Biodistribution and pharmacokinetics of [89Zr]-anti-VEGF mAbs using PET in glioblastoma rat models.

INTRODUCTION: Glioblastomas present intensive angiogenesis, thus anti-Vascular Endothelial Growth Factor (VEGF) antibodies (mAbs) have been proposed as promising therapies. However, the results of clinical trials reported moderate toxicity and limited effectiveness. This study evaluates the in vivo pharmacokinetics and biodistribution of these mAbs in a growing model of glioblastoma in rats using Positron Emission Tomography (PET). MATERIAL: &Methods: mAbs were radiolabeled with zirconium-89. Four days after the model induction, animals were injected with 2.33 ± 1.3 MBq of [89Zr]-DFO-bevacizumab (n = 8) or 2.35 ± 0.26 MBq of [89Zr]-DFO-aflibercept (n = 6). PETs were performed at 0H, 48H, 168H, 240H, and 336H post-injection. Tumor induction was confirmed using [18F]-Fluorodeoxyglucose-PET and immunohistochemistry. Radiotracer uptake was estimated in all pre-defined Volumes-of-Interest. RESULTS: Anti-VEGF mAbs showed 100 % Radiochemical-Purity. [89Zr]-DFO-bevacizumab showed a significantly higher bioavailability in whole-blood. A significant increase in the tumor uptake was detectable at 168H PET with [89Zr]-DFO-bevacizumab meanwhile with [89Zr]-DFO-aflibercept it was only detectable at 336H. [89Zr]-DFO-bevacizumab tumor uptake was significantly higher than that of [89Zr]-DFO-aflibercept in all the scans. Tumor induction was confirmed in all animal models. CONCLUSION: MAbs detect VEGF-expression in glioblastoma models. Tumors were earlier targeted by Bevacizumab. The lower blood availability of aflibercept resulted in a lower tumor uptake than bevacizumab in all the scans.

Primary pulmonary angiosarcoma, an exceptional neoplasm with a poor prognosis: reports of two cases and review of the literature.

Primary pulmonary angiosarcoma is a rare type of malignant vascular tumour characterised by proliferation of tumour cells with endothelial features. Up to date, only sixteen cases have been reported in English Literature. Treatment modalities vary from none to surgery, chemotherapeutic regimens, radiotherapy or immunotherapy, but none of them have been shown to be effective. Unfortunately, these tumours are usually very aggressive and overall mortality is very high. We present two cases of patients with a diagnosis of primary pulmonary angiosarcoma, the largest case series ever described, and a review of the scientific literature.

Multiple congenital familial smooth muscle hamartoma in two siblings.

Smooth muscle hamartoma (SMH) is a cutaneous malformation mainly composed of a disorganized proliferation of normal muscle fibers that arise from arrector pili. It usually presents as a single congenital lesion that frequently involves the back and the lower limbs. Unusual clinical presentations, such as atypical localizations, multiple disseminated lesions, and generalized forms have been rarely described. In 2001, Gualandri et al. reported the presence of multiple SMH in three members of the same family, namely two brothers and their mother. This is, as far as we know, the only familial case reported in the English literature. We herein describe a similar case affecting two siblings who presented with identical congenital lesions in the same location.

Nephrogenic adenoma: an immunohistochemical analysis using biotin-free methods.

Nephrogenic adenoma (NA) has been considered as a metaplastic process of the urothelium. It has been suggested that this lesion is of renal tubular cell origin or differentiation. Immunohistochemical studies of NA emphasize its staining with α-methylacyl-coenzyme A racemase (AMACR), and prostatic adenocarcinoma may be a possible differential diagnosis. This reactivity was recently discussed as an artifact due to endogenous biotin. Kidney-specific cadherin (Ksp-cad) is a marker of distal nephron. CD10 and KIT are also expressed in the kidney. We studied the immunohistochemical expression of AMACR, p63, Ksp-cad, CD10, and KIT in 9 cases of NA (forming a total of 12 lesions). Practically all of the lesions stained for AMACR with 2 different antibodies and 2 high-sensitivity (multimer or polymer based) biotin-free methods (83% and 100%). The staining was similar for both methods in 9 of these 12 lesions. All of the NAs were negative for p63 and KIT, except 1 case, with focal reactivity for KIT. CD10 was expressed very focally in 4 of the 12 lesions (33%). We observed weak staining for Ksp-cad in 6 lesions (50%) and 3 (25%) showed a moderate positivity in 15% to 50% of the cells. In conclusion, positivity of NA for AMACR is not an artifact, as we confirmed using 2 different methods. Besides, p63, a basal cell marker, is usually negative. Immunoreactivity for Ksp-cad seems to support the differentiation of NA to distal nephron cells, at least in some of the cases. Other markers expressed by the nephron, such as CD10 and KIT, are usually negative in NA.

[Phenotype of the C634Y mutation in the RET proto-oncogene in MEN2A: report of a family]. / Fenotipo de la mutación C634Y del protooncogén RET en el MEN2A: a propósito de una familia.

BACKGROUND AND OBJECTIVES: Genetic testing of RET proto-oncogen allows an early diagnosis of Multiple Endocrine Neoplasia syndrome type 2 and establish a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of an early diagnosis with genetic testing followed by prompt surgery on the cure of MTC versus a later diagnosis with serum calcitonin. PATIENTS AND METHOD: Retrospective descriptive study of 8 members of a MEN 2A family by C634Y mutation. We performed serum calcitonin screening until 1999 and subsequently RET genetic testing was obtained. Carriers underwent total thyroidectomy and periodic determination of calcitonin, urinary metanephrines, calcium, phosphorus and neck and abdominal imaging techniques. RESULTS: Five patients were diagnosed by calcitonin familial screening and all of them have high calcitonin by now. Three patients were diagnosed by genetic testing (an adult and two children) and they are free of disease. Calcitonin was closely monitored in children and they underwent surgery when it started to raise, at 6 and 10 years old respectively, finding nodular C-cell hyperplasia in both. Of 8 carriers 3 developed pheochromocytomas, bilateral and asynchronous, one-half had normal urinary metanephrines and two of them were simultaneous with MTC. No patient had biochemical data suggesting hyperparathyroidism although in one patient multiple parathyroid adenomas were found at thyroidectomy. CONCLUSIONS: RET genetic analysis has achieved an early diagnosis and treatment with no development of MTC in our patients, adjusting the time and type of surgery and allowing a genotype-phenotype correlation. It demonstrates how a genetic alteration is associated with a pathology that we can prevent and manage improving the prognosis of our patients.

Fenotipo de la mutación C634Y del protooncogén RET en el MEN2A: a propósito de una familia / Phenotype of the C634Y Mutation in the RET Proto-oncogene in MEN2A: Report of a Family

Antecedentes y objetivos: El estudio genético del protooncogén RET permite un diagnóstico precoz del síndrome de neoplasia endocrina múltiple tipo 2 y establece una correlación entre el genotipo y las manifestaciones clínicas. El objetivo del presente trabajo es demostrar los beneficios del diagnóstico precoz por estudio genético seguido de tratamiento temprano en la curación del carcinoma medular de tiroides (CMT) frente al diagnóstico más tardío con la calcitonina sérica. Pacientes y método: Estudio descriptivo retrospectivo de 8 miembros de una familia con MEN2A por mutación C634Y. Se realizó despistaje con calcitonina sérica hasta 1999 y estudio genético de RET posteriormente. A los portadores se les realizó tiroidectomía total y determinaciones periódicas de calcitonina, metanefrinas urinarias, calcio, fósforo y pruebas de imagen a nivelcervical y abdominal. Resultados: Los 5 pacientes diagnosticados por despistaje familiar con calcitonina presentan en la actualidad cifras de calcitonina elevadas. Los 3 diagnosticados por estudio genético (un adulto y dos niños) se encuentran libres de enfermedad. En los niños se monitorizó la calcitonina y se les intervino cuando esta comenzó a elevarse, a los 6 y 10 años respectivamente, hallándose hiperplasia nodular de células C en ambos. De los 8 afectos 3 presentaron feocromocitomas, bilaterales y asincrónicos, la mitad con metanefrinas urinarias (..) (AU)

Background and objectives: Genetic testing of RET proto-oncogen allows an early diagnosis of Multiple Endocrine Neoplasia syndrome type 2 and establish a correlation between genotype and clinical manifestations. The purpose of this study was to demonstrate the benefits of a nearly diagnosis with genetic testing followed by prompt surgery on the cure of MTC versus alater diagnosis with serum calcitonin. Patients and method: Retrospective descriptive study of 8 members of a MEN 2A family byC634Y mutation. We performed serum calcitonin screening until 1999 and subsequently RET genetic testing was obtained. Carriers underwent total thyroidectomy and periodic determination of calcitonin, urinary metanephrines, calcium, phosphorus and neck and abdominal imagingte chniques. Results: Five patients were diagnosed by calcitonin familial screening and all of them have highcalcitonin by now. Three patients were diagnosed by genetic testing (an adult and two children)and they are free of disease. Calcitonin was closely monitored in children and they underwentsurgery when it started to raise, at 6 and 10 years old respectively, finding nodular C-cellhyperplasia in both. Of 8 carriers 3 developed pheochromocytomas, bilateral and asynchronous,one-half had normal urinary metanephrines and two of them were simultaneous with MTC. Nopatient had biochemical data suggesting hyperparathyroidism although in one patient multipleparathyroid adenomas were found at thyroidectomy. Conclusions: RET genetic analysis has achieved an early diagnosis and treatment with nodevelopment of MTC in our patients, adjusting the time and type of surgery and allowing agenotype-phenotype correlation. It demonstrates how a genetic alteration is associated with apathology that we can prevent and manage improving the prognosis of our patients (AU)