Genotype and Phenotype Characterization of Patients with Mucopolysaccharidosis IV-A in Chile.

Introduction: Morquio syndrome or mucopolysaccharidosis type IV-A (MPS IV-A) is an autosomal recessive disease caused by biallelic variants in the GALNS gene, encoding the lysosomal enzyme GalN6S, responsible for glycosaminoglycan keratan sulfate and chondroitin-6-sulfate degradation. Studies have shown that the degree of evolutionary and chemical divergence of missense variants in GalN6S when compared to ancestral amino acids is associated with the severity of the syndrome, suggesting a genotype-phenotype correlation. There is little information on Latin American patients with MPS IV-A that replicate these findings. This study aimed to characterize the phenotype and genotype from patients with MPS IV-A, who are under Enzyme Replacement Therapy at the Children's Neuropsychiatry Service of the Hospital Clínico San Borja Arriarán, Santiago, Chile, and to determine if there is any association between genotype and phenotype with those findings. Methods: Information was collected from medical charts, all patients went through a GalN6S enzymatic activity measurement in leukocytes from peripheral blood, and the GALNS gene was sequenced for all cases. Results: 12 patients with MPS IV-A were recruited, all patients presented multisystem involvement, mostly skeletal, and 75% of cases underwent surgical interventions, and cervical arthrodesis was the most frequent procedure. In regards of the genotype, the two most frequent variants were c.319+2T>C (n = 10, 41.66%) and p.(Arg386Cys) (n = 8, 33.33%), the first one was previously described in 2018 in a patient from Chile [Bochernitsan et al., 2018]. Conclusion: This is the first time that a genotype-phenotype correlation has been studied by analyzing the variants effect on the molecular structure of human GalN6S and the evolutionary conservation degree of affected residues in a cohort of patients in Chile. Albeit our work could not find statistically significant associations, we may infer that the evolutionary conservations of affected amino acids and the effect of variants on enzyme structure may play a main role. Further analyzes should consider a meta-analysis of published cases with genotype data and larger samples and include other variables that could provide more information. Finally, our data strongly suggest that variant c.319+2T>C could have a founder effect in Chilean patients with MPS IV-A.

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

Introduction The number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer. Methods Data from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity. Results The mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7). Conclusions This retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Comparison of radiological criteria for hyperprogressive disease in response to immunotherapy.

Hyperprogressive disease (HPD) is a concerning paradoxical acceleration of cancer growth induced by immune drugs. The lack of standard radiological criteria makes its study challenging. We reviewed the literature and compared the main criteria for HPD proposed by Ferté, Le Tourneau, Garralda and Caramella to address this relevant unmet need in Immune-oncology. Among 182 consecutive patients with advanced cancer treated with immunotherapy in early-phase clinical trials, 71 with progressive disease at the first evaluation were eligible. HPD patients were studied regarding tumor growth dynamics and clinical impact. HPD occurred in 17 (23.9%), 17 (23.9%), 23 (32.4%) and 6 (8.4%) patients, as defined by Ferté, Le Tourneau, Garralda and Caramella, respectively. The strongest association was found between the Ferté and Le Tourneau criteria (Kappa = 0.61), and the Jaccard similarity index varied from 55% (Ferté and Le Tourneau) to 21% (Le Tourneau and Caramella). The Ferté and Le Tourneau criteria showed statistically significant differences between pre-baseline and post-baseline tumor growth rate in patients with HPD, which could not be confirmed with the Caramella and Garralda criteria. Significant differences in progression-free survival were observed between non-hyperprogressors and hyperprogressors, with all criteria. The proportion of patients that could not receive additional lines of therapy was higher in the HPD group. HPD is an immunotherapy-related acceleration of tumor growth kinetics, with a consequent negative clinical impact. Pre-baseline CT scans and tumor growth rate evaluations are required to identify HPD. Our analysis favors the use of the Le Tourneau method, as it captures adequately the HPD phenomenon and is more convenient to use.

Estudio del consumo de antibióticos en pacientes de farmacia comunitaria / No disponible

INTRODUCCIÓN: España presenta una de las cifras más elevadas de resistencias bacterianas de Europa y paralelamente se sitúa entre los países que más antibióticos consume. La participación del farmacéutico comunitario educando al paciente sobre el buen uso de los antibióticos es importante para conseguir los objetivos marcados en el PRAN 2019-21. OBJETIVOS: El objetivo de este estudio fue describir en pacientes de Farmacia Comunitaria: I) el tipo de antibiótico que el paciente retiraba, II) el perfil de prescripción en Atención Primaria y III) el conocimiento que los pacientes tenían sobre el tratamiento. MÉTODOS: Se realizó un estudio observacional descriptivo en 86 pacientes de 5 oficinas de farmacia. Para ello, se elaboró un cuestionario basado en el de Molinero y cols. (2018), al que se han incluido nuevas preguntas para evaluar el conocimiento y el tipo de infección/antibiótico que tenía el paciente RESULTADOS: El 90% de los pacientes encuestados mostró un buen conocimiento del tratamiento prescrito (duración y/o pauta); sin embargo, sólo un 56% retiraba el antibiótico sobrante en el punto SIGRE. El tratamiento antibiótico más utilizado en las infecciones más prevalentes en nuestro estudio, infecciones respiratorias y urinarias, siguió las recomendaciones de las guías terapéuticas, amoxicilina en el 39% y fosfomicina (75% mujeres)/ciprofloxacino (80% hombres), respectivamente. CONCLUSIONES: Las campañas dirigidas contra la resistencia a antibióticos están empezando a dar resultados positivos tanto en los pacientes como en los prescriptores de Atención Primaria. El farmacéutico comunitario constituye un pilar fundamental en la promoción del correcto uso de antibióticos

INTRODUCTION: Spain presents one of the highest numbers of bacterial resistances in Europe and in parallel it constitutes one of the countries that consume higher amounts of antibiotics. The contribution of community pharmacists in educating patients on the appropriate use of antibiotics is important to achieve the objectives set in the PRAN 2019-21. OBJECTIVES: The aim of this study was to describe in Community Pharmacy patients: I) the type of antibiotic that patients withdrew, II) the prescription profile in Primary Care and III) the knowledge that patients had about the treatment. METHODS: A descriptive observational study was performed in 86 patients from 5 pharmacies. For this, a questionnaire based on that of Molinero et al. (2018) was designed and several questions were added to assess the knowledge and type of infection / antibiotic that patients presented. RESULTS: 90% of the patients surveyed showed a good knowledge of the prescribed treatment (duration and / or pattern); however, only 56% left the remaining antibiotic at the SIGRE point. The most commonly used antibiotics for the most prevalent infections in our study were amoxicillin in 39% of respiratory infections, fosfomycin in 75% of urinary infections in women and ciprofloxacin in 80% of urinary infections in men, following the recommendations of current therapeutic guidelines. CONCLUSIONS: The dispensation of antibiotics was carried out in all the cases under medical prescription which was done, basically, by primary care physicians and mainly as an initial treatment in respiratory and urinary infections

Loss of Nm23 is associated with a more favorable tumor microenvironment in patients with breast cancer.

AIM: Nm23 is a metastasis suppressor gene whose downregulation triggers metastatic progression. The aim of this study was to investigate the expression of Nm23 in breast carcinomas and its relationship with tumor microenvironment markers. METHODS: A retrospective study was done (128 breast cancer patients from 2007 to 2010). Nm23, LPA1, SMA, CD34, CD8, and CD68 protein expressions were evaluated using immunohistochemistry. Image analysis was used to determine the immunostaining percentage area of Nm23, LPA1, and SMA; the number of the total vessel fraction CD34 positive; and the number of CD8+ and CD68+ cells. The mean ± SE was calculated. The differences among groups were evaluated using Student t-test for parametric data and Mann Whitney U test for nonparametric data. RESULTS: Cases were divided into two groups: Nm23+ and Nm23-. LPA1 immunostaining was significantly increased in Nm23- group. Immunostaining percentage area of SMA was not significantly higher when Nm23 was negative. CD34 immunopositive blood vessels, number of T CD8+ cells, and the number of macrophage CD68+ cells were increased when Nm23 was absent. CONCLUSION: Our results suggest that the absence of Nm23 causes an increase in LPA1, CD8+ and CD68+ inflammatory cells, and angiogenesis marker. Therefore, Nm23 loss could be associated with a more favorable environment for the development and dissemination of breast cancer. However, more studies are needed to determine this association.