La macrobiopsia endoscópica en el diagnóstico de la enfermedad de Menetrier

For the anatompathological diagnosis of Menetrier's disease to be made, it is necessary to have a biopsy covering the entire thickness of the mucosa. Until a few years ago, to obtain this it was necessary to resort to a surgical biopsy performed during the course of a laparotomy. We present our experience in 6 patients suffering from this disease, in whom the conventional biopsies taken during the course of a gastroscopy, did not enable us to make the anatomopathological diagnosis of the said entity. The performing during the same exploration of an endoscopic macrobiopsy taken with a polypectomy loop provided us with the diagnosis. The simplicity, harmlessness and abscence of complications as well as its diagnostic efficiency, along with the fact that a laparotomy is avoided, mean that this technique is vitally important in the diagnosis of Menetrier's disease

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs

Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System

Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032)

Desarrollo de un nuevo modelo ortotópico de tumor difuso de protuberancia (DIPG) en ratón a través de sistema guiado por bolt. Nuevas vías de tratamiento en modelos preclínicos de DIPG

Los tumores difusos de protuberancia (DIPG) constituyen los tumores más frecuentes del troncoencéfalo en el rango de edad de 0-19 años y junto con otras entidades como los ATRT y los PNET representan los tumores pediátricos con peor pronóstico. Presentan un comportamiento clínico rápidamente progresivo con desarrollo de los síntomas en menos de 3 meses con afectación cerebelosa, vías descendentes largas y pares craneales. Su diagnóstico estaba basado en la presencia de una lesión difusa en la protuberancia y un cuadro clínico compatible. Presentan un comportamiento agresivo con unas medianas de supervivencia que oscilan en torno a 8-11 meses. El único tratamiento eficaz que ha demostrado controlar temporalmente la enfermedad es la radioterapia. Ningún esquema de quimioterapia ha demostrado ninguna eficacia. El desarrollo de protocolos de biopsias ha permitido caracterizar genéticamente estas lesiones. Existen 3 grupos de alteraciones que regulan la oncogénesis en DIPG: vías carcinogénicas canónicas, alteración en genes reguladores de la cromatina y otros genes. Si nos centramos en las mutaciones que regulan la transcripción de la cromatina, encontramos mutaciones recurrentes a nivel de la Histona 3 (genes H3F3A e HIST1H3B) las cuales pueden presentar mutaciones a nivel de dos residuos de la histona correspondiente: K27M y G34V/R. Inicialmente tratamos de establecer la validez de un modelo in vivo ortotópico de DIPG el cual buscaba superar alguna de las limitaciones de las técnicas establecias hasta ahora basadas en estereotaxia. En primer lugar, establecimos un nuevo modelo ortotópico de DIPG a través de la inserción de un tornilo o bolt a nivel de unas coordenadas específicas en la fosa posterior del animal localizando la coordenada de profundidad a 6.5 mm. Tras haber validado el modelo de DIPG, el siguiente paso era establecer la toxicidad de la radioterapia. Establecimos un protocolo de administración de dicha terapia en nuestro modelo animal. Para ello realizamos inicialmente una escalada de dosis y dividimos un grupo control y un grupo terapeútico aleatorizado a recibir dosis crecientes de 4,6,8 y 12 Gy. Los resultados obtenidos confirman que la radioterapia, al igual que lo que sucede en un paciente con DIPG, constituye una terapia eficaz. Por tanto, una vez evaluada la viabilidad de la radioterapia en nuestro modelo animal seleccionamos la dosis de 6 Gy para evitar efectos inmunosupresores derivados de dosis mayores como 8-10 Gy. El siguiente paso fue evaluar la eficacia de un nuevo esquema inmunomodulador aplicado en nuesto modelo de DIPG con el fin de apoyar una traslación de inmunoterapia a la práctica clínica. DIcho experimento constaba de 4 grupos: control, anticuerpo anti-4-1BB en monoterapia, radioterapia (6Gy), y combinación de ambas estrategias terapeúticas. El grupo control desarrolló signos de afectación de tronco de forma precoz. Respecto a los grupos de monoterapia, la radioterapia demostró mayor eficacia respecto al anticuerpo. Finalmente el grupo con la combinación, radioterapia y anticuerpo, alcanzó un beneficio en supervivencia estadísticamente significativo. Se realizó una determinación de CD3, confirmando la generación de una respuesta inmune como responsable del efecto clínico generado. Dicho efecto permite concluir que la generación de una respuesta inmune robusta puede constituir una terapia válida en el futuro de los DIPG aunque requerirá de nuevos esudios mecanísticos más exhautivos

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences

Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System

International audienceObjective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model