Dendritic Cells in Cancer Immunology and Immunotherapy.

Cancer immunotherapy modulates the immune system, overcomes immune escape and stimulates immune defenses against tumors. Dendritic cells (DCs) are professional promoters of immune responses against tumor antigens with the outstanding ability to coordinate the innate and adaptive immune systems. Evidence suggests that there is a decrease in both the number and function of DCs in cancer patients. Therefore, they represent a strong scaffold for therapeutic interventions. DC vaccination (DCV) is safe, and the antitumoral responses induced are well established in solid tumors. Although the addition of checkpoint inhibitors (CPIs) to chemotherapy has provided new options in the treatment of cancer, they have shown no clinical benefit in immune desert tumors or in those tumors with dysfunctional or exhausted T-cells. In this way, DC-based therapy has demonstrated the ability to modify the tumor microenvironment for immune enriched tumors and to potentiate systemic host immune responses as an active approach to treating cancer patients. Application of DCV in cancer seeks to obtain long-term antitumor responses through an improved T-cell priming by enhancing previous or generating de novo immune responses. To date, DCV has induced immune responses in the peripheral blood of patients without a significant clinical impact on outcome. Thus, improvements in vaccines formulations, selection of patients based on biomarkers and combinations with other antitumoral therapies are needed to enhance patient survival. In this work, we review the role of DCV in different solid tumors with their strengths and weaknesses, and we finally mention new trends to improve the efficacy of this immune strategy.

Modification of Breast Cancer Milieu with Chemotherapy plus Dendritic Cell Vaccine: An Approach to Select Best Therapeutic Strategies.

BACKGROUND: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. METHODS: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. RESULTS: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). CONCLUSION: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.

Identification of HLA class I-restricted immunogenic neoantigens in triple negative breast cancer.

Immune checkpoint inhibitor (ICI)-based immunotherapy in triple negative breast cancer (TNBC) is achieving limited therapeutic results, requiring the development of more potent strategies. Combination of ICI with vaccination strategies would enhance antitumor immunity and response rates to ICI in patients having poorly infiltrated tumors. In heavily mutated tumors, neoantigens (neoAgs) resulting from tumor mutations have induced potent responses when used as vaccines. Thus, our aim was the identification of immunogenic neoAgs suitable as vaccines in TNBC patients. By using whole exome sequencing, RNAseq and HLA binding algorithms of tumor samples from a cohort of eight TNBC patients, we identified a median of 60 mutations/patient, which originated a putative median number of 98 HLA class I-restricted neoAgs. Considering a group of 27 predicted neoAgs presented by HLA-A*02:01 allele in two patients, peptide binding to HLA was experimentally confirmed in 63% of them, whereas 55% were immunogenic in vivo in HLA-A*02:01+ transgenic mice, inducing T-cells against the mutated but not the wild-type peptide sequence. Vaccination with peptide pools or DNA plasmids expressing these neoAgs induced polyepitopic T-cell responses, which recognized neoAg-expressing tumor cells. These results suggest that TNBC tumors harbor neoAgs potentially useful in therapeutic vaccines, opening the way for new combined immunotherapies.

A Fibrosis Biomarker Early Predicts Cardiotoxicity Due to Anthracycline-Based Breast Cancer Chemotherapy.

Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio ≥ 2.95 per doubling PICP, p ≤ 0.025) in both BC-cohorts, adding prognostic value to the early assessment of GLS and LVEF. ACC-HF-patients: PICP was inversely associated with LVEF (p = 0.004). In ACC-treated BC-patients, an early increase in PICP is associated with early sLVD and predicts cardiotoxicity 1 year after ACC. PICP is also associated with LVD in ACC-HF-patients.

Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer.

ABSTRACT: Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, ENPP1 abrogation obliterates LRF. Mechanistically, ENPP1-generated adenosinergic metabolites enhance haptoglobin (HP) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse. SIGNIFICANCE: CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival. This article is highlighted in the In This Issue feature, p. 1171.

Final results regarding the addition of dendritic cell vaccines to neoadjuvant chemotherapy in early HER2-negative breast cancer patients: clinical and translational analysis.

BACKGROUND: Primary breast cancer (BC) has shown a higher immune infiltration than the metastatic disease, justifying the optimal scenario for immunotherapy. Recently, neoadjuvant chemotherapy (NAC) combined with immune checkpoint inhibitors has demonstrated a gain in pathological complete responses (tpCR) in patients with BC. The aim of our study is to evaluate the safety, feasibility, and efficacy of the addition of dendritic cell vaccines (DCV) to NAC in HER2-negative BC patients. METHODS: Thirty-nine patients with early BC received DCV together with NAC conforming the vaccinated group (VG) and compared with 44 patients as the control group (CG). All patients received anthracyclines and taxanes-based NAC (ddECx4→Dx4) followed by surgery ± radiotherapy ± hormonotherapy. RESULTS: The tpCR rate was 28.9% in the VG and 9.09% in the CG (p = 0.03). Pathological CR in the triple negative (TN) BC were 50.0% versus 30.7% (p = 0.25), 16.6% versus 0% in luminal B (p = 0.15), and none among luminal A patients in VG versus CG, respectively. Impact of DCV was significantly higher in the programmed cell death ligand 1 (PD-L1) negative population (p < 0.001). PD-L1 expression was increased in patients with residual disease in the VG as compared with the CG (p < 0.01). No grade ⩾3 vaccine-related adverse events occurred. With a median follow-up of 8 years, no changes were seen in event-free survival or overall survival. Phenotypic changes post DCV in peripheral blood were observed in myeloid-derived suppressor cells (MDSC), NK, and T cells. Increase in blood cell proliferation and interferon (IFN)-γ production was detected in 69% and 74% in the VG, respectively. Humoral response was also found. Clonality changes in TCR-ß repertoire were detected in 67% of the patients with a drop in diversity index after treatment. CONCLUSION: The combination of DCV plus NAC is safe and increases tpCR, with a significant benefit among PD-L1-negative tumors. DCV modify tumor milieu and perform cellular and humoral responses in peripheral blood with no impact in outcome. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01431196. EudraCT 2009-017402-36.

Body shape trajectories and risk of breast cancer: results from the SUN ('Seguimiento Universidad De Navarra') Project.

OBJECTIVE: The aim of this study was to assess body shape trajectories in childhood and midlife in relation to subsequent risk of breast cancer (BC) in a Mediterranean cohort. DESIGN: The 'Seguimiento Universidad de Navarra' (SUN) Project is a dynamic prospective cohort study of university graduates initiated in 1999. With a group-based modelling approach, we assessed body shape trajectories from age 5 to 40 years. Multivariable Cox regression models were used to estimate the hazard ratio (HR) for BC after the age of 40 years according to the body shape trajectory. SETTING: City of Pamplona, in the North of Spain. PARTICIPANTS: 6498 women with a mean age of 40 years (sd 9). RESULTS: We identified four distinct body shape trajectories ('childhood lean-midlife increase' (19·9 %), 'childhood medium-midlife stable' (53 %), 'childhood heavy-midlife stable' (21 %) and 'childhood heavy-midlife increase' (6·1 %)). Among 54 978 women-years of follow-up, we confirmed eighty-two incident cases of BC. Women in the 'childhood lean-midlife increase' group showed a higher risk of BC (HR = 1·84, 95 % CI 1·11, 3·04) compared with women in the 'childhood medium-midlife stable' category. This association was stronger for postmenopausal BC (HR = 2·42, 95 % CI 1·07, 5·48). CONCLUSIONS: Our results suggest a role for lifetime adiposity in breast carcinogenesis.

Palbociclib combined with endocrine therapy in heavily pretreated HR+/HER2- advanced breast cancer patients: Results from the compassionate use program in Spain (PALBOCOMP).

BACKGROUND: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. PATIENTS AND METHODS: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. RESULTS: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. CONCLUSIONS: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET.

GEICAM Guidelines for the Management of Patients with Breast Cancer During the COVID-19 Pandemic in Spain.

Breast cancer (BC) is the most common cancer in women in Spain. During the COVID-19 pandemic caused by the SARS-CoV-2 virus, patients with BC still require timely treatment and follow-up; however, hospitals are overwhelmed with infected patients and, if exposed, patients with BC are at higher risk for infection and serious complications if infected. Thus, health care providers need to evaluate each BC treatment and in-hospital visit to minimize pandemic-associated risks while maintaining adequate treatment efficacy. Here we present a set of guidelines regarding available options for BC patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the lack of evidence about COVID-19 infection, these recommendations are mainly based on expert opinion, medical organizations' and societies' recommendations, and some published evidence. We consider this a useful tool to facilitate medical decision making in this health crisis situation we are facing. IMPLICATIONS FOR PRACTICE: This work presents a set of guidelines regarding available options for breast cancer (BC) patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the suddenness of this health crisis, specialists have to make decisions with little evidence at hand. Thus, these expert guidelines may be a useful tool to facilitate medical decision making in the context of a worldwide pandemic with no resources to spare.

Binge Drinking and Risk of Breast Cancer: Results from the SUN ('Seguimiento Universidad de Navarra') Project.

Alcohol intake is associated with the risk of breast cancer. Different patterns of alcohol-drinking may have different effects on breast cancer even when keeping constant the total amount of alcohol consumed. We aimed to assess the association between binge drinking and breast cancer risk. The SUN Project is a Spanish dynamic prospective cohort of university graduates initiated in 1999. In the 556-item lifestyle baseline questionnaire a validated food-frequency questionnaire was embedded. Participants completed biennial follow-up questionnaires. Cox regression models were used to estimate the hazard ratio (HR) for breast cancer associated with the exposure to binge drinking. A stratified analysis was performed according to menopausal status. We included 9577 women (mean age = 34 years, SD = 10 years), with a median follow-up of 11.8 years. Among 104,932 women-years of follow-up, we confirmed 88 incident cases of breast cancer. Women in the binge drinking group showed a higher risk of breast cancer (HR = 1.76; 95% CI: 1.03-2.99) compared to women in the non-binge drinking category. In the stratified analysis, a 2-fold higher risk for premenopausal breast cancer was associated with binge drinking habit (HR = 2.06; 95% CI: 1.11-3.82). This study adds new evidence on the association of binge drinking with breast cancer risk.

Assessing the impact of the addition of dendritic cell vaccination to neoadjuvant chemotherapy in breast cancer patients: A model-based characterization approach.

AIMS: Immunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naïve BC patients. METHODS: Eighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination. Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n = 111) were used to validate the model. RESULTS: Tumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P = .04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects. Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis. CONCLUSIONS: Dendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.

Perioperative high-dose-rate brachytherapy in locally advanced and recurrent gynecological cancer: Final results of a Phase II trial.

PURPOSE: To determine the long-term results of a Phase II trial of perioperative high-dose-rate brachytherapy (PHDRB) in primary advanced or recurrent gynecological cancer. METHODS AND MATERIALS: Fifty patients with locally advanced and recurrent gynecological cancer suitable for salvage surgery were included. Unirradiated patients (n = 25) received preoperative chemoradiation followed by surgery and PHDRB (16-24 Gy). Previously irradiated patients (n = 25) received surgery and PHDRB alone (32-40 Gy). RESULTS: Median followup was 11.5 years. Eight unirradiated patients (32%) developed Grade ≥3 toxic events including two fatal events. Local and locoregional control rates at 16 years were 87.3% and 78.9%, respectively. Sixteen-year disease-free and overall survival rates were 42.9% and 46.4%, respectively. Ten previously irradiated patients (40.0%) developed Grade ≥3 adverse events, including four fatal events. Local and locoregional control rates at 14 years were 59.6% and 42.6%, respectively. Fourteen-year disease-free and overall survival rates were 16.0% and 19.2%, respectively. CONCLUSIONS: PHDRB allows effective salvage of a subset of unfavorable gynecological tumors with high-risk surgical margins. Toxicity was unacceptable at the initial dose levels but deescalation resulted in the absence of severe toxicity without a negative impact on locoregional control. A substantial percentage of patients remain alive and controlled at >10 years including a few previously irradiated cases with positive margins.

Combination of pegylated liposomal doxorubicin plus gemcitabine in heavily pretreated metastatic breast cancer patients: Long-term results from a single institution experience.

The combination of Pegylated Liposomal Doxorubicin (PLD) plus Gemcitabine (GEM) has been previously investigated in the treatment of metastatic breast cancer (MBC). PLD is a doxorubicin formulation with prolonged circulation time and better tissue distribution. GEM is a nucleoside analog with nonoverlapping toxicity compared to PLD. The aim of our study was to assess efficacy, toxicity, and long-term outcome of this combination. Patients with heavily treated MBC were retrospectively analyzed. Chemotherapy consisted of PLD 25 mg/m2 and GEM 800 mg/m2 day 1, on a three-week schedule. Cardiac function was evaluated baseline and during treatment. Radiological response was graded according to RECIST criteria v1.1. Toxicity was scored according to CTCAE v4.0. Progression-free survival (PFS) and overall survival (OS) were evaluated. From 2001 to 2014, 122 pts were included. Median age was 55 (range: 28-84). Median previous treatment schedules in the metastatic scenario were 3 (range: 1-15). Most patients received prior anthracyclines (85%). Median number of metastatic sites was 2 (range: 1-7). Median number of cycles delivered was 5 (range: 1-36). Overall response rate was 31% (5% complete responses; 26% partial responses). Stable and progressive diseases were observed in 32% and 26% of patients. Grade ≥3 neutropenia was observed in 29 patients (24%). Grade ≥3 hand-foot syndrome was detected in 17 patients (14%), mostly since cycle 3 (88%). Median cumulative PLD dose was 125 mg/m2 . At a median follow-up of 101 months, median PFS and OS were 7 and 22 months, respectively. PLD-GEM combination achieves remarkable long-term outcomes with an acceptable toxicity profile in patients with MBC.

Ideación suicida y conductas autolesivas en adolescentes con Trastornos de la Conducta Alimentaria / Suicidal ideation and self-injurious behavior in adolescents with eating disorders

Introducción. Es conocida la presencia de ideas suicidas y comportamientos autolesivos en pacientes con Trastornos de la Conducta Alimentaria (TCA), sin embargo, esta asociación no está claramente definida empíricamente. El objetivo del estudio es determinar la prevalencia de ideación suicida y conductas autolesivas en adolescentes con TCA. Un segundo objetivo es estudiar la asociación entre conducta autolesiva e ideación suicida, gravedad de la sintomatología alimentaria, depresiva, ansiosa, motivación para el cambio y perfeccionismo. Metodología. Se evaluaron a 109 pacientes (edad media: 14,74 años (DE:1,53); 87,2% mujeres) con el Inventario de TCA (EDI-2), el Inventario de Depresión de Beck (BDI-II), el Inventario de Ansiedad Estado/Rasgo (STAI), la Escala de Perfeccionismo en Niños y Adolescentes (CAPS) y el Cuestionario de Etapas de Cambio en la Anorexia Nerviosa (ANSOCQ). Resultados. Cuarenta y siete pacientes (43,1%) presentaron ideación suicida y 34 (31,2%) conductas autolesivas. La presencia de ideación suicida no discriminó entre pacientes TCA con y sin comportamiento autolesivo. Los pacientes con comportamiento autolesivo presentaron una puntuación significativamente mayor en todas las escalas del EDI-2, a excepción de Miedo a Madurar, en la puntuación total del BDI-II, STAI y en la CAPS. Se encontró una asociación entre la conducta autolesiva y la motivación para el cambio. Conclusiones. Un porcentaje importante de adolescentes con TCA presentan ideación suicida y comportamientos autolesivos, siendo el perfil psicopatológico de estos pacientes más grave. La presencia de ideación suicida en adolescentes con TCA no tiene necesariamente implicaciones con la conducta autolesiva, este comportamiento podría explicarse como consecuencia de la necesidad de regular emociones negativas intensas (AU)

Introduction. The presence of suicidal thoughts and self-injurious behaviors in patients with eating disorders (ED) is well-known; however, this association is currently not defined empirically. The aim of the study is to determine the prevalence of suicidal ideation and self-harm in adolescents with eating disorders. A second objective is to study the association between self-injurious behavior and suicidal ideation, severity of eating disorder symptoms and symptoms of depression and anxiety, motivation to change and perfectionism. Methodology. We evaluated 109 patients (mean age, 14.74 years (SD: 1.53); 87.2% female) using the Eating Disorder Inventory (EDI-2), the Beck Depression Inventory (BDI-II), the State-Trait Anxiety Inventory (STAI), the Child and Adolescent Perfectionism Scale (CAPS) and the Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ). Results. Forty-seven patients (43.1%) had suicidal ideation and 34 (31.2%), self-injurious behavior. The presence of suicidal ideation did not discriminate between patients with or without self-injurious behavior. Patients who self-harm had significantly higher scores on all scales of the EDI-2, except for ‘maturity fears’, in the total scores of BDI-II, STAI and CAPS. An association between self-injurious behavior and motivation to change was found. Conclusions. A significant percentage of adolescents with eating disorders present suicidal ideation and self-injurious behavior, making the psychopathological profile of these patients more severe. The presence of suicidal ideation in adolescents with eating disorders does not necessarily mply that they have self-injurious behavior; rather, such behavior could be a result of the need to regulate intense negative emotions (AU)

Suicidal ideation and self-injurious behavior in adolescents with eating disorders.

INTRODUCTION: The presence of suicidal thoughts and self-injurious behaviors in patients with eating disorders (ED) is well-known; however, this association is currently not defined empirically. The aim of the study is to determine the prevalence of suicidal ideation and self-harm in adolescents with eating disorders. A second objective is to study the association between self-injurious behavior and suicidal ideation, severity of eating disorder symptoms and symptoms of depression and anxiety, motivation to change and perfectionism. METHODOLOGY: We evaluated 109 patients (mean age, 14.74 years (SD: 1.53); 87.2% female) using the Eating Disorder Inventory (EDI-2), the Beck Depression Inventory (BDI-II), the State-Trait Anxiety Inventory (STAI), the Child and Adolescent Perfectionism Scale (CAPS) and the Anorexia Nervosa Stages of Change Questionnaire (ANSOCQ). RESULTS: Forty-seven patients (43.1%) had suicidal ideation and 34 (31.2%), self-injurious behavior. The presence of suicidal ideation did not discriminate between patients with or without self-injurious behavior. Patients who self-harm had significantly higher scores on all scales of the EDI-2, except for “maturity fears”, in the total scores of BDI-II, STAI and CAPS. An association between selfinjurious behavior and motivation to change was found. CONCLUSIONS: A significant percentage of adolescents with eating disorders present suicidal ideation and selfinjurious behavior, making the psychopathological profile of these patients more severe. The presence of suicidal ideation in adolescents with eating disorders does not necessarily imply that they have self-injurious behavior; rather, such behavior could be a result of the need to regulate intense negative emotions.

EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth.

BACKGROUND: Activated protein C/endothelial protein C receptor (APC/EPCR) axis is physiologically involved in anticoagulant and cytoprotective activities in endothelial cells. Emerging evidence indicates that EPCR also plays a role in breast stemness and human tumorigenesis. Yet, its contribution to breast cancer progression and metastasis has not been elucidated. METHODS: Transcriptomic status of EPCR was examined in a cohort of 286 breast cancer patients. Cell growth kinetics was evaluated in control and EPCR and SPARC/osteonectin, Cwcv, and kazal-like domains proteoglycan (SPOCK1/testican 1) silenced breast cancer cells in 2D, 3D, and in co-culture conditions. Orthotopic tumor growth and lung and osseous metastases were evaluated in several human and murine xenograft breast cancer models. Tumor-stroma interactions were further studied in vivo by immunohistochemistry and flow cytometry. An EPCR-induced gene signature was identified by microarray analysis. RESULTS: Analysis of a cohort of breast cancer patients revealed an association of high EPCR levels with adverse clinical outcome. Interestingly, EPCR knockdown did not affect cell growth kinetics in 2D but significantly reduced cell growth in 3D cultures. Using several human and murine xenograft breast cancer models, we showed that EPCR silencing reduced primary tumor growth and secondary outgrowths at metastatic sites, including the skeleton and the lungs. Interestingly, these effects were independent of APC ligand stimulation in vitro and in vivo. Transcriptomic analysis of EPCR-silenced tumors unveiled an effect mediated by matricellular secreted proteoglycan SPOCK1/testican 1. Interestingly, SPOCK1 silencing suppressed in vitro 3D growth. Moreover, SPOCK1 ablation severely decreased orthotopic tumor growth and reduced bone metastatic osteolytic tumors. High SPOCK1 levels were also associated with poor clinical outcome in a subset breast cancer patients. Our results suggest that EPCR through SPOCK1 confers a cell growth advantage in 3D promoting breast tumorigenesis and metastasis. CONCLUSIONS: EPCR represents a clinically relevant factor associated with poor outcome and a novel vulnerability to develop combination therapies for breast cancer patients.

MRI fused with prone FDG PET/CT improves the primary tumour staging of patients with breast cancer.

OBJECTIVE: Our aim was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in primary tumour staging of patients with breast cancer. METHODS: This retrospective study evaluated 45 women with 49 pathologically proven breast carcinomas. MRI and prone PET-CT scans with time-of-flight and point-spread-function reconstruction were performed with the same dedicated breast coil. The studies were assessed by a radiologist and a nuclear medicine physician, and evaluation of fused images was made by consensus. The final diagnosis was based on pathology (90 lesions) or follow-up ≥ 24 months (17 lesions). RESULTS: The study assessed 72 malignant and 35 benign lesions with a median size of 1.8 cm (range 0.3-8.4 cm): 31 focal, nine multifocal and nine multicentric cases. In lesion-by-lesion analysis, sensitivity, specificity, positive and negative predictive values were 97%, 80%, 91% and 93% for MRI, 96%, 71%, 87%, and 89% for prone PET, and 97%. 94%, 97% and 94% for MRI fused with PET. Areas under the curve (AUC) were 0.953, 0.850, and 0.983, respectively (p < 0.01). CONCLUSIONS: MRI fused with FDG-PET is more accurate than FDG-PET in primary tumour staging of breast cancer patients and increases the specificity of MRI. KEY POINTS: • FDG PET-CT may improve the specificity of MRI in breast cancer staging. • MRI fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose PET-CT has better overall diagnostic performance than MRI. • The clinical role of fused PET-MRI has not yet been established.

Multicatheter breast implant during breast conservative surgery: Novel approach to deliver accelerated partial breast irradiation.

PURPOSE: To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer. METHODS AND MATERIALS: Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation. RESULTS: From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4-14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3-160.5); median D90 was 3.32 Gy (range, 3.11-3.85); median dose homogeneity index was 0.72 (range, 0.48-0.82). With a median followup of 38.4 months (range, 8.7-98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%). CONCLUSION: The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures.

Impact of epidermal growth factor receptor (EGFR) activating mutations and their targeted treatment in the prognosis of stage IV non-small cell lung cancer (NSCLC) patients harboring liver metastasis.

OBJECTIVES: Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between EGFR mutations, liver infiltration and clinical outcomes. METHODS: A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed. RESULTS: At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 vs. 21 months; p = 0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 vs. 13 months; p = 0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tyrosin-kinase inhibitors (TKI's) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 months; p = 0.81). CONCLUSION: Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis of liver metastasis in first-line treatment of EGFR mutated NSCLC patients.