A systematic review of the impact of simulation on students' confidence in performing clinical pharmacy activities.

BACKGROUND: Although confidence does not automatically imply competence, it does provide pharmacy students with a sense of empowerment to manage a pharmacotherapeutic problem independently. Among the methods used in higher education, there is growing interest in simulation. AIM: To evaluate the impact of simulation on pharmacy students' confidence in performing clinical pharmacy activities. METHOD: Articles that reported the use of simulation among pharmacy students with fully described outcomes about confidence were included. Studies for which it was impossible to extract data specific to pharmacy students or simulation were excluded. The search was carried out in Medline, Embase, Lissa and PsycInfo from inception to August the 31th, 2022. The results were synthesized into 4 parts: confidence in collecting information, being an expert in a procedure/pathology, counselling and communicating, and other results. The quality assessment of included studies was conducted using the Mixed Methods Appraisal Tool "MMAT" tool. RESULTS: Among the 39 included articles, the majority were published in the last 5 years and conducted in the United States. The majority included pharmacy students in years 1 through 3 (69.2%). The most common study design was the pre-post uncontrolled design (66.7%). Studies measuring the effects of human and/or virtual simulation were mainly focused on confidence to counsel and/or communicate with patients and colleagues (n = 20). Evaluations of the effects of these types of simulation on confidence in information gathering by health professionals were also well represented (n = 16). CONCLUSION: Simulation-based training generally yielded positive impact on improving pharmacy students' confidence in performing clinical pharmacy activities. Rigorous assessment methods and validated confidence questionnaires should be developed for future studies.

[Implementation of pharmaceutical consultations in digestive oncology in a teaching hospital: one-year outcomes]. / Mise en place de consultations pharmaceutiques d'initiation en oncologie digestive dans un centre hospitalo-universitaire : bilan à un an.

INTRODUCTION: The announcement of a cancer diagnosis is traumatic for the patient. In France, an announcement system has been in place, providing medical time for announcement and treatment proposal, nursing time for support, without including the pharmacist. In order to improve management of patients treated with intravenous anticancer drugs, we set up introductory pharmaceutical consultations in digestive oncology. The aims were to assess the situation one year after the introduction of these consultations, and to assess their contribution. METHODS: When a patient was diagnosed with digestive cancer and receiving intravenous treatment, a pharmaceutical initiation consultation was scheduled. Indicators of activity (number of consultations, average duration, average preparation time and various delays) and results (number and type of pharmaceutical interventions, patient satisfaction) were collected in order to assess activity. RESULTS: Forty-seven pharmaceutical initiation consultations were carried out. The average duration of the consultations was 39.3minutes. Consultations were carried out on average 12.1 days after the medical consultation and 9.6 days before the first chemotherapy treatment. Twenty-nine patients responded to the satisfaction questionnaire. All were satisfied, and the majority of patients said they had improved their knowledge of cancer treatment. DISCUSSION: This activity enables us to review with patients essential aspects of their care, such as implanting an implantable chamber catheter, anti-cancer treatment and managing potential side effects and improve their self-care skills.

Multi-professional development of a competency framework for patients with a Port-a-Cath (PAC).

PURPOSE: In France, 40,000 Port-a-Cath (PAC) are inserted each year. These medical devices are prone to complications during their insertion or use. The education of patients wearing these devices could be a lever to reduce the risk of complications. The objective of this work was to develop, in a multi-professional and consensual manner, a unique and specific skills reference framework for patients with PAC and to propose it as a reference tool for health professionals. METHODS: A multidisciplinary working group was set up to draw up this reference framework of skills. The first stage of the work consisted of a reflection leading to an exhaustive list of competencies necessary for the patient. These skills were then classified according to three different fields of knowledge (theoretical, know-how and attitudes). Finally, the working group identified priority competencies and established a grid that can be used to evaluate the level of acquisition of these competencies. RESULTS: Fifteen competencies were identified: five relating to theoretical knowledge, six relating to know-how and four relating to attitudes. These competencies were broken down into sub-competences. Seven competencies or sub-competencies were selected to constitute the list of priority competencies. DISCUSSION: This competency framework provides a reference framework for the education of patients with PAC and will help to harmonise practices within the different teams that care for patients with PAC.

Are the deprescribing guidelines for proton pump inhibitors in palliative care applicable? A monocentric observational study.

OBJECTIVES: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications. The aim of this study was to assess the appropriateness of prescribing PPIs in the palliative care unit on admission and during hospitalisation to determine the applicability of deprescribing recommendations. METHODS: A monocentric observational study was conducted over a 6-month period in 2020 in a university palliative care unit. Data on indication, starting date, dose and posology were collected at discharge from the medical record and by contacting the prescriber. A physician and a pharmacist evaluated PPI prescription appropriateness according to guidelines. RESULTS: 131 patients (mean age: 69.5 years; 82% with cancer) were included. Prior to admission, 41% (54/131) of patients were already prescribed PPIs. During hospitalisation, 50% of prescriptions were discontinued, while 12% were initiated. The indication was known for 50% of patients on admission and 59% during their stay. Among patients with PPI prescriptions, 56% had a relevant indication on admission, and 63% during their stay. The prevalence of potential drug interactions was low (<1/10). CONCLUSIONS: While PPIs remain essential for specific indications, this study highlights their excessive prescription even during palliative care. Implementing deprescribing recommendations in this population is crucial to optimise treatment plans.

Pediatric parenteral nutrition and hydroperoxide toxicity: Evaluation of the effectiveness of photoprotection medical devices.

Exposure of parenteral nutrition (PN) to light induces hydroperoxide (HPO) formation whose toxicity, especially in pediatrics, is documented. In this context, we evaluated the efficacy of photoprotection medical devices used in our institution to protect PN from degradation after two different exposures to light. A mixed oil lipid emulsion (Smoflipid®) in standard or opaque syringes and a ternary PN mixture bags (Numetah®) with or without opaque overwrap were exposed for at least 420 min to a xenon lamp. Samples of Smoflipid® in standard or opaque syringes were also exposed for 24 h to conditions reproducing those of a neonatal intensive care unit. The use of opaque syringes for Smoflipid® administration or opaque overwraps for Numetah® administration reduced HPO formation by an average of 14% and 40%, respectively, compared to standard conditions after at least 420 min to a xenon lamp. When Smoflipid® samples were administered with standard or opaque syringes and exposed to a phototherapy lamp, the fold-change in the HPO concentration increased, respectively, by 6.3 or 5.4 at 24 h compared with syringes unexposed to phototherapy lamp. Although the observed differences were non-significant, it nonetheless appears prudent to use photoprotection of PN during administration, particularly in patients with immature or compromised antioxidant capacity.

Evaluation of the impact of pharmacist-led educational intervention on knowledge and skills of cancer patients with totally implantable venous access port: a single-centre, non-randomised controlled study.

BACKGROUND: Totally implantable venous access port (TIVAP) is a type of implantable medical device that enables repetitive access to the intravenous system through use of a Huber needle. This device facilitates the administration of aggressive or long-term treatments while ensuring the comfort and safety of the patient. To ensure proper use of the medical device and lower the risk of complications, it is essential that patients acquire the necessary knowledge and skills regarding TIVAP. OBJECTIVE: The main objective of the study was to assess the impact of a pharmaceutical interview on patients' knowledge and skills for patients with TIVAP. METHODS: To achieve this goal, a pharmaceutical interview guide and an 18-item questionnaire were developed, based on a three-part competency framework (knowledge, know-how and attitudes) previously constructed by a multidisciplinary team. The intervention consisted of a pharmacist-led interview with every patient on the day of the TIVAP insertion. Patients in the control group received usual care. Patients included were interviewed by telephone 14 days after implantation. χ2 tests were conducted to compare the scores obtained by each group. RESULTS: The average score obtained by the control group (n=30) was 8.97, while the intervention group (n=59) achieved an average score of 12.66 (p<0.001). The intervention group demonstrated increases in correct responses for all items, with eight questions displaying significantly higher scores. Six of these pertained to theoretical knowledge, one to know-how and one to attitudes. CONCLUSION: The interviews had a clear impact on the knowledge and skills of TIVAP patients.

Factors influencing French community pharmacists' willingness to participate in research projects: a mixed method study.

BACKGROUND: French community pharmacists are facing an increasing demand to provide a wider range of services to meet the needs of the population. These new missions must be evaluated by primary care research studies. This study aims to explore the factors that influence French community pharmacists' willingness to participate in research projects. METHODS: A mixed-method design was adopted for this study, comprising an initial quantitative online survey followed by semi-directed interviews. The investigation was conducted at two French faculties of pharmacy, Angers and Nantes, involving students in their 6th and final year of pharmacy education, and their community pharmacist tutors. The survey items were based on a study by Saini et al. and participants responded using five-point Likert scales. The semi-directed interviews were conducted after the quantitative analysis, only with volunteer and already graduated community pharmacists. RESULTS: A total of 131 people participated in the quantitative analysis, comprising 75 students and 56 pharmacists. Pharmacists and students agreed on the significance of two key aspects: the research must possess a clear and meaningful purpose, and researchers must keep the pharmacists informed about the study's results. Among the 27 proposed items, only three showed significantly different results between students and pharmacists. Moreover, 11 semi-structured interviews were conducted. Research in the community pharmacy domain is relatively new for many pharmacists. Despite limited training, their willingness to participate is contingent on being actively involved from the outset, receiving appropriate support and training. However, the research should be seamlessly integrated into their daily practice, without being too time-consuming and administratively burdensome. Time constraints emerged as the main obstacle, along with concerns about the availability of human resources. Pharmacists expressed strong motivation driven by the research topic's relevance, and its potential impact on patients or the profession. While financial compensation is desirable, it did not appear to be the main criterion for participation in a study. CONCLUSIONS: French pharmacists are willing to participate in research projects to improve patient care and develop the profession. Research teams must guide and involve from the project's inception.

Evaluation of the effectiveness of a joint general practitioner-pharmacist intervention on the implementation of benzodiazepine deprescribing in older adults (BESTOPH-MG trial): protocol for a cluster-randomized controlled trial.

Background: Deprescribing benzodiazepines and related drugs (BZDR) is a challenge due to a lack of time on physicians' part, a lack of involvement of other health professionals, and the need for adapted tools. This study is based on primary care collaboration, by evaluating the effectiveness of a joint intervention between general practitioners and community pharmacists on the implementation of BZDR deprescribing in older adults. Methods: This is a cluster randomized controlled trial in which each cluster will be formed by a physician-pharmacist pair. Within a cluster allocated to the intervention, the pharmacist will be trained in motivational interviewing (MI), and will offer the patient 3 interviews after inclusion by the physician. They will base their intervention on validated deprescribing guidelines. The pharmacist will receive methodological support during the first interviews. Interprofessional collaboration will be encouraged by writing reports for the physician after each interview. The following implementation outcomes will be evaluated: acceptability/adoption, appropriateness, cost, and fidelity. They will be measured by means of sociological interviews, observations, logbooks, and cost-utility analysis. Focus groups with physicians and pharmacists will be carried out to identify levers and barriers experienced in this collaboration. Observations will be conducted with pharmacists to assess their approach of the MIs. Effectiveness outcomes will be based on medication (discontinuation or reduction of BZDR) and clinical outcomes (such as quality of life, insomnia or anxiety), assessed by health insurance databases and validated questionnaires. Discussion: This study will determine whether collaboration in primary care between physicians and pharmacists, as well as training and coaching of pharmacists in motivational interviewing, allows the implementation of BZDR deprescribing in the older adults.This study will provide an understanding of the processes used to implement deprescribing guidelines, and the contribution of collaborative practice in implementing BZDR discontinuation. The cluster methodology will allow to assess the experience of the relationship between the different primary care actors, and the related obstacles and levers.The results obtained will make it possible to produce guidelines on the involvement of community pharmacists in the management of substance abuse in older adults, or even to legislate new missions or care pathways. Clinical trial registration: ClinicalTrials.gov, identifier, NCT05765656.

The experience of being a caregiver of patients with digestive cancer, from patients and caregivers' perception: A mixed study.

BACKGROUNDS: Caregivers are essential in the care of a patient with digestive cancer. Considering their experience and needs is crucial. OBJECTIVES: To explore the experience of caregivers of patients with digestive cancer and to compare the perspectives of patients and caregivers. METHODS: A mixed-methods study with a cross-sectional prospective and a comprehensive qualitative dimension was performed in a medical oncology unit in a French tertiary hospital. Dyads made of patients with digestive cancer and their caregiver were recruited. The Caregiver Reaction Assessment (CRA) and the Supportive Care Needs Survey for Partners and Caregivers (SCNS-PC) questionnaires were distributed to caregivers. The CRA was used to measure the caregiver burden and the SCNS-PC was used to identify the unmet supportive care needs of caregivers. Semi-structured interviews with the dyads were conducted. Qualitative interviews addressed various dimensions of the caregiver's experience from each dyad's member perspective. RESULTS: Thirty-two caregivers completed the questionnaires. Responses showed high self-esteem, schedule burden, and a need for care and information services. Ten dyads participated in the interviews. Three themes emerged from the caregiver's interviews: illness is an upheaval; loneliness and helplessness are experienced; caring is a natural role with positive outcomes. Four themes emerged from patient's interviews: the caregiver naturally assumes the role and gets closer; he is the patient's anchor; his life is disrupted; anxiety and guilt accompany the desire to protect him. In comparing patient and caregiver data, the main theme of disagreement was their relationship. CONCLUSIONS: Caregiver care does not appear to be optimal, particularly in terms of their need for information. Patients have a fairly good representation of their experience, but the caregivers' opinion need to be considered.

Outcomes in deprescribing implementation trials and compliance with expert recommendations: a systematic review.

BACKGROUND: Deprescribing, defined as discontinuing or reducing the dose of medications that are no longer needed or for which the risks outweigh the benefits is a way to reduce polypharmacy. In 2022, the US Deprescribing Research Network (USDeN) published recommendations concerning the measurement of outcomes for deprescribing intervention studies. The objectives of this systematic review were to identify the outcome categories used in deprescribing intervention trials and to relate them to the previously published recommendations. METHODS: We searched MEDLINE, Embase, PsychInfo, and the Cochrane library from January 2012 through January 2022. Studies were included if they were randomized controlled trials evaluating a deprescribing intervention. After data extraction, outcomes were categorized by type: medication outcomes, clinical outcomes, system outcomes, implementation outcomes, and other outcomes based on the previously published recommendations. RESULTS: Thirty-six studies were included. The majority of studies focused on older adults in nursing homes and targeted inappropriate medications or polypharmacy. In 20 studies, the intervention was a medication review; in seven studies, the intervention was educational or informative; and three studies based their intervention on motivational interviewing or patient empowerment. Thirty-one studies presented a medication outcome (primary outcome in 26 studies), 25 a clinical outcome, 18 a system outcome, and seven an implementation outcome. Only three studies presented all four types of outcomes, and 10 studies presented three types of outcomes. CONCLUSIONS: This review provides an update on the implementation of gold standard deprescribing studies in clinical practice. Implementation outcomes need to be developed and specified to facilitate the implementation of these practices on a larger scale and clinical outcome need to be prioritized. Finally, this review provides new elements for future real-life deprescribing studies.

Patients' preferences in therapeutic decision-making in digestive oncology: a single centre cross-sectional observational study.

Considering the preferences in Shared Decision Making (SDM) of patients with Digestive Cancer (DC) is crucial to ensure the quality of care. To date, there is limited information on preferences in SDM of patients with DC. The objectives of this study were to describe digestive cancer patients' preference for involvement in therapeutic decision-making and to identify variables associated with these preferences. An observational prospective study in a French university cancer center has been conducted. Patients completed two questionnaires to qualify and quantify their preference for involvement in therapeutic decision-making: the Control Preference Scale (CPS) and the Autonomy Preference Index (API), which is composed of the Decision Making (DM) score and the Information Seeking (IS) score. Associations between these scores and socio-demographic data, disease-related data, coping strategies (Brief-COPE), physical (QLQ-C30) and psychological (HADS) quality of life were tested. One-hundred fifteen patients returned the questionnaires. The majority of patients reported a passive (49.1%) or a collaborative (43.0%) CPS status. The mean DM score was 39.4 Variables associated with decision-making preferences were occupational status and time since diagnosis. The identification of variables associated with patients' preferences for involvement in decision-making can help make clinicians aware of patients' needs and wishes. However, it can only be determined by interviewing the patient individually.

Differential MMP-14 targeting by biglycan, decorin, fibromodulin, and lumican unraveled by in silico approach.

Small leucine-rich proteoglycans (SLRPs) are major regulators of extracellular matrix assembly and cell signaling. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess antitumor activity by interacting directly with the catalytic domain of MMP-14 leading to the inhibition of its activity. The aim of the present report was to characterize by in silico three-dimensional (3D) modeling the structure and the dynamics of four SLRPs including their core protein and their specific polysaccharide chains to assess their capacity to bind to MMP-14 and to regulate its activity. Molecular docking experiments were performed to identify the specific amino acids of MMP-14 interacting with each of the four SLRPs. The inhibition of each SLRP (100 nM) on MMP-14 activity was measured and the constants of inhibition (Ki) were evaluated. The impact of the number of glycan chains, structures, and dynamics of lumican on the interaction with MMP-14 was assessed by molecular dynamics simulations. Molecular docking analysis showed that all SLRPs bind to MMP-14 through their concave face, but in different regions of the catalytic domain of MMP-14. Each SLRPs inhibited significantly the MMP-14 activity. Finally, molecular dynamics showed the role of glycan chains in interaction with MMP-14 and shielding effect of SLRPs. Altogether, the results demonstrated that each SLRP exhibited inhibition of MMP-14 activity. However, the differential targeting of MMP-14 by the SLRPs was shown to be related not only to the core protein conformation but also to the glycan chain structures and dynamics.

Exploring the factors influencing adherence to oral anticancer drugs in patients with digestive cancer: a qualitative study.

PURPOSE: The aim of this study was to explore the beliefs, perceptions and representations of patients in order to identify the determinants of oral anticancer drugs adherence and to take action in current practice to improve patient support in digestive oncology. METHODS: We constructed a semi-directed interview guide which aimed to explore the patient's relationship with medication, their health history, their experiences at the time of the announcement of treatment, their confidence, their fears, their motivations to adhere to their treatment and the constraints linked to their treatment. The data were analysed and discussed using a thematic approach. RESULTS: Seventeen patients agreed to participate in the study. The median age was 60 years. Ten patients had colorectal cancer, 3 patients had hepatocellular carcinoma, 3 patients had gastrointestinal stromal tumour and 1 patient had neuroendocrine pancreatic tumour. We identified five categories of factors influencing adherence: demographic and socioeconomic, disease-related, treatment-related, care system-related, and patient representation and pathways' factors. A majority of patients emphasised the importance of family support in the adherence process and the convenience of per os treatment compared to other intravenous treatments. However, several negative determinants emerged such as the toxicity of the treatment, fears of forgetting to take the medication, difficulties with the galenic formulation and negative beliefs of the family. CONCLUSION: This study demonstrates the need to address the different dimensions of the patient in order to understand his or her behaviour with regard to adherence and to identify the levers for improvement.

Assessment of Ovarian Tumor Growth in Wild-Type and Lumican-Deficient Mice: Insights Using Infrared Spectral Imaging, Histopathology, and Immunohistochemistry.

Ovarian cancer remains one of the most fatal cancers due to a lack of robust screening methods of detection at early stages. Extracellular matrix (ECM) mediates interactions between cancer cells and their microenvironment via specific molecules. Lumican, a small leucine-rich proteoglycan (SLRP), maintains ECM integrity and inhibits both melanoma primary tumor development, as well as metastatic spread. The aim of this study was to analyze the effect of lumican on tumor growth of murine ovarian epithelial cancer. C57BL/6 wild type mice (n = 12) and lumican-deficient mice (n = 10) were subcutaneously injected with murine ovarian epithelial carcinoma ID8 cells, and then sacrificed after 18 days. Analysis of tumor volumes demonstrated an inhibitory effect of endogenous lumican on ovarian tumor growth. The ovarian primary tumors were subjected to histological and immunohistochemical staining using anti-lumican, anti-αv integrin, anti-CD31 and anti-cyclin D1 antibodies, and then further examined by label-free infrared spectral imaging (IRSI), second harmonic generation (SHG) and Picrosirius red staining. The IR tissue images allowed for the identification of different ECM tissue regions of the skin and the ovarian tumor. Moreover, IRSI showed a good correlation with αv integrin immunostaining and collagen organization within the tumor. Our results demonstrate that lumican inhibits ovarian cancer growth mainly by altering collagen fibrilogenesis.

Differential MMP-14 Targeting by Lumican-Derived Peptides Unraveled by In Silico Approach.

Lumican, a small leucine-rich proteoglycan (SLRP) of the extracellular matrix (ECM), displays anti-tumor properties through its direct interaction with MMP-14. Lumican-derived peptides, such as lumcorin (17 amino acids) or L9M (10 amino acids), are able to inhibit the proteolytic activity of MMP-14 and melanoma progression. This work aimed to visualize the interactions of lumican-derived peptides and MMP-14. Molecular modeling was used to characterize the interactions between lumican-derived peptides, such as lumcorin, L9M, and cyclic L9M (L9Mc, 12 amino acids), and MMP-14. The interaction of L9Mc with MMP-14 was preferential with the MT-Loop domain while lumcorin interacted more with the catalytic site. Key residues in the MMP-14 amino acid sequence were highlighted for the interaction between the inhibitory SLRP-derived peptides and MMP-14. In order to validate the in silico data, MMP-14 activity and migration assays were performed using murine B16F1 and human HT-144 melanoma cells. In contrast to the HT-144 melanoma cell line, L9Mc significantly inhibited the migration of B16F1 cells and the activity of MMP-14 but with less efficacy than lumican and lumcorin. L9Mc significantly inhibited the proliferation of B16F1 but not of HT-144 cells in vitro and primary melanoma tumor growth in vivo. Thus, the site of interaction between the domains of MMP-14 and lumcorin or L9Mc were different, which might explain the differences in the inhibitory effect of MMP-14 activity. Altogether, the biological assays validated the prediction of the in silico study. Possible and feasible improvements include molecular dynamics results.

Evaluation of the Ability of Emergency Room Doctors at a French University Hospital Center to Identify Adverse Drug Events.

OBJECTIVES: Numerous adverse drug events (ADEs) are not identified by doctors in medical emergencies, and they are a barrier to optimal treatment of patients. Identification of the factors that influence awareness of ADEs by doctors could allow events that compromise patient safety to be avoided. The aims of this study were to quantify the recognition of ADEs by emergency room (ER) doctors and to identify the factors associated with the lack of identification of drug-related risks. METHODS: This study was carried out at the ER of a French teaching hospital between January 1, 2014, and the December 31, 2017. A previously used form was administered to the patients being treated in the ER, and it was completed using medical files to identify ADEs. The ADEs were then validated by a doctor and a senior pharmacist. RESULTS: Of the 1870 included patients, 279 (14.9%) exhibited an ADE. Of these 279 ADEs, 201 (72%) had been identified by the doctor. The probability of an ADE being identified was higher when the drug was directly linked with the main ailment of the patient (odds ratio, 1.72; 95% confidence interval, 1.01-2.97). Adverse drug events were identified less well when their severity was limited (spontaneous regression without treatment) (odds ratio, 0.5; 95% confidence interval, 0.27-0.93). CONCLUSIONS: This study showed that ADEs are identified less well when their severity is limited, as well as when the ADE is not directly linked with the main ailment of the patient.

Label-Free Infrared Spectral Histology of Skin Tissue Part II: Impact of a Lumican-Derived Peptide on Melanoma Growth.

Melanoma is the most aggressive type of cutaneous malignancies. In addition to its role as a regulator of extracellular matrix (ECM) integrity, lumican, a small leucine-rich proteoglycan, also exhibits anti-tumor properties in melanoma. This work focuses on the use of infrared spectral imaging (IRSI) and histopathology (IRSH) to study the effect of lumican-derived peptide (L9Mc) on B16F1 melanoma primary tumor growth. Female C57BL/6 mice were injected with B16F1 cells treated with L9Mc (n = 10) or its scrambled peptide (n = 8), and without peptide (control, n = 9). The melanoma primary tumors were subjected to histological and IR imaging analysis. In addition, immunohistochemical staining was performed using anti-Ki-67 and anti-cleaved caspase-3 antibodies. The IR images were analyzed by common K-means clustering to obtain high-contrast IRSH that allowed identifying different ECM tissue regions from the epidermis to the tumor area, which correlated well with H&E staining. Furthermore, IRSH showed good correlation with immunostaining data obtained with anti-Ki-67 and anti-cleaved caspase-3 antibodies, whereby the L9Mc peptide inhibited cell proliferation and increased strongly apoptosis of B16F1 cells in this mouse model of melanoma primary tumors.