Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties ...in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283.
The effect of TAT-Cx43266-283, temozolomide (TMZ) and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by Western blot (WB) and Fluorescence In Situ Hybridization (FISH) in these cells, and compared with Src activity and survival in GBM samples from TCGA.
The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations, showed a decrease in growth, invasiveness and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice.
Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step towards the clinical application of TAT-Cx43266-283.
BACKGROUND // The incidence of COVID-19 infections among health professionals during the sixth wave has suffered an exponential
increase, mainly due to the rapid community transmission caused by the ...Omicron variant. The main objective of the study was
to evaluate the time to negativization in COVID-positive health professionals during the sixth wave, according to the PDIA result; and
secondarily, to evaluate the possible influence of other factors (previous infection, vaccination, sex, age, job position) on the time to
get negative status.
METHODS // A descriptive, longitudinal, observational and retrospective study was carried out at Infanta Sofía University Hospital
(Madrid, Spain). Made from the registry of the Occupational Risk Prevention Service of suspected or confirmed cases of SARS-COV-2
infection in health professionals, during the period between November 1, 2021 and February 28, 2022. Bivariate comparisons were made
using Mann Whitney, Kruskal Wallis or Chi-square test (or exact test) according to variables. Subsequently, logistic regression (explanatory
model) was performed.
RESULTS // The cumulative incidence of SARS-COV-2 infection in health professionals was 23.07%. The mean time to become
negative was 9.94 days. Only the history of previous SARS-COV-2 infection had a statistically significant influence on the time to
negativization of PDIA. The variables vaccination, sex and age had no effect on the time to negativization of PDIA.
CONCLUSIONS // Professionals with a history of COVID-19 infection present lower times of negativization than those who had not
have the disease. The results of our study confirm the immune escape of the vaccine against COVID-19, since more than 95% of those
infected had received a complete vaccination schedule.
FUNDAMENTOS // La incidencia de contagios por COVID-19 entre profesionales sanitarios durante la sexta ola ha sufrido un incremento
exponencial, motivado principalmente por la rápida trasmisión comunitaria ocasionada por la variante Ómicron. El objetivo
principal del estudio fue evaluar el tiempo de negativización en los profesionales sanitarios COVID positivos durante la sexta ola,
según resultado de PDIA; y, de forma secundaria, evaluar la posible influencia de otros factores (infección previa, vacunación, sexo,
edad, puesto de trabajo) en el tiempo de negativización.
MÉTODOS // Se realizó un estudio descriptivo, longitudinal, observacional y retrospectivo en el Hospital Universitario Infanta Sofía
(Madrid), a partir del registro del Servicio de Prevención de Riesgos Laborales de casos sospechosos o confirmados de infección por
SARS-COV-2 en profesionales sanitarios, durante el periodo comprendido entre el 1 de noviembre de 2021 y el 28 de febrero de 2022.
Se hicieron comparaciones bivariadas mediante Mann Whitney, Kruskal Wallis o test de Chi-cuadrado (o test exacto) según variables.
Posteriormente se realizó regresión logística (modelo explicativo).
RESULTADOS // La incidencia acumulada de infección por SARS-COV-2 en profesionales sanitarios fue del 23,07%. El tiempo medio
en negativizar fue de 9,94 días. Únicamente el antecedente de infección previa por SARS-COV-2 influyó de forma estadísticamente
significativa en el tiempo de negativización de PDIA. Las variables vacunación, sexo y edad no tuvieron efecto en el tiempo de
negativización de PDIA.
CONCLUSIONES // Los profesionales con antecedente de infección por COVID-19 presentan tiempos inferiores de negativización
que aquellos que no han pasado la enfermedad. Los resultados de nuestro estudio constatan el escape inmunológico de la vacuna
frente al COVID-19, pues más del 95% de los infectados habían recibido una pauta de vacunación completa.
Background: Current guidelines recommend the use of antifungal prophylaxis during, at least, the first three months post allogeneic stem cell transplantation (allo-SCT). However, these drugs are not ...exempt of adverse effects due to their own toxicity or drug-drug interactions. In addition, breakthrough mold infections seem to be emerging as a new problem in this setting.
Objectives: The aim of this study was to analyze the benefit of a strategy in which allo-SCT patients were not routinely prescribed antifungal drugs except for the case of the development of neutropenic fever and/or exposure to high dose of corticosteroids. Main objectives were 1) requirement and time of exposure to antifungal treatment and 2) cumulative incidence (CI) of proven or probable IFI at 1, 3 and 6 months after transplant. Other objectives were IFI description and overall survival (OS).
Patients and methods: 319 patients who underwent a first allo-SCT at our center between 2010 and 2017 and were not under antifungal prophylaxis at the moment of transplant were included. 181 patients (57%) were males and median age was 51 years, range (4-74). Acute myeloid leukemia (35%) was the most frequent diagnosis and myeloablative conditioning regimen was mostly used (69%). 99 patients (31%) received the stem cells from a mismatched donor and BM was the preferred stem cell source (72%). Fourteen patients (4%) did not engraft. The median length of neutropenia <0.5x109/L and <0.1x109/L were 12 days and 6 days, respectively. Forty-two patients (14%) developed acute GVHD grade III-IV. Post-mortem study was performed in 28 of the deceased patients (43%).
Results:Thirty-one 31 patients (9.7%) did not receive antifungal drugs along the course of the transplantation, 58 patients (18%) required it for less than 1 week and only 24% were on therapy more than 3 weeks. The median total days on antifungal drugs was 13 days (0-175) for the entire population and 11 days (0-109) in patients who did not develop fungal infection and/or acute GVHD II-IV.
Fluconazole (61%) was the main antifungal drug used during the neutropenic phase, followed by caspofungin (27%). Time on fluconazole was significantly shorter than caspofungin, 8 vs. 11 days, p=0.001. A change on antifungal therapy was needed in 130 (45%) patients and was more frequent in those who were receiving fluconazole (57%) compared to those who were receiving caspofungin (20%), p<0.0001.
The CI of proven or probable IFI at day 30, 90 and 180 after transplant was 2.5%, 5.1% and 5.5%, respectively. Very importantly, none of the 106 patients who did not receive antifungal drugs or received less than one-week developed IFI. Twelve mold infection, 4 in the postmortem study, and 5 yeast infection were diagnosed. Microbiological identification was obtained in 9 patients; C. parapsilosis (3), Rhizopus (2), C. orthopsilosis (1), Criptococo laurentii (1), A. fumigatus (1), Alternaria spp. (1).
The restricted administration of antifungal drugs did not affect the overall survival, Figure 1.
Conclusion: In our experience, a restrictive strategy for the use of antifungal drugs in the setting of allo-SCT is feasible and effective. It results in similar cumulative incidences of fungal infection than the recommended policy. Moreover, it allows almost 10% of patients to remain free of antifungal treatment throughout the procedure and one fourth of them being exposed for less than a week. This data supports the change in the antifungal prophylactic paradigm for allo-SCT patients.
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No relevant conflicts of interest to declare.
•39,848 cancer patients were registered between Feb-May 2020 in 66 ROD in Spain.•For COVID-19, incidence was 0.8%. Mortality was 22%. 64,3% required hospitalization.•Compared to the general ...population, higher severity and mortality of COVID-19 was observed.•Patient and treatment selection is crucial. Hypofractionation should be considered.
Background: Venetoclax is a BCL-2 inhibitor particularly effective in patients with multiple myeloma (MM) harboring the t(11;14). However, resistance to venetoclax has been linked to MCL-1 ...overexpression. On the other hand, it is wellknown that MM cells depend on MCL-1 rather than BCL-2 for survival, and this dependence has recently been reported to be enhanced by the tumor-associated microenvironment. Therefore, the combination of venetoclax with the potent MCL-1 inhibitor S63845 arises as a promising and novel approach for the treatment of MM.
Aims: To evaluate the efficacy and mechanism of action of S63845 alone and in combination with venetoclax in absence and presence of the bone marrow tumor microenvironment in preclinical in vitro, ex vivo and in vivo models of MM.
Methods: S63845 was provided by an agreement with Servier and Novartis. In vitro activity of S63845 and venetoclax alone and in combination was evaluated by bioluminescence on a MM cell line expressing luciferase (MM.1S-luc) in absence and presence of mesenchymal stromal cells isolated from bone marrow aspirates of MM patients (pMSCs). MM.1S cells cultured in absence or presence of pMSCs were analyzed for MCL-1 and BCL-2 protein levels by Western blot. Interactions between these anti-apoptotic proteins with the pro-apoptotic protein BIM were assessed by immunoprecipitation assays. The efficacy of S63845 and venetoclax alone and in combination was also evaluated ex vivo in MM cells and normal lymphocytes from MM patients. Finally, a disseminated MM model in BRG mice was used for in vivo studies.
Results: S63845 and venetoclax showed a strong antimyeloma dose-dependent effect on MM.1S-luc cells co-cultured with pMSCs. However, whereas the presence of tumor-associated MSCs increased the IC50 value of venetoclax in MM.1S-luc cells from 6.2 to 9.8 mM, it reduced that of S63845 from 94.1 to 81 nM, suggesting a mild sensitization to this drug in the context of the microenvironment. Neither S63845 nor venetoclax affected pMSC viability even at high concentrations by MTT assay. The co-culture with the BM stromal microenvironment increased MCL-1 expression on untreated MM.1S cells in two out of four experiments performed with MSCs from different MM patients, whereas it surprisingly induced a decrease on BCL-2 levels in all of them. Treatment with S63845 completely blocked MCL-1 binding to BIM, both in the absence or presence of pMSCs but did not induce the compensatory increase of BCL-2/BIM complexes observed in MM.1S cells in monoculture. Venetoclax also completely blocked the binding of BCL-2 to BIM in MM.1S alone or in co-culture, and induced a similar compensatory increase of MCL-1/BIM complexes in both situations. Importantly, the double combination S63845 + venetoclax was significantly superior to both drugs in monotherapy in killing MM.1S-luc cells co-cultured in the presence of the stromal microenvironment. BIM immunoprecipitation assays showed that the double combination was able to counteract the compensatory upregulation of MCL-1 bound to BIM observed on MM.1S cells treated with venetoclax and to entirely disrupt BCL-2/BIM complexes, both in the absence and presence of pMSCs. Furthermore, S63845 + venetoclax increased the percentage of apoptotic MM plasma cells from three MM patients with respect to single treatments with moderate toxicity detected on normal lymphocytes, suggesting the existence of a therapeutic window for the double combination. Finally, the combination of S63845 + venetoclax clearly delayed tumor growth as compared with the agents in monotherapy in a disseminated model of MM with statistically significant differences from day 19 of treatment. This in vivo effect translated into a significatively improved survival for mice treated with the double combination (median 60 days) vs control mice (median 32 days; log-rank test P=0.045).
Conclusion: Our preclinical data demonstrate the potent activity of the combination of venetoclax with S63845 in MM even in presence of the stromal associated-tumor microenvironment, and provides the rationale for the clinical development of this combination in relapsed or refractory MM patients.
This project was supported by Novartis Pharmaceuticals and by the Spanish , ISCIII-FIS PI15/00067 and PI15/02156, GRS 1604/A/17 and CRMRTC de Castilla y León. Predoctoral grant to EMA by Consejería de Educación de Castilla y León.
Schoumacher:Servier: Employment. Banquet:Servier: Employment. Kraus-Berthier:servier: Employment. Kloos:Servier: Employment; Novartis: Other: Partnership. Halilovic:Novartis: Employment, Equity Ownership. Maacke:Novartis: Employment. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:AbbVie: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmamar: Consultancy; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding.
One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of ...the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data.
Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/μL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve.
Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.
Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic ...stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin.
The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid.
Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX).
The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials.
Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and ...others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.
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