Development of the Melanoma Concerns Questionnaire (MCQ-28); refinement of the EORTC QLQ-MEL38 module.

OBJECTIVE: Few patient-reported outcome measures (PROMs) have been developed that adequately measure the patient-experience following diagnosis and treatment of melanoma. Building on previous research, which developed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Module (QLQ-MEL38), the aim of this study was to further test the hypothesised domain structure and psychometric properties of the phase 3 module, in a new larger sample of melanoma patients. METHODS: Melanoma patients (n = 270) were recruited from four countries (Australia, England, Serbia, and Spain). Patients completed the EORTC core questionnaire (QLQ-C30), the QLQ-MEL38, and a sociodemographic survey. Using this new larger dataset, comparisons were made with the hypothesised domain structure of the EORTC phase 3 module using principal component analysis. Items which formed subscales in a revised domain structure were then tested for goodness of fit (GoF) to the Rasch model. RESULTS: The original hypothesised and final domain structures were similar but not identical. Twenty-four items (83%) loaded onto the same distinct subscales previously generated by phase 3, and item-by-item comparison of the two pattern matrices indicated an extremely close match. Ten items were removed from the QLQ-MEL38 phase 3 module, and rescoring of some items was required. Four subscales, together with five individual items, comprised the final instrument. CONCLUSION: The newly developed measure (named the Melanoma Concerns Questionnaire; MCQ-28) was found to tap into several important psychosocial domains of concern to melanoma patients, particularly those being managed in "usual" clinic settings.

Incidence rate and clinicopathological features of 62 atypical fibroxanthomas in a North-Western Spanish population.

BACKGROUND/OBJECTIVES: Atypical fibroxanthoma (AFX) is a mesenchymal neoplasm of unknown incidence. It has been determined that AFX is a tumour with low aggressiveness as long as it is properly diagnosed. Our objectives were to exclude pleomorphic dermal sarcomas or other skin tumours incorrectly diagnosed as AFX in our centre after applying strict diagnostic criteria and to assess the behaviour of appropriately diagnosed AFX. METHODS: We conducted an observational retrospective analysis of 73 patients diagnosed with AFX in our centre between 1998 and 2018. After selecting cases fulfilling AFX criteria, we made an analysis of predictive factors for local recurrence. Crude and sex-adjusted incidence rates were calculated. RESULTS: Out of 73 cases, 62 were eventually diagnosed as AFX. We examined for absence of tumour necrosis, lymphovascular or perineural invasion and infiltration of deep structures. Cytokeratin AE1-AE3, desmin and CD34 were negative in all cases. The remaining tumours were reclassified. The incidence of AFX in our health-care area was estimated at 0.59 cases every 100 000 inhabitants per year. In our series, 72.6% of the patients were men with mean age at diagnosis of 81 years. Average tumour diameter was 12 mm. The most common location was head and neck (96.8%). Only four local recurrences were detected over a mean of 47-month follow-up. CONCLUSIONS: We report a series of AFX in our health-care area. We verify its indolent course when it is properly diagnosed.

Levofloxacin-induced rhabdomyolysis in a patient on concurrent atorvastatin: Case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: The combination of HMG-CoA reductase inhibitors (statins) and fluoroquinolones generally is not considered a significant risk factor for rhabdomyolysis. Rhabdomyolysis is a known risk associated with statin therapy but has seldom been described with fluoroquinolone use. We describe a case of acute rhabdomyolysis involving the co-administration of atorvastatin and levofloxacin. CASE DESCRIPTION: A 65-year-old white male presented with clinical and laboratory evidence of rhabdomyolysis after approximately 19 days of levofloxacin therapy for treatment of a prosthetic joint infection. His symptoms resolved after discontinuation of levofloxacin and atorvastatin therapy and did not recur following reintroduction of atorvastatin therapy. WHAT IS NEW AND CONCLUSION: Delayed-onset rhabdomyolysis may occur in patients receiving levofloxacin. Weekly complete metabolic panels along with patient education about symptoms of rhabdomyolysis should be considered, particularly in patients on concurrent medications known to cause rhabdomyolysis.

Therapeutic impact and routine application of next-generation sequencing: A single institute study.

Genomic sequencing of tumor tissues provides information on actionable gene aberrations that have diagnostic and therapeutic significance and may guide clinical management through the use of targeted therapies. The indications for these techniques and their possible limitations for application in daily practice should be established as a priority. In the present study, a group of patients with few suitable therapeutic options who were eligible for a next-generation sequencing (NGS) analysis were analyzed, and the molecular targets identified and their therapeutic impact are described. A series of 26 patients treated at the Virgen Macarena Hospital for whom an NGS study was requested between January 2017 and December 2019 were reviewed. Actionable molecular alterations were identified in 20 of the cases, and 4 patients received NGS-guided treatment. NGS techniques represent a novel opportunity for guiding treatment in cancer patients. Patients with few therapeutic alternatives, either due to diagnosis, atypical evolution or resistance to standard therapy, may be suitable candidates.

Sentinel Lymph Node Biopsy vs. Observation in Thin Melanoma: A Multicenter Propensity Score Matching Study.

The therapeutic value of sentinel lymph node biopsy (SLNB) in thin melanoma remains controversial. The aim of this study is to determine the role of SLNB in the survival of thin melanomas (≤1 mm). A multicenter retrospective observational study was designed. A propensity score matching was performed to compare patients who underwent SLNB vs. observation. A multivariate Cox regression was used. A total of 1438 patients were matched by propensity score. There were no significant differences in melanoma-specific survival (MSS) between the SLNB and observation groups. Predictors of MSS in the multivariate model were age, tumor thickness, ulceration, and interferon treatment. Results were similar for disease-free survival and overall survival. The 5- and 10-year MSS rates for SLN-negative and -positive patients were 98.5% vs. 77.3% (p < 0.001) and 97.3% vs. 68.7% (p < 0.001), respectively. SLNB does not improve MSS in patients with thin melanoma. It also had no impact on DSF or OS. However, a considerable difference in MSS, DFS, and OS between SLN-positive and -negative patients exists, confirming its value as a prognostic procedure and therefore we recommend discussing the option of SLNB with patients.

The presence of Merkel cell carcinoma polyomavirus is associated with a distinct phenotype in neoplastic Merkel cell carcinoma cells and their tissue microenvironment.

AIMS: Merkel cell carcinoma (MCC) is an aggressive primary neuroendocrine tumor of the skin, associated with Merkel cell polyomavirus (MCPyV) in 49-89% of cases, depending on the country of origin and the techniques of detection. The presence of MCPyV defines heterogeneity in MCC; MCPyV-negative cases bear a much higher mutational load, with a distinct ultraviolet signature pattern featuring C > T transitions, as a consequence of exposure to ultraviolet light radiation. MCC stroma has not been thoroughly studied, although MCC patients benefit from therapy targeting PD1/PDL1. METHODS AND RESULTS: In this study, using Tissue Microarrays and immunohistochemistry, we have analyzed a series of 219 MCC cases in relation to the presence of MCPyV, and confirmed that the presence of MCPyV is associated with changes not only in the neoplastic cells, but also in the composition of the tumor stroma. Thus, MCPyV, found in 101/176 (57,4%) analyzable cases, exhibits changes in its tumor morphology, the density of the inflammatory infiltrate, the phenotype of the neoplastic cells, and the cell composition of the tumor stroma. MCPyV presence is negatively correlated with a higher level of p53 expression, and associated with a very high frequency (86%) of HLA-I expression loss, a higher apoptotic index, and a stroma richer in T-cells, cytotoxic T-cells, macrophages, PDL1-positive macrophages, and B-cells. CONCLUSIONS: Our findings provide evidence of the basic heterogeneity of MCC, supporting the hypothesis that the presence of MCPyV may induce a rich inflammatory response, which is at least partially avoided through loss of HLA-I antigen expression. On the other hand, MCPyV-negative cases show a much higher frequency of stronger p53 expression and, probably, p53 alterations.

Survival analysis and sentinel lymph node status in thin cutaneous melanoma: A multicenter observational study.

Mitotic rate is no longer considered a staging criterion for thin melanoma in the 8th edition of the American Joint Committee on Cancer Staging Manual. The aim of this observational study was to identify prognostic factors for thin melanoma and predictors and prognostic significance of sentinel lymph node (SLN) involvement in a large multicenter cohort of patients with melanoma from nine tertiary care hospitals. A total of 4249 consecutive patients with thin melanoma diagnosed from January 1, 1998 to December 31, 2016 were included. The main outcomes were disease-free interval and melanoma-specific survival for the overall population and predictors of SLN metastasis (n = 1083). Associations between survival and SLN status and different clinical and pathologic variables (sex, age, tumor location, mitosis, ulceration, regression, lymphovascular invasion, histologic subtype, Clark level, and Breslow thickness) were analyzed by Cox proportional hazards regression and logistic regression. SLN status was the most important prognostic factor for melanoma-specific survival (hazard ratio, 13.8; 95% CI, 6.1-31.2; P < 0.001), followed by sex, ulceration, and Clark level for patients who underwent SLNB. A mitotic rate of >2 mitoses/mm2 was the only factor associated with a positive SLN biopsy (odds ratio, 2.9; 95% CI, 1.22-7; P = 0.01. SLN status is the most important prognostic factor in thin melanoma. A high mitotic rate is associated with metastatic SLN involvement. SLN biopsy should be discussed and recommended in patients with thin melanoma and a high mitotic rate.

14-3-3 zeta and tau genes interactively decrease Alzheimer's disease risk.

Abnormal tau hyperphosphorylation has been suggested as being one of the central events in the development of neurofibrillary tangles, which are one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains. 14-3-3 zeta protein is associated with tau in brain and stimulates tau phosphorylation. In a case-control study in 293 AD patients and 396 healthy controls, we examined whether the combined gene effects between 14-3-3 zeta (intron 4, rs 983583) polymorphism and tau (intron 9, rs 2471738) polymorphism might be responsible for susceptibility to AD. Subjects carrying both the 14-3-3 zeta (intron 4, rs 983583) AA and the tau (intron 9, rs 2471738) CC genotypes had a two and a half times lower risk of developing AD than subjects without these risk genotypes (OR = 0.4, 95% CI = 0.2-0.8, p = 0.016). Considering synergistic effects between polymorphisms in tau phosphorylation related genes may help in determining the risk profile for AD.

No association of genetic variants of liver X receptor-beta with Alzheimer's disease risk.

Apolipoprotein E (APOE) epsilon4 allele is the strongest hitherto known risk factor for sporadic Alzheimer's disease (AD). Liver X receptor-beta (LXRbeta) is a transcription factor that controls expression of genes involved in brain cholesterol metabolism, and one of the main LXRbeta targets is APOE. To evaluate the relationship between LXRbeta genetic variants and AD, independently or in concert with the APOE epsilon4 allele, we examined three LXRbeta polymorphisms located in introns 2 (rs 2695121), 5 (rs 1052533), and 7 (rs 1405655), in 414 Spanish AD patients and 447 controls. The current study does not demonstrate an association between LXRbeta genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Análisis biomecánico de la marcha en paciente con secuelas de poliomielitis y artroplastia de rodilla / Análise biomecânica da marcha em um paciente com sequelas de poliomielite e artroplastia do joelho / Clinical gait analysis in patient with poliomyelitis sequelae and total knee arthroplasty

Resumen: La poliomielitis es una enfermedad que puede provocar secuelas irreversibles, generando pérdida de fuerza muscular, parálisis e hiporreflexia, entre otras. Hoy en día las infecciones por poliovirus están controladas, pero se siguen tratando personas con secuelas que pueden ver afectada su calidad de vida y funciones cotidianas, tales como la marcha. Habiendo agotado las opciones de tratamiento conservadoras, la artroplastia total de rodilla (ATR) es una de las intervenciones quirúrgicas más habituales cuando las secuelas afectan la morfología y funcionalidad de dicha articulación. El objetivo del estudio es realizar un análisis instrumentado de la marcha de un paciente con secuelas de poliomielitis y una ATR, con el fin de definir las mejores estrategias de rehabilitación y mejorar la recuperación de la máxima funcionalidad. El estudio se realizó en un Laboratorio de Análisis de Movimiento con 8 cámaras, mediante la colocación de marcadores reflectivos en el cuerpo del paciente. Los resultados muestran alteraciones del patrón de marcha en todas las articulaciones de las extremidades inferiores y en cada uno de los planos anatómicos, siendo la más relevante la rotación interna de la articulación de la cadera derecha y una flexión fija en 9 ° de la articulación de la rodilla ipsilateral, durante la primera mitad del ciclo de marcha. El análisis sugiere que el paciente adopta estrategias que favorecen la activación del tensor de la fascia lata como flexor de cadera y estabilizador de la articulación de la rodilla en la máxima extensión disponible (9 ° de flexión), en sustitución del músculo cuádriceps, debilitado debido a las secuelas de la poliomielitis.

Resumo: A poliomielite é uma doença que pode causar sequelas irreversíveis, causando perda de força muscular, paralisia e hiporreflexia, entre outras. Hoje as infecções por poliovírus são controladas, mas ainda existen pessoas en tratamento pelas sequelas que podem danificar sua qualidade de vida e funções diárias, como caminhar. Esgotadas as opções de tratamento conservador, a artroplastia total do joelho (ATJ) é uma das intervenções cirúrgicas mais comuns quando as sequelas afetam a morfologia e a funcionalidade dessa articulação. O objetivo deste trabalho é realizar uma análise instrumentada da marcha de um paciente com sequela de poliomielite e ATJ, a fim de definir as melhores estratégias de reabilitação e melhorar a recuperação da funcionalidade máxima. O estudo foi realizado em um Laboratório de Análise de Movimento com 8 câmeras, por meio da colocação de marcadores reflexivos no corpo do paciente. Os resultados mostram alterações no padrão de marcha em todas as articulações dos membros inferiores e em cada um dos planos anatômicos, sendo as mais relevantes a rotação interna do quadril direito e a flexão fixa do joelho ipsilateral a 9 ° durante o primeiro ciclo do meio da marcha. A análise sugere que o paciente adote estratégias que favoreçam a ativação do tensor da fáscia lata como flexor do quadril e estabilizador do joelho na extensão máxima disponível (9 ° de flexão), substituindo o músculo quadríceps, enfraquecido pelas sequelas de poliomielite.

Abstract: Poliomyelitis is a disease that may cause irreversible sequelae, generating muscle strength deficits, flaccid paralysis and hyporeflexia, among others. Even though poliovirus infections are under control, people with sequelae that can affect their quality of life and everyday functions such as walking, are still being treated. When these sequelae affect the morphology and functionality of the knee joint, and every other conservative option has been exhausted, the total knee arthroplasty (TKA) is one of the most common surgical interventions. The main goal of the present study is to perform an instrumented gait analysis test of a patient with poliomyelitis sequelae and TKA, in order to define the best rehabilitation strategy and achieve the highest level possible of the patient's function. 3D Gait Analysis was performed with an 8-camera motion capture system and reflective markers placed on specific body landmarks. Results show gait pattern disturbances in every joint and at every anatomical plane, being the most relevant the right hip internal rotation and a fixed 9 degrees ipsilateral knee flexion during the first half of the gait cycle. The analysis suggests that the patient adopts strategies that promote the activation of the tensor fascia lata as hip flexor and knee stabilizer at the maximum available extension (9 ° of flexion) replacing the weakened quadriceps muscle due to the poliomyelitis sequelae.

CD14 receptor polymorphism and Alzheimer's disease risk.

Activation of microglial cells is involved in the inflammatory component of Alzheimer's disease (AD), and it may be triggered by infectious pathogens. CD14, a receptor upregulated in activated microglia, plays a central role in innate immunity through recognition of bacterial lipopolysaccharide and initiation of inflammatory response. A polymorphism in the promoter region (-260) of the CD14 receptor has been found to be related to increased risk of bacterial infections and inflammatory diseases such as atherosclerosis. In a case-control study utilizing a clinically well-defined group of 310 sporadic AD patients and 310 control subjects, we investigated whether the CD14 (-260) polymorphism might be responsible for susceptibility to AD, and we also examined the combined gene effects between CD14 and APOE and several other proinflammatory cytokine genes. The current study does not demonstrate an association between CD14 (-260) polymorphism and AD, neither through an independent effect nor through interaction with APOE epsilon4 allele or interleukin (IL)-1A, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and intercellular adhesion molecule-1 polymorphisms.

The myeloperoxidase gene in Alzheimer's disease: a case-control study and meta-analysis.

Myeloperoxidase (MPO) presence has been demonstrated in microglia associated with senile plaques, and contributes to Alzheimer's disease (AD) pathology through oxidation-induced damage. Recently, a functional biallelic (G/A) polymorphism in the promotor region (-463) of the MPO gene has been associated with susceptibility to AD, but the reports of this association have been inconsistent. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 327 control subjects was performed to test this association. The current study does not demonstrate any significant difference in MPO genotype or allele frequencies between AD patients and controls. A meta-analysis of all studies available gave a non-significant (P=0.83) odds ratio of 1.02 for the MPO GG genotype. Our study in the Spanish population as well as the meta-analysis argue against the hypothesis that the MPO gene is causally related to AD.

The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer's disease.

Chronic local inflammatory reaction involving reactive microglia is one of the major pathological events in Alzheimer's disease (AD). There is growing evidence that the chemokine receptor CCR5 is up-regulated in AD brain and plays a role in the recruitment and accumulation of microglia in senile plaques. A 32-base pair deletion in the CCR5 gene (CCR5-Delta32 mutant allele) confers resistance to HIV-1 infection by preventing expression of the receptor on the cell surface. Several other reports have shown a similar protective effect of CCR5-Delta32 mutation towards certain chronic inflammatory diseases. Given the potential importance of CCR5 in brain inflammation, we hypothesized that individuals carrying the CCR5-Delta32 allele would show a reduced risk of AD. So, we performed a case-control study in 376 Spanish AD patients and 369 healthy controls. The frequency of the CCR5-Delta32 allele in our AD sample was 7.8%, not significantly different from our control sample group (5.8%). The present study indicates that the CCR5-Delta32 allele is not a preventive factor for AD.

Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer's disease risk.

Excessive release of proinflammatory cytokines by activated microglia surrounding senile plaques might contribute to the neurodegeneration associated with Alzheimer's disease (AD). Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear protein recently implicated in the initial inflammatory response by modulating expression of inflammation-related genes, like interleukin 1 (IL-1). As PARP-1 overactivity has been shown in the AD brain, we tested the hypothesis that the PARP-1 -410 and -1672 polymorphisms would predispose people to AD due to overexpression of the PARP-1 gene, independently or in concert with the proinflammatory IL-1A -889 polymorphism. So, we performed a case-control study in 263 Spanish AD patients and 293 healthy controls. PARP-1 -410 and PARP-1 -1672 haplotypes were associated with an increased risk for AD (global haplotype association p value=0.019), and, in addition, PARP-1 haplotypes increased the risk of AD by interaction with the IL-1A -889 allele 2.

Association of the F352V variant of the Klotho gene with bone mineral density.

Klotho gene codes for a protein with glucuronidase activity and is thought to influence bone and vascular homeostasis. We studied the relationship of a common T/G polymorphism, resulting in a phenylalanine (F) to valine (V) substitution at aminoacid position 352, with bone mineral density (BMD) and osteoporotic fractures. The study group comprised 914 Spanish women, including 438 control subjects, 190 patients with osteoporosis, 198 with hip fractures, and 88 patients with severe osteoarthritis. BMD was measured by DEXA in 540 women from the control and osteoporosis groups. Allele frequencies were 86% and 14%, for the F and V alleles, respectively. In comparison with the most common FF genotype, postmenopausal women with FV/VV genotypes had higher hip BMD (femoral neck: 0.673 +/- 0.011 vs. 0.644 +/- 0.006 g/cm(2); P = 0.02; total hip: 0.807 +/- 0.014 vs. 0.774 +/- 0.008 g/cm(2); P = 0.03). Klotho alleles explained about 1.5% of BMD variance, but were not associated to the risk of osteoporotic spine or hip fractures. The Klotho genotype was not associated to BMD in premenopausal women. In conclusion, the F352V Klotho polymorphism is associated with BMD in postmenopausal women, suggesting that Klotho gene variants influence skeletal aging.

Age-dependent association between the Q7R polymorphism in the Saitohin gene and sporadic Alzheimer's disease.

A vigorous controversy exists over whether tau tangles or amyloid-beta plaques are the primary cause of neurodegeneration in Alzheimer's disease (AD), and it is not well established whether genetic variation in tau is associated with AD. A recently identified novel protein, named Saitohin (STH), shares tissue expression pattern with tau, and preliminary evidence in a North American population indicates that a polymorphism at codon 7 (Q7R) of the STH gene is a predisposing factor for sporadic AD. A case-control study utilizing a clinically well-defined group of 315 sporadic AD patients and 307 control subjects was performed to test this association. The current study reveals that increased risk of AD associated with the STH RR genotype (OR 2.17, p = 0.04) is limited to late-onset (after the age of 72 years) AD cases.

Vigilancia epidemiológica para el infarto agudo al miocardio, experiencia obtenida en el Hospital Calderón Guardia / Monitoring epidemiologist for the acute infart of myocardium experience obtained in the Hospital Calderón Guardia

Justificación y objetivo: Debido a que el infarto agudo al miocardio representa una de las principales causas de muerte en nuestro país, las autoridades de salud decidieron, en 2003, incluirlo como una enfermedad sujeta a vigilancia epidemiológica. El presente trabajo tiene como propósito dar a conocer la información mas sobresaliente del sistema de vigilancia epidemiológica para el IAM, implementando en el servicio de Medicina Interna del Hospital Calderón Guardia. Metodología: Se realizó un análisis descrpitivo de la información recolectada desde el 1 de octubre de 2003, al 30 de setiembre de 2004. Las variables cualitativas se analizaron mediante frecuencias y proporciones. Las variables cuantitativas se expresaron por medio de medidas de tendencia central y dispersión. Las diferencias entre promedios y proporciones se compararon mediante la prueba de t Student. La significancia estadística fue fijada en p<0.05. Se utilizó el programa EpiInfo 2002 para el procesamiento de los datos. Resultados: El promedio de edad fue de 64.5 años (DE + 12,2 años). El 66,1 por ciento (n=84) de los pacientes eran hombres. El porcentaje de paciente con dislipidemias fue significativamente mayor en la mujeres que en los hombres (p=0,007). El mismo resultado se obtuvo con la hipertensión arterial (p=0,007). Por el contrario, el porcentaje de pacientes que fumaban fue significativamente mayor en los hombres que en las mujeres (p=0,0001). El 71,7 por ciento (n=91) de los pacientes fueron clasificados como Killip-Kimball I. El 18.4 por ciento (n=23) presentaron complicaciones durante su estancia hospitalaria. La mortalidad en el servicio de Medicina Interna del Hospital Calderón Guardia fue del 6,3 por ciento (n=8). Conclusión: El sistema de vigilancia epidemiológica para el infarto agudo al miocardio propuesto en este trabajo, se presenta como una herramienta útil para orientar las estrategias necesarias que contribuyan a mejorar el conocimiento que se tiene del paciente que padece de un IAM. Descriptores: infarto agudo al miocardio, epidemiolgía, vigilancia epidemiológica.