First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

Safety and clinical activity of atezolizumab in head and neck cancer: results from a phase I trial.

Background: Head and neck cancer (HNC) has a poor prognosis at advanced stages. Given the immunosuppressive tumor microenvironment in HNC, inhibition of the programmed death-ligand 1/programmed death-1 (PD-L1/PD-1) signaling pathway represents a promising therapeutic approach. Atezolizumab (anti-PD-L1) is efficacious against many tumor types. Here we report the clinical safety and activity from the HNC cohort of the phase Ia PCD4989g clinical trial. Patients and methods: Patients with previously treated, advanced HNC received atezolizumab i.v. every 3 weeks for 16 cycles, up to 1 year or until loss of clinical benefit. Patients were monitored for safety and tolerability and evaluated for response at least every 6 weeks. Baseline PD-L1 expression level and human papillomavirus (HPV) status were evaluated. Results: Thirty-two patients were enrolled; 7 patients (22%) had a primary tumor in the oral cavity, 18 (56%) in the oropharynx, 1 (3%) in the hypopharynx, 2 (6%) in the larynx, and 4 (13%) in the nasopharynx. Seventeen patients (53%) had ≥2 prior lines of therapy. Twenty-one patients (66%) experienced a treatment-related adverse event (TRAE), with three experiencing grade 3 TRAEs and one experiencing a grade 4 TRAE (per CTCAE v4.0). No grade 5 TRAEs were reported. Objective responses by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) occurred in 22% of patients, with a median duration of response of 7.4 months (range 2.8-45.8 months). Median progression-free survival was 2.6 months (range 0.5-48.4 months), and median overall survival was 6.0 months (range 0.5-51.6+ months). Responses showed no association with HPV status or PD-L1 expression level. Conclusions: In this heavily pre-treated advanced HNC cohort, atezolizumab had a tolerable safety profile and encouraging activity, with responses observed regardless of HPV status and PD-L1 expression level. These findings warrant further investigation of atezolizumab in HNC. ClinicalTrials.gov number: NCT01375842.

Epidermal Langerhans cells promote skin allograft rejection in mice with NF-kappa B-impaired T cells.

T cells play a major role in the acute rejection of transplanted organs. Using mice transgenic for a T-cell-restricted NF-kappaB super-repressor (IkappaBalphaDeltaN-Tg mice), we have previously shown that T-cell-NF-kappaB is essential for the acute rejection of cardiac but not skin allografts. In this study, we investigated the mechanism by which skin grafts activate IkappaBalphaDeltaN-Tg T cells. Rejection was not due to residual T-cell-NF-kappaB activity as mice with p50/p52(-/-) T cells successfully rejected skin grafts. Rather, skin but not cardiac allografts effectively induced proliferation of graft-specific IkappaBalphaDeltaN-Tg T cells. Rejection of skin grafts by IkappaBalphaDeltaN-Tg mice was in part dependent on the presence of donor Langerhans cells (LC), a type of epidermal dendritic cells (DC), as lack of LC in donor skin grafts resulted in prolongation of skin allograft survival and injection of LC at the time of cardiac transplantation was sufficient to promote cardiac allograft rejection by IkappaBalphaDeltaN-Tg mice. Our results suggest that LC allow NF-kappaB-impaired T cells to reach an activation threshold sufficient for transplant rejection. The combined blockade of T-cell-NF-kappaB with that of alternative pathways allowing activation of NF-kappaB-impaired T cells may be an effective strategy for tolerance induction to highly immunogenic organs.

[Unawareness of the K/DOQI guidelines for bone and mineral metabolism in predialysis chronic kidney disease: results of the OSERCE Spanish multicenter-study survey]. / Desconocimiento de las guías K/DOQI sobre la alteración del metabolismo óseo-mineral asociada a la enfermedad renal crónica no en diálisis: resultados de la encuesta en el estudio multicéntrico español OSERCE.

Since its publication in 2003, the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) have become a worldwide reference. The aim of this study was to analyze the observance to these guidelines in patients with a glomerular filtration rate < 60 ml/min/1,73m2 not yet included in dialysis in a Spanish multicenter cohort. A questionnaire by investigator/centre was completed by 32 different nephrologists participating in the OSERCE study and representing the overall Spanish public health net. We observed that biochemical parameters were measured less frequently than recommended, except in CKD stage 3. The therapeutic goals for intact PTH were not properly reported by 59 % of the consulted nephrologists for stages 3 and 4, whereas only 22% did not report them properly for stage 5. The goals for phosphorus were not adequately reported in 50 % of cases (stages 3 y 4) and 60 % (stage 5). For calcium, these values were 70 %, 73.3 % and 65.5 % for stages 3, 4 and 5, respectively. A corrected plasma calcium between 9.5 and 10.2 mg/dl is still considered adequate for 31%. As much as 87% nephrologists stated that they did not sistematically measure calcidiol plasma levels. In general, these results demonstrate that there is a great degree of unawareness of K/DOQITM predialysis guidelines. Thus, their poor implementation is probably not only due to the lower availability of approved therapeutic agents, the difficult achievement of goals or the disbelief on current recommendations. It would be desirable that forthcoming guidelines such as the KDIGO could also consider the need of educational efforts for CKD-Mineral and Bone Disorder.

[Children's and adolescents' perception of their quality of life in cases of attention deficit hyperactivity disorder with and without pharmacological treatment and in controls]. / Percepcion de niños y adolescentes sobre la calidad de vida en casos de trastorno por deficit de atencion/hiperactividad con y sin tratamiento farmacologico y en controles.

INTRODUCTION: Health-related quality of life perceived by children and teenagers is important to assess the effects of therapeutic intervention. AIM: To analyze quality of life, comparing cases of attention deficit hyperactivity disorder (ADHD) treated with methylphenidate, untreated cases and controls. SUBJECTS AND METHODS: Sampling of 228 participants between 8 and 14 years-old. Consecutive sampling in ADHD according to DSM-IV criteria (ADHD Rating Scales IV) and random sampling of matched controls by sex and age. Evaluation of quality of life using KIDSCREEN-52 (children version). ANOVA with Bonferroni correction was used. RESULTS: There is a moderate significant correlation between greater intensity of ADHD symptoms and worse quality of life, except in the dimension of physical well-being. Cases of untreated ADHD have significantly worse quality of life than controls on psychic well-being, mood, autonomy school environment and social acceptance. Cases of treated ADHD present similar results, except in the school environment and psychological well-being. The cases of ADHD treated only differ significantly from ADHD not treated in having a better school environment. CONCLUSIONS: The cases of ADHD present dimensions of KIDSCREEN-52 with worse quality of life than controls and the cases of ADHD treated with methylphenidate only differ significantly from those not treated in presenting better results in the school environment.

TITLE: Percepcion de niños y adolescentes sobre la calidad de vida en casos de trastorno por deficit de atencion/hiperactividad con y sin tratamiento farmacologico y en controles.Introduccion. La calidad de vida relacionada con la salud percibida por niños y adolescentes es un factor importante para valorar los efectos de una intervencion terapeutica. Objetivo. Analizar la calidad de vida comparando casos con trastorno por deficit de atencion/hiperactividad (TDAH) tratados farmacologicamente con metilfenidato, casos no tratados y controles. Sujetos y metodos. Muestra de 228 participantes de 8-14 años. Muestreo consecutivo de casos de TDAH segun los criterios del Manual diagnostico y estadistico de los trastornos mentales, cuarta edicion, y muestreo aleatorio de controles emparejados por sexo, edad y zona sociodemografica. Evaluacion de la calidad de vida mediante el KIDSCREEN-52 (version niños y adolescentes). Para responder al objetivo se utilizo ANOVA con correccion de Bonferroni. Resultados. Observamos una correlacion significativa moderada entre mayor intensidad de sintomas de TDAH y peor calidad de vida, excepto en el bienestar fisico. Los casos de TDAH no tratados tienen significativamente peor calidad de vida que los controles en bienestar psiquico, autonomia, estado de animo, entorno escolar y aceptacion social. Los casos de TDAH tratados observan similares resultados excepto en el entorno escolar y el bienestar psiquico, que no presentan diferencias significativas con los controles. Los casos de TDAH tratados por comparacion con los de TDAH no tratados solo presentan significativamente mejor calidad de vida en el entorno escolar. Conclusion. Los casos de TDAH presentan dimensiones del KIDSCREEN-52 con peor calidad de vida que los controles y los casos de TDAH tratados con metilfenidato solo se diferencian significativamente de los no tratados porque presentan mejores resultados en el entorno escolar.

Osmotic stress sensitizes naturally resistant cells to TNF-alpha-induced apoptosis.

Most cells are naturally resistant to TNF-alpha-induced cell death and become sensitized when NF-kappaB transactivation is blocked or in the presence of protein synthesis inhibitors that prevent the expression of anti-apoptotic genes. In this report we analyzed the role of osmotic stress on TNF-alpha-induced cell death. We found that it sensitizes the naturally resistant HeLa cells to TNF-alpha-induced apoptosis, with the involvement of an increase in the activity of several kinases, the inhibition of Bcl-2 expression, and a late increase on NF-kappaB activation. Cell death occurs regardless of the enhanced NF-kappaB activity, whose inhibition produces an increase in apoptosis. The inhibition of p38 kinase, also involved in NF-kappaB activation, significantly increases the effect of osmotic stress on TNF-alpha-induced cell death.

Role of natural killer cell subsets in cardiac allograft rejection.

To achieve donor-specific immune tolerance to allogeneic organ transplants, it is imperative to understand the cell types involved in acute allograft rejection. In wild-type mice, CD4(+) T cells are necessary and sufficient for acute rejection of cardiac allografts. However, when T-cell responses are suboptimal, such as in mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted patients taking immunosuppressive drugs, the participation of other lymphocytes such as CD8(+) T cells and NK1.1(+) cells becomes apparent. We found that host NK but not NKT cells were required for cardiac rejection. Ly49G2(+) NK cells suppressed rejection, whereas a subset of NK cells lacking inhibitory Ly49 receptors for donor MHC class I molecules was sufficient to promote rejection. Notably, rejection was independent of the activating receptors Ly49D and NKG2D. Finally, our experiments supported a mechanism by which NK cells promote expansion and effector function of alloreactive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in settings of impaired T-cell function.

TLR engagement prevents transplantation tolerance.

In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.

Codominant expression of the polymorphic MICA alloantigens encoded by genes in the HLA region.

The HLA-related, polymorphic MHC class I-related chain A (MICA) gene encodes a 383-amino acid polypeptide, with three extracellular domains (alpha1, alpha2 and alpha3), a transmembrane region and a cytoplasmic tail. We have previously shown that freshly isolated endothelial cells, fibroblasts, keratinocytes and monocytes express MICA, while peripheral blood CD4+, CD8+ or CD19+ lymphocytes do not. This polymorphic MICA molecule is a target for specific alloantibodies in sera from kidney, heart and lung transplant recipients, although its possible role during graft rejection remains to be demonstrated. In this study we investigated whether there is codominance in the expression of MICA. We isolated RNA from a heterozygous cell line (HCT116), previously shown by sequencing-based typing to be MICA*001/MICA*00902, as well as 12 clones derived from it. Thereafter, we retrotranscribed the RNA into cDNA, and performed a molecular typing using MICA-sequence specific oligonucleotides (SSOP). Using this approach, we detected the RNA encoding MICA*001 and MICA*00902 in all the clones and in the parental cell line, indicating that MICA is codominantly expressed. This codominant expression was further confirmed by cloning and sequencing plasmids encoding these two alleles produced from the same HCT116 RNA preparation. We also produced the two recombinant MICA proteins (MICA*001 and MICA*00902). They reacted with rabbit anti-MICA polyclonal antibodies by ELISA and Western blot, indicating that the plasmids carrying the cDNA inserts probably encode functional MICA proteins. This strongly suggests that, like the HLA class I and class II proteins, MICA is codominantly expressed. The codominant expression of the polymorphic, HLA-like MICA alloantigens may have implications for the immune response elicited by the allograft in organ transplantation.

The PDQ-39 Spanish version: reliability and correlation with the short-form health survey (SF-36).

BACKGROUND AND METHODS: The Parkinson's Disease Questionnaire (PDQ-39) was the first specific instrument for evaluation of the "health-related quality of life" (QoL) in Parkinson's disease patients. The PDQ-39 has been subjected to adaptation to Spanish language and culture (PDQ-39 Spanish version, PDQ-39SV) and this version has been validated in aspects of internal consistency and construct validity. The present study assess the test-retest reliability and the convergent validity of the PDQ-39SV with a generic QoL instrument (SF-36). RESULTS: Most of the PDQ-39 dimensions showed an adequate consistency-Cronbach's alpha > 0.7 for six dimensions. As a whole, test-retest reliability resulted satisfactory. Two dimensions-activities of daily living and emotional well-being- showed a low grade significant difference (paired Student t-test, p < 0.05) due to improvement in the second survey (at 10 to 14 days from the first one) perhaps related to adjustments of the treatment at the first visit. A strong association (Spearman r, p < 0.001), indicative of convergent validity, was obtained for the PDQ-39 dimensions and the relevant SF-36 scales, as well as for the physical and mental component summary scores of the SF-36. CONCLUSIONS: Taking into account these results and previous studies, it is concluded that the PDQ-39 SV is a reliable measure that has construct validity.