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Neuro-oncology Oct 2022Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors...
BACKGROUND
Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non-small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors.
METHODS
STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D.
RESULTS
At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4).
CONCLUSIONS
Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions.
Topics: Benzamides; Carcinoma, Non-Small-Cell Lung; Child; Humans; Indazoles; Lung Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Young Adult
PubMed: 35395680
DOI: 10.1093/neuonc/noac087 -
Medicine and Pharmacy Reports Aug 2021Whipple's disease (WD) is a rare chronic systemic disease caused by the Gram-positive bacillus Tropheryma whipplei. Despite over 100 years of observation and study...
BACKGROUND
Whipple's disease (WD) is a rare chronic systemic disease caused by the Gram-positive bacillus Tropheryma whipplei. Despite over 100 years of observation and study history of this disease, it still remains a difficult diagnostic and therapeutic challenge.
CLINICAL CASE PRESENTATION
Authors report the case of a 38-year-old man with long-time PPIs treatment because of GERD and no other clinical and paraclinical symptoms. Endoscopic slightly enlarged villi, accumulation of whitish matter at the tip of the villi of distal duodenal mucosa and periodic acid-Schiff staining positive inclusions in the stromal tissue may be typical signs of Whipple's disease. In discussion the possible explication of this case are presented.
CONCLUSIONS
It is still a challenge to diagnose Whipple's disease. Histological findings may confirm the diagnosis in patients with a combination of typical clinical manifestations, but histological signs alone are not pathognomic, and are not enough for a definitive diagnosis.
PubMed: 34527918
DOI: 10.15386/mpr-2237 -
Acta Neuropathologica Oct 2022Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or...
Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.
Topics: Adult; Astrocytoma; Brain Neoplasms; Glioma; Homozygote; Humans; Neurofibromatosis 1; Sequence Deletion
PubMed: 35945463
DOI: 10.1007/s00401-022-02478-5 -
Cureus Jul 2023Whipple's disease is a rare systemic disease caused by a infection. Although older literature reports a low rate of incidence, case reports continue to rise due to...
Whipple's disease is a rare systemic disease caused by a infection. Although older literature reports a low rate of incidence, case reports continue to rise due to increased awareness of the disease. Classic Whipple's disease presents as weight loss, diarrhea, and arthralgia and may involve the heart, central nervous system (CNS), or any other organ system. Some patients with Whipple's disease do not have the classic signs and symptoms of the disease. We present a case of Whipple's disease in a patient with poor appetite, weight loss, and granulomatous inflammation of various organs, including the kidneys and spleen, mimicking sarcoidosis. She had presented three years earlier with acute kidney injury (AKI) and hypercalcemia. The renal biopsy revealed diffuse granulomatous interstitial nephritis. Both AKI and hypercalcemia resolved with prednisone; however, her weight loss and decreased appetite continued. The initial positron emission tomography (PET) scan showed increased fluorodeoxyglucose (FDG) avidity in the spleen and large intestine, and the splenic biopsy revealed non-caseating granulomas. A diagnosis of sarcoidosis was made, and she was started on methotrexate with prednisone. Nevertheless, the weight loss and poor appetite were relentless. A repeat PET scan showed increased FDG avidity in loops of the small and large intestines. A small intestinal biopsy revealed positive periodic acid-Schiff (PAS) and negative acid-fast bacilli (AFB) revealing the diagnosis of Whipple's disease. Whipple's disease should be considered in the differential diagnosis of sarcoidosis, especially in those patients worsening on standard immunosuppression.
PubMed: 37575808
DOI: 10.7759/cureus.41839 -
Clinical Liver Disease Mar 2021
Review
PubMed: 33868662
DOI: 10.1002/cld.1004 -
Surgical Neurology International 2022Whipple disease (WD) is an infection caused by , which might present in three different forms: classical, localized, and isolated in the central nervous system (CNS). (Review)
Review
BACKGROUND
Whipple disease (WD) is an infection caused by , which might present in three different forms: classical, localized, and isolated in the central nervous system (CNS).
METHODS
We report the result of a systematic review of the literature on WD unusually presenting with exclusively neurological symptoms, including two previously unpublished cases. A description of two cases with isolated CNS WD was performed, as well as a literature search in , and .
RESULTS
Two male adult patients presented with exclusively neurological symptomatology. Both magnetic resonance imaging (MRI) showed an intracranial mass suggestive of brain tumor. The histopathological examination was consistent with WD, with no systemic involvement. In the review of the literature, 35 cases of isolated CNS WD were retrieved. The median age at diagnosis was 43.5 (IQR 31.5-51.5). In 13 patients, the MRI showed a brain mass consistent with a brain tumor. The most common finding in the biopsy was the periodic-acid Schiff-stained foamy macrophages. Only five cases presented the pathognomonic sign of oculomasticatory myorhythmia. Thirteen cases had an adverse outcome that resulted in death during follow-up, whereas another 13 improved. The other nine patients remained stable or presented moderate improvement.
CONCLUSION
Isolated CNS WD is a rare disease that should be considered among the differential diagnosis of CNS mass lesions. Brain biopsy is necessary to establish the diagnosis. It is stressed in the literature that an extended antibiotic course is required to prevent relapses and to control the disease.
PubMed: 36324907
DOI: 10.25259/SNI_591_2022