidal obstruction syndrome was 9.5%. The 1-year cumulative incidence of non-relapse mortality, relapse and event-free survival were 14%, 12% and 75%, respectively. Compared with MSD and MUD, haploidentical transplantation had a higher incidence of CMV DNAemia requiring therapy (34% vs 35% and 52%, respectively, p = 0.04) and was a risk factor for grade III–IV acute GVHD (RR 2.8, p = 0.05). Our study shows that PT-CY-Sir-MMF is not only feasible and effective in preventing GVHD after haploidentical HSCT, but also in allo-HSCT from MSD and MUD.

Background Solid tumour growth is the consequence of a complex interplay between cancer cells and their microenvironment. Recently, a new global transcriptomic immune classification of solid tumours has identified six immune subtypes (ISs) (C1–C6). Our aim was to specifically characterise ISs in colorectal cancer (CRC) and assess their interplay with the consensus molecular subtypes (CMSs). Methods Clinical and molecular information, including CMSs and ISs, were obtained from The Cancer Genome Atlas (TCGA) (N = 625). Immune cell populations, differential gene expression and gene set enrichment analysis were performed to characterise ISs in the global CRC population by using CMSs. Results Only 5 ISs were identified in CRC, predominantly C1 wound healing (77%) and C2 IFN-γ dominant (17%). CMS1 showed the highest proportion of C2 (53%), whereas C1 was particularly dominant in CMS2 (91%). CMS3 had the highest representation of C3 inflammatory (7%) and C4 lymphocyte depleted ISs (4%), whereas all C6 TGF-β dominant cases belonged to CMS4 (2.3%). Prognostic relevance of ISs in CRC substantially differed from that reported for the global TCGA, and ISs had a greater ability to stratify the prognosis of CRC patients than CMS classification. C2 had higher densities of CD8, CD4 activated, follicular helper T cells, regulatory T cells and neutrophils and the highest M1/M2 polarisation. C2 had a heightened activation of pathways related to the immune system, apoptosis and DNA repair, mTOR signalling and oxidative phosphorylation, whereas C1 was more dependent of metabolic pathways. Conclusions The correlation of IS and CMS allows a more precise categorisation of patients with relevant clinical and biological implications, which may be valuable tools to improve tailored therapeutic interventions in CRC patients., This work was funded by projects DTS15/00157 , PI16/01827 and CIBER-ONC CB16/12/00442 from the Instituto de Salud Carlos III ( Ministry of Economy, Industry and Competitiveness, Spain ) and cofunded by the European Regional Development Fund (ERDF, European Union), and approved by the Ethics Committee or our Institution. BS is funded by AECC (Spain). MCR is funded by Instituto de Salud Carlos III and SEOM (Spain) CCP and BRC are funded by CAM (Programa de Empleo Juvenil (YEI))

Motivation Genetic alterations lead to tumor progression and cell survival but also uncover cancer-specific vulnerabilities on gene dependencies that can be therapeutically exploited. Results vulcanSpot is a novel computational approach implemented to expand the therapeutic options in cancer beyond known-driver genes unlocking alternative ways to target undruggable genes. The method integrates genome-wide information provided by massive screening experiments to detect genetic vulnerabilities associated to tumors. Then, vulcanSpot prioritizes drugs to target cancer-specific gene dependencies using a weighted scoring system based on well known drug-gene relationships and drug repositioning strategies. Availability and implementation http://www.vulcanspot.org. Supplementary information Supplementary data are available at Bioinformatics online.

Patients with postransplant lymphoproliferative disease (PTLD) who are refractory to rituximab-based regimens have extremely poor prognosis. Data is lacking in the setting of solid organ transplantation (SOT)-related PTLD treated with chimeric antigen receptor T-cell (CAR-T) therapy. Moreover, limited information is available on the influence of concomitant immunosuppressive drugs on CAR-T function. Here, we describe the clinical outcome in one PTLD patient and propose a strategy for tailoring immunosuppressive treatment and organ monitoring in patients with kidney allografts after CAR-T infusion. This report also reviews the limited published data in the setting of SOT-related PTLD treated with CAR-T, which appears to be a feasible treatment in this clinical scenario, without severe toxicity and capable of inducing sustained responses. A noteworthy finding is that in most reported cases patients underwent complete or partial discontinuation of immunosuppressive drugs, with only one documented case of allograft rejection.

Late cardiomyopathy CMP is regarded as a potential severe long-term complication after anthracycline-based regimens for acute promyelocitic leukaemia (APL). We assess by MRI the incidence and severity of clinical and subclinical long-term CMP in a cohort of adult APL patients in first complete remission with PETHEMA trials. Adult patients diagnosed with APL in first complete remission lasting ≥2 years underwent anamnesis and physical examination and were asked to perform a cardiac MRI. Clinical CMP was defined as radiographic and physical signs of heart failure accompanied by symptoms or by left ventricle ejection fraction (LVEF)

We analyzed the incidence, clinical characteristics, prognostic factors, and outcome of central nervous system (CNS) infections in consecutive patients with receiving umbilical cord blood transplantation (UCBT) (n = 343) or HLA-matched sibling donor stem cell transplantation (MST) (n = 366). Thirty-four CNS infections were documented at a median time of 116 days after transplantation (range, 7 to 1161). The cumulative incidence (CI) risk of developing a CNS infection was .6% at day +30, 2.3% at day +90, and 4.9% at 5 years. The 5-year CI of CNS infection was 8.2% after UCBT and 1.7% after MST (P .001). The causative micro-organisms of CNS infections were fungi (35%), virus (32%), Toxoplasma spp. (12%), and bacteria (12%). Fungal infections occurred in 11 patients after UCBT and 1 after MST and were due to Aspergillus spp. (n = 8), Cryptococcus neoformans (n = 2), Scedosporium prolificans (n = 1), and Mucor (n = 1). Except for 1 patient, all died from CNS fungal infection. Viral infections occurred in 9 patients after UCBT and 1 after MST and were due to human herpes virus 6 (n = 7), cytomegalovirus (n = 2), and varicella zoster virus (n = 1). CNS toxoplasmosis was diagnosed in 3 patients after UCBT and 1 after MST. Other pathogens were Staphylococcus spp, Nocardia spp, Streptococcus pneumoniae, and Mycobacterium tuberculosis. Twenty of the 34 patients (59%) died from the CNS infection. In multivariable analysis, UCBT and disease stage beyond first complete remission were independently associated with the risk of developing CNS infections. The 5-year overall survival was 19% in patients who developed a CNS and 39% for those who did not (P = .006). In conclusion, our study showed that CNS infections are a significant clinical problem after stem cell transplantation associated with poor survival. They were more frequent after UCBT compared to MST.

Background There is growing evidence that community‐acquired respiratory virus (CARV) increases the risk of pulmonary invasive fungal disease (IFD) in the allogeneic hematopoietic stem cell transplantation (allo‐HSCT) setting. To date, there is a lack of knowledge regarding the risk factors (RFs), as well as the most critical period for subsequent onset of IFD after CARV infections in allo‐HSCT recipients. Methods In this prospective longitudinal observational CARV survey, we analyzed the effect of CARV on subsequent IFD development in 287 adult allo‐HSCT recipients diagnosed with 597 CARV episodes from December 2013 to December 2018. Multiplex PCR panel assays were used to test CARVs in respiratory specimens. Findings Twenty‐nine out of 287 allo‐HSCT recipients (10%) developed IFD after a CARV episode. The median time of IFD onset was 21 days (range, 0‐158 days) from day of the first CARV detection. Generalized estimating equation model identified 4 risk factors for IFD: ATG‐based conditioning regimen [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.05‐5.2, P = .038], CARV lower respiratory tract disease (OR 10.6, 95% CI 3.7‐30.8, P

The effect of timing of community acquired respiratory virus (CARV) infection after allogeneic hematopoietic stem cell transplant (allo-HCT) is an as yet unsettled issue. We evaluate this issue by including all consecutive allo-HCT recipients with molecularly-documented CARV infection during the first year after transplant. The study cohort was drawn from a prospective longitudinal survey of CARV in allo-HCT recipient having respiratory symptoms conducted from December 2013 to December 2018 at two Spanish transplant centers. Respiratory viruses in upper and/or lower respiratory specimens were tested using multiplex PCR panel assays. The study cohort comprised 233 allo-HCT recipients with 376 CARV infection episodes diagnosed during the first year after allo-HCT. Overall, 60% of CARV episodes occurred within the first 6 months (227 out of 376). Thirty patients (13%) had died at 3 months after CARV detection, of which 25 (83%) were recipients developing CARV within the first 6 months after transplant. Multivariate analysis identified four risk factors for mortality: ATG used as part of conditioning regimen [odds ratio (OR) 2.8, 95% confidence interval (C.I.) 1.21–6.4, p = 0.01], CARV lower respiratory tract disease (OR 3.4, 95% C.I. 1.4–8.4, p = 0.007), CARV infection within the first 6 months of transplant (OR 3.04, 95% C.I. 1.1–8.7, p = 0.03), and absolute lymphocyte count

This paper describes the main thermo-mechanical design features and performances of the Co-Alignment Sensor (CAS) developed by LIDAX and CRISA under ESA program with AIRBUS Defence and Space as industry prime.

BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001). RESULTS There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001). To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, 12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients. Disclosures Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau.

Purpose: Acute myeloid leukemia (AML) is associated with progressive accumulation of genetic alterations in hematopoietic progenitors. Massive sequencing allows inference of the clonal architecture of hematologic malignancies, by determining the presence of subclones, their genetic composition and evolution. The objective of the present study was to determine the spectrum of mutations present at relapse and define the proportion of cellular clones and the genetic architecture of the evolution of patients with de novo AML. Methods: Paired samples (diagnostic/relapse) of 44 patients of the University Hospital La Fe with de novo AML and treated with consecutive PETHEMA schemes were studied. The samples were provided by the Biobanco La Fe. The median age was 59 years (range 17 - 89); 21M/13F; 17 patients with normal karyotype; 14 patients with FLT3-ITD positive and 9 with mutations in NPM1. Using an amplicon panel (Ampliseq, Life Technologies) for deep sequencing (10.000x) with an Ion Torrent Proton, the complete coding regions of the following genes were sequenced, BCOR, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, GNAS, LUC7L2, NF1, PHF6, PTPN11, RAD21, RPS14, SF1, SF3A1, SMC3, SPARC, SRSF2, STAG2 and ZRSR2, as well as, the hotspot regions of ASXL1, MPL, NPM1, JAK2, KRAS, NRAS, TET2, U2AF1, KIT, IDH1, RUNX1, IDH2, SETBP1, TP53, WT1, CBL, SF3B1 and FLT3. Primary bioinformatic analysis was performed using an in-house protocol and variants were selected based on VAF ≥ 1%, its absence in the healthy population (UCSC Common SNPs; MAF < 0.01) and its putative effect on the protein. Results: At least one alteration was detected in 98% of patients, (n = 43). At a mean sequencing depth of 8967x, in total, 249 mutations were detected with an average of 3.3 mutations per patient and sample (range 0 - 8). Comparing the two time points, we noted that 45% of the mutations were present at both moments, with rather similar VAF values. However, 24% were acquired during progression while 31% went missing at the time of relapse. Regarding the mutated genes analyzed at diagnosis, in 8 of 44 patients one single gene clone was detected, in 26 two subclones and in 10 three or more subclones. In addition, two different patterns of clonal evolution were detected. In model 1 the dominant founder clone persisted at relapse (n = 32, 71%), occasionally acquiring new changes, either in the same clone (n = 5) or in a new subclone (n = 17). In model 2 the founder clone was displaced at relapse by new subclones (n = 12, 29%), probably due to selective pressure through competition between subclones or as a consequence of the chemotherapy. Furthermore, the clonal hematopoiesis models did not show an association with clinical variables or prognostic impact on OS or EFS (P = 0.317; P = 0.12, respectively). Conclusions: AML cells can acquire additional mutations at relapse. Some of those may contribute to the clonal selection responsible for disease progression. Two models of clonal evolution were observed: model 1, where the dominant founder clone persists during relapse, and, model 2, where the founder clone is displaced by new cell subclones, displaying, both models, a similar impact on outcome. Financed by the Spanish Foundation of Hematology (FEHH), PI12/01047, RD12/0036/0014, PIE13/00046, PI13/01640, PI13/02837, PT13/0010/0026, PI14/01649, ACOMP2015/0335 and PROMETEOII/2015/study/025. Disclosures No relevant conflicts of interest to declare.

The continental shelf surrounding the Spanish coast is very narrow. This is of great importance when studying the wave and surge dynamics in the region and contrasts with other well-studied regions like the North Sea, both in the physics and in the modelling techniques applied to obtain predictions of waves and sea surface elevation at the coastline. This paper describes those differences and presents the approach to the problem implemented in the wave and surge prediction system operational at Clima Maritimo (CM). The narrowness of the Spanish continental shelf requires very high resolution grids to be applied to localised regions near the coast. The usual configuration of a local system nested to a global system (e.g. grids covering the North Sea nested to the European Centre for Medium Range Weather Forecasting global model) cannot be used in this case. Interpolation and coarse grid errors from boundary conditions provided by a global grid very near the coast will not be corrected by a small-scale local application. It was found that self-contained systems, solving in the same run the basin and local scales by means of variable grid spacing techniques, were the optimal solution. Some new techniques were developed in the process (two-way nesting for the wave generation model, a transfer function technique for the wave spectra) and implemented in the system. Although some of these developments have been already published [Gomez, M., Carretero, J.C., 1997. A two-way nesting procedure for the WAM model: application to the Spanish coast. J. Offshore Mech. Arctic Eng. 119 (February 1997).], the final set-up of both systems is presented here for the first time. Both systems are regularly verified with experimental data from the Spanish network of buoy and tide gauges. Results from this intercomparison are discussed in this paper. The PROMISE Spanish Coast Data Set was used to carry out much of the work presented here (i.e. the forcing and validation of the surge prediction system). This is a collection of physical oceanographic and meteorological data in the Bay of Biscay during stormy periods from November 1995 to March 1996.

A generic module in which tides, surges and waves are incorporated has been developed, tested and prepared for dissemination within the framework of the MAST III PROMISE (PRe-Operational Modelling In the Seas of Europe) project. Two existing pre-operational numerical models, a wave model and a hydrodynamic model, were incorporated into a coupling framework that allows an efficient exchange of information between them. Minimal adaptation of the models was needed. The module has then been implemented and applied to the North Sea, then a series of experiments were performed to investigate the sensitivity of waves and surges to coupling. These experiments show that the sensitivity of waves to coupling increases from deep to shallow water, The sensitivity of surges is more uniformly distributed. The sensitivity of surges to coupling along the Spanish coast was also studied. The model results were less sensitive than in the North Sea. This is explained by the relative importance of the two forcing components, the atmospheric pressure and the wind stress, in both areas. (C) 2000 Elsevier Science B.V, All rights reserved.

An efficient chiral Lewis acid-catalyzed inverse-electron-demand Diels−Alder reaction of 1-azadienes is described. This procedure is based on the combination of NiII-DBFOX complex as catalyst and the use of a metal-coordinating (8-quinolyl)sulfonyl moiety at the iminic nitrogen of the N-sulfonyl 1-aza-1,3-diene, providing highly functionalized piperidine derivatives in good yields with excellent endo-selectivity, and enantioselectivities typically in the range of 77−92% ee.

New features have been added and several necessary changes have been made to the standard WAM-cycle4 (WAMC4) model code for it to run efficiently when applied to shallow water regions. The restriction of having a source term integration time step smaller than or equal to the propagation time step was relaxed, considerably reducing the computational time needed. An additional reduction in computing time and an increase in accuracy were obtained by introducing a split-frequency time step. There is now a choice of using the octant or quadrant coordinate system for the propagation of the wave energy. The source term integration and, more particularly, the use of a limiter on the energy growth, were studied. For the evaluation of the energy decay in shallow water areas, different bottom friction formulations and an expression for the energy dissipation due to depth-induced wave breaking were added to the code. The procedure to make nested runs was changed in order to save data storage space and time spent on input/output (I/O) operations. Several other changes were done in order to improve the accuracy in high-resolution applications. A number of simple or idealised example applications are included to illustrate some of these enhancements.

Le premier compose du titre cristallise dans le systeme monoclinique avec le groupe d'espace P2 1 /a. Le second cristallise dans le systeme orthorhombique avec le groupe d'espace P2 1 2 1 2 1 . Affinement de la structure jusqu'a 0,041 et 0,045 respectivement