Abdominal tumors in patients with neurofibromatosis type I: Genotype-phenotype relationships.

BACKGROUND: Gastrointestinal stromal tumors have been detected in 25% of the necropsies performed on NF1 patients, but have been reported only in 7% of NF1 patients in the largest series. Such data imply an important gap between the true presence of tumors and those diagnosed. Few genotype-phenotype relationships have been described but to date none referring to abdominal tumors. OBJECTIVES: Evaluate retrospectively the efficacy of a regular and proactive follow-up of NF1 patients to early diagnose abdominal tumors and report their mutations. METHODS: Cohort study performed between 2010 and 2020, with 43 NF1 adult patients followed at our Dermatology department. RESULTS: Eight abdominal tumors were diagnosed in six patients, meaning that 14% of the followed patients developed an abdominal tumor. Five patients (83%) were asymptomatic. Five (83.3%) had a family history of NF1 with abdominal tumors (patients 1,2 and 3,4,5 were relatives). CONCLUSIONS: Although currently gastrointestinal routine screening investigations for asymptomatic patients are not recommended in the guidelines, the family aggregation in our series suggests it should be considered a close follow-up of the relatives of a patient with an NF1-related abdominal tumor. Also, for the first time, two mutations [c.2041C > T (p.Arg681Ter) and c.4537C > T (p.Arg1513*)] have been associated with family aggregation of abdominal tumors in NF1 patients.

M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors.

BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.

Designed proteins assemble antibodies into modular nanocages.

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.

Are artificial intelligence systems useful in breast cancer screening programs? / ¿Son los sistemas de inteligencia artificial una herramienta útil para los programas de cribado de cáncer de mama?

Population-based breast cancer screening programs are efficacious in reducing the mortality due to breast cancer. These programs use mammography to screen the women who are invited to participate. Digital mammography makes it possible to develop computer-assisted diagnosis (CAD) systems that promise to reduce the workload of radiologists participating in screening programs. However, various studies have shown that CAD results in a high rate of false positive diagnoses. Systems based on artificial intelligence are being more widely implemented, and studies have shown that these systems have better diagnostic performance than traditional CAD systems. This article explains the fundamentals of artificial intelligence systems and an overview of possible applications of these systems within the framework of breast cancer screening programs.

Prognostic factors in patients with primary cutaneous anaplastic large cell lymphoma: a multicentric, retrospective analysis of the Spanish Group of Cutaneous Lymphoma.

BACKGROUND: Reliable prognostic factors for patients with primary cutaneous anaplastic large cell lymphoma (PCALCL) are lacking. OBJECTIVE: To identify prognostic factors for specific survival in patients with PCALCL. METHODS: Using the convenience sampling method, patients with PCALCL diagnosed from May 1986 to August 2017 in 16 University Departments were retrospectively reviewed. RESULTS: One hundred eight patients were included (57 males). Median age at diagnosis was 58 years. All of them showed T1-3N0M0 stages. Seventy per cent of the cases presented with a solitary lesion, mostly at the limbs. Complete response rate after first-line treatment was 87%, and no advantage was observed for any of them (surgery, radiotherapy, chemotherapy or other approaches). Nodal and visceral progression rate was 11% and 2%, respectively. 5-year specific survival (SSV) reached 93%; 97% for T1 patients and 84% for T2/T3 patients (P = 0.031). Five-year SSV for patients developing early cutaneous relapse was 64%; for those with late or no relapse, 96% (P = 0.001). Estimated median SSV for patients showing nodal progression was 103 months (95% CI: 51-155 months); for patients without nodal progression, estimated SSV did not reach the median (P < 0.001). Nodal progression was an independent predictive parameter for shorter survival (P = 0.011). CONCLUSION: Multiple cutaneous lesions at presentation, early skin relapse and nodal progression portrait worse prognosis in patients with PCALCL.

Descriptive study of naevus involution in a series of 74 patients with atypical naevus syndrome under SIAscopy digital follow-up.

BACKGROUND: Characterization of nevi involution could help to understand the biological behaviour of melanocytic neoplasms. OBJECTIVE: To describe the frequency and morphology of naevus involution in a series of patients with atypical naevus syndrome under digital follow-up with a SIAscopy program and, in a small sample of fading nevi, to analyse histopathological features and immunohistochemical biomarkers. METHODS: Seventy-four patients registered from April 2007 to July 2014 in the SIAscopy system of the Department of Dermatology of Hospital Arnau de Vilanova of Lleida, Spain, were reviewed. Fourteen naevus cases with fading features were prospectively excised during follow-up. Eleven already excised naevus controls were randomly selected from our archive. RESULTS: We observed that 81% of patients showed, at least, one involutive naevus and 25% of recorded nevi presented this phenomenon; the mean time of involution was 46.7 months. The predominant structural pattern was reticular (>70%), and the most frequently observed regression structures were vascular (33.8%). Histopathological significant higher intensity of inflammatory infiltrate in controls and higher presence of laminar and compact fibrosis and increase of vessels in cases were demonstrated. Regarding immunohistochemical biomarkers, only higher expression of cytoplasmic activated caspase 3 in controls was significant. CONCLUSIONS: Naevus involution is a common phenomenon in patients with dysplastic naevus syndrome. It is usually a slow process, more frequent in naevus with reticular pattern. SIAscopy regression structures are uncommon, with the exception of vascular ones. Histologically, fading involutive pattern is characterized by scarce inflammatory infiltrate and melanophages, delicate fibrosis and increase of vessels.

Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens.

Upon Ag exposure, naive B cells expressing BCR able to bind Ag can undergo robust proliferation and differentiation that can result in the production of Ab-secreting and memory B cells. The factors determining whether an individual naive B cell will proliferate following Ag encounter remains unclear. In this study, we found that polyclonal naive murine B cell populations specific for a variety of foreign Ags express high levels of the orphan nuclear receptor Nur77, which is known to be upregulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naive human B cells specific for clinically-relevant Ags derived from respiratory syncytial virus and HIV-1 also exhibited an IgMLOW IgD+ phenotype, which is associated with self-antigen cross-reactivity. Functionally, naive B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following Ag injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naive B cells specific for foreign Ags and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following Ag exposure.

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study.

BACKGROUND: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. AIM: To assess the daily clinical practice approach to LyP and the response to first-line treatments. METHODS: This was a retrospective study enrolling 252 patients with LyP. RESULTS: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. CONCLUSIONS: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse.

Abnormally High Ankle-Brachial Index is Associated with All-cause and Cardiovascular Mortality: The REGICOR Study.

INTRODUCTION: The clinical significance of a high ankle brachial index (ABI) and its relationship to cardiovascular disease (CVD) and mortality is controversial. The aim of this study was to estimate the association between abnormally high ABI ≥ 1.4 and coronary heart disease (CHD), cerebrovascular disease, and all-cause mortality in a Mediterranean population without CVD. METHODS: A prospective population based cohort study of 6352 subjects was followed up for a median 6.2 years. Subjects under 35 years, with a history of CVD or an ABI < 0.9 were excluded. All CHD events (angina, myocardial infarction, coronary revascularisation), cerebrovascular events (stroke, transient ischaemic attack), and all-cause mortality were recorded. RESULTS: A total of 5679 subjects fulfilled the inclusion criteria, of which 5517 (97.1%) had a normal ABI whereas 162 (2.9%) had an ABI ≥ 1.4. The profile of individuals with abnormally high ABI revealed as independent related factors age (OR = 1.0; p = .045), female sex (OR = 0.4; p < .01), diabetes (OR = 1.9; p = .02), and lower diastolic blood pressure (OR = 0.9; p < .001). During follow-up 309 (5.4%) participants presented with a CV event and 286 (5.0%) died. An ABI ≥ 1.4 was associated with a higher incidence of CV events in the univariate (HR = 1.7) but not in the multivariate survival Cox regression analysis. An ABI ≥ 1.4 was independently associated with all-cause mortality (HR = 2.0; IC 95% 1.32-2.92) and cardiovascular mortality (HR = 3.1; IC 95% 1.52-6.48). CONCLUSIONS: In subjects without CVD, those with abnormally high ABI do not have a greater CV event rate than those with a normal ABI. However, there seems to be a trend towards higher mortality risk, supporting the guidelines that consider this subgroup to be a high risk population.

Immunohistochemical analysis of T-type calcium channels in acquired melanocytic naevi and melanoma.

BACKGROUND: Cutaneous malignant melanoma arises from transformed melanocytes de novo or from congenital or acquired melanocytic naevi. We have recently reported that T-type Ca2+ channels (TT-Cs) are upregulated in human melanoma and play an important role in cell proliferation. OBJECTIVES: To describe for the first time in formalin-fixed paraffin-embedded tissue the immunoexpression of TT-Cs in biopsies of normal skin, acquired melanocytic naevi and melanoma, in order to evaluate their role in melanomagenesis and/or tumour progression, their utility as prognostic markers and their possible use in targeted therapies. METHODS: Tissue samples from normal skin, melanocytic naevi and melanoma were subjected to immunohistochemistry for two TT-Cs (Cav3.1, Cav3.2); markers of proliferation (Ki67), the cell cycle (cyclin D1), hypoxia (Glut1), vascularization (CD31) and autophagy (LC3); BRAF V600E mutation (VE1) and phosphatase and tensin homologue (PTEN). Immunostaining was evaluated by histoscore. In silico analysis was used to assess the prognostic value of TT-C overexpression. RESULTS: TT-C immunoexpression increased gradually from normal skin to common naevi, dysplastic naevi and melanoma samples, but with differences in the distribution of both isoforms. Particularly, Cav3.2 expression was significantly higher in metastatic melanoma than in primary melanoma. Statistical correlation showed a linear interaction between PTEN loss/BRAF V600E/Cav3.1/LC3/ Ki67/cyclin D1/Cav3.2/Glut1. Disease-free survival (DFS) and overall survival correlated inversely with overexpression of Cav3.2. DFS also correlated inversely with overexpression of Cav3.1. CONCLUSIONS: TT-C immunoexpression on melanocytic neoplasms is consistent with our previous in vitro studies and appears to be related to tumour progression. TT-C upregulation can be considered as a prognostic marker using The Cancer Genome Atlas database. The high expression of Cav3.2 in metastatic melanoma encourages the investigation of the use of TT-C blockers in targeted therapies.

Corrigendum to "Calcium Channel Expression and Applicability as Targeted Therapies in Melanoma".

[This corrects the article DOI: 10.1155/2015/587135.].

Peripheral Arterial Disease Incidence and Associated Risk Factors in a Mediterranean Population-based Cohort. The REGICOR Study.

OBJECTIVES: The reported incidence of lower extremity peripheral arterial disease (PAD) in Western countries ranges between 530 and 2,380 per 100,000 person years. The aims of this study were to determine the incidence of PAD and identify associated risk factors in a Mediterranean population. METHODS: Cardiovascular risk factors, the Edinburgh questionnaire, and ankle brachial index (ABI) were collected from 5,434 individuals, aged 35-79 years, from a population based cohort study at baseline and after a mean of 5.7 years follow up. PAD was defined as ABI <0.9 or a clinical diagnosis during follow up. Logistic and regression tree analyses were used to identify factors associated with PAD. RESULTS: In total, 118 new cases of confirmed PAD were identified. The cumulative population incidence rate of PAD was 377 cases per 100,000 person years. For symptomatic PAD, this figure was 102 per 100,000 person years. The most important risk factors for PAD were current (OR 2.30; 95% CI 1.27-4.16) or former smoking (OR 2.02; 95% CI 1.19-3.43), diabetes (OR 1.78; 95% CI 1.17-2.72), age (OR 1.04; 95% CI 1.02-1.07), history of cardiovascular disease (OR 2.06; 95% CI 1.22-3.51), triglycerides level (OR 1.56; 95% CI 1.07-2.29), and systolic blood pressure (OR 1.02; 95% CI 1.01-1.03). In the population ≤65 years the most relevant risk factor was diabetes, whereas in those >65 years smoking was the leading factor. Long-term uncontrolled diabetes was the strongest risk factor for PAD (OR 10.14; 95% CI 3.57-28.79). CONCLUSION: The incidence of lower extremity PAD is lower in the Mediterranean area than has been reported for other areas. The data suggest that patients with long-term uncontrolled diabetes and former and current smokers older than 65 years should be considered for PAD screening.

Core Content for Undergraduate Medical Education in Spain: Recommendations of the Instructors' Group of the Spanish Academy of Dermatology and Venereology (AEDV).

BACKGROUND: Skin problems are among the most frequent reasons for seeking medical attention in primary care. In recent years, as a result of the process of adapting medical curricula to the requirements of the European Higher Education Area, the amount of time students spend learning the concepts of dermatology has been reduced in many universities. MATERIAL AND METHODS: In order to reach a consensus on core content for undergraduate education in dermatology, we sent a survey to the 57 members of the instructors' group of the Spanish Academy of Dermatology and Venereology (AEDV), asking their opinions on what objectives should be set for a dermatology course in Spain. A total of 131 previously selected objectives were listed. We then applied the Delphi method to achieve consensus on which ones the respondents considered important or very important (score≥4 on a Likert scale). RESULTS: Nineteen responses (33%) were received. On the second round of the Delphi process, 68 objectives achieved average scores of at least 4. The respondents emphasized that graduates should understand the structure and functions of the skin and know about bacterial, viral, and fungal skin infections, the most common sexually transmitted diseases (STDs), and the 4 main inflammatory dermatoses. Students should also learn about common complaints, such as itching and bald patches; the management of dermatologic emergencies; purpura and erythema nodosum as signs of internal disease; and the prevention of STDs and skin cancer. During clinical clerkships students should acquire the communication skills they will need to interview patients, write up a patient's medical history, and refer the patient to a specialist. CONCLUSIONS: The AEDV's group of instructors have defined their recommendations on the core content that medical faculties should adopt for the undergraduate subject of dermatology in Spain.

Calcium channel expression and applicability as targeted therapies in melanoma.

The remodeling of Ca(2+) signaling is a common finding in cancer pathophysiology serving the purpose of facilitating proliferation, migration, or survival of cancer cells subjected to stressful conditions. One particular facet of these adaptive changes is the alteration of Ca(2+) fluxes through the plasma membrane, as described in several studies. In this review, we summarize the current knowledge about the expression of different Ca(2+) channels in the plasma membrane of melanoma cells and its impact on oncogenic Ca(2+) signaling. In the last few years, new molecular components of Ca(2+) influx pathways have been identified in melanoma cells. In addition, new links between Ca(2+) homeostasis and specific cell processes important in melanoma tumor progression have been unveiled. Thus, not only do Ca(2+) channels appear to have a potential as prognostic markers, but their pharmacological blockade or gene silencing is hinted as interesting therapeutic approaches.

Derivation and validation of BOREAS, a risk score identifying candidates to develop cold-induced hypertension.

INTRODUCTION: Blood pressure increases in cold periods, but its implications on prevalence of hypertension and on individual progression to hypertension remain unclear. Our aim was to develop a pre-screening test for identifying candidates to suffer hypertension only in cold months among non-hypertensive subjects. METHODS: We included 95,277 subjects registered on a primary care database from Girona (Catalonia, Spain), with ≥ 3 blood pressure measures recorded between 2003 and 2009 and distributed in both cold (October-March) and warm (April-September) periods. We defined four blood pressure patterns depending on the presence of hypertension through these periods. A Cox model determined the risk to develop vascular events associated with blood pressure patterns. A logistic regression distinguished those nonhypertensive individuals who are more prone to suffer cold-induced hypertension. Validity was assessed on the basis of calibration (using Brier score) and discrimination (using the area under the receiver operating characteristics). RESULTS: In cold months, the mean systolic blood pressure increased by 3.3 ± 0.1 mmHg and prevalence of hypertension increased by 8.2%. Cold-induced hypertension patients were at higher vascular events risk (Hazard ratio=1.44 [95% Confidence interval 1.15-1.81]), than nonhypertensive individuals. We identified age, diabetes, body mass index and prehypertension as the major contributing factors to cold-induced hypertension onset. DISCUSSION: Hypertension follows a seasonal pattern in some individuals. We recommend screening for hypertension during the cold months, at least in those nonhypertensive individuals identified as cold-induced hypertensive by this assessment tool.

Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy.

Suicide gene therapy (SGT) is a promising strategy for treating cancer. In this work, we show that thymidine phosphorylase (TP) deficiency, the underlying genetic defect in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presents an opportunity to apply SGT using capecitabine, a commonly used prodrug that is converted into 5-fluorouracil by TP. Using an immortalised B-lymphoblastoid cell line from a patient with MNGIE, the tumourigenic EL-4 cell line, lentiviral vectors encoding TP and a double knockout (Tymp(-/-)Upp1(-/-)) murine model, we found that EL-4 cell-derived TP(+) tumours were exquisitely sensitive to capecitabine and generated a significant local bystander effect. In addition, we detected a spontaneous cytolytic immune response in a significant fraction of the animals surviving more than 20 days after termination of the therapy. These data indicate that, in individuals lacking TP expression, TP is a highly specific suicide gene, which can be used to treat tumours that could hypothetically arise in MNGIE patients undergoing gene therapy, as these tumours will likely originate from the gene-modified cells and will be selectively targeted by capecitabine. These observations have important implications for gene therapy for MNGIE.

Evaluating clinical dermatology practice in medical undergraduates.

The acquisition of competences (the set of knowledge, skills and attitudes required to perform a job to a professional level) is considered a fundamental part of medical training. Dermatology competences should include, in addition to effective clinical interviewing and detailed descriptions of skin lesions, appropriate management (diagnosis, differentiation, and treatment) of common skin disorders and tumors. Such competences can only be acquired during hospital clerkships. As a way of certifying these competences, we propose evaluating the different components as follows: knowledge, via clinical examinations or critical incident discussions; communication and certain instrumental skills, via structured workplace observation and scoring using a set of indicators; and attitudes, via joint evaluation by staff familiar with the student.

[Joint-preserving osteotomy of malunited ankle and pilon fractures]. / Gelenkerhaltende Osteotomien fehlverheilter Sprunggelenk- und Pilonfrakturen.

Malunion and nonunion after ankle and pilon fractures regularly lead to the development of painful functional impairment even in cases of only mild axial deviation or residual joint incongruity. Involvement of the tibial pilon results in rapid progression of posttraumatic ankle arthritis. Corrective osteotomy with joint preservation aims at secondary anatomical reconstruction with functional rehabilitation. This requires a careful preoperative analysis and will be possible in carefully selected cases only. Prerequisites for successful reconstruction are intact cartilage, sufficient bone quality, residual joint function and good patient compliance. Since the works of B. G. Weber, joint-sparing osteotomy is an established treatment option for malunited malleolar fractures with reliable long-term results and low rates of complications and secondary fusions. Key to success is the re-establishment of the length of the distal fibula and repositioning into the tibial incisura in cases of syndesmotic instability. Corrections of the medial malleolus and posterior tibial fragment are less frequent. Corrective intra-articular osteotomies for malunited pilon fractures are rarely feasible because of manifest arthritis at the time of patient presentation in most cases. Besides case reports there is only one series of 14 patients available in the literature. At 5-year follow-up, a good to excellent result was seen in 10 cases and secondary ankle fusion was done in 2 patients with a poor result. Anatomical reconstruction of malunited tibial pilon fractures appears to be a viable treatment option besides arthroplasty and fusion in carefully selected patients.

Unilateral milia-type intradermal tophi associated with underlying urate subcutaneous deposition: an uncommon cutaneous presentation of gout.

Tophi develop during the most advanced clinical stage of gout, and are usually located on or around the joints. However, unusual skin features caused by intradermal and/or subcutaneous deposition of tophaceous material at locations other than articular regions have been reported. We present the case of a patient with a condition that has been recently termed 'miliarial gout'. which is only the second such case, to our knowledge. A 51-year-old woman, who had a chronic joint disease that had been diagnosed and treated as psoriatic arthritis, presented with multiple asymptomatic, yellowish-white, firm papules (1-3 mm in size) on erythematous areas on the outside of her left leg. On histological examination of a skin biopsy, uric acid crystals were seen in the dermis and subcutis. The patient also had a raised level of serum urate, consistent with a diagnosis of gout. Treatment with allopurinol led to rapid improvement. Intake of corticosteroids and diuretics was a possible triggering factor for the development of cutaneous tophi in this patient.