Preliminary results of a vaginal constraint for reducing G2 late vaginal complications after postoperative brachytherapy in endometrial cancer: a prospective analysis

PurposeTo evaluate the preliminary results of the use of 68 Gy EQD2(α/β=3 Gy) as a dose limit to the lowest dose in the most exposed 2 cm3 of the vagina in order to reduce G2 late vaginal problems in postoperative endometrial carcinoma (EC).MethodsFrom November 2016 to October 2019, 69 postoperative EC patients receiving vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) were prospectively analyzed. The median EBRT dose was 45 Gy (range: 44–50.4 Gy), 1.8−2 Gy/day, 5 fractions(Fr)/week. VBT was administered with the following schedule: 1Fr of 7 Gy after EBRT and 2 daily Fr × 7.5 Gy in exclusive VBT. The dose was prescribed at 0.5 cm from the applicator surface with an active length of 2.5 cm; 56 patients were treated with vaginal cylinders (49–3.5 cm, 6–3 cm, and 1–2.5 cm) and 13 with the colpostat technique. The overall VBT dose was adjusted to meet the vaginal restriction of < 68 Gy EQD2(α/β=3 Gy) at 2 cm3. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum, and the objective LENT-SOMA criteria for vagina.ResultsWith a median follow-up of 31.0 months, no vaginal-cuff recurrences were found. Late toxicity: only 1G1(1.4%) rectal toxicity; 21G1(30.4%) and 3G2(4.3%) vaginal complications. Only one (1.4%) of 3 G2 manifested as vaginal shortening.ConclusionsIn postoperative EC patients treated with VBT, only one developed G2 vaginal stenosis with the use of 68 Gy EQD2(α/β=3 Gy) as a dose constraint. These preliminary results seem to indicate the value of this dose limit for reducing G2 vaginal stenosis. Nonetheless, these findings should be confirmed in a larger number of patients with longer follow-up.

Preliminary results of a vaginal constraint for reducing G2 late vaginal complications after postoperative brachytherapy in endometrial cancer: a prospective analysis.

PURPOSE: To evaluate the preliminary results of the use of 68 Gy EQD2(α/ß=3 Gy) as a dose limit to the lowest dose in the most exposed 2 cm3 of the vagina in order to reduce G2 late vaginal problems in postoperative endometrial carcinoma (EC). METHODS: From November 2016 to October 2019, 69 postoperative EC patients receiving vaginal brachytherapy (VBT) ± external beam radiotherapy (EBRT) were prospectively analyzed. The median EBRT dose was 45 Gy (range: 44-50.4 Gy), 1.8-2 Gy/day, 5 fractions(Fr)/week. VBT was administered with the following schedule: 1Fr of 7 Gy after EBRT and 2 daily Fr × 7.5 Gy in exclusive VBT. The dose was prescribed at 0.5 cm from the applicator surface with an active length of 2.5 cm; 56 patients were treated with vaginal cylinders (49-3.5 cm, 6-3 cm, and 1-2.5 cm) and 13 with the colpostat technique. The overall VBT dose was adjusted to meet the vaginal restriction of < 68 Gy EQD2(α/ß=3 Gy) at 2 cm3. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum, and the objective LENT-SOMA criteria for vagina. RESULTS: With a median follow-up of 31.0 months, no vaginal-cuff recurrences were found. Late toxicity: only 1G1(1.4%) rectal toxicity; 21G1(30.4%) and 3G2(4.3%) vaginal complications. Only one (1.4%) of 3 G2 manifested as vaginal shortening. CONCLUSIONS: In postoperative EC patients treated with VBT, only one developed G2 vaginal stenosis with the use of 68 Gy EQD2(α/ß=3 Gy) as a dose constraint. These preliminary results seem to indicate the value of this dose limit for reducing G2 vaginal stenosis. Nonetheless, these findings should be confirmed in a larger number of patients with longer follow-up.

Chronic toxicity and long-term outcome in intraoperative electron radiotherapy as boost followed by whole-breast irradiation.

PURPOSE: The administration of a dose boost to the tumor bed after breast-conserving surgery has proven to reduce local recurrence. Intra-operative electron radiotherapy (IOERT) offers an alternative method to deliver a boost with several advantages, such as direct visualization of the tumor bed, less inter- and intrafraction motion and a reduction in the number of medical appointments. The objective of our study is to assess chronic toxicity and long-term outcome for our patients after IOERT boost. MATERIAL AND METHODS: Forty-six patients treated at our institution between July 2013 and June 2020 with IOERT boost during Breast-Conserving Surgery and consecutive whole breast irradiation were prospectively analyzed. A 10-12 Gy boost was prescribed to 42 patients and 4 patients received a 20 Gy boost. An analysis for overall survival, local relapse and distant progression was performed. Acute and chronic toxicity was assessed by CTCAE 4.0. RESULTS: The median age was 64.5 years (40-90). The median follow-up was 62 months (4-86). We had no local recurrences but 2 patients (4.3%) presented a distant recurrence. Mean pathological tumor size was 16 mm (6-52). 84.8% (39) of the patients had invasive ductal carcinoma. 52.2% (24) presented histological grade II. 52.2% (24) were Luminal A like, 21.7% (10) Luminal B like, 13% (6) HER2 positive, 13% (6) triple negative. No Grade 3-4 chronic toxicity was observed. Grade 1-2 fibrosis was evidenced in 13% (6) of the patients, 4.3% (2) patients presented fat necrosis, 6.5% (3) presented seroma, 4.3% (2) had localized pain, 2.2% (1) presented localized hematoma and 2.2% (1) presented localized edema. CONCLUSIONS: IOERT boost in breast cancer treatment during BCS is a safe option with low chronic toxicity. The recurrence rates are comparable to published data and emphasize that IOERT as boost is an effective treatment.

LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells.

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Is one brachytherapy fraction of 7 Gy similar to more fractions after external beam irradiation in postoperative endometrial carcinoma?

PURPOSE: To determine whether brachytherapy with a single hypofractionated dose of 7 Gy provides the similar vaginal-cuff relapses and safety profile in terms of complications compared to schedules of 2 or 3 fractions of lower doses in patients treated previously with external beam irradiation in postoperative endometrial carcinoma. METHODS/MATERIAL: From June 2003 to December 2016, 325 patients were treated with 3 different schedules of high-dose-rate brachytherapy after external beam irradiation for postoperative endometrial carcinoma. The patients were divided into 3 groups: Group-1: 125 patients were treated with 3 fractions of 4-6 Gy per fraction (3 fractions/week) between 2003 and 2008; Group-2: 93 patients were treated with 2 consecutive daily fractions of 5-6 Gy between 2008 and 2011; Group-3: 107 patients received a single fraction of 7 Gy between 2011 and 2016. Bladder and rectum complications were assessed using RTOG scores and with the objective scores of LENT-SOMA for the vagina. STATISTICS: the chi-square test. RESULTS: The mean follow-up of Groups 1, 2 and 3 was 95, 67 and 51 months, respectively. Three patients in Group-1, 2 in Group-2, 1 in Group-3 developed vaginal-cuff relapse (p = 0.68). No differences were found in late toxicity among the three groups. CONCLUSIONS: One single dose of 7 Gy is safe and effective and may be the best treatment schedule with a similar incidence of vaginal-cuff relapses, complications and patient comfort with less hospital attendance.

Are endometrial cancer radiotherapy results age related?

Objective: To analyze the impact of age on radiotherapy results based on cancer-specific survival (CSS), vaginal-cuff relapses (VCR) and complications analysis in 438 patients with endometrial carcinoma (EC) receiving postoperative radiotherapy (PRT) divided into three age groups for analysis. Materials and methods: From 2003 to 2015, 438 patients with EC were treated with PRT and divided into three age groups: Group-1: 202 patients < 65 years; Group-2: 210 patients ≥ 65 and < 80 years; Group-3: 26 patients ≥ 80 years. Vaginal toxicity was assessed using the objective LENT-SOMA criteria and RTOG scores were recorded for the rectum, bladder, and small bowel. Statistics: Chi square and Student’s t tests, Kaplan-Meier survival study for analysis of CSS. Results: The mean follow-up was 5.6 years in Group-1, 5.6 years in Group-2 and 6.3 years in Group-3 (p = 0.38). No differences were found among the groups in distribution of stage, grade, myometrial invasion, Type 1 vs. 2 EC and VLSI (p = 0.97, p = 0.52, p = 0.35, p = 0.48, p = 0.76, respectively). There were no differences in rectal, bladder and vagina late toxicity (p = 0.46, p = 0.17, p = 0.75, respectively). A better CSS at 5 years was found in Group-1 (p = 0.006), and significant differences were found in late severe small bowel toxicity in Group-3 (p = 0.005). VCR was increased in Group-3 (p = 0.017). Conclusions: Patients ≥ 65 years had a worse outcome in comparison to younger patients. Late vaginal, rectal and bladder toxicities were similar in the three groups, although an increase of severe late small bowel toxicity led to IMRT in patients ≥ 80 years. Further larger studies are needed including quality of life analysis in patients ≥ 80 years

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Are endometrial cancer radiotherapy results age related?

OBJECTIVE: To analyze the impact of age on radiotherapy results based on cancer-specific survival (CSS), vaginal-cuff relapses (VCR) and complications analysis in 438 patients with endometrial carcinoma (EC) receiving postoperative radiotherapy (PRT) divided into three age groups for analysis. MATERIALS AND METHODS: From 2003 to 2015, 438 patients with EC were treated with PRT and divided into three age groups: Group-1: 202 patients < 65 years; Group-2: 210 patients ≥ 65 and < 80 years; Group-3: 26 patients ≥ 80 years. Vaginal toxicity was assessed using the objective LENT-SOMA criteria and RTOG scores were recorded for the rectum, bladder, and small bowel. STATISTICS: Chi square and Student's t tests, Kaplan-Meier survival study for analysis of CSS. RESULTS: The mean follow-up was 5.6 years in Group-1, 5.6 years in Group-2 and 6.3 years in Group-3 (p = 0.38). No differences were found among the groups in distribution of stage, grade, myometrial invasion, Type 1 vs. 2 EC and VLSI (p = 0.97, p = 0.52, p = 0.35, p = 0.48, p = 0.76, respectively). There were no differences in rectal, bladder and vagina late toxicity (p = 0.46, p = 0.17, p = 0.75, respectively). A better CSS at 5 years was found in Group-1 (p = 0.006), and significant differences were found in late severe small bowel toxicity in Group-3 (p = 0.005). VCR was increased in Group-3 (p = 0.017). CONCLUSIONS: Patients ≥ 65 years had a worse outcome in comparison to younger patients. Late vaginal, rectal and bladder toxicities were similar in the three groups, although an increase of severe late small bowel toxicity led to IMRT in patients ≥ 80 years. Further larger studies are needed including quality of life analysis in patients ≥ 80 years.

Características de la población general incluida en el estudio RICARTO (RIesgo CARdiovascular y eventos cardiovasculares en la población general del área sanitaria de TOledo): resultados con los primeros 1.500 individuos incluidos en el estudio / Characteristics and cardiovascular events in a general population included in the RICARTO (RIesgo CARdiovascular TOledo) study: data from the first 1.500 individuals included in the study

Introducción. El objetivo fue investigar prevalencias de factores de riesgo cardiovascular (FRCV), lesión de órgano diana (LOD) y enfermedad cardiovascular (ECV) en población general del Área Sanitaria de Toledo para determinar el riesgo cardiovascular (RCV). Material y métodos. Estudio epidemiológico observacional que analizó una muestra de población general ≥18años seleccionada de la base de datos de tarjeta sanitaria por muestreo aleatorio sistemático estratificado por sexo y grupos de edad. Se realizaron anamnesis, exploración clínica y pruebas complementarias, congelándose a −85°C alícuotas de sangre total y suero para valorar posibles estudios genéticos. Se realizó análisis estadístico estándar. El RCV se estimó con las escalas del Proyecto SCORE calibrada para población española y del Framingham Heart Study. Resultados. Se incluyeron a 1.500 individuos (edad media 49,1±15,8años; 55,6% mujeres). Prevalencias: dislipemia 56,9% (intervalo de confianza al 95% [IC95%]: 54,3-59,4), hipertensión arterial 33,0% (IC95%: 30,6-35,4), diabetes mellitus 8,6% (IC95%: 7,17-10,1), tabaquismo 24,2% (IC95%: 22,0-26,4), obesidad 25,3% (IC95%:23,1-27,5) y sedentarismo 39,4% (IC95%: 36,9-41,8). El 21,1% no mostró ningún FRCV y el 18,6% presentó de 3 a 5. LOD: hipertrofia ventricular izquierda electrocardiográfica 4,3%, arteriopatía periférica con eco-doppler10,1% y con dispositivo oscilométrico 15,3%, microalbuminuria 4,3%, enfermedad renal oculta 3,2% y nefropatía 3,8% (CKD-EPI). El 9,2% padecía alguna ECV. El 44,6% mostró RCV (SCORE) bajo. Conclusiones. De cada 10 personas, 6 presentan dislipemia, 4 sedentarismo, 3 hipertensión, 2 tabaquismo, 2 obesidad, y casi una diabetes. Más de la mitad de los individuos muestran RCV moderado-alto-muy alto y las prevalencias de LOD y ECV son importantes

Introduction. The aim of this study was to assess cardiovascular risk (CVR) by investigating the prevalence of CVR factors (CVRF), target organ damage (TOD), and cardiovascular disease (CVD) in general population of the health area of Toledo, Spain. Material and methods. Epidemiological and observational study that analysed a sample from the general population aged 18years or older, randomly selected from a database of health cards stratified by age and gender. Clinical history, physical examination, and complementary tests were performed. Total blood and serum samples were frozen at −85°C to evaluate genetic studies in the future. Standard statistical analysis was performed. CVR was assessed by the SCORE scale calibrated for the Spanish population, and the Framingham Heart Study scale. Results. A total of 1,500 individuals (mean age 49.1±15.8years, 55.6% women) were included. Prevalences: dyslipidaemia 56.9% (95% confidence interval [95% CI]: 54.3-59.4), hypertension 33.0% (95%CI: 30.6-35.4), diabetes mellitus 8.6% (95%CI: 7.17-10.1), smoking 24.2% (95%CI; 122.0-26.4), obesity 25.3% (95%CI; 23.1-27.5), and sedentary life-style 39.4% (95%CI; 36.9-41.8). No CVRF was reported in 21.1% of cases, and 18.6% had 3-5 CVRF. TOD: electrocardiographic left ventricular hypertrophy, 4.3%, peripheral artery disease, 10.1% (Doppler ultrasound), and 15.3% (oscillometric device), microalbuminuria, 4.3%, sub-clinical renal disease, 3.2%, and nephropathy in 3.8% (CKD-EPI). At least one CVD was reported in 9.2% of cases. A low CVR (SCORE) was present in 44.6% of individuals. Conclusions. Dyslipidaemia was found in 60% of individuals, 40% had a sedentary life-style, 30% with hypertension, 20% smoked, 20% obesity, and almost 10% with diabetes. More than a half of individuals have a moderate-high-very high risk. The prevalence of TOD and CVD are significant

Justificación, objetivos y diseño metodológico del estudio RICARTO (RIesgo CARdiovascular y eventos cardiovasculares en la población general del área sanitaria de TOledo) / Cardiovascular risk and cardiovascular events in the general population of the sanitary area of Toledo. RICARTO Study

Introducción. El objetivo principal es conocer en la población del Área Sanitaria de Toledo las prevalencias de factores de riesgo cardiovascular (FRCV), lesión de órgano diana (LOD) y enfermedad cardiovascular (ECV), así como los hábitos de vida (ejercicio físico y consumo de alcohol y de dieta mediterránea), para determinar el riesgo cardiovascular (RCV). Material y métodos. Estudio epidemiológico observacional que analizará una muestra de población general≥ 18 años seleccionada de la base de datos de tarjeta sanitaria por muestreo aleatorio sistemático estratificado por sexo y grupos de edad. Se realizarán anamnesis, exploración clínica y pruebas complementarias, y se congelarán a -85°C alícuotas de sangre total y suero para valorar futuros estudios genéticos. El RCV se estimará con las escalas del proyecto SCORE calibrada para población española y del Framingham Heart Study. Alcanzado el tamaño muestral estimado y transcurridos al menos 5 años de la inclusión, se realizará seguimiento de la muestra final de sujetos, analizando la evolución de FRCV, LOD, ECV y del control de FRCV, y los eventos sucedidos mortales y no mortales. Discusión. El estudio RICARTO pretende conocer las prevalencias de los principales FRCV, LOD y ECV, para determinar el RCV de la población general del Área Sanitaria de Toledo, y realizar un seguimiento de la muestra final de individuos cuando hayan transcurrido al menos 5 años de la inclusión para analizar la incidencia de eventos cardiovasculares y la evolución temporal de los estilos de vida, las prevalencias de FRCV, LOD y ECV

Introduction. The main aim of this study is to ascertain the prevalence of cardiovascular risk factors (CVRF), target organ damage (TOD), cardiovascular disease (CVD), as well as life habits (physical exercise, alcohol consumption, and Mediterranean diet) in the population of a Health Area in Toledo, Spain, to assess cardiovascular risk (CVR). Material and methods. Epidemiological and observational study that will analyse a sample from the general population aged 18 years or older, randomly selected from a database of health cards, and stratified by age and gender. Clinical history, physical examination, and complementary tests will be performed. Aliquots of whole blood and serum samples will be stored at a temperature of -85°C to evaluate future genetic studies. CVR will be estimated by using SCORE project scales calibrated for Spanish population and the Framingham Heart Study scale. When the estimated sample size has been achieved and after a minimum follow-up of 5 years, a final visit will performed in which CVRF, TOD, CVD, CVRF control, and fatal and non-fatal outcomes will be evaluated. Discussion. The RICARTO study is aimed to assess the prevalence of the main CVRF, TOD and CVD in order to determine the CVR in the general population of a health area of Toledo. An analysis will be repeated on the final sample after at least 5 years of follow-up to ascertain the incidence of CV outcomes and the temporal trends of life style, as well as the prevalence of CVRF, TOD, and CVD

[Cardiovascular risk and cardiovascular events in the general population of the sanitary area of Toledo. RICARTO Study]. / Justificación, objetivos y diseño metodológico del estudio RICARTO (RIesgo CARdiovascular y eventos cardiovasculares en la población general del área sanitaria de TOledo).

INTRODUCTION: The main aim of this study is to ascertain the prevalence of cardiovascular risk factors (CVRF), target organ damage (TOD), cardiovascular disease (CVD), as well as life habits (physical exercise, alcohol consumption, and Mediterranean diet) in the population of a Health Area in Toledo, Spain, to assess cardiovascular risk (CVR). MATERIAL AND METHODS: Epidemiological and observational study that will analyse a sample from the general population aged 18 years or older, randomly selected from a database of health cards, and stratified by age and gender. Clinical history, physical examination, and complementary tests will be performed. Aliquots of whole blood and serum samples will be stored at a temperature of-85°C to evaluate future genetic studies. CVR will be estimated by using SCORE project scales calibrated for Spanish population and the Framingham Heart Study scale. When the estimated sample size has been achieved and after a minimum follow-up of 5 years, a final visit will performed in which CVRF, TOD, CVD, CVRF control, and fatal and non-fatal outcomes will be evaluated. DISCUSSION: The RICARTO study is aimed to assess the prevalence of the main CVRF, TOD and CVD in order to determine the CVR in the general population of a health area of Toledo. An analysis will be repeated on the final sample after at least 5 years of follow-up to ascertain the incidence of CV outcomes and the temporal trends of life style, as well as the prevalence of CVRF, TOD, and CVD.

[Characteristics and cardiovascular events in a general population included in the RICARTO (RIesgo CARdiovascular TOledo) study: Data from the first 1,500 individuals included in the study]. / Características de la población general incluida en el estudio RICARTO (RIesgo CARdiovascular y eventos cardiovasculares en la población general del área sanitaria de TOledo): resultados con los primeros 1.500 individuos incluidos en el estudio.

INTRODUCTION: The aim of this study was to assess cardiovascular risk (CVR) by investigating the prevalence of CVR factors (CVRF), target organ damage (TOD), and cardiovascular disease (CVD) in general population of the health area of Toledo, Spain. MATERIAL AND METHODS: Epidemiological and observational study that analysed a sample from the general population aged 18years or older, randomly selected from a database of health cards stratified by age and gender. Clinical history, physical examination, and complementary tests were performed. Total blood and serum samples were frozen at -85°C to evaluate genetic studies in the future. Standard statistical analysis was performed. CVR was assessed by the SCORE scale calibrated for the Spanish population, and the Framingham Heart Study scale. RESULTS: A total of 1,500 individuals (mean age 49.1±15.8years, 55.6% women) were included. Prevalences: dyslipidaemia 56.9% (95% confidence interval [95% CI]: 54.3-59.4), hypertension 33.0% (95%CI: 30.6-35.4), diabetes mellitus 8.6% (95%CI: 7.17-10.1), smoking 24.2% (95%CI; 122.0-26.4), obesity 25.3% (95%CI; 23.1-27.5), and sedentary life-style 39.4% (95%CI; 36.9-41.8). No CVRF was reported in 21.1% of cases, and 18.6% had 3-5 CVRF. TOD: electrocardiographic left ventricular hypertrophy, 4.3%, peripheral artery disease, 10.1% (Doppler ultrasound), and 15.3% (oscillometric device), microalbuminuria, 4.3%, sub-clinical renal disease, 3.2%, and nephropathy in 3.8% (CKD-EPI). At least one CVD was reported in 9.2% of cases. A low CVR (SCORE) was present in 44.6% of individuals. CONCLUSIONS: Dyslipidaemia was found in 60% of individuals, 40% had a sedentary life-style, 30% with hypertension, 20% smoked, 20% obesity, and almost 10% with diabetes. More than a half of individuals have a moderate-high-very high risk. The prevalence of TOD and CVD are significant.

Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling.

This corrects the article DOI: 10.1038/onc.2016.209.

Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling.

Canonical Wnt signaling induces the stabilization of ß-catenin, its translocation to the nucleus and the activation of target promoters. This pathway is initiated by the binding of Wnt ligands to the Frizzled receptor, the association of the LRP5/6 co-receptor and the formation of a complex comprising Dvl-2, Axin and protein kinases CK1α, ɛ, γ and GSK3. Among these, activation of CK1ɛ, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the components. We describe here that CK1ɛ is activated by the PP2A/PR61ɛ phosphatase. Binding of Wnt ligands promotes the interaction of LRP5/6-associated CK1ɛ with Frizzled-bound PR61ɛ regulatory subunit, facilitating the access of PP2A catalytic subunit to CK1ɛ and its activation, what enables the recruitment of Dvl-2 to the receptor complex and the initiation of the Wnt pathway. Our results uncover the mechanism of activation of the canonical Wnt pathway by its ligands.

Vaginal-cuff control and toxicity results of a daily HDR brachytherapy schedule in endometrial cancer patients

PURPOSE: To analyze the vaginal-cuff local control (VCC) and toxicity in postoperative endometrial carcinoma patients (EC) underwent high-dose-rate brachytherapy (HDR-BT) administered daily. Materials and methods: 154 consecutive patients received postoperative HDR-BT for EC from January 2007 to September 2011. FIGO-staging I-IIIC2 patients were divided into two groups according to risk classification: Group 1 (94/154) included high-risk or advanced disease patients and Group 2 (60/154) included intermediate-risk EC patients. Group 1 underwent external beam irradiation (EBI) plus HDR-BT (2 fractions of 5 Gy) and Group 2 underwent HDR-BT alone (4 fractions of 5 Gy). Toxicity evaluation was done with RTOG scores for bladder and rectum, and the objective criteria of LENT-SOMA for vagina. Results: With a median follow-up of 46.7 months (36.6-61 months) only two patients developed vaginal-cuff recurrence in Group 1 (2.1 %) and none in group 2 (0 %). Early toxicity in Group 1 appeared 5.3 % in rectum, 7.5 % in bladder (G1-G2) and 2.1 % in vagina (G1); late toxicity was present in 7.3 % in rectum (all G1-G2 but 1 G3) and in 27.7 % in vagina (all G1-G2 but one G4). In Group 2, 6.7 % developed acute G1-G2 bladder and 6.6 % acute vaginal (G1-G2) toxicity. No late rectal or bladder toxicity was observed; 21.7 % of G1-G2 presented late problems in vagina. Conclusions: The present HDR-BT schedule of 2 fractions of 5 Gy after EBI and 4 fractions of 5 Gy administered daily showed excellent results in terms of VCC and toxicity

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Vaginal-cuff control and toxicity results of a daily HDR brachytherapy schedule in endometrial cancer patients.

PURPOSE: To analyze the vaginal-cuff local control (VCC) and toxicity in postoperative endometrial carcinoma patients (EC) underwent high-dose-rate brachytherapy (HDR-BT) administered daily. MATERIALS AND METHODS: 154 consecutive patients received postoperative HDR-BT for EC from January 2007 to September 2011. FIGO-staging I-IIIC2 patients were divided into two groups according to risk classification: Group 1 (94/154) included high-risk or advanced disease patients and Group 2 (60/154) included intermediate-risk EC patients. Group 1 underwent external beam irradiation (EBI) plus HDR-BT (2 fractions of 5 Gy) and Group 2 underwent HDR-BT alone (4 fractions of 5 Gy). Toxicity evaluation was done with RTOG scores for bladder and rectum, and the objective criteria of LENT-SOMA for vagina. RESULTS: With a median follow-up of 46.7 months (36.6-61 months) only two patients developed vaginal-cuff recurrence in Group 1 (2.1 %) and none in group 2 (0 %). Early toxicity in Group 1 appeared 5.3 % in rectum, 7.5 % in bladder (G1-G2) and 2.1 % in vagina (G1); late toxicity was present in 7.3 % in rectum (all G1-G2 but 1 G3) and in 27.7 % in vagina (all G1-G2 but one G4). In Group 2, 6.7 % developed acute G1-G2 bladder and 6.6 % acute vaginal (G1-G2) toxicity. No late rectal or bladder toxicity was observed; 21.7 % of G1-G2 presented late problems in vagina. CONCLUSIONS: The present HDR-BT schedule of 2 fractions of 5 Gy after EBI and 4 fractions of 5 Gy administered daily showed excellent results in terms of VCC and toxicity.

Reprogramming human B cells into induced pluripotent stem cells and its enhancement by C/EBPα.

B cells have been shown to be refractory to reprogramming and B-cell-derived induced pluripotent stem cells (iPSC) have only been generated from murine B cells engineered to carry doxycycline-inducible Oct4, Sox2, Klf4 and Myc (OSKM) cassette in every tissue and from EBV/SV40LT-immortalized lymphoblastoid cell lines. Here, we show for the first time that freshly isolated non-cultured human cord blood (CB)- and peripheral blood (PB)-derived CD19+CD20+ B cells can be reprogrammed to iPSCs carrying complete VDJH immunoglobulin (Ig) gene monoclonal rearrangements using non-integrative tetracistronic, but not monocistronic, OSKM-expressing Sendai Virus. Co-expression of C/EBPα with OSKM facilitates iPSC generation from both CB- and PB-derived B cells. We also demonstrate that myeloid cells are much easier to reprogram than B and T lymphocytes. Differentiation potential back into the cell type of their origin of B-cell-, T-cell-, myeloid- and fibroblast-iPSCs is not skewed, suggesting that their differentiation does not seem influenced by 'epigenetic memory'. Our data reflect the actual cell-autonomous reprogramming capacity of human primary B cells because biased reprogramming was avoided by using freshly isolated primary cells, not exposed to cytokine cocktails favoring proliferation, differentiation or survival. The ability to reprogram CB/PB-derived primary human B cells offers an unprecedented opportunity for studying developmental B lymphopoiesis and modeling B-cell malignancies.

Data from proteomic characterization of the role of Snail1 in murine mesenchymal stem cells and 3T3-L1 fibroblasts differentiation.

The transcription factor (TF) Snail1 is a major inducer of the epithelial-mesenchymal transition (EMT) during embryonic development and cancer progression. Ectopic expression of Snail in murine mesenchymal stem cells (mMSC) abrogated their differentiation to osteoblasts or adipocytes. We used either stable isotopic metabolic labeling (SILAC) for 3T3-L1 cells or isobaric labeling with tandem mass tags (TMT) for mMSC stably transfected cells with Snail1 or control. We carried out a proteomic analysis on the nuclear fraction since Snail is a nuclear TF that mediates its effects mainly through the regulation of other TFs. Proteomics data have been deposited in ProteomeXchange via the PRIDE partner repository with the dataset identifiers PXD001529 and PXD002157 (Vizcaino et al., 2014) [1]. Data are associated with a research article published in Molecular and Cellular Proteomics (Pelaez-Garcia et al., 2015) [2].

Recommendations of the Spanish Brachytherapy Group of SEOR for HDR endoluminal treatments. Part 1: oesophagus

The endoesophageal brachytherapy technique provides good results in the treatment of oesophageal cancer, when indicated. In a consensus meeting, the Spanish Brachytherapy Group of SEOR and the Spanish Society of Medical Physics (SEFM) agreed on the indications, dose, fractionation schedule, prescription and reporting to be performed in endoesophageal brachytherapy. The results of this consensus are presented here as recommendations for medical practice (AU)

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Recommendations of the Spanish Brachytherapy Group of SEOR for HDR endoluminal treatments. Part 1: Oesophagus.

The endoesophageal brachytherapy technique provides good results in the treatment of oesophageal cancer, when indicated. In a consensus meeting, the Spanish Brachytherapy Group of SEOR and the Spanish Society of Medical Physics (SEFM) agreed on the indications, dose, fractionation schedule, prescription and reporting to be performed in endoesophageal brachytherapy. The results of this consensus are presented here as recommendations for medical practice.

Regulation of the protein stability of EMT transcription factors.

The epithelial to mesenchymal transition (EMT) consists of a rapid change of cell phenotype, characterized by the loss of epithelial characteristics and the acquisition of a more invasive phenotype. Transcription factors regulating EMT (Snail, Twist and Zeb) are extremely labile proteins, rapidly degraded by the proteasome system. In this review we analyze the current mechanisms controlling degradation of EMT transcription factors, focusing on the role of new E3 ubiquitin-ligases involved in EMT. We also summarize the regulation of the stability of these EMT transcription factors, specially observed in different stress conditions, such as hypoxia, chemotherapeutic drugs, oxidative stress or γ-irradiation.