Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study.

BACKGROUND: We evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients. METHODS: HER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m2 [DL0]; 1,000 mg/m2 [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. RESULTS: Fourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) ≥ 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated ≥ 6 months before progression. Fourteen patients reported grade ≥ 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment. CONCLUSION: Pembrolizumab 200 mg and gemcitabine 1,250 mg/m2 were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for ≥ 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit. TRIAL REGISTRATION: ClinicalTrials.gov and EudraCT (NCT03025880 and 2016-001,779-54, respectively). Registration dates: 20/01/2017 and 18/11/2016, respectively.

Treatment and Outcome of Patients with Stage IS Testicular Cancer: A Retrospective Study from the Spanish Germ Cell Cancer Group.

PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Identification of oestrogen, progesterone receptor and human epidermal growth factor receptor 2 expression in mediastinal metastases of breast cancer obtained by endobronchial ultrasound-guided transbronchial needle aspiration.

BACKGROUND: In breast cancer patients, the expression statuses of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are crucial in the choice of treatment. Receptor expression in metastatic lesions can differ from the primary tumour. The aim of our study was to analyse the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to obtain samples allowing the identification of ER, PR and HER2 expression in patients with mediastinal metastases of breast cancer. PATIENTS AND METHODS: The clinical files of all patients with a final diagnosis of breast cancer mediastinal metastases diagnosed by EBUS-TBNA in our institution were retrospectively analysed. The ability of EBUS-TBNA to obtain samples that allowed hormone receptor and HER2 expression analysis was calculated. RESULTS: Twenty-four patients were included. ER, PR and HER2 assessments could be performed in 22, 20 and 22 patients, respectively. In 20 of the 24 patients it was possible to investigate all three types of receptor expression. In the remaining four cases, where ER, PR or HER2 expression tests could not be performed, it was due to a lack of tissue. In cases with adequate results for EBUS-TBNA and the primary tumour agreement was greater for ER (16/19) and HER2 (12/14) than PR (8/17). Based on receptor status, there was a change in the choice of treatment for five patients. CONCLUSION: In patients with breast cancer mediastinal metastases, ER, PR and HER2 expression can be assessed in samples obtained by EBUS-TBNA whenever a sufficient tissue sample is collected.

DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer.

Platinum-based chemoradiotherapy (CRT) is a preferred standard of care for locally advanced head and neck cancer (HNC). However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance that could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells' ability to survive in genotoxic stress environments afforded by therapy. We assessed mRNA expression levels of DNA repair-related genes BRCA1, RAP80, 53 binding protein 1 (53BP1), mediator of DNA damage checkpoint 1 (MDC1), and RNF8. We correlated our findings with response and overall survival in 72 head and neck patients treated with weekly carboplatin AUC 2 and radiotherapy. Complete response (CR) to CRT was 50 % in patients with low levels of 53BP1 compared to 6.3 % in patients with high levels (p = 0.0059). Of high BRCA1 mRNA expressors, 41.2 % had CR compared to 29.4 % of low expressors (p = 0.72). For a small group of patients with low 53BP1 and either high BRCA1 or RAP80, CRs were 66.7 and 71.4 %, respectively. A trend for better overall survival (OS) was found for patients with low 53BP1 (15 vs 8 m; p = 0.056). Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and overall survival in HNC patients treated with chemoradiotherapy. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.

Neoadjuvant letrozole and palbociclib in patients with HR-positive/HER2-negative early breast cancer and Oncotype DX Recurrence Score ≥18: DxCARTES study.

BACKGROUND: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18. PATIENTS AND METHODS: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR). RESULTS: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified. CONCLUSIONS: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen.

BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer.

BACKGROUND: neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. PATIENTS AND METHODS: we assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival. RESULTS: a significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors. CONCLUSIONS: our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.

Assessment of neurocognitive decline in cancer patients, except brain cancer, under long-term treatment with bevacizumab.

PURPOSE: We performed a cross-sectional study of neurocognitive function in non-brain cancer patients treated with long-term bevacizumab. METHODS/PATIENTS: From 2015 to 2017, we included patients with different types of cancer treated with bevacizumab with or without chemotherapy (BEV; N = 20) or only chemotherapy (ChT; N = 19) for at least 34 weeks, patients who received non-brain radiotherapy (RxT; N = 19), and healthy controls (HC; N = 19) were assessed once at week 34 of treatment (BEV and ChT) or at completion of radiotherapy. Neurocognition was evaluated with the Hopkins Verbal Learning Test-Revised (HVLT-R) total and delayed recall, the Trail Making Test A and B, and the Controlled Oral Word Association Test in the four groups. Non-parametric tests were used to assess differences between groups. RESULTS: The BEV, ChT, and RxT groups scored significantly lower than the HC group on all tests and especially on the HVLT-R total recall. In no case were the mean scores of the BEV group significantly lower than those of the ChT or RxT groups. CONCLUSIONS: Neurocognitive impairment was seen even in patients treated with local non-brain radiotherapy. Treatment with bevacizumab for a long period of time does not seem to worsen neurocognitive function to a greater extent than chemotherapy.

Teledermatology in Remote Parts of Chile: Experience in 4 Isolated Rural Areas. / Teledermatología aplicada en zonas extremas: experiencia de 4 centros asistenciales chilenos en ámbito rural y aislamiento extremo.

BACKGROUND: Teledermatology was introduced in Chile to make up for the lack of dermatologists and improve the primary care system's ability to resolve problems. This strategy was implemented in the province of Palena in 2013, but outcomes were not analyzed and reported until now. MATERIAL AND METHODS: Descriptive, cross-sectional study with analysis of inter-rater agreement on diagnoses. All the teledermatology consultations made on behalf of patients in Ayacara, Chaitén, Futaleufú, and Palena from 2013 through 2017 were analyzed. Data were extracted from the MINSAL platform. The κ statistic was used to assess diagnostic agreement. RESULTS: A total of 326 teledermatology consultations were made. The mean (SD) age of the patients was 35.8 (22.4) years. The majority (59.8%) were female. Palena generated the largest volume of cases (40.8%). The mean time until a teledermatology diagnosis was given was 12.6 (22.8) days. This response time decreased to 6.4 (5.2) days after a staff dermatologist from Hospital Puerto Montt joined the program (P=.0005). Diagnosis concordance between the general practitioner and the dermatologist was moderate (κ=0.5). Physical examination by the dermatologist at the hospital of reference (Puerto Montt) was necessary for 20.6% of the patients, and time until a definitive diagnosis for the patient took longer in such cases (25.7 [41.2] days) than for the cases that didn't need a physical evaluation at the Hospital of Puerto Montt (P<.0001). CONCLUSIONS: Teledermatology provides a necessary diagnostic and therapeutic resource for general practitioners in isolated locations. Diagnostic agreement is moderate between the generalist and the specialist, similar to agreement in international studies but lower than agreement reported in other Chilean studies. The reduction in diagnostic response time after incorporation of a dermatologist on staff at the hospital of Puerto Montt was significant. The significant difference between the time for diagnosis under teledermatology and the delay when physical examination is required at the hospital of Puerto Montt identifies an aspect of care management to improve.

Efectos de la curva de aprendizaje en los resultados de la duodenopancreatectomía cefálica en un hospital de nivel II / Effects of the learning curve on the results of cephalic pancreaticoduodenectomy in a level II hospital

Resumen Introducción: La duodeno pancreatectomía cefálica es una operación compleja cuyos resultados a corto plazo son multifactoriales. Objetivo: Evaluar el impacto de la curva de aprendizaje en los resultados a corto plazo de la duodenopancreatectomía cefálica en un hospital de nivel II. Materiales y Método: Se analizaron los datos obtenidos a partir de una base de datos mantenida prospectivamente desde 2005. Se definieron dos periodos de tiempo: de 2005 a 2011 y de 2012 a 2017. Se compararon la morbilidad, mortalidad y estancia postoperatoria de ambos períodos. Resultados: Durante el período de tiempo estudiado se hicieron 126 duodenopancreatectomías cefálicas, 61 durante la primera etapa y 65 durante la segunda. La tasa de transfusión intraoperatoria se redujo de 33% a 15% (p = 0,011). La tasa de transfusión postoperatoria se redujo de 39 a 23% (p = 0,021). No hubo diferencias significativas con respecto a la incidencia global de complicaciones postoperatorias (59% y 52,3%). La incidencia de abscesos intraabdominales fue significativamente menor en el segundo período (18% y 4,6%, respectivamente; p = 0,038). La tasa de reintervenciones se redujo significativamente, de 22% a 9% (p = 0,049). También se redujo significativamente la tasa de mortalidad, de 6,56% a 0% (p = 0,032). La estancia media postoperatoria disminuyó significativamente en el segundo período, pasando de 19,6 a 15,8 días (p = 0,001), con una mayor proporción de pacientes dados de alta en los 8 primeros días de postoperatorio (11,5% y 38,5%, respectivamente; p = 0,001). Conclusión: La curva de aprendizaje es un factor que permite mejorar los resultados de la duodenopancreatectomía cefálica, en un hospital de nivel II, hasta alcanzar valores similares a los de un hospital de nivel III.

Introduction: The duodenum pancreatectomy cephalic is a complex operation whose short-term results are multifactorial. Aim: To assess the impact of the learning curve on the short-term outcomes of cephalic duodenopancreatectomy at a level II hospital. Materials Method: We analyze the data obtained from a database maintained prospectively since 2005. Two time periods were defined: from 2005 to 2011 and from 2012 to 2017. The morbidity, mortality and postoperative stay of both periods were compared. Results: 126 cephalic duodenopancreatectomies were performed, 61 during the first period and 65 during the second. The intraoperative transfusion rate was reduced from 33% to 15% (p = 0.011). The postoperative transfusion rate was reduced from 39 to 23% (p = 0.021). There were no significant differences with respect to the overall incidence of postoperative complications (59% and 52.3%, respectively). However, the incidence of intra-abdominal abscesses was significantly lower in the second period (18% and 4.6%, respectively, p = 0.038). The rate of reoperations was significantly reduced, from 22% to 9% (p = 0.049). The mortality rate was also significantly reduced, from 6.56% to 0% (p = 0.032). The mean postoperative stay decreased significantly in the second period, from 19.6 to 15.8 days (p = 0.001), with a higher proportion of patients discharged in the first 8 postoperative days (11.5% and 38.5%, respectively, p = 0.001). Conclusion: The learning curve is a factor allows improving the results of cephalic pancreaticoduodenectomy, in a level II hospital, until reaching values similar to those of a level III hospital.

Excretion of arsenic (As) in urine of children, 7-11 years, exposed to elevated levels of As in the city water supply in Hermosillo, Sonora, México.

Arsenic (As) is a common element in the environment with many industrial uses, but it also can be a contaminant in drinking water and present serious health concerns. Earlier studies on the quality of drinking water in the city of Hermosillo, Sonora, México, showed high levels of As (> 0.05 ppm) in water from wells located in the northern part of the city. Additionally a high positive correlation between the levels of Fluoride (F) and As in the same wells was found. Therefore, the objective of this study was to determine the excretion of As in children, 7-11 years of age, that had been exposed to elevated levels of As in their drinking water. Twenty-four-hour urine samples and a water sample taken directly in the home were collected from school age children living in two different areas with known high levels of As in their drinking water. A control group with normal levels of As in their water was also included. As was determined by an atomic absorption-hydride generator, verified with the use of NBS certified standards (SRM 1643a and SRM 2670). None of the water samples exceeded the limit established for drinking water; however, there was a significant difference between the intake of As and the As in drinking water among the three areas of the study. Average As in water was 0.009 +/- 0.002 and 0.030 +/- 0.011 micrograms/ml between the control and high areas. Intake (in micrograms/day) was 15 +/- 3 and 54 +/- 18. In the group consuming water with high levels of As, 65% of the children exceeded the recommended dose of < 1 micrograms/kg/day (EPA, 1988). Several children in this study also had high levels of As in their urine. Even though As levels in the drinking water are within the norms, it appears that children exposed to high levels of As in their drinking water may have a health risk.

Síndrome de apnea obstructiva del sueño en niños (SAOS) / Obstructive sleep apnea syndrome in children (OSAS)

El síndrome de la apnea obstructiva del sueño (SAOS) es ocasionado por una obstrucción de las vías aéreas superiores, resultado de un desequilibrio entre la fuerza de succión respiratoria y la compensación de los músculos dilatadores faríngeos. El diagnóstico positivo es establecido por el registro polisomnográfico nocturno durante el sueño que define las características y la severidad de esta enfermedad. El objetivo del siguiente artículo es difundir los diversos aspectos clínicos y diagnósticos de una enfermedad recientemente descripta de alta prevalencia y que cruza las fronteras de múltiples especialistas (pediatras, neurólogos, neumólogos, otorrinolaringólogos, psiquiatras, psicólogos, odontoestomatólogos, ortodoncistas), así contribuiremos a su diagnóstico precoz a partir de los niños que roncan, evitando las importantes secuelas del SAOS infantil...

Universidad saludable: una estrategia interdisciplinaria para la construcción de un entorno saludable / Healthy university: an interdisciplinary strategy for the construction of a healthy environment

Los entornos o escenarios universitarios son definidos como aquellos luga- res y contextos sociales donde las personas desarrollan actividades diarias y en los cuales interactúan factores ambientales, organizativos y personales que afectan la salud y el bienestar de los que trabajan, y aprenden en ellos. Las Instituciones de Educación Superior no son ajenas al concepto salud y de hecho han venido formando profesionales relacionados con la salud en un entorno de transmisión y producción del conocimiento, pero también de interacción y comunicación, abierto y accesible, que favorece la vida salu- dable, la cultura y el disfrute de sus espacios; sin embargo poco sabemos cómo hacer buen uso de tantos recursos para llegar a ser una universidad promotora de la salud. En particular, la Universidad Santiago de Cali, reúne varias de las carac- terísticas de estos entornos; por un lado, es un centro de trabajo, un centro educativo y además es una institución de especial relevancia en tanto que en ella confluye un gran número de estudiantes, profesores, empleados y directivos que se ven expuestos a los factores determinantes de la salud que este entorno propicia. Muchos de los hábitos de vida que influyen en la salud se inician y se con- solidan en la etapa universitaria, sin embargo los espacios de atención en este entorno se orientan a atender problemas relacionados con la enferme- dad sin lograr estilos de vida saludable ni conductas de autocuidado. Este libro es el resultado de un sinnúmero de discusiones académicas en- tre los grupos de investigación de la Facultad de Salud de la Universidad Santiago de Cali, durante los años 2012-2013, en torno a cómo mejorar la salud de las personas pertenecientes a la comunidad universitaria.