An Integrated Multidisciplinary Circuit Led by Hospital and Community Pharmacists to Implement Clopidogrel Pharmacogenetics in Clinical Practice.

The use of pharmacogenetics to optimize pharmacotherapy is growing rapidly. This study evaluates the feasibility and operability of a collaborative circuit involving hospital and community pharmacists to implement clopidogrel pharmacogenetics in Barcelona, Catalonia, Spain. We aimed to enroll patients with a clopidogrel prescription from cardiologists at the collaborating hospital. Community pharmacists collected patients' pharmacotherapeutic profiles and saliva samples, which were then sent to the hospital for CYP2C19 genotyping. Hospital pharmacists collated the obtained data with patients' clinical records. Data were analyzed jointly with a cardiologist to assess the suitability of clopidogrel. The provincial pharmacists' association coordinated the project and provided IT and logistic support. The study began in January 2020. However, it was suspended in March 2020 due to the COVID-19 pandemic. At that moment, 120 patients had been assessed, 16 of whom met the inclusion criteria and were enrolled in the study. The processing of samples obtained before the pandemic had an average delay of 13.8 ± 5.4 days. A total of 37.5% patients were intermediate metabolizers and 18.8% were ultrarapid metabolizers. No poor metabolizers were detected. Pharmacists rated their experience with a 7.3 ± 2.7 likelihood of recommending that fellow pharmacists participate. The net promoter score among participating pharmacists was +10%. Our results show that the circuit is feasible and operable for further initiatives.

Developing a mHealth intervention to redesign the current journey for people living with HIV: A qualitative study.

OBJECTIVE: People living with human immunodeficiency virus could particularly benefit from mobile health (mHealth). The objective of the study was to  contribute to the design and development of a new standard of care for people  living with human immunodeficiency virus and the mHealth app needed to  support it by 1) exploring the view of people living with human  immunodeficiency virus and healthcare professionals on the possibilities of  mHealth tools on HIV care, and 2) implementing their feedback into the new  app and into the new journey of people living with human immunodeficiency  virus. METHOD: The study was conducted in two different phases: phase one was to  apprise patients' and healthcare professionals' perspectives on mHealth using  the qualitative methodology of the focus groups, whereas phase two aimed to  implement their feedback into the application. RESULTS: A total of five people living with human immunodeficiency virus and  nine healthcare professionals (three clinical pharmacists, three nurses, two  physicians, and one pharmacy technician) participated in the focus groups. The  patients identified the following main aspects to be improved in the  current patients' journey: insufficient information (n = 5), lack of general  population disease awareness (n = 5), and medication dispensation model (n =  3). Moreover, healthcare professionals identified the next health outcomes  to be enhanced with mHealth tools: patients' quality of life (n = 7), control of  the disease (n = 5) and comorbidities (n = 3), and adherence to medication (n = 5). According to these needs, the new healthcare model was designed. The  mHealth was provided with different features, such as information about the  disease, health promotion and prevention, the possibility of two-way patient- healthcare professionals communication, or synchronization with other devices. The new human immunodeficiency virus care journey and the app are currently being tested in a group of people living with human immunodeficiency virus in real-world conditions in our hospital. CONCLUSIONS: Improving patients' quality of life, therapeutic adherence, or  disease control are key objectives for optimizing people living with human  immunodeficiency virus care. Our digital health tool and the new healthcare  model have been implemented based on end-users' feedback to achieve better  patients-healthcare professionals communication and patient engagement with their care.

OBJETIVO: Las personas que viven con el virus de la inmunodeficiencia humana podrían beneficiarse de nuevas estrategias de salud móvil (mSalud). El  objetivo del estudio fue contribuir al diseño y desarrollo de un nuevo modelo  asistencial en la población con virus de la inmunodeficiencia humana y de la  aplicación móvil necesaria para apoyarlo mediante: 1) la exploración de la  visión de personas que viven con el virus de la inmunodeficiencia humana y  profesionales sanitarios sobre las herramientas digitales en la atención a este  colectivo, y 2) la implementación de sus perspectivas en la nueva aplicación y  en la nueva ruta asistencial.Método: El estudio se realizó en dos fases: la primera tenía como objetivo conocer las perspectivas de los participantes sobre la salud móvil mediante la metodología cualitativa de los grupos focales, y la segunda implementar estas valoraciones en la aplicación. RESULTADOS: Participaron cinco pacientes y nueve profesionales sanitarios (tres farmacéuticos clínicos, tres enfermeras, dos médicas y una  técnico de farmacia). Los pacientes consideraron que debían mejorarse los siguientes aspectos en su ruta asistencial: información insuficiente (n = 5),  falta de conocimiento de la enfermedad (n = 5) y modelo de dispensación de la medicación (n = 3). Los profesionales identificaron que debían mejorarse: la  calidad de vida de los pacientes (n = 7), el control de su enfermedad (n = 5) y de sus comorbilidades (n = 3), y la adherencia terapéutica (n = 5). De acuerdo con estas necesidades, se diseñó el nuevo modelo asistencial. Las siguientes  características se incorporaron a la mHealth: información sobre la enfermedad,  promoción y prevención de la salud, posibilidad de comunicación  bidireccional profesional-paciente o sincronización con otros dispositivos. La  nueva ruta asistencial y la aplicación están siendo estudiadas en un grupo de  personas que viven con el virus de la inmunodeficiencia humana en  condiciones de vida real y en seguimiento en nuestro hospital. CONCLUSIONES: La mejora de la calidad de vida, la adherencia terapéutica y el  control de la enfermedad son factores clave para la optimización de la atención de las personas que viven con el virus de la inmunodeficiencia humana.  Nuestra herramienta de salud digital y el modelo asistencial han sido diseñados en base a la opinión de pacientes para mejorar la comunicación profesional- paciente sanitario y conseguir un mayor compromiso de los pacientes con su  cuidado.

Desarrollo de una intervención mHealth para rediseñar la ruta asistencial de las personas que viven con VIH: Estudio cualitativo / Developing a mHealth intervention to redesign the current journey for people living with HIV: A qualitative study

Objetivo: Las personas que viven con el virus de la inmunodeficienciahumana podrían beneficiarse de nuevas estrategias de salud móvil (mSalud). El objetivo del estudio fue contribuir al diseño y desarrollo de unnuevo modelo asistencial en la población con virus de la inmunodeficiencia humana y de la aplicación móvil necesaria para apoyarlo mediante:1) la exploración de la visión de personas que viven con el virus de lainmunodeficiencia humana y profesionales sanitarios sobre las herramientas digitales en la atención a este colectivo, y 2) la implementación desus perspectivas en la nueva aplicación y en la nueva ruta asistencial.Método: El estudio se realizó en dos fases: la primera tenía como objetivo conocer las perspectivas de los participantes sobre la salud móvilmediante la metodología cualitativa de los grupos focales, y la segundaimplementar estas valoraciones en la aplicación.Resultados: Participaron cinco pacientes y nueve profesionales sanitarios (tres farmacéuticos clínicos, tres enfermeras, dos médicas y una técnico de farmacia). Los pacientes consideraron que debían mejorarse lossiguientes aspectos en su ruta asistencial: información insuficiente (n = 5), falta de conocimiento de la enfermedad (n = 5) y modelo de dispensación de la medicación (n = 3). Los profesionales identificaron que debíanmejorarse: la calidad de vida de los pacientes (n = 7), el control de suenfermedad (n = 5) y de sus comorbilidades (n = 3), y la adherencia terapéutica (n = 5). De acuerdo con estas necesidades, se diseñó el nuevomodelo asistencial. (AU)

Objective: People living with human immunodeficiency virus couldparticularly benefit from mobile health (mHealth). The objective of thestudy was to contribute to the design and development of a new standard of care for people living with human immunodeficiency virus andthe mHealth app needed to support it by 1) exploring the view of peopleliving with human immunodeficiency virus and healthcare professionals onthe possibilities of mHealth tools on HIV care, and 2) implementing theirfeedback into the new app and into the new journey of people living withhuman immunodeficiency virus.Method: The study was conducted in two different phases: phase onewas to apprise patients’ and healthcare professionals’ perspectives onmHealth using the qualitative methodology of the focus groups, whereasphase two aimed to implement their feedback into the application.Results: A total of five people living with human immunodeficiency virusand nine healthcare professionals (three clinical pharmacists, three nurses, two physicians, and one pharmacy technician) participated in thefocus groups. The patients identified the following main aspects to be improved in the current patients’ journey: insufficient information (n = 5),lack of general population disease awareness (n = 5), and medicationdispensation model (n = 3). Moreover, healthcare professionals identifiedthe next health outcomes to be enhanced with mHealth tools: patients’quality of life (n = 7), control of the disease (n = 5) and comorbidities(n = 3), and adherence to medication (n = 5). According to these needs,the new healthcare model was designed. (AU)

Risk factors for emergency department revisit in elderly patients with gastrointestinal bleeding secondary to anticoagulant therapy.

OBJECTIVE: To evaluate the frequency of emergency department (ED) revisits among elderly patients with gastrointestinal bleeding secondary to anticoagulant treatment and identify factors associated with an increased risk of ED revisits. METHODS: A 3-year retrospective observational study was designed, including elderly patients (≥65 years) with atrial fibrillation and undergoing oral anticoagulation therapy who visited the ED for gastrointestinal bleeding. To evaluate the risk factors for 30-day revisit, a multivariate analysis was designed including comorbidities, concomitant treatment, change in anticoagulant treatment and prescription of direct-acting oral anticoagulants. RESULTS: 80 patients were included. At discharge, anticoagulation therapy was modified in 21 (26.2%) patients; and changed from an oral anticoagulant to heparin in 17 (21.2%) patients and to another oral anticoagulant in 4 (5.0%) patients. Anticoagulant treatment was withdrawn in 5 (6.3%) patients at discharge. Eleven (13.7%) patients revisited the ED 30 days after hospital discharge for bleeding episodes. No differences in the frequency of revisit to the ED were observed in the patients who changed their anticoagulant treatment at discharge. In the multivariate analysis, chronic kidney disease was the only factor significantly associated with revisits at 30 days. CONCLUSIONS: Elderly patients who experience a first episode of gastrointestinal bleeding have a high risk of revisiting the ED for a bleeding episode, with no particular differences between the types of anticoagulant prescribed at discharge.

Sarilumab (IL-6R antagonist) in critically ill patients with cytokine release syndrome by SARS-CoV2.

ABSTRACT: Blocking IL-6 pathways with sarilumab, a fully human anti-IL-6R antagonist may potentially curb the inflammatory storm of SARS-CoV2. In the present emergency scenario, we used "off-label" sarilumab in 5 elderly patients in life-threatening condition not candidates to further active measures. We suggest that sarilumab can modulate severe COVID-19-associated Cytokine Release Syndrome.

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells.

BACKGROUND AND PURPOSE: Around 40-50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4+) and associated with poor prognosis. METHODS: The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4+ DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4+ DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs. RESULTS: We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4+ DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4+ DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs. CONCLUSION: T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4+ DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4+ DLBCL patients.

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models.

One-third of diffuse large B-cell lymphoma patients are refractory to initial treatment or relapse after rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy. In these patients, CXCR4 overexpression (CXCR4+) associates with lower overall and disease-free survival. Nanomedicine pursues active targeting to selectively deliver antitumor agents to cancer cells; a novel approach that promises to revolutionize therapy by dramatically increasing drug concentration in target tumor cells. In this study, we intravenously administered a liganded protein nanocarrier (T22-GFP-H6) targeting CXCR4+ lymphoma cells in mouse models to assess its selectivity as a nanocarrier by measuring its tissue biodistribution in cancer and normal cells. No previous protein-based nanocarrier has been described as specifically targeting lymphoma cells. T22-GFP-H6 achieved a highly selective tumor uptake in a CXCR4+ lymphoma subcutaneous model, as detected by fluorescent emission. We demonstrated that tumor uptake was CXCR4-dependent because pretreatment with AMD3100, a CXCR4 antagonist, significantly reduced tumor uptake. Moreover, in contrast to CXCR4+ subcutaneous models, CXCR4- tumors did not accumulate the nanocarrier. Most importantly, after intravenous injection in a disseminated model, the nanocarrier accumulated and internalized in all clinically relevant organs affected by lymphoma cells with negligible distribution to unaffected tissues. Finally, we obtained antitumor effect without toxicity in a CXCR4+ lymphoma model by administration of T22-DITOX-H6, a nanoparticle incorporating a toxin with the same structure as the nanocarrier. Hence, the use of the T22-GFP-H6 nanocarrier could be a good strategy to load and deliver drugs or toxins to treat specifically CXCR4-mediated refractory or relapsed diffuse large B-cell lymphoma without systemic toxicity.

Design of a relative value unit-based tool for the measurement and reimbursement of pharmacy services for clinical trials.

OBJECTIVE: To develop a relative value unit (RVU)-based tool for the measurement and reimbursement of pharmacy services for clinical trials. METHODS: A portfolio of activities was agreed by consensus in four tertiary hospitals. Related activities were pooled into several categories or intermediate products. We recorded the duration of each activity by multiple determinations. We then calculated the average time of all determinations. The reference activity was assigned a value of 1. All other activities were compared to the reference activity to obtain the RVU. To establish which items should be invoiced to third parties for the activities performed, we defined the final products (different types of clinical trials according to their complexity). RESULTS: Ten intermediate products and five final products were differentiated. Six intermediate products could be repeated over the course of a clinical trial and seven were performed whether or not the clinical trial had included patients. Each final product consisted of different categories. The total number of RVUs produced for a clinical trial was the sum of each constant category value plus the repetitive category values multiplied by the number of repetitions. CONCLUSION: The application of RVU methodology in investigational drug services allows a more precise quantification of services performed. After a prospective validation to confirm the applicability of this tool, it may contribute to more appropriate invoicing to third parties for these services.

Determinants of medication adherence among chronic patients from an urban area: a cross-sectional study.

BACKGROUND: Medication adherence is a complex area of behaviour. Little is known about what influences chronic patients to take their medicines. This study has aimed to compare and contrast the health-related beliefs, experiences and types of behaviour typical among patients who have at least one chronic condition and are following a pharmacological treatment in accordance with their level of medication adherence. METHODS: A questionnaire-based cross-sectional study, consisting of socio-demographic data, the 4-item Morisky-Green scale and 37 statements about health beliefs, perceptions and experiences, was conducted at different levels of healthcare (primary and tertiary settings). RESULTS: A total of 577 questionnaires were analyzed. Respondents had a mean age of 64 and took an average of 4.6 drugs. Optimal adherence was reported by 58.6% of respondents. Bivariate analysis showed adherent subjects were older, took more medications, were in better spirits and had greater confidence and information regarding their treatment. Multivariate analysis found older age and the statements 'My doctor periodically reviews my treatment' and 'I am motivated to continue with the treatment' to be significantly related to medication adherence, while 'I make variations when taking medication depending on how I feel' was significant for medication non-adherence. CONCLUSION: Medication non-adherence is common among chronic patients. Patient-centred approaches should be implemented in daily clinical practice as patient health beliefs, experiences and conduct influence medication-taking. Motivational interviewing might improve medication adherence in permitting emotional state managing and increasing educational skills, patient motivation and confidence between patients and healthcare providers.

Effect of serpinE1 overexpression on the primary tumor and lymph node, and lung metastases in head and neck squamous cell carcinoma.

BACKGROUND: Serpin Family E Member 1 (SerpinE1) overexpression associates with poor clinical outcome in head and neck squamous cell carcinoma (HNSCC) patients. This study analyzed the role of serpinE1 in HNSCC dissemination. METHODS: We studied the phenotypic characteristics and dissemination of HNSCC cells overexpressing serpinE1 using an orthotopic model and the association between serpinE1 overexpression and clinicopathological variables in patients included in The Cancer Genome Atlas database. RESULTS: SerpinE1 overexpression increased proliferation, tumor budding, and the stromal component, while inhibiting apoptosis in primary tumors. It also enhanced the affectation and metastatic growth in lymph nodes, and the dispersion and growth of metastatic foci in the lung. High serpinE1 expression was associated with larger tumor size, undifferentiated tumors, lymph node metastasis, extracapsular spread, and the presence of perineural and angiolymphatic invasion. CONCLUSION: SerpinE1 overexpression promotes tumor aggressiveness and metastatic dissemination to lymph nodes and lung consistently with its association with poor outcome in HNSCC patients.

Non-pharmacological Effects in Switching Medication: The Nocebo Effect in Switching from Originator to Biosimilar Agent.

The nocebo effect is defined as the incitement or the worsening of symptoms induced by any negative attitude from non-pharmacological therapeutic intervention, sham, or active therapies. When a patient anticipates a negative effect associated with an intervention, medication or change in medication, they may then experience either an increase in this effect or experience it de novo. Although less is known about the nocebo effect compared with the placebo effect, widespread interest in the nocebo effect observed with statin therapy and a literature review highlighting the nocebo effect across at least ten different disease areas strongly suggests this is a common phenomenon. This effect has also recently been shown to play a role when introducing a medication or changing an established medication, for example, when switching patients from a reference biologic to a biosimilar. Given the important role biosimilars play in providing cost-effective alternatives to reference biologics, increasing physician treatment options and patient access to effective biologic treatment, it is important that we understand this phenomenon and aim to reduce this effect when possible. In this paper, we propose three key strategies to help mitigate the nocebo effect in clinical practice when switching patients from reference biologic to biosimilar: positive framing, increasing patient and healthcare professionals' understanding of biosimilars and utilising a managed switching programme.

Selective depletion of metastatic stem cells as therapy for human colorectal cancer.

Selective elimination of metastatic stem cells (MetSCs) promises to block metastatic dissemination. Colorectal cancer (CRC) cells overexpressing CXCR4 display trafficking functions and metastasis-initiating capacity. We assessed the antimetastatic activity of a nanoconjugate (T22-GFP-H6-FdU) that selectively delivers Floxuridine to CXCR4+ cells. In contrast to free oligo-FdU, intravenous T22-GFP-H6-FdU selectively accumulates and internalizes in CXCR4+ cancer cells, triggering DNA damage and apoptosis, which leads to their selective elimination and to reduced tumor re-initiation capacity. Repeated T22-GFP-H6-FdU administration in cell line and patient-derived CRC models blocks intravasation and completely prevents metastases development in 38-83% of mice, while showing CXCR4 expression-dependent and site-dependent reduction in foci number and size in liver, peritoneal, or lung metastases in the rest of mice, compared to free oligo-FdU. T22-GFP-H6-FdU induces also higher regression of established metastases than free oligo-FdU, with negligible distribution or toxicity in normal tissues. This targeted drug delivery approach yields potent antimetastatic effect, through selective depletion of metastatic CXCR4+ cancer cells, and validates metastatic stem cells (MetSCs) as targets for clinical therapy.

Impact of a pharmaceutical care programme for patients with chronic disease initiated at the emergency department on drug-related negative outcomes: a randomised controlled trial.

BACKGROUND: The resolution of potential drug-related problems is a priority of pharmaceutical care programmes. OBJECTIVES: To assess the clinical impact on drug-related negative outcomes of a pharmaceutical care programme focusing on the resolution of potential drug-related problems, initiated in the emergency department for patients with heart failure (HF) and/or chronic obstructive pulmonary disease (COPD). METHODS: Controlled trials, in which older adults (≥65 years) receiving four or more medications admitted to the emergency department for ≥12 hours for worsening of HF and/or COPD were randomised (1:1) to either a pharmaceutical care programme focusing on resolving potential drug-related problems initiated at the emergency department (intervention group (IG)) or standard care (control group). Comparisons between the groups were made for the proportion of patients with drug-related negative outcomes, number of drug-related negative outcomes per patient, mean stay, patients readmitted within 180 days and 180-day mortality. RESULTS: 118 patients were included, 59 in each group. Fewer patients in the IG had drug-related negative outcomes (37 (62.7%) vs 47 (79.7%) in the control group (p=0.042)). Fewer drug-related negative outcomes per patient occurred in the IG (56 (0.95 per patient) vs 85 (1.44 per patient) in the control group (p=0.01)). The mean stay was similar between groups (194.7 hours in the IG vs 242.5 hours in the control group (p=0.186)). No difference in revisits within 180 days was found (32 (54.24%) in the IG vs 22 (37.3%) in the control group (p=0.065)). 180-Day mortality was detected in 11 (18.6%) patients in the IG compared with 13 (22%) in the control group (p=0.647). CONCLUSION: A pharmaceutical care programme focusing on resolving potential drug-related problems initiated at the emergency department has a favourable clinical impact, as it reduces the number and prevalence of drug-related negative outcomes. No difference was found in other outcome variables.Trial registration number NCT02368548.

Patients' Perspective of Medication Adherence in Chronic Conditions: A Qualitative Study.

INTRODUCTION: About 50% of patients do not take their long-term therapy for chronic conditions as prescribed. Many studies have centered on patients' adherence to a specific treatment or single conditions, but few have taken all chronic conditions into consideration from a patient's perspective. This study aims to explore factors that impact on drug compliance and to identify strategies to improve this from the perspective of patients with at least one chronic condition. METHODS: Patients were recruited by healthcare professionals from a hospital pharmacy, four community pharmacies, patient associations, and a primary care center in Barcelona. Five focus groups were conducted (N = 36). Conversations were audiotaped and transcribed verbatim to allow qualitative analysis. RESULTS: Study subjects were aged 39-90 years (mean 65 years) and the mean number of comorbidities per patient was 2.3 (range 1-7). The main modifiers of therapeutic conduct were: patients' health beliefs, patient-prescriber relationships, and patients' motivation and perception of illness control. Study participants wanted greater participation in decision-making concerning their health and increased education about their illness and medication. They also wanted individualized healthcare that took their preferences and personal and emotional issues into account. CONCLUSION: Our results highlight how the patient-prescriber's relationship and factors such as health beliefs, motivation and perception of illness control impact on medication adherence in chronic patients. Future interventions to optimize adherence to treatment should focus on shared decision-making and more extensive health education. FUNDING: Celgene Corporation.

Cancer-specific uptake of a liganded protein nanocarrier targeting aggressive CXCR4+ colorectal cancer models.

Unliganded drug-nanoconjugates accumulate passively in the tumor whereas liganded nanoconjugates promote drug internalization in tumor cells via endocytosis and increase antitumor efficacy. Whether or not tumor cell internalization associates with enhanced tumor uptake is still under debate. We here compared tumor uptake of T22-GFP-H6, a liganded protein carrier targeting the CXCR4 receptor, and the unliganded GFP-H6 carrier in subcutaneous and metastatic colorectal cancer models. T22-GFP-H6 had a higher tumor uptake in primary tumor and metastatic foci than GFP-H6, with no biodistribution or toxicity on normal tissues. T22-GFP-H6 was detected in target CXCR4+ tumor cell cytosol whereas GFP-H6 was detected in tumor stroma. SDF1-α co-administration switched T22-GFP-H6 internalization from CXCR4+ tumor epithelial cells to the stroma. Therefore, the incorporation of a targeting ligand promotes selective accumulation of the nanocarrier inside target tumor cells while increasing whole tumor uptake in a CXCR4-dependent manner, validating T22-GFP-H6 as a CXCR4-targeted drug carrier.

CKMT1 and NCOA1 expression as a predictor of clinical outcome in patients with advanced-stage head and neck squamous cell carcinoma.

BACKGROUND: We studied the association between the expression of a subset of previously identified genes and clinical outcome in patients with head and neck cancer. METHODS: We analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of 89 genes in tumor biopsies from stage III to IVa/b chemotherapy treated patients (n = 46). Two additional cohorts analyzed by RNAseq (The Cancer Genome Atlas [TCGA] project; n = 371) or immunohistochemistry (IHC; n = 73) were used to validate results. RESULTS: Thirty genes were associated with local-recurrence or progression-free survival. The best multi-gene decision-tree model to predict local recurrence included nuclear receptor coactivator 1 (NCOA1) and serum-amyloid A2 (SAA2) expression, whereas the best model to predict disease recurrence included creatine kinase mitochondrial 1 (CKMT1) and metal-regulatory transcription factor 1 (MTF1). Both models were associated with cancer-specific survival. Results were confirmed analyzing the RNAseq data included in the TCGA project. CKMT1 and NCOA1 were identified as independent risk factors for survival in an independent cohort analyzed by immunohistochemistry. CONCLUSION: CKMT1 and NCOA1 expression has prognostic significance in advanced-stage head and neck carcinoma. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1392-E1403, 2016.

Enhanced cell migration and apoptosis resistance may underlie the association between high SERPINE1 expression and poor outcome in head and neck carcinoma patients.

High SERPINE1 expression is a common event in head and neck squamous cell carcinoma (HNSCC); however, whether it plays a role in determining clinical outcome remains still unknown. We studied SERPINE1 as a prognostic marker in two HNSCC patient cohorts. In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival. In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival. SERPINE1 expression was identified as an independent risk factor for progression-free survival in patients treated with chemo-radiotherapy or radiotherapy (p = 0.043). In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029). The association between SERPINE1 expression and survival was confirmed using the HNSCC cohort included in The Cancer Genome Atlas project (n = 507). Once again, patients showing high expression had a poorer survival (p < 0.001). SERPINE1 over-expression in HNSCC cells reduced cell proliferation and enhanced migration. It also protected cells from cisplatin-induced apoptosis, which was accompanied by PI3K/AKT pathway activation. Downregulation of SERPINE1 expression had the opposite effect. We propose SERPINE1 expression as a prognostic marker that could be used to stratify HNSCC patients according to their risk of recurrence.

Prevalence and detection of neuropsychiatric adverse effects during hepatitis C treatment.

BACKGROUND: Current treatment combinations for chronic hepatitis C virus infection still include pegylated interferon and ribavirin despite the new therapeutic options available. Interferon-based treatments are associated with a high incidence of adverse effects. Central nervous system events are among the most frequent adverse drug reactions and their influence on treatment adherence and effectiveness is controversial. OBJECTIVE: The aim of the study was to evaluate neuropsychiatric adverse effects of interferon-based treatment for chronic hepatitis C in standard multidisciplinary clinical practice. Risk factors for these adverse effects and their impact on adherence and sustained viral response were also evaluated. Setting Ambulatory care pharmacy in coordination with the liver unit and the infectious diseases unit at a 650-bed tertiary university hospital. METHODS: We included all consecutive patients with chronic hepatitis C who completed treatment with pegylated interferon and ribavirin between 2005 and 2013. All patients underwent a multidisciplinary follow-up during treatment. MAIN OUTCOME MEASURES: Neuropsychiatric adverse effects were evaluated in relation to severity, management and outcome. The presence of anxiety and depression was evaluated by means of specific tests. RESULTS: A total of 717 treatments in 679 patients were included. During treatment, we detected 1679 neuropsychiatric adverse effects in 618 patients (86.2 %), generating 1737 clinical interventions. Fifty-seven (3.3 %) neuropsychiatric adverse effects were severe and 2 (0.1 %) were life-threatening (suicidal attempts). Most neuropsychiatric adverse effects (1555 events, 92.6 %) resolved without sequelae. Psychiatric medication was required in 289 patients (40.3 %). Sustained viral response was achieved in 400 cases (55.8 %) and was associated with adherence (OR = 1.942, 95 % CI = 1.235-3.052, p = 0.004). A multivariate analysis did not show any relationship between neuropsychiatric adverse effects and treatment adherence or sustained viral response. A psychiatric history was a strong risk factor for depression, anxiety and other psychiatric disorders during treatment. CONCLUSION: Neuropsychiatric adverse effects during interferon-based treatments in patients with chronic hepatitis C were common but mostly mild or moderate. Early detection and accurate multidisciplinary management avoided treatment discontinuation, ensuring adherence and attaining sustained viral response. The identified risk factors could be used to determine patients eligible for interferon-free combinations, thus optimizing health system economics.

Higher metastatic efficiency of KRas G12V than KRas G13D in a colorectal cancer model.

Although all KRas (protein that in humans is encoded by the KRas gene) point mutants are considered to have a similar prognostic capacity, their transformation and tumorigenic capacities vary widely. We compared the metastatic efficiency of KRas G12V (Kirsten rat sarcoma viral oncogene homolog with valine mutation at codon 12) and KRas G13D (Kirsten rat sarcoma viral oncogene homolog with aspartic mutation at codon 13) oncogenes in an orthotopic colorectal cancer (CRC) model. Following subcutaneous preconditioning, recombinant clones of the SW48 CRC cell line [Kras wild-type (Kras WT)] expressing the KRas G12V or KRas G13D allele were microinjected in the mouse cecum. The percentage of animals developing lymph node metastasis was higher in KRas G12V than in KRas G13D mice. Microscopic, macroscopic, and visible lymphatic foci were 1.5- to 3.0-fold larger in KRas G12V than in KRas G13D mice (P < 0.05). In the lung, only microfoci were developed in both groups. KRas G12V primary tumors had lower apoptosis (7.0 ± 1.2 vs. 7.4 ± 1.0 per field, P = 0.02), higher tumor budding at the invasion front (1.2 ± 0.2 vs. 0.6 ± 0.1, P = 0.04), and a higher percentage of C-X-C chemokine receptor type 4 (CXCR4)-overexpressing intravasated tumor emboli (49.8 ± 9.4% vs. 12.8 ± 4.4%, P < 0.001) than KRas G13D tumors. KRas G12V primary tumors showed Akt activation, and ß5 integrin, vascular endothelial growth factor A (VEGFA), and Serpine-1 overexpression, whereas KRas G13D tumors showed integrin ß1 and angiopoietin 2 (Angpt2) overexpression. The increased cell survival, invasion, intravasation, and specific molecular regulation observed in KRas G12V tumors is consistent with the higher aggressiveness observed in patients with CRC expressing this oncogene.