High accuracy of a blood ctDNA-based multimodal test to detect colorectal cancer.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.

GEIS-SEHOP clinical practice guidelines for the treatment of rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma (STS) in children and adolescents. In Spain the annual incidence is 4.4 cases per million children < 14 years. It is an uncommon neoplasm in adults, but 40% of RMS are diagnosed in patients over 20 years of age, representing 1% of all STS in this age group. RMS can appear anywhere in the body, with some sites more frequently affected including head and neck, genitourinary system and limbs. Assessment of a patient with suspicion of RMS includes imaging studies (MRI, CT, PET-CT) and biopsy. All patients with RMS should receive chemotherapy, either at diagnosis in advanced or metastatic stages, or after initial resection in early local stages. Local control includes surgery and/or radiotherapy depending on site, stage, histology and response to chemotherapy. This guide provides recommendations for diagnosis, staging and treatment of this neoplasm.

Baseline description of the Spanish Academy of Dermatology infantile haemangioma nationwide prospective cohort. Comparison of patients treated with propranolol in routine clinical practice with previous pivotal clinical trial data. / Descripción basal de la cohorte prospectiva de hemangioma infantil a nivel nacional de la Asociación Española de Dermatología. Comparación de los pacientes tratados con propranolol en la práctica clínica rutinaria y los datos de un ensayo clínico pivotal previo.

BACKGROUND: There are several therapeutic options for infantile haemangiomas (IH). Propranolol is used according to a pivotal trial. We aimed to describe the characteristics of IH in clinical practice, including the therapies used, and to compare the characteristics of patients treated with propranolol with those of the trial to assess its external validity. METHODS: Consecutive patients attending 12 Spanish hospitals from June 2016 to October 2019 were included (n=601). RESULTS: The mean age was 3.9 (SD:1.9) months, with a 2:1 female-to-male ratio. Most IHs were localized (82%, 495), superficial (64%, 383) and located in the face (25%, 157) and trunk (31%, 188). Median size was 17 (IR: 10-30) x 12 (IR: 7-20) mm. Complications were found in 16 (3%) patients. Treatment was initiated for 52% (311). Most patients received timolol (76%, 237); propranolol was reserved for complications or high-risk IHs. Aesthetic impairment was the main reason for starting therapy (64%, 199). Several characteristics of the patients and IHs treated with propranolol are similar to those of the pivotal clinical trial, but 1/3 of IHs did not reach the minimum diameter to meet the inclusion criteria, and important prognostic information was not reported. CONCLUSIONS: As most patients receive treatment for aesthetic impairment, there is a need to better understand the aesthetic results of therapies and to increase evidence on the use of timolol, which is currently the most common therapy. Propranolol is being used in a population generally similar to that of the trial; however, this statement cannot be definitely confirmed.

Programming effects of peripubertal stress on spatial learning.

Exposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.

Lymphogranuloma Venereum in a Public Health Service Hospital in Southern Spain: A Clinical and Epidemiologic Study. / Estudio clínico y epidemiológico del linfogranuloma venéreo en un hospital público del sur de España.

Lymphogranuloma venereum (LGV) is an emerging disease in men who have sex with men (MSM): the incidence was 1.15 cases per 100,000 population in Spain in 2017. Patients with LGV characteristically have severe proctitis that can cause abscesses, fistulas, and anal stenosis. Genital ulcers and inflammatory inguinal adenopathy may occasionally be present. The aim of this study was to describe a series of patients with LGV treated in a public health service hospital in Andalusia, Spain. MATERIAL AND METHODS: Retrospective, observational description of a series of patients diagnosed with LGV. We gathered epidemiologic, clinical, microbiologic, and treatment data. Patients' sexual behaviors were also noted. RESULTS: We found 17 cases of LGV diagnosed in MSM between October 2016 and May 2019. Twelve of the patients were also infected with the human immunodeficiency virus, and 13 had severe proctitis with ulcers in the anal canal and rectum. Four patients had genital or inguinal manifestations. The following high-risk sexual behaviors were on record: a high number of sexual partners, receptive anal sex with strangers and without a condom, seeking sexual partners online, participation in group sex, and sex with partners from outside Andalusia. Chlamydia trachomatis serovar L2 was identified in all cases, and the infection responded well to oral doxycycline. Two patients with the most characteristic form of LGV required longer treatment cycles. Three required surgery. CONCLUSIONS: When symptomatic proctitis is found in MSM who engage in high-risk sex, the LGV exudate should be sampled and the C trachomatis serovar identified. Genital ulcers or inguinal buboes are also highly suggestive of LGV. Clinical suspicion and early treatment are the keys to preventing complications and disease transmission.

ECLIM-SEHOP, a new platform to set up and develop international academic clinical trials for childhood cancer and blood disorders in Spain.

INTRODUCTION: Cancer and blood disorders in children are rare. The progressive improvement in survival over the last decades largely relies on the development of international academic clinical trials that gather the sufficient number of patients globally to elaborate solid conclusions and drive changes in clinical practice. The participation of Spain into large international academic trials has traditionally lagged behind of other European countries, mainly due to the burden of administrative tasks to open new studies, lack of financial support and limited research infrastructure in our hospitals. METHODS: The objective of ECLIM-SEHOP platform (Ensayos Clínicos Internacionales Multicéntricos-SEHOP) is to overcome these difficulties and position Spain among the European countries leading the advances in cancer and blood disorders, facilitate the access of our patients to novel diagnostic and therapeutic approaches and, most importantly, continue to improve survival and reducing long-term sequelae. ECLIM-SEHOP provides to the Spanish clinical investigators with the necessary infrastructural support to open and implement academic clinical trials and registries. RESULTS: In less than 3 years from its inception, the platform has provided support to 20 clinical trials and 8 observational studies, including 8 trials and 4 observational studies where the platform performs all trial-related tasks (integral support: trial setup, monitoring, etc.) with more than 150 patients recruited since 2017 to these studies. In this manuscript, we provide baseline metrics for academic clinical trial performance that permit future comparisons. CONCLUSIONS: ECLIM-SEHOP facilitates Spanish children and adolescents diagnosed with cancer and blood disorders to access state-of-the-art diagnostic and therapeutic strategies.

Percepción del personal de salud sobre un programa de detección oportuna del cáncer cervical / Health personnel perceptions on a cervical cancer early detection program / Percepção do pessoal de saúde sobre um programa de detecção oportuna do câncer cervical

Objetivo: Conocer la percepción que el personal de salud del primer nivel de atención tiene respecto al programa Detección Oportuna del Cáncer Cervical en México. Método: Estudio cualitativo, se realizaron 15 entrevistas semi-estructuradas a médicos y enfermeras de tres centros de salud rurales del Estado de Morelos, México. La información se analizó siguiendo los planteamientos de la Teoría Fundamentada. Resultados: El personal de salud percibe el programa Detección Oportuna del Cáncer Cervical como un programa de salud con fines preventivos, identifica la prueba de citología cervical como el medio para prevenir el cáncer cervicouterino, considera que el objetivo del programa es la obtención de muestras citológicas. La percepción está definida por el cumplimiento de metas, las barreras que se presentan para su operación, la elevada demanda y la escasez de recursos materiales, así como por los sentimientos del personal y sus condiciones de trabajo. Conclusiones: Es necesario reforzar los planes y programas de estudio de las carreras de enfermería y medicina para que los estudiantes obtengan conocimientos, desarrollen habilidades y adquieran competencias con base en conocimientos científicos, generar el correcto uso de términos médicos, la lectura crítica, la búsqueda de información y el interés por la actualización y crecimiento profesional.

Objective: To identify the perceptions which first level of attention health personnel have on the Cervical Cancer Early Detection National Health Program in Mexico. Method: This is a qualitative study which included 15 semi-structured interviews on medicine and nursing personnel of three rural health centers in the State of Morelos, Mexico. Data were analyzed in line with the Grounded Theory. Results: The health personnel perceives the Cervical Cancer Early Detection Program as a preventive initiative which relies on the cervical cytology as a main procedure to prevent cervical cancer. These perceptions are modulated by issues on the achievement of goals, operation barriers, high demand of the tests, scarcity of resources, and working conditions feelings. Conclusions: It is important to keep strengthening the nursing and medicine study plans so that students keep developing their knowledge, competencies, and skills to support health initiatives such as the Cervical Cancer Early Detection Program while they develop their scientific interest and professional growth.

Objetivo: Conhecer a percepção que o pessoal de saúde do primeiro nível de atenção tem ao respeito do programa Detecção Oportuna do Câncer Cervical no México. Método: Estudo qualitativo, realizaram-se 15 entrevistas semiestruturadas a médicos e enfermeiras de três centros de saúde rurais do Estado de Morelos, México. A informação analisou-se seguindo as abordagens da Teoria Fundamentada. Resultados: O pessoal de saúde percebe o programa Detecção Oportuna do Câncer Cervical como um programa de saúde com fins preventivos, identifica a proba de citologia cervical como o médio para prevenir o câncer de colo do útero, considera que o objetivo do programa é a obtenção de amostras citológicas. A percepção está definida pela realização de metas, as barreiras que se apresentam para sua operação, a elevada demanda e a escassez de recursos materiais, assim como pelos sentimentos do pessoal e suas condições de trabalho. Conclusões: É necessário reforçar os planos e programas de estudo das carreiras de enfermagem e medicina para que os estudantes obtenham conhecimentos, desenvolvam habilidades e adquiram competências com base em conhecimentos científicos, gerar o correto uso de termos médicos, a leitura crítica, a busca de informação e o interesse pela atualização e crescimento profissional.

Applicability and accuracy improvement of transient elastography using the M and XL probes by experienced operators.

Transient elastography (TE) is the reference method to obtain liver stiffness measurements (LSM), but no results are obtained in 3.1% and unreliable in 15.8%. We assessed the applicability and diagnostic accuracy of TE re-evaluation using M and XL probes. From March 2011 to April 2012 868 LSM were performed with the M probe by trained operators (50-500 studies) (LSM1). Measurements were categorized as inadequate (no values or ratio <60% and/or IQR/LSM >30%) or adequate. Inadequate LSM1 were re-evaluated by experienced operators (>500 explorations) (LSM2) and inadequate LSM2 using XL probe (LSMXL). Inadequate LSM1 were obtained in 187 (21.5%) patients, IQR/LSM >30% in 97 (51%), ratio <60% in 24 (13%) and TE failed to obtain a measurement in 67 (36%). LSM2 achieved adequate registers in 123 (70%) of 175 registers previously considered as inadequate. Independent variables (OR, 95%CI) related to inadequate LSM1 were body mass index (1.11, 1.04-1.18), abdominal circumference (1.03, 1.01-1.06) and age (1.03, 1.01-1.04) and to inadequate LSM2 were skin-capsule distance (1.21, 1.09-1.34) and abdominal circumference (1.05, 1.01-1.10). The diagnostic accuracy (AUROC) to identify significant fibrosis improved from 0.89 (LSM1) to 0.91 (LSM2) (P = 0.046) in 334 patients with liver biopsy or clinically significant portal hypertension. A third evaluation (LSMXL) obtained adequate registers in 41 (93%) of 44 patients with inadequate LSM2. Operator experience increases the applicability and diagnostic accuracy of TE. The XL probe may be recommended for patients with inadequate values obtained by experienced operators using the M probe. http://clinicaltrials.gov (NCT01900808).

Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study.

BACKGROUND: In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. PATIENTS AND METHODS: In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. RESULTS: Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. CONCLUSION: This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression.

Although adverse early life experiences have been found to increase lifetime risk to develop violent behaviors, the neurobiological mechanisms underlying these long-term effects remain unclear. We present a novel animal model for pathological aggression induced by peripubertal exposure to stress with face, construct and predictive validity. We show that male rats submitted to fear-induction experiences during the peripubertal period exhibit high and sustained rates of increased aggression at adulthood, even against unthreatening individuals, and increased testosterone/corticosterone ratio. They also exhibit hyperactivity in the amygdala under both basal conditions (evaluated by 2-deoxy-glucose autoradiography) and after a resident-intruder (RI) test (evaluated by c-Fos immunohistochemistry), and hypoactivation of the medial orbitofrontal (MO) cortex after the social challenge. Alterations in the connectivity between the orbitofrontal cortex and the amygdala were linked to the aggressive phenotype. Increased and sustained expression levels of the monoamine oxidase A (MAOA) gene were found in the prefrontal cortex but not in the amygdala of peripubertally stressed animals. They were accompanied by increased activatory acetylation of histone H3, but not H4, at the promoter of the MAOA gene. Treatment with an MAOA inhibitor during adulthood reversed the peripuberty stress-induced antisocial behaviors. Beyond the characterization and validation of the model, we present novel data highlighting changes in the serotonergic system in the prefrontal cortex-and pointing at epigenetic control of the MAOA gene-in the establishment of the link between peripubertal stress and later pathological aggression. Our data emphasize the impact of biological factors triggered by peripubertal adverse experiences on the emergence of violent behaviors.

Retrospective study assessing the role of MRI in the diagnostic procedures for early breast carcinoma: a correlation of new foci in the MRI with tumor pathological features.

BACKGROUND: Use of breast magnetic resonance imaging (MRI) to detect breast cancer has generated significant debate. We analyze the role of breast MRI in the detection of additional disease and the need to perform additional biopsies in early breast carcinoma patients. In addition, we correlate the detection of new foci with tumor pathological features. METHODS: Early breast carcinoma patients that had undergone an MRI as well as a mammography as diagnostic procedures were included in the study. The following pathologic features were studied: carcinoma type, histological grade, estrogen receptors (ER), progesterone receptors (PR), HER2 and Ki67. Univariate analysis was conducted to ascertain significant correlation among detection of new foci and each of the tumor pathological features. RESULTS: Data from 98 patients have been analyzed: median age 49 years (range 35-79); carcinoma type: (a) infiltrative ductal carcinoma (n = 73, 74 %), (b) infiltrative lobular cancer (n = 12, 12 %), (c) ductal carcinoma in situ (n = 6, 6 %); amplified HER2 (n = 18, 18 %); grade III (n = 33, 33 %); Ki67 ≥ 25 % (n = 33, 33.67 %); positive ER and PR (n = 79, 80 %); triple negative tumors (n = 8, 8 %). MRI detected additional disease in 38 cases (39.58 %), and 20 led to an additional biopsy (20.4 %). Thirty-eight patients (39 %) underwent mastectomy. We found a statistically significant correlation between new foci in MRI and high Ki67 ≥ 25 % (p < 0.005). No other statistically significant correlation was established. CONCLUSION: MRI detected additional disease in 39 % cases, requiring an additional biopsy 20 %. Tumors with high proliferative index were significantly correlated with the detection of new foci in MRI.

[Study of the expression of neural stem cell markers in neuroblastoma tumor samples and correlation with prognostic factors]. / Estudio de expresión de marcadores de células madre neurales en neuroblastoma y correlación con factores pronóstico.

INTRODUCTION: The existence of cancer stem cells (CSC) in neuroblastoma (NB) has been associated with the development of metastasis, resistance to chemotherapy and recurrence. Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples, and to correlate this expression with clinical variables such as histology, genetics and response to conventional therapy. MATERIAL AND METHODS: We performed a retrospective-experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010-2012 in our Hospital. Fluorescence immunohistochemistry was used to analyze the expression of the different markers: CD44, CD74, CD133, tyrosine hydroxylase, endothelin receptors type A (ETA) and B (ETB), p75, nestina y and Phox2b, all of them related to neural stem cell biology. The level of expression of the markers was then correlated with clinical variables. RESULTS: Nestin expression was positive in 72.2% of samples and ETA in 66.7%. PHOX2B and CD74 expression were lower, being positive in less than 30%. The markers CD44, ETB and PHOX2B were expressed in more aggressive tumors. ETA expression correlated significantly with unfavorable histology tumors (p= 0.01), N-myc amplification (p= 0.05) and recurrence/progression (p= 0.05). CONCLUSION: The expression of CD44, ETB and ETA was associated with more aggressive tumors and poor prognostic factors. These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets.

Dynamic conformal arc cranial stereotactic radiosurgery: implications of multileaf collimator margin on dose-volume metrics.

OBJECTIVE: The effect of multileaf collimator (MLC) margin on target and normal tissue dose-volume metrics for intracranial stereotactic radiosurgery (SRS) was assessed. METHODS: 118 intracranial lesions of 83 SRS patients formed the basis of this study. For each planning target volume (PTV), five separate treatment plans were generated with MLC margins of -1, 0, 1, 2 and 3 mm, respectively. Identical treatment planning parameters were employed with a median of five dynamic conformal arcs using the Varian/BrainLab high-definition MLC for beam shaping. Prescription dose (PD) was such that 22 Gy covered at least 95% of the PTV. Dose-volume and dose-response comparative metrics included conformity index, heterogeneity index, dose gradient, tumour control probability (TCP) and normal tissue complication probability (NTCP). RESULTS: Target dose heterogeneity decreased with increasing MLC margin (p<0.001); mean heterogeneity index decreased from 70.4 ± 12.7 to 10.4 ± 2.2%. TCP decreased with increasing MLC margin (p<0.001); mean TCP decreased from 81.0 ± 2.3 to 62.2 ± 1.8%. Normal tissue dose fall-off increased with MLC margin (p<0.001); mean gradient increased from 3.1 ± 0.9 mm to 5.3 ± 0.7 mm. NTCP was optimal at 1 mm MLC margin. No unambiguous correlation was observed between NTCP and PTV volume. Plan delivery efficiency generally improved with larger margins (p<0.001); mean monitor unit per centigray of the PD decreased from 3.60 ± 1.30 to 1.56 ± 0.13. Conclusion Use of 1 mm MLC margins for dynamic conformal arc-based cranial radiosurgery resulted in optimal tumour control and normal tissue sparing. Clinical significance of these comparative findings warrants further investigation.

[Decrease in hospitalizations due to polyvalent medical day hospital]. / Ingresos evitados por el hospital de día médico polivalente.

INTRODUCTION: The day hospital is an alternative to hospitalization. This alternative improves accessibility and comfort of the patients, and avoids hospitalizations. Nevertheless, the efficacy of the polyvalent medical day hospital in avoiding hospitalizations has not been evaluated. OBJECTIVE: To analyze hospital stays avoided by the polyvalent medical day hospital of a university hospital of the Andalusian Health Service. METHODS: An observational prospective study of the patients studied and/or treated in the polyvalent medical day hospital of the Hospital Universitario Puerto Real over a one year period. RESULTS: A total of 9640 patients were attended to, with 1413 procedures and 4921 i.v. treatments. There were 3182 visits to the priority consultation of the polyvalent medical day hospital. The most frequent consultation complaints were constitutional symptoms (15.9%) and anemia (14.5%). After the first visit, 21.5% of the patients were discharged and fewer than 3% were hospitalized. Hospitalization was avoided in 16.8% of the patients, there being a 6.0% decrease in the need for hospital beds (5.0% reduction in the internal medicine unit). Inadequate hospitalizations and 30-day readmissions decreased 93.3% and 4.2%, respectively. The most frequent diagnosis was neoplasm (26.0%), and most of the beds freed up were generated by patients diagnosed of neoplasm (26.7%). CONCLUSION: With this type of polyvalent medical day hospital, we have observed improved efficiency of health care, freeing up hospital beds by reducing hospitalizations, inadequate hospitalizations and re-admissions in the medical units involved.