Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma.

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatment-emergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma. European Clinical Trials Database number: 2015-002993-19.

Sociodemographic and clinical factors associated with the preference between NNRTIs and PIs for the initial treatment of HIV infection: Perfil-es study.

The Perfil-es study demonstrated that, while non-nucleoside reverse transcriptase inhibitor (NNRTI)-based initial antiretroviral therapy (ART) is more frequently used in human immunodeficiency virus (HIV)-infected naïve patients, ritonavir-boosted protease inhibitors (PI/r)-based regimens are the preferred option in patients with advanced infectious stages or high baseline viral load. The present analysis focused on the second phase of the Perfil-es study, where sociodemographic and clinical data were retrospectively collected from patients starting NNRTI- or PI/r-based regimens in order to identify factors that could influence the choice of initial ART. Patients' characteristics were compared by both bivariate and multivariate analyses. A total of 642 patients were evaluated. The main transmission group was men who have sex with men (MSM) (48%), and 24% of patients were coinfected with hepatitis B or C. Patients with cardiovascular risk accounted for 56%, and 15% had a neuropsychiatric history. Anxiolytics (29%), antidepressants (18%) and methadone (18%) were the most frequent concomitant medications. The use of PI/r-based regimens was more frequent in older patients, childbearing potential women patients coinfected with hepatitis B or C, and those with cardiovascular risk and a neuropsychiatric history. The presence of a neuropsychiatric disorder (OR: 1.912; CI 95%: 1.146-3.191; p < .05) and the use of concomitant medication (OR: 1.736; CI 95%: 1.204-2.502; p < .01) were identified as independent factors associated with the selection of PI/r-based regimens. MSM sexual conduct was the only independent factor related to the selection of NNRTI-based ART (OR: 0.699; CI 95%: 0.504-0.970; p < .05). Neither the physicians' characteristics nor the geographical area where HIV patients were attended influenced the choice of ART. In conclusion, patients' comorbidity, pregnancy potential and lifestyle seem to influence the choice of ART. Neuropsychiatric comorbidity and concomitant medication, mainly related to this condition, appear to be associated with the use of PI/r-based initial ART while MSM seem more likely to receive NNRTI-based regimens in Spain.

Tratamiento antirretroviral de inicio en pacientes infectados por el virus de la inmunodeficiencia humana en España: decisiones con relación a características inmunovirológicas específicas (estudio PERFIL-es) / Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)

INTRODUCCIÓN: El objetivo del estudio Perfil-es era conocer, en la práctica clínica, la proporción de TARV de inicio basado en ITINAN o IP/r e identificar los factores implicados en la decisión terapéutica. Métodos Estudio observacional, retrospectivo en 65 hospitales. Resultados Se iniciaron 1.687 TARV: un 53% basado en ITINAN y un 42% en IP/r. Se analizaron 642 pacientes. El 72% presentaba un recuento de CD4 < 350 células/μl. Conclusión En España el TARV de inicio sigue siendo tardío. Los ITINAN son la elección más frecuente aunque los IP/r desempeñan un importante papel

INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-makingin standard clinical practice. METHODS: An observational restrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the642 patients analyzed, 72% had a CD4 count < 350 cells/l. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role

[Initial antiretroviral treatment in human immunodeficiency virus-infected patients in Spain: Decisions made in relation to particular immunovirological characteristics (PERFIL-es study)]. / Tratamiento antirretroviral de inicio en pacientes infectados por el virus de la inmunodeficiencia humana en España: decisiones con relación a características inmunovirológicas específicas (estudio PERFIL-es).

INTRODUCTION: The purpose of Perfil-es study was to identify the proportion of patients starting ARV treatment based on NNRTIs or PI/r, and to identify the variables involved in the therapeutic decision-making in standard clinical practice. METHODS: An observational retrospective study performed in 65 Spanish hospitals. RESULTS: Was a total of 1,687 starts: 53% with NNRTI-based regimen and 42% with PI/r, and of the 642 patients analyzed, 72% had a CD4 count<350 cells/µl. CONCLUSION: The initiation of ARV treatment is still late in Spain. NNRTIs are the more frequent choice, although PI/r plays an important role.

[Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients]. / Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida.

INTRODUCTION: In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. METHODS: Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient's enrollment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. RESULTS: 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). CONCLUSIONS: Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period.

Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida / Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients

Introducción. En el año 2009 se produjo un cambio muy sustancial en el tratamiento antirretroviral (ARV) de nuestro país con la introducción de nuevos fármacos antiretrovirales. El objetivo fue conocer la situación clínica de los pacientes en los que se introducía darunavir (DRV/r) en el tratamiento antirretroviral. Métodos. Estudio observacional, transversal y retrospectivo, en el que participaron 91 centros españoles de referencia. El periodo de reclutamiento del estudio se llevó a cabo entre 2008 y 2009. Se recogieron datos relacionados con la práctica clínica habitual. Resultados. Se revisaron 719 historias clínicas. La situación clínica prevalente entre los pacientes que necesitaban un ajuste al tratamiento antirretroviral era diferente a la actual con predominio de multirresistencias que llevaban a fracaso. El motivo principal por el que se había incluido DRV/r en la pauta fue el fracaso virológico (54,2%). Conclusiones. En esa situación, DRV/r constituyó una opción terapéutica que supuso un cambio en el paradigma del tratamiento antirretroviral de la época(AU)

Introduction. In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. Methods. Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient’s enrolment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. Results. 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). Conclusions. Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period(AU)

Methylthioadenosine reverses brain autoimmune disease.

OBJECTIVE: To assess the immunomodulatory activity of methylthioadenosine (MTA) in rodent experimental autoimmune encephalomyelitis (EAE) and in patients with multiple sclerosis. METHODS: We studied the effect of intraperitoneal MTA in the acute and chronic EAE model by quantifying clinical and histological scores and by performing immunohistochemistry stains of the brain. We studied the immunomodulatory effect of MTA in lymphocytes from EAE animals and in peripheral blood mononuclear cells from healthy control subjects and multiple sclerosis patients by assessing cell proliferation and cytokine gene expression, by real-time polymerase chain reaction, and by nuclear factor-kappaB modulation by Western blot. RESULTS: We found that MTA prevents acute EAE and, more importantly, reverses chronic-relapsing EAE. MTA treatment markedly inhibited brain inflammation and reduced brain damage. Administration of MTA suppressed T-cell activation in vivo and in vitro, likely through a blockade in T-cell signaling resulting in the prevention of inhibitor of kappa B (IkappaB-alpha) degradation and in the impaired activation transcription factor nuclear factor-kappaB. Indeed, MTA suppressed the production of proinflammatory genes and cytokines (interferon-gamma, tumor necrosis factor-alpha, and inducible nitric oxide synthase) and increased the production of antiinflammatory cytokines (interleukin-10). INTERPRETATION: MTA has a remarkable immunomodulatory activity and may be beneficial for multiple sclerosis and other autoimmune diseases.

Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma.

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis.

5'-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes.

5'-methylthioadenosine (MTA) is a nucleoside generated from S-adenosylmethionine (AdoMet) during polyamine synthesis. Recent evidence indicates that AdoMet modulates in vivo the production of inflammatory mediators. We have evaluated the anti-inflammatory properties of MTA in bacterial lipopolysaccharide (LPS) challenged mice, murine macrophage RAW 264.7 cells, and isolated rat hepatocytes treated with pro-inflammatory cytokines. MTA administration completely prevented LPS-induced lethality. The life-sparing effect of MTA was accompanied by the suppression of circulating tumor necrosis factor-alpha (TNF-alpha), inducible NO synthase (iNOS) expression, and by the stimulation of IL-10 synthesis. These responses to MTA were also observed in LPS-treated RAW 264.7 cells. MTA prevented the transcriptional activation of iNOS by pro-inflammatory cytokines in isolated hepatocytes, and the induction of cyclooxygenase 2 (COX2) in RAW 264.7 cells. MTA inhibited the activation of p38 mitogen-activated protein kinase (MAPK), c-jun phosphorylation, inhibitor kappa B alpha (IkappaBalpha) degradation, and nuclear factor kappaB (NFkappaB) activation, all of which are signaling pathways related to the generation of inflammatory mediators. These effects were independent of the metabolic conversion of MTA into AdoMet and the potential interaction of MTA with the cAMP signaling pathway, central to the anti-inflammatory actions of its structural analog adenosine. In conclusion, these observations demonstrate novel immunomodulatory properties for MTA that may be of value in the management of inflammatory diseases.