RESUMO
La enfermedad de Lhermitte-Duclos, o gangliocitoma displásico cerebeloso, es una rara entidad que se manifiesta como un proceso expansivo de crecimiento lento en la fosa posterior, específicamente en el cerebelo, con una patogenia no muy bien comprendida, que puede estar relacionada con anomalías congénitas y mutaciones del gen PTEN (fosfatasa y homólogo de tensina) sobre todo en la forma de presentación adulta. Los casos documentados de esta enfermedad son escasos, con alrededor de 230 registros en la literatura médica y una prevalencia menor a 1 por cada millón de personas. Presentamos el primer caso en Paraguay de Enfermedad de Lhermitte-Duclos en un paciente masculino de 44 años, sin antecedentes médicos o familiares relevantes, que fue intervenido quirúrgicamente por proceso expansivo de fosa posterior, con hallazgos característicos en la resonancia magnética, que permitió sospechar preoperatoriamente de la enfermedad, con diagnóstico diferencial de meduloblastoma, debido a restricciones observadas en la secuencia de Difusión. La resección fue completa con adecuada evolución y sin recaídas del proceso.
Lhermitte-Duclos disease, or cerebellar dysplastic gangliocytoma, is a rare entity that manifests as a slow-growing expansive process in the posterior fossa, specifically in the cerebellum, with a pathogenesis that is not well understood, which may be related to congenital anomalies and PTEN gene mutations (phosphatase and tensin homologue), especially in the form of adult presentation. Documented cases of this disease are scarce, with around 230 records in the medical literature and a prevalence of less than 1 per million people. We present the first case in Paraguay of dysplastic gangliocytoma or Lhermitte-Duclos disease in a 44-year-old male patient, with no relevant medical or family history, who underwent surgery due to an expansive process in the posterior fossa, with characteristic findings on magnetic resonance, which allowed preoperative suspicion of the disease, with differential diagnosis of medulloblastoma, due to restrictions observed in the Diffusion sequence. The resection was complete with adequate evolution and without relapses of the process. Keywords: Lhermitte- Duclos; Gangliocytoma; dysplastic; cerebellar; neuroradiology.
RESUMO
Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance.
