Case report: Challenges in immune reconstitution following hematopoietic stem cell transplantation for CTLA-4 insufficiency-like primary immune regulatory disorders.

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is a T-cell hyperactivation disorder that can manifest with both immunodeficiency and immune dysregulation. Approximately one-third of patients may present mild symptoms and remain stable under supportive care. The remaining patients may develop severe multiorgan autoimmunity requiring lifelong immunosuppressive treatment. Hematopoietic stem cell transplantation (HSCT) is potentially curable for patients with treatment-resistant immune dysregulation. Nevertheless, little experience is reported regarding the management of complications post-HSCT. We present case 1 (CTLA-4 haploinsufficiency) and case 2 (CTLA-4 insufficiency-like phenotype) manifesting with severe autoimmunity including cytopenia and involvement of the central nervous system (CNS), lung, and gut and variable impairment of humoral responses. Both patients underwent HSCT for which the main complications were persistent mixed chimerism, infections, and immune-mediated complications [graft-versus-host disease (GVHD) and nodular lung disease]. Detailed management and outcomes of therapeutic interventions post-HSCT are discussed. Concretely, post-HSCT abatacept and human leukocyte antigen (HLA)-matched sibling donor lymphocyte infusions may be used to increase T-cell donor chimerism with the aim of correcting the immune phenotype of CTLA-4 haploinsufficiency.

Outcome of Non-hematological Autoimmunity After Hematopoietic Cell Transplantation in Children with Primary Immunodeficiency.

PURPOSE: Knowledge of post-hematopoietic cell transplantation (HCT) non-hematological autoimmune disease (AD) is far from satisfactory. METHOD: This multicenter retrospective study focuses on incidence, risk factors, and outcomes of post-HCT AD in 596 children with primary immunodeficiency (PID) who were transplanted from 2009 to 2018. RESULTS: The indications of HCT were severe combined immunodeficiency (SCID, n = 158, 27%) and non-SCID PID (n = 438, 73%). The median age at HCT was 2.3 years (range, 0.04 to 18.3 years). The 5-year overall survival for the entire cohort was 79% (95% cumulative incidence (CIN), 74-83%). The median follow-up of surviving patients was 4.3 years (0.08 to 14.7 years). The CIN of post-HCT AD was 3% (2-5%) at 1 year post-HCT, 7% (5-11%) at 5 years post-HCT, and 11% (7-17%) at 8 years post-HCT. The median onset of post-HCT AD was 2.2 years (0.12 to 9.6 years). Autoimmune thyroid disorder (n = 19, 62%) was the most common post-HCT AD, followed by neuromuscular disorders (n = 7, 22%) and rheumatological manifestations (n = 5, 16%). All patients but one required treatment for post-HCT AD. After multivariate analysis, age at transplant (p = 0.01) and T cell-depleted graft (p < 0.001) were significant predictors of post-HCT AD. None of the T cell-depleted graft recipients developed post-HCT AD. Patients with a lower CD3+ count at 6 months post-HCT had a significant higher incidence of post-HCT AD compared to disease controls. Graft-versus-host disease, viral infection, and donor chimerism had no association with post-HCT AD. CONCLUSION: Post-HCT AD occurred in 11% at 8 years post-HCT and its occurrence was associated with older age at HCT and unmanipulated graft.

Antitumor Effects of Anti-Semaphorin 4D Antibody Unravel a Novel Proinvasive Mechanism of Vascular-Targeting Agents.

One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell-derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs. SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5328/F1.large.jpg.See related commentary by Tamagnone and Franzolin, p. 5146.

Características epidemiológicas de las tentativas de suicidio en adolescentes atendidos en Urgencias / Epidemiological characteristics in suicidal adolescents seen in the Emergency Department

INTRODUCCIÓN: La tentativa de suicidio en adolescentes es un grave problema de salud a nivel mundial. Para desarrollar medidas preventivas es necesario identificar factores de riesgo. El objetivo del estudio es describir y analizar las características epidemiológicas y clínicas de los pacientes que acuden al Servicio de Urgencias Pediátrico (SUP) tras presentar una tentativa de suicidio. MATERIALES Y MÉTODOS: Estudio retrospectivo de los pacientes menores de 18 años visitados en un SUP tras tentativa de suicidio entre 2008 y 2012. RESULTADOS: Se obtuvo una muestra de 241 pacientes, 84,2% mujeres, con una mediana de edad de 15,6 años. El 65,1% de los pacientes presentaba antecedentes psiquiátricos, siendo el más frecuente el trastorno depresivo (61 pacientes). El mecanismo suicida más frecuente fue la intoxicación medicamentosa con 94,2% de los casos. La presencia de ideación suicida estable previamente a la tentativa fue más frecuente en los varones y en pacientes con tentativas previas, y se relacionó con la aparición de secuelas en mayor proporción. Además, en los pacientes con intoxicación se relacionó también con presentar antecedentes psiquiátricos y con la aparición de clínica de toxicidad. CONCLUSIONES: Los pacientes varones, con antecedentes psiquiátricos, con antecedentes de tentativas suicidas previas y/o con clínica de toxicidad en el momento de atención en el SUP presentan con más frecuencia ideación suicida estable previa a la realización de la tentativa y, por tanto, mayor gravedad y riesgo de repetirla. Requieren, por tanto, una valoración psiquiátrica cuidadosa y un seguimiento estrecho

INTRODUCTION: Suicide attempt in adolescents is a major global health problem. In order to prevent them, the risks factors need to be identified. The present study evaluates the clinical and epidemiological aspects of adolescent patients after attempted suicide, who were seen in an emergency department. MATERIALS AND METHODS: Description of retrospective study of patients younger than 18 years who visited emergency department unit after a suicide attempt, during the period from 2008 to 2012. RESULTS: A total of 241 patients were included, of whom 203 were female. The median age of the patients was 15.6 years. Psiquiatric history was present in 65.1% of the patients. The most frequent suicide mechanism was drug overdose (94.2%). Attempted suicide ideation was more common in males and in patients with previous attempts, and were also more related to sequels. Moreover, patients with an overdose were associated with psychiatric history and clinical toxicity. CONCLUSIONS: Patients with any of the following characteristics; male, psychiatric history, a history of previous suicide attempts and/or clinical toxicity at the time of the visit in the emergency center, were more associated suicidal ideation before the attempt. Therefore, they had greater severity and risk repeating the attempt. They require a careful psychiatric evaluation and close monitoring

Therapeutic Benefit of Selective Inhibition of p110α PI3-Kinase in Pancreatic Neuroendocrine Tumors.

PURPOSE: Mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance to mTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. EXPERIMENTAL DESIGN: In the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110α-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. RESULTS: Human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110α PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. CONCLUSIONS: Our data provide a rationale for p110α-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis. Clin Cancer Res; 22(23); 5805-17. ©2016 AACR.

[Epidemiological characteristics in suicidal adolescents seen in the Emergency Department]. / Características epidemiológicas de las tentativas de suicidio en adolescentes atendidos en Urgencias.

INTRODUCTION: Suicide attempt in adolescents is a major global health problem. In order to prevent them, the risks factors need to be identified. The present study evaluates the clinical and epidemiological aspects of adolescent patients after attempted suicide, who were seen in an emergency department. MATERIALS AND METHODS: Description of retrospective study of patients younger than 18 years who visited emergency department unit after a suicide attempt, during the period from 2008 to 2012. RESULTS: A total of 241 patients were included, of whom 203 were female. The median age of the patients was 15.6 years. Psiquiatric history was present in 65.1% of the patients. The most frequent suicide mechanism was drug overdose (94.2%). Attempted suicide ideation was more common in males and in patients with previous attempts, and were also more related to sequels. Moreover, patients with an overdose were associated with psychiatric history and clinical toxicity. CONCLUSIONS: Patients with any of the following characteristics; male, psychiatric history, a history of previous suicide attempts and/or clinical toxicity at the time of the visit in the emergency center, were more associated suicidal ideation before the attempt. Therefore, they had greater severity and risk repeating the attempt. They require a careful psychiatric evaluation and close monitoring.

PTEN mediates Notch-dependent stalk cell arrest in angiogenesis.

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch-PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.

Toxicity of a dental adhesive compared with ionizing radiation and zoledronic acid.

BACKGROUND: To determine the toxicity of aqueous dilutions of a universal self-priming dental adhesive (DA) and comparing these with those elicited by exposure to ionizing radiation (IR), Zoledronic acid (Z) treatment and the synergic effects of the combined treatment with IR+Z. MATERIAL AND METHODS: The genotoxic effect of DA was determined by the increase in the frequency of micronuclei in cytokinesis-blocked in cultured human lymphocytes before and after exposure to 2Gy of X-rays. The cytotoxic effect was studied by using the MTT cell viability test in normal prostate cell lines (PNT2) after exposure to different X-ray doses (0Gy-20Gy). The cell lines divided into different groups and treated with different test substances: DA in presence of O2, DA in absence of O2, Z-treated and control. RESULTS: An in vitro dose-dependent and time-dependent cytotoxic effect of DA, Z and IR on PNT2 cells (p>0.001) was demonstrated. DA without-O2, following the recommendations of manufacturers, had a more pronounced effect of increasing cell death than DA with-O2 (p<0.001). In the genotoxicity assay, DA at 25% of its original concentration significantly increased chromosome damage (p<0.001). The samples studied were found to be toxic, and the samples photo-polymerized in absence of O2 showed a bigger cytotoxic effect comparable to the additive toxic effect showed by the combined treatment of IR+Z. CONCLUSIONS: Additional effort should be carried out to develop adhesives, which would reduce the release of hazardous substances; since toxic effects are similar to that reported by other agents whose clinical use is controlled by the health authorities.

PI3K at the crossroads of tumor angiogenesis signaling pathways.

Tumors need blood vessels for their growth, thus providing the rationale for antiangiogenic therapy in cancer treatment. However, intrinsic and acquired resistance and low response rates have turned out to be major limitations of antiangiogenic therapy. This emphasizes the need to further understand how the vasculature in cancer can be targeted. Although endothelial cells (ECs) rely on multiple growth factors and cytokines to grow, antiangiogenic therapies have mainly centered on targeting vascular endothelial growth factor (VEGF). Phosphoinositide 3-kinases (PI3Ks) form a family of 8 isoenzymes with non-redundant functions in normal biology and cancer. The subgroup of class I PI3Ks are situated at the crossroad of a plethora of proangiogenic signals and control cell growth, survival, motility, and metabolism. These isoenzymes have pleiotropic roles in the tumor microenvironment, including cell-autonomous functions in ECs, underscoring the complexity of targeting this pathway in cancer. Here, we describe how the PI3K axis influences angiogenesis in different cell compartments and summarize the diversity of vascular responses to PI3K inhibition. Targeting PI3K signaling by isoform-selective inhibitors, together with readjusting the current doses below the maximum tolerated dose, may improve clinical responses to class I PI3K anticancer agents.

Toxicidad cutánea a corto plazo de pacientes con cáncer de mama tratados con radioterapia hipofraccionada / Short-term dermal toxicity of breast cancer patients treated with hypofractionated radiotherapy

Antecedentes: reportar la factibilidad y resultados de toxicidad cutánea en una cohorte de pacientes portadores de cáncer de mama, tratados con un esquema de hipofraccionamiento de radioterapia externa, con un manejo multidisciplinario. Métodos: utilizando un software SPSS v18, se realizó un análisis retrospectivo de 299 pacientes (6H y 293 M), tratados entre marzo de 2009 y diciembre de 2011, en el Instituto Oncológico del Sureste, Murcia, España. La mediana de edad fue de 54 años (rango, 31-89); 145 (48,49 por ciento) pacientes con cáncer de mama derecha y 154 (51,50 por ciento) de mama izquierda. Con base en la 7ma ed AJCC, la etapificación patológica fue: 118 (39,5 por ciento) pacientes T1, 114 (38,1 por ciento) T2, 43 (14,1 por ciento) T3, 11 (3,8 por ciento) T4, 5 (1,7 por ciento) Tis, 4 (1,3 por ciento) Tx; 137 pacientes (45,8 por ciento) eran N0, 94 (31,5 por ciento) N1, 45 (15 por ciento) N2, 20 (6,70 por ciento) N3 y 3 (1,00 por ciento) Nx. Todos los pacientes se sometieron a RTE con técnicas 3D conformada con esquema hipofraccionado de 2,67 Gy/día, en fracciones para una dosis total de Gy. Se realizó irradiación electiva a la región supraclavicular en 169 pacientes, con igual fraccionamiento. El 100 por ciento de la muestra se sometió a cirugía, el 84,3 por ciento recibió quimioterapia (66,21 por ciento postoperatoria y 18,1 por ciento neoadyuvante). Resultados: sesenta y siete pacientes (23,1 por ciento) presentaron toxicidad cutánea grado 2 al finalizar el tratamiento. No se reportó toxicidad cutánea aguda severa. Conclusión: el esquema de hipofraccionamiento empleado en cáncer de mama es factible y no ha demostrado incremento en la toxicidad aguda severa a nivel de piel...

Inhibition of the p110α isoform of PI 3-kinase stimulates nonfunctional tumor angiogenesis.

Understanding the direct, tumor cell-intrinsic effects of PI 3-kinase (PI3K) has been a key focus of research to date. Here, we report that cancer cell-extrinsic PI3K activity, mediated by the p110α isoform of PI3K, contributes in an unexpected way to tumor angiogenesis. In syngeneic mouse models, inactivation of stromal p110α led to increased vascular density, reduced vessel size, and altered pericyte coverage. This increased vascularity lacked functionality, correlating with enhanced tumor hypoxia and necrosis, and reduced tumor growth. The role of p110α in tumor angiogenesis is multifactorial, and includes regulation of proliferation and DLL4 expression in endothelial cells. p110α in the tumor stroma is thus a regulator of vessel formation, with p110α inactivation giving rise to nonfunctional angiogenesis, which can stunt tumor growth. This type of vascular aberration differs from vascular endothelial growth factor-centered antiangiogenesis therapies, which mainly lead to vascular pruning. Inhibition of p110α may thus offer a new antiangiogenic therapeutic opportunity in cancer.