Stereotactic body radiation therapy for adrenal gland metastases: A multi-institutional outcome analysis.

Aim: The adrenal gland is a common site of metastasis with a rate of up to 27% in autopsy series. The incidence of these metastases is increasing due to greater use of Positron Emission Tomography scans and improved overall survival of patients with metastatic cancers. Stereotactic body radiation therapy (SBRT) is a non-invasive treatment option for metastasis. The aim of this study is to assess prognostic factors influencing local control, progression-free and overall survival in oligometastatic patients treated with SBRT for an adrenal metastasis. Methods: In this multicentric retrospective study, we included patients with adrenal metastases treated with SBRT between 2010 and 2021 in eleven french centers. All primary tumors were included. Results: A total of 110 patients treated for 121 adrenal lesions were included. Non-small-cell lung cancer was the predominant histologic type (55.4 %). Eighty-two percent of patients had at least 2 metastatic sites. The median Planning Target Volume was 70 cm3 with a median prescription dose of 40 Gray (Gy). The mean Biologically Effective Dose (BED) 10 dose was 74.2 Gy. Local control at 1 and 2 years was 85.9 % and 72.5 % respectively. The median overall survival and progression-free survival were 31.6 and 8.5 months respectively. Local control was significantly improved by systemic treatment one month before or after SBRT (p = 0.009) and by a BED10 greater than or equal to 50 Gy (p = 0.003).In multivariate analysis, oligometastatic presentation (p = 0.009) and a metachronous metastatic presentation (p = 0.008) were independent factors for progression-free survival.Tolerance was excellent, no grade 3 and 4 toxicities were described due to SBRT. Conclusion: Stereotactic radiotherapy of adrenal metastases makes possible a local control of more than 85% at one year and was well tolerated. The factors influencing survival in oligometastatic patients still need to be found in order to better select those who benefit the most from this type of treatment.

Hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: experience in a pediatric oncological institution. / Cistitis hemorrágica tras trasplante alogénico de progenitores hematopoyéticos: experiencia en un centro oncológico pediátrico.

OBJECTIVE: To analyze the risk factors associated with hemorrhagic cystitis (HC) severity and the treatment strategies available in HC patients following allogeneic hematopoietic stem cell transplantation (AHSCT). MATERIALS AND METHODS: A retrospective study of medical records was carried out. Patients with HC following AHSCT treated from 2017 to 2021 were divided into two groups according to severity -mild and severe. Demographic data, disease-specific characteristics, urological sequelae, and overall mortality were compared between both groups. The hospital's protocol was used for patient management. RESULTS: 33 episodes of HC were collected in 27 patients, 72.7% of whom were male. HC incidence following AHSCT was 23.4% (33/141). 51.5% of HCs were severe (grades III-IV). Severe graft host disease (GHD) (grades III-IV) and thrombopenia at HC onset were associated with severe HC (p= 0.043 and p= 0.039, respectively). This group had longer hematuria times (p< 0.001) and required more platelet transfusions (p= 0.003). In addition, 70.6% required bladder catheterization, but only 1 case needed percutaneous cystostomy. None of the patients with mild HC required catheterization. No differences were found in terms of urological sequelae or overall mortality. CONCLUSIONS: Severe HC could be predicted thanks to the presence of severe GHD or thrombopenia at HC onset. Severe HC can be managed with bladder catheterization in most of these patients. A standardized protocol may help reduce the need for invasive procedures in patients with mild HC.

OBJETIVO: Analizar factores de riesgo asociados a la gravedad de la cistitis hemorrágica (CH) y estrategias de tratamiento en pacientes con CH tras trasplante alogénico de progenitores hematopoyéticos (TAPH). MATERIAL Y METODOS: Estudio retrospectivo de historias clínicas. Los pacientes con CH tras TAPH tratados entre 2017 y 2021 se dividieron en dos grupos según la gravedad del cuadro (leve y grave). Se compararon datos demográficos, características específicas de la enfermedad, secuelas urológicas y mortalidad global entre ambos grupos. Se utilizó el protocolo del hospital para el manejo de los pacientes. RESULTADOS: Se recogieron 33 episodios de CH en 27 pacientes, de los cuales el 72,7% fueron varones. La incidencia de CH tras TAPH fue del 23,4% (33/141). El 51,5% de las CH fueron graves (grados III-IV). La enfermedad de injerto contra huésped (EICH) grave (grados III-IV) y la trombopenia al inicio se asociaron a CH grave (p= 0,043 y p= 0,039, respectivamente). Este grupo tuvo mayor tiempo de hematuria (p< 0,001) y necesitó más transfusiones de plaquetas (p= 0,003). Además, el 70,6% precisó sondaje vesical, pero solo un caso cistostomía percutánea. Ningún paciente con CH leve precisó sondaje. No hubo diferencias en las secuelas urológicas ni en la mortalidad global. CONCLUSIONES: Una CH más grave podría predecirse por la presencia de EICH grave o trombopenia al inicio del cuadro. La CH grave puede manejarse con sondaje vesical en la mayoría de estos pacientes. Seguir un protocolo estandarizado puede reducir la necesidad de procedimientos invasivos en pacientes con CH leve.

Pediatric perianal Crohn's disease behavior in the era of biologic therapy. / Comportamiento de la afectación perianal en pacientes pediátricos con enfermedad de Crohn en la era de la terapia biológica.

AIM OF THE STUDY: To describe perianal Crohn's disease behavior and the role of biological therapy in a sample of pediatric patients. METHODS: A retrospective study of pediatric patients with Crohn's disease (CD) treated in our institution from 2017 to 2021, with a minimum follow up period of 6 months, was conducted. Patients were divided whether they had perianal disease (PD) or not. Baseline characteristics, extension of disease, growth failure rate, aggressive pattern rate, use of biological therapy and need for surgery, among other variables, were compared between both groups. Clinical and/or radiological improvement in the last 6 months of follow up was considered good control of PD. RESULTS: Seventy eight pediatric patients with CD were included. Median age at diagnosis was 10.5 years, and median follow up time was 3.8 years. 64.1% patients were male. Of all, 15 (19.2%) had perianal disease, of which 10 had fistulizing findings and 5 had non fistulizing findings. PD was presented at diagnosis in 8 patients, and the rest developed it in a median time of 1 year from diagnosis. PD was associated with growth failure (p = 0.003), use of biological therapies (p = 0.005), and need for second line of biologics (p = 0.005). Most patients (12/15, 80%) had good control of PD with the treatment received. CONCLUSIONS: CD patients with PD seem to need a more aggressive treatment, with biological therapies playing a key role for its handling nowadays. These patients require close nutritional evaluation that ensures proper development and growth.

OBJETIVO DEL ESTUDIO: Describir el comportamiento de la enfermedad de Crohn perianal y el papel de la terapia biológica en una muestra de pacientes pediátricos. METODOS: Estudio retrospectivo de pacientes pediátricos con enfermedad de Crohn (EC) tratados en nuestro centro entre 2017 y 2021, con un seguimiento mínimo de seis meses. Los pacientes se dividieron en función de si tenían enfermedad perianal (EP) o no. Se compararon entre ambos grupos las características iniciales, la extensión de la enfermedad, el índice de retraso en el crecimiento, el índice de patrón agresivo, el empleo de terapia biológica y la necesidad de cirugía, entre otras variables. Se consideró un buen control de la EP una mejoría clínica o radiológica en los 6 últimos meses de seguimiento. RESULTADOS: Se incluyeron 78 pacientes pediátricos con EC. La edad mediana en el momento del diagnóstico fue de 10,5 años, y el tiempo mediano de seguimiento fue de 3,8 años. El 64,1% de los pacientes eran varones. Del total, 15 (19,2%) tenían enfermedad perianal, de los cuales 10 presentaban hallazgos fistulizantes y 5 no fistulizantes. La EP estaba presente en el momento del diagnóstico en 8 pacientes, y el resto la desarrolló en una mediana de 1 año desde el diagnóstico. La EP se asoció con retraso en el crecimiento (p = 0,003), empleo de terapias biológicas (p = 0,005) y necesidad de una segunda línea de terapia biológica (p = 0,005). La mayoría de los pacientes (12/15, 80%) tuvieron un buen control de la EP con el tratamiento recibido. CONCLUSIONES: Los pacientes de EC con EP parecen necesitar un tratamiento más agresivo, en el que las terapias biológicas desempeñan hoy en día un papel fundamental. Estos pacientes precisan de una estrecha evaluación nutricional que garantice su correcto crecimiento y desarrollo.

Comportamiento de la afectación perianal en pacientes pediátricos con enfermedad de Crohn en la era de la terapia biológica / Pediatric perianal Crohn’s disease behavior in the era of biologic therapy

Objetivo del estudio: Describir el comportamiento de la enfermedad de Crohn perianal y el papel de la terapia biológica en una muestra de pacientes pediátricos. Métodos: Estudio retrospectivo de pacientes pediátricos con enfermedad de Crohn (EC) tratados en nuestro centro entre 2017 y 2021, con un seguimiento mínimo de seis meses. Los pacientes se dividieron en función de si tenían enfermedad perianal (EP) o no. Se compararon entre ambos grupos las características iniciales, la extensión de la enfermedad, el índice de retraso en el crecimiento, el índice de patrón agresivo, el empleo de terapia biológica y la necesidad de cirugía, entre otras variables. Se consideró un buen control de la EP una mejoría clínica o radiológica en los 6 últimos meses de seguimiento. Resultados: Se incluyeron 78 pacientes pediátricos con EC. La edad mediana en el momento del diagnóstico fue de 10,5 años, y el tiempo mediano de seguimiento fue de 3,8 años. El 64,1% de los pacientes eran varones. Del total, 15 (19,2%) tenían enfermedad perianal, de los cuales 10 presentaban hallazgos fistulizantes y 5 no fistulizantes. La EP estaba presente en el momento del diagnóstico en 8 pacientes, y el resto la desarrolló en una mediana de 1 año desde el diagnóstico. La EP se asoció con retraso en el crecimiento (p = 0,003), empleo de terapias biológicas (p = 0,005) y necesidad de una segunda línea de terapia biológica (p = 0,005). La mayoría de los pacientes (12/15, 80%) tuvieron un buen control de la EP con el tratamiento recibido. Conclusiones: Los pacientes de EC con EP parecen necesitar un tratamiento más agresivo, en el que las terapias biológicas desempeñan hoy en día un papel fundamental. Estos pacientes precisan de una estrecha evaluación nutricional que garantice su correcto crecimiento y desarrollo.(AU)

Aim of the study: To describe perianal Crohn’s disease behavior and the role of biological therapy in a sample of pediatric patients. Methods: A retrospective study of pediatric patients with Crohn’s disease (CD) treated in our institution from 2017 to 2021, with a minimum follow up period of 6 months, was conducted. Patients were divided whether they had perianal disease (PD) or not. Baseline characteristics, extension of disease, growth failure rate, aggressive pattern rate, use of biological therapy and need for surgery, among other variables, were compared between both groups. Clinical and/or radiological improvement in the last 6 months of follow up was considered good control of PD. Results: Seventy eight pediatric patients with CD were included. Median age at diagnosis was 10.5 years, and median follow up time was 3.8 years. 64.1% patients were male. Of all, 15 (19.2%) had perianal disease, of which 10 had fistulizing findings and 5 had non fistulizing findings. PD was presented at diagnosis in 8 patients, and the rest developed it in a median time of 1 year from diagnosis. PD was associated with growth failure (p = 0.003), use of biological therapies (p = 0.005), and need for second line of biologics (p = 0.005). Most patients (12/15, 80%) had good control of PD with the treatment received. Conclusions: CD patients with PD seem to need a more aggressive treatment, with biological therapies playing a key role for its handling nowadays. These patients require close nutritional evaluation that ensures proper development and growth.(AU)

Interactions of radiation therapy with common and innovative systemic treatments: Antidiabetic treatments, antihypertensives, lipid-lowering medications, immunosuppressive medications and other radiosensitizing methods.

The invention and approval of innovative anticancer therapies in the last decade have revolutionized oncology treatment. Radiotherapy is one of the three traditional pillars in oncology treatment with surgery and systemic therapies. Some standard-of-care combinations of chemoradiotherapy widened the therapeutic window of radiation, while some other chemotherapies such as gemcitabine caused unacceptable toxicities when combined with radiation in lung cancers. Fast-paced progress are specially focused on immunotherapies, targeted-therapies, anti-angiogenic treatment, DNA repair inhibitors, hormonotherapy and cell cycle inhibitors. New anticancer therapeutic arsenals provided new possibilities of combined oncological treatments. The interactions of the radiotherapy with other systemic treatments, such as non-anticancer immunomodulatory/immunosuppressive medications are sometimes overlooked even though they could offer a real therapeutic benefit. In this review, we summarize the new opportunities and the risks of historical and novel combined therapies with radiation: non-anticancer immunomodulatory/immunosuppressive drugs, systemic reoxygenation, new therapies such as nanoparticles and SMAC mimetics. Key biological mechanisms, pre-clinical and available clinical data will be provided to demonstrate the promising opportunities in the years to come.

Routine anti-reflux surgery combined with gastrostomy in children: is it really necessary? Our single-center experience. / ¿Es realmente necesario asociar una técnica antirreflujo a la gastrostomía de forma rutinaria? Experiencia en nuestro centro.

OBJECTIVE: To study gastroesophageal reflux (GER) in children undergoing gastrostomy in a single pediatric institution. MATERIAL AND METHODS: A retrospective study of patients undergoing gastrostomy from 2000 to 2017 was carried out. Demographic data, clinical data, progression, and complications were recorded. GER was considered positive in patients with clinical signs requiring antisecretory treatment, prokinetic treatment, or anti-reflux surgery to control symptoms. RESULTS: 207 patients with a median age of 2 years [R: 0.25-18] were included. Neurological impairment was the most frequent underlying condition (74%). Swallowing difficulty and undernourishment were the main surgical indications for gastrostomy. Prior to gastrostomy, 96 out of 207 patients (46%) showed GER symptoms. Combined fundoplication and gastrostomy was performed in 41 (43%) patients with preexisting GER, 6 of whom showed GER worsening (4 required redo fundoplication). 5 complications following fundoplication were noted - gastric perforation, sustained Dumping syndrome, and gastroesophageal stenosis. 55 out of 96 (57%) patients with preexisting GER underwent gastrostomy alone. Clinical signs disappeared in 16 of them (29%) and improved or stabilized in 19 (35%). GER worsening occurred in 20 patients (36%), with subsequent fundoplication being required in 10 cases. In patients with no previous clinical signs (111 out of 207), GER symptoms occurred following gastrostomy in just 18 cases (16%), and only 2 patients required fundoplication. CONCLUSIONS: In our experience, routine anti-reflux surgery combined with gastrostomy is not justified. Individualized fundoplication should be considered in case of medical treatment failure. Further studies with an adequate design are required to establish which patients could really benefit from this procedure.

OBJETIVO: Estudio del reflujo gastroesofágico (RGE) en los pacientes en los que se ha realizado una gastrostomía en nuestro centro. MATERIAL Y METODOS: Revisión de los pacientes intervenidos de gastrostomía en el periodo 2000-2017. Registro de datos demográficos, clínicos, evolución y complicaciones. Definimos RGE como la presencia de clínica compatible en pacientes que requirieron tratamiento médico o quirúrgico antirreflujo. RESULTADOS: Incluimos 207 pacientes con una mediana de edad de 2 años [r:0,25-18]. La patología subyacente más frecuente fue déficit neurológico (74%). Las indicaciones quirúrgicas fueron trastornos deglutorios y/o desnutrición. Previamente a la gastrostomía, 96/207 pacientes (46%) presentaban clínica de RGE. Se realizó funduplicatura asociada a gastrostomía en 41/96 (43%) de los pacientes con RGE previo. En 6/41 pacientes (15%) el RGE empeoró, requiriendo 4 de ellos una segunda funduplicatura. Se registraron 5 complicaciones tras funduplicatura (perforaciones gástricas, síndromes de Dumping prolongados y estenosis esofagogástrica). En 55/96 pacientes con RGE previo a la gastrostomía no se asoció funduplicatura. La clínica desapareció en 16/55 (29%), y mejoró o se estabilizó en 19/55 pacientes (35%). En 20/55 (36%) la sintomatología empeoró, y 10 de ellos precisaron una funduplicatura posterior. De los pacientes sin clínica previa de RGE (111/207), presentaron síntomas de RGE tras la gastrostomía 18/111 (16%), y solo 2 pacientes requirieron funduplicatura. CONCLUSIONES: Según nuestra experiencia, la funduplicatura de rutina asociada a la gastrostomía no está justificada. En caso de fracaso del tratamiento médico del RGE, una técnica antirreflujo debe plantearse de forma individualizada. Son necesarios estudios adecuadamente diseñados para definir qué pacientes realmente se beneficiarían de este procedimiento.

¿Es realmente necesario asociar una técnica antirreflujo a la gastrostomía de forma rutinaria? Experiencia en nuestro centro / Routine anti-reflux surgery combined with gastrostomy in children: is it really necessary? Our single-center experience

Objetivos: Estudio del reflujo gastroesofágico (RGE) en los pacientes en los que se ha realizado una gastrostomía en nuestro centro. Material y métodos: Revisión de los pacientes intervenidos degastrostomía en el periodo 2000-2017. Registro de datos demográficos,clínicos, evolución y complicaciones. Definimos RGE como la presenciade clínica compatible en pacientes que requirieron tratamiento médicoo quirúrgico antirreflujo. Resultados: Incluimos 207 pacientes con una mediana de edadde 2 años [r:0,25-18]. La patología subyacente más frecuente fue déficit neurológico (74%). Las indicaciones quirúrgicas fueron trastornosdeglutorios y/o desnutrición. Previamente a la gastrostomía, 96/207pacientes (46%) presentaban clínica de RGE. Se realizó funduplicatu-ra asociada a gastrostomía en 41/96 (43%) de los pacientes con RGEprevio. En 6/41 pacientes (15%) el RGE empeoró, requiriendo 4 deellos una segunda funduplicatura. Se registraron 5 complicaciones trasfunduplicatura (perforaciones gástricas, síndromes de Dumping prolongados y estenosis esofagogástrica). En 55/96 pacientes con RGE previoa la gastrostomía no se asoció funduplicatura. La clínica desaparecióen 16/55 (29%), y mejoró o se estabilizó en 19/55 pacientes (35%). En20/55 (36%) la sintomatología empeoró, y 10 de ellos precisaron unafunduplicatura posterior. De los pacientes sin clínica previa de RGE(111/207), presentaron síntomas de RGE tras la gastrostomía 18/111(16%), y solo 2 pacientes requirieron funduplicatura. Conclusiones: Según nuestra experiencia, la funduplicatura de rutina asociada a la gastrostomía no está justificada. En caso de fracaso del tratamiento médico del RGE, una técnica antirreflujo debe plantearsede forma individualizada. Son necesarios estudios adecuadamente di-señados para definir qué pacientes realmente se beneficiarían de esteprocedimiento.(AU)

Objective: To study gastroesophageal reflux (GER) in childrenundergoing gastrostomy in a single pediatric institution. Materials and methods: A retrospective study of patients undergoing gastrostomy from 2000 to 2017 was carried out. Demographic data,clinical data, progression, and complications were recorded. GER wasconsidered positive in patients with clinical signs requiring antisecretory treatment, prokinetic treatment, or anti-reflux surgery to controlsymptoms. Results: 207 patients with a median age of 2 years [R: 0.25-18]were included. Neurological impairment was the most frequent underlying condition (74%). Swallowing difficulty and undernourishment werethe main surgical indications for gastrostomy. Prior to gastrostomy, 96out of 207 patients (46%) showed GER symptoms. Combined fun-doplication and gastrostomy was performed in 41 (43%) patients withpreexisting GER, 6 of whom showed GER worsening (4 required redofundoplication). 5 complications following fundoplication were noted –gastric perforation, sustained Dumping syndrome, and gastroesophagealstenosis. 55 out of 96 (57%) patients with preexisting GER underwentgastrostomy alone. Clinical signs disappeared in 16 of them (29%) andimproved or stabilized in 19 (35%). GER worsening occurred in 20patients (36%), with subsequent fundoplication being required in 10cases. In patients with no previous clinical signs (111 out of 207), GERsymptoms occurred following gastrostomy in just 18 cases (16%), andonly 2 patients required fundoplication.Conclusions: In our experience, routine anti-reflux surgery combined with gastrostomy is not justified. Individualized fundoplicationshould be considered in case of medical treatment failure. Further studieswith an adequate design are required to establish which patients couldreally benefit from this procedure.(AU)

Microbiological analysis of autologous bone particles obtained by low-speed drilling and treated with different decontamination agents.

The aim of this study was to compare the effectiveness of three agents - two antibiotics (amoxicillin and clindamycin) and an antiseptic (chlorhexidine) - to decontaminate bone grafts obtained by low-speed drilling. The study included 248 bone tissue samples harvested from 62 patients by low-speed drilling before dental implant placement. Each of four samples obtained from every patient was dropped, using a sterile instrument, into a sterile tube containing a 500-µl solution of 400µg/mL amoxicillin, 150µg/mL clindamycin, 0.12% chlorhexidine, or physiological saline for 1min. The number of colony-forming units (CFU) was determined at 48h of culture. The use of clindamycin, amoxicillin, or chlorhexidine as decontaminant for 1min significantly reduced the CFU count when compared to physiological saline (control agent). In both anaerobic and CO2-rich atmospheres, significant differences in CFU/mL were found between the control and chlorhexidine groups (P<0.001), control and amoxicillin groups (P<0.001), control and clindamycin groups (P<0.001), chlorhexidine and amoxicillin groups (P<0.0001), and chlorhexidine and clindamycin groups (P<0.0001). In conclusion, clindamycin had the highest decontaminating effect on bone particles obtained by low-speed drilling, followed by chlorhexidine and amoxicillin. Clindamycin may therefore be a valid alternative option for the routine decontamination of intraoral bone grafts.

Volumetric changes in alveolar ridge preservation with a compromised buccal wall: a systematic review and meta-analysis.

BACKGROUND: Many studies have addressed socket preservation, though fewer publications considering buccal wall loss can be found, since the literature typically considers sockets with four walls. A systematic review was made on the influence of type II buccal bone defects, according to Elian's Classification, in socket grafting materials upon volumetric changes in width and height. MATERIAL AND METHODS: An electronic and manual literature search was conducted in accordance to PRISMA statement. The search strategy was restricted to randomized controlled trials (RCTs) and controlled clinical trials (CCTs) describing post-extraction sockets with loss of buccal wall in which alveolar ridge preservation (ARP) was carried out in the test group and spontaneous healing of the socket (SH) was considered in the control group. RESULTS: The search strategy yielded 7 studies. The meta-analysis showed an additional bone loss of 2.37 mm in width (p > 0.001) and of 1.10 mm in height (p > 0.001) in the absence of ARP. The reconstruction of the vestibular wall was not evaluated in any study. The results also showed moderate to great heterogeneity among the included studies in terms of the changes in width and height. CONCLUSIONS: Despite the heterogeneity of the included studies, the results indicate a benefit of ARP versus SH. Further studies are needed to determine the volumetric changes that occur when performing ARP in the presence of a buccal bone wall defect.

Peripheral blood tumor-infiltrating lymphocytes in a neuroblastoma model. / Linfocitos infiltrantes de tumor en sangre periférica en un modelo de neuroblastoma.

OBJECTIVE: To detect tumor-infiltrating lymphocytes (TILs) in the peripheral blood (PB) of a preclinical neuroblastoma model. MATERIALS AND METHODS: Two types of preclinical models - immunodeficient mice and immunocompetent mice - were generated by injecting a cell suspension of neuroblastoma cell line NB36769 with MYCN gene (TH-MYCN+) overexpression. Spleen, tumor, and peripheral blood were studied using flow cytometry to detect PD-1+ T-cells. TCR-ß immunosequencing was performed in matched samples (tumor and peripheral blood). RESULTS: Most PB T-cells of immunodeficient mice were CD4 (control: 83.1%; tumor: 86.1%), with a small proportion of PD-1+ T-cells (control: 0.4%; tumor: 0.3%). However, the percentage of PD-1+ T-cells in the spleen was higher (control: 6.5%; tumor: 6.2%), and it was expressed in the CD4+ subset only. Regarding the TCR repertoire of immunocompetent mice, the proportion of the 10 most frequent sequences was significantly higher in tumors (11.09% ± 2.83%) than in the peripheral blood (1.59% ± 0.59%) (p=0.024). These findings are suggestive of clonotype enrichment within the tumor. 9 out of the 10 most frequent tumor clones were identified in the matched peripheral blood sample in 2 mice, and 6 out of 10 in one mouse. In addition, TILs with shared sequences from different animals were found. CONCLUSIONS: Our results in terms of immunophenotype and clonality suggest the presence of PB T-cells which could include TILs in a preclinical neuroblastoma model.

OBJETIVO: Comprobar la existencia de linfocitos T que incluyen linfocitos infiltrantes de tumor (TILs) en la sangre periférica (SP) de un modelo preclínico de neuroblastoma. MATERIAL Y METODOS: Utilizamos un modelo en ratones inmunodeficientes y otro en inmunocompetentes mediante inyección de suspensiones de la línea tumoral NB36769 con mutación de MYCN (TH-MYCN+). Se realizaron análisis por citometría de flujo (bazo, SP y tumor) y secuenciación del TCR-ß en el ADN de muestras pareadas de tumor y SP. RESULTADOS: En los ratones inmunodeficientes el componente principal en SP fue CD4: 83,1% (control) y 86,1% (tumor), siendo PD-1+ el 0,4 y el 0,3%. En el bazo obtuvimos un mayor porcentaje de linfocitos T PD-1+ que en SP, siendo similar en el control (6,5%) y en el ratón con tumor (6,2%), en subpoblación CD4+ exclusivamente. En los ratones inmunocompetentes observamos que la proporción de los 10 clones más frecuentes en los tumores constituía el 11,09% ± 2,83% del repertorio del TCR, mientras en SP representaba el 1,59% ± 0,59% (p= 0,024). Estos resultados sugieren un enriquecimiento de clonotipos dentro del tumor. De los 10 clones más frecuentes en las muestras tumorales, localizamos 9 también en la SP en dos ratones y 6 en el tercero. Además, encontramos secuencias compartidas por TILs de animales diferentes. CONCLUSIONES: Nuestros resultados de inmunofenotipo y clonalidad apuntan a la existencia de linfocitos en SP que podrían contener TILs en un modelo experimental de neuroblastoma.

[Stereotactic body radiotherapy: Prospective study to evaluate asthenia and quality of life]. / Radiothérapie en conditions stéréotaxiques : étude prospective évaluant la fatigue et la qualité de vie.

PURPOSE: To evaluate prospectively asthenia and the quality of life in patients treated by stereotactic body irradiation and to determine their predictive factors. METHODS AND MATERIALS: Quality of life was assessed by the EORTC QLQ-C30 and asthenia was evaluated with the Brief Fatigue Inventory (BFI), on the first day (T1), last day (T2) and 1-3 weeks after the end of treatment (T3). RESULTS: Sixty-three patients were treated with stereotactic body irradiation from February 2017 to May 2017 and 41 were included in the analysis (22 patients excluded for lack of understanding, organization, psychologic disorders or refusal). The mean number of fractions was 5 (±2). The compliance to quality of life assessment was 98%, 95% was 81% at T1, T2 and T3, respectively. An increase of asthenia and a worsened quality of life were found in 12 (29%) and 14 (34%) patients between T1 and T2. Univariate analysis demonstrated a correlation between asthenia and quality of life were correlated with performans status (P=0.03 and 0.05 respectively), hemoglobin level (p=0.01 and 0.004), albumin level (P=0.01 and 0.06), distance between home and radiotherapy department (P=0.05 and 0.02). Multivariate analysis demonstrated a correlation between female gender (P=0.012), albumin level (P<0.001), distance over 25km (P<0.001) with asthenia, and albumin level (P=0.003), hemoglobin level (P=0.004) and previous chemotherapy (P=0.003) with quality of life. No influence of stereotactic body ratiotherapy parameters was seen. CONCLUSION: Despite hypofractionation, stereotactic body radiotherapy induced asthenia and deterioration of quality of life.

[New insights in the pathogenesis of pulmonary arterial hypertension]. / Nouveau regard sur la physiopathologie de l'hypertension artérielle pulmonaire.

Pulmonary arterial hypertension (PAH) is a severe and incurable cardiopulmonary disorder. Research from the past 10 years illustrates the complex and multifactorial aspects of PAH pathophysiology. Furthermore, latest advances in the field have led to a better understanding of the key components underlying this inadequate accumulation of pulmonary vascular cells within the pulmonary arterial walls, leading to pulmonary vascular remodelling. Among the underlying molecular and cellular mechanisms, pulmonary endothelial dysfunction, alterations of the inter-cell communications within the pulmonary arterial walls as well as defects of the inflammatory component and the loss of BMPRII activity play critical roles in the pathogenesis of the disease.

[Chemoradiation for oesophageal cancer: A critical review of the literature]. / Chimioradiothérapie des cancers de l'œsophage : revue critique de la littérature.

Locally advanced oesophageal cancer treatment requires a multidisciplinary approach with the combination of chemotherapy and radiotherapy for preoperative and definitive strategy. Preoperative chemoradiation improves the locoregional control and overall survival after surgery for locally advanced oesophageal cancer. Definitive chemoradiation can also be proposed for non-resectable tumours or medically inoperable patients. Besides, definitive chemoradiation is considered as an alternative option to surgery for locally advanced squamous cell carcinomas. Chemotherapy regimen associated to radiotherapy consists of a combination of platinum derived drugs (cisplatinum or oxaliplatin) and 5-fluorouracil or a weekly scheme combination of carboplatin and paclitaxel according to CROSS protocol in a neoadjuvant strategy. Radiation doses vary from 41.4Gy to 45Gy for a preoperative strategy or 50 to 50.4Gy for a definitive treatment. The high risk of lymphatic spread due to anatomical features could justify the use of an elective nodal irradiation when the estimated risk of microscopic involvement is higher than 15% to 20%. An appropriate delineation of the gross tumour volume requires an exhaustive and up-to-date evaluation of the disease. Intensity-modulated radiation therapy represents a promising approach to spare organs-at-risk. This critical review of the literature underlines the roles of radiotherapy for locally advanced oesophageal cancers and describes doses, volumes of treatment, technical aspects and dose constraints to organs-at-risk.

[Management of patients with pacemakers or implantable cardioverter defibrillator undergoing radiotherapy]. / Prise en charge des patients porteurs de stimulateurs cardiaques ou défibrillateurs automatiques implantables traités par irradiation.

An increasing number of patients with cardiac implantable electronic devices benefit from radiotherapy, warranting specific collaborative management between both radiation oncologists and cardiologists. Interactions between electromagnetic fields, secondary particles and cardiac implantable electronic devices may result in transient and reversible malfunctions with significant consequences depending on the underlying cardiac pathology and the level of patient's cardiac implantable electronic devices dependency. Numerous international guidelines on patients' management have been proposed and all agree on a total cumulated dose limit at the battery of 5Gy and on the need for an initial as well as repeated evaluation over time, up to 6months after the last radiation. The analysis of the published data revealed relatively rare incidence of significant adverse events. The most recent international guidelines underline the feasibility and safety of radiotherapy for cardiac implantable electronic devices holders, with the need for systematic local protocol in all radiotherapy centers.

[Recurrence of uncomplicated intestinal intussusception. Can it be treated as an outpatient?] / Recurrencia de la invaginación intestinal no complicada. ¿Es posible el manejo ambulatorio?

OBJECTIVES: To estimate the recurrence rate of intussusception after successful enema reduction and to analyze the costs of hospital admission with the current management of this pathology. MATERIAL AND METHODS: A retrospective study over 5 years of 97 patients with confirmed diagnosis of intussusception was undertaken. Medical records were evaluated for patient demographic, clinical and radiological data. Patients with enema-reduced intussusception were selected and data respecting to timing and outcome of recurrences, and length of stay were analyzed. Recurrence was defined as a new episode of intussusception within 72 hours of the initial presentation. Costs were calculated using hospital-specific data. RESULTS: During the study period there were 81/97 children with successful enema reduction. Mean length of stay was 35 hours in the conservative treatment group. There were 8 episodes of recurrence, 5 of them within the first 24 hours (6.17%), for an overall recurrence rate of 9.88%. 7 children were treated by repeated enema and only one patient needed surgery for persistent illness. Assuming the overall recurrence rate of 9.88%, it would require hospitalizing 16 patients to identify a single recurrence with a cost of 1,723.75 € per patient. CONCLUSIONS: Given the low recurrence rate for enema-reduced intussusception and the possibility of repeated enema for their treatment in most of recurrences, we strongly advocated for the outpatient management as a safe and cost-effective alternative.

OBJETIVOS: Estimar la tasa de recurrencia en la invaginación intestinal tras reducción con hidroenema. Analizar los costes de estancia hospitalaria según el manejo actual de esta patología. MATERIAL Y METODOS: Estudio retrospectivo de los 97 pacientes con diagnóstico ecográfico de invaginación intestinal en los últimos 5 años. Revisamos datos demográficos, clínicos y ecográficos. Seleccionamos los casos tratados de forma conservadora, analizando las recurrencias, su tratamiento y la estancia hospitalaria. Consideramos recurrencia a un nuevo episodio de invaginación intestinal en las siguientes 72 horas a la reducción. Los costes fueron calculados según los grupos relacionados por diagnóstico en base a datos específicos del centro. RESULTADOS: En los 81/97 (83,5%) pacientes con tratamiento conservador se diagnosticaron 8 episodios de recurrencia, 5 en las primeras 24 horas. En 7 casos se resolvió la recurrencia con hidroenema, mientras que 1 requirió tratamiento quirúrgico por recidivas persistentes. La media de estancia hospitalaria fue de 35 horas en el grupo de tratamiento conservador (81/97 pacientes). La tasa global de recurrencia fue del 9,88%, (6,17% antes de 24 horas), siendo necesario el ingreso de 16 pacientes para el diagnóstico de un caso de recurrencia en las primeras 24 horas. Según estos resultados, y los costes hospitalarios/24 horas, el manejo ambulatorio supondría un ahorro de 1.723,75 €/paciente. CONCLUSIONES: Dado que el riesgo de recurrencia en la invaginación intestinal no complicada es bajo y su tratamiento es conservador en la mayoría de los casos, estaría justificada la implantación de un protocolo de manejo ambulatorio como alternativa segura y costo-efectiva.

Pelvic radiotherapy in the setting of rheumatoid arthritis: Refining the paradigm.

PURPOSE: Conflicting results concerning the toxicity of radiotherapy in the setting of rheumatoid arthritis were reported in literature. This work describes the toxicity profiles of patients with rheumatoid arthritis undergoing pelvic radiotherapy for gynecologic malignancies at our institution. PATIENTS AND METHODS: Charts of patients with rheumatoid arthritis who underwent pelvic radiotherapy for cervical or endometrial cancer in a curative intent at the Gustave-Roussy Cancer Campus between 1990 and 2015 were reviewed for treatment-related toxicities. Acute and late effects were graded as per the Common Terminology Criteria for Adverse Events version 4.0 scoring system. RESULTS: Eight patients with cervical cancer and three with endometrial cancer were identified. Median follow-up was 56 months. Median external beam radiotherapy dose was 45Gy. All patients received a brachytherapy boost using either pulse- or low-dose rate technique. Concomitant chemotherapy was used in seven cases. Median time from rheumatoid arthritis diagnosis to external beam radiation therapy was 5 years. No severe acute gastrointestinal or genitourinary toxicity was reported. One patient had grade 3 dermatitis. Any late toxicity occurred in 7 /11 patients, and one patient experienced severe late toxicities. One patient with overt systemic rheumatoid arthritis symptoms at the time of external beam radiation therapy experienced late grade 3 ureteral stenosis, enterocolitis and lumbar myelitis. CONCLUSION: Pelvic radiotherapy, in the setting of rheumatoid arthritis, appears to be feasible, with potentially slight increase in low grade late events compared to other anatomic sites. Patients with overt systemic rheumatoid arthritis manifestation at the time of radiotherapy might be at risk of potential severe toxicities.

HPV-16 variants' impact on uterine cervical cancer response to radiotherapy: A descriptive pilot study.

PURPOSE: Although the large impact of Human papilloma virus (HPV) in cervical cancer is established, its place as a therapeutic target is new and according to the growing literature, could be promising. In the present study, radiosensitivity's difference based on HPV-16 variants is assessed. PATIENTS AND METHODS: Variants of Human papilloma virus were identified before the exclusive radiotherapy in patients with cervical cancer. Data were prospectively collected. Fifty-nine patients were screened. RESULTS: Among the 59 screened patients, 34 (57.6%) were identified to be HPV-16 (+), with 13 European and two non-European variants. Of the 34 patients, 15 experienced exclusive radiotherapy. Among them, eight had complete response (seven with European and one with non-European variants), four with European variant had partial response, three with European variant had tumour persistence and one with non-European variant progressed at 3 months. CONCLUSION: No radiosensitivity difference was established, probably because of the limited population. Non-European variant aggressiveness might be suggested in accordance with the literature, as it was associated with the only tumour progression. Exclusive radiotherapy provides a unique and "pure" model of radioresistance in cervical cancer and could be the missing link between in vitro studies and state of the art chemoradiotherapy studies that probably feature too many parameters to identify radioresistance causes. The present study was a first step, with the future prospects of building a larger cohort study in order to better understand HPV-induced radioresistance and then to be able to propose new made-to-measure treatments.

FIGO stage IB1 cervical carcinoma: Place and principles of brachytherapy.

The treatment of cervical cancers according to FIGO staging is well defined. For FIGO stage IB2 or more, chemoradiotherapy followed by uterovaginal brachytherapy boost is the standard treatment. Surgery is the preferred choice for less advanced tumors. However, most French institutions propose preoperative brachytherapy followed by hysterectomy with pelvic lymphadenectomy for FIGO stage IB1 tumors over 2cm. Brachytherapy is also used for the boost after adjuvant pelvic external beam radiotherapy. Tridimensional dosimetry with optimization allows better treatment planning, delivering high doses to target volumes with limited irradiation to the organs at risk. We will discuss the indications of brachytherapy for FIGO stage IB1 tumors and the principles of pulsed-dose rate and high-dose rate techniques.

[Hepatic tumors and radiotherapy]. / Radiothérapie des tumeurs hépatiques.

Recent technological developments led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumors as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. For hepatocellular carcinoma 5 to 10cm (or more), a conformational radiation with or without intensity modulation is performed. Stereotactic body radiotherapy (SBRT) is being evaluated and is increasingly proposed as an alternative to radiofrequency ablative treatment for primary or secondary tumors (typically less than 5cm). Tumor (and liver) movements induced by respiratory motions must be taken into account. Strict dosimetric criteria must be met with particular attention to the dose-volume histograms to liver and the hollow organs, including cases of SBRT.

Persistent natural acidification drives major distribution shifts in marine benthic ecosystems.

Ocean acidification is receiving increasing attention because of its potential to affect marine ecosystems. Rare CO2 vents offer a unique opportunity to investigate the response of benthic ecosystems to acidification. However, the benthic habitats investigated so far are mainly found at very shallow water (less than or equal to 5 m depth) and therefore are not representative of the broad range of continental shelf habitats. Here, we show that a decrease from pH 8.1 to 7.9 observed in a CO2 vent system at 40 m depth leads to a dramatic shift in highly diverse and structurally complex habitats. Forests of the kelp Laminaria rodriguezii usually found at larger depths (greater than 65 m) replace the otherwise dominant habitats (i.e. coralligenous outcrops and rhodolith beds), which are mainly characterized by calcifying organisms. Only the aragonite-calcifying algae are able to survive in acidified waters, while high-magnesium-calcite organisms are almost completely absent. Although a long-term survey of the venting area would be necessary to fully understand the effects of the variability of pH and other carbonate parameters over the structure and functioning of the investigated mesophotic habitats, our results suggest that in addition of significant changes at species level, moderate ocean acidification may entail major shifts in the distribution and dominance of key benthic ecosystems at regional scale, which could have broad ecological and socio-economic implications.