Case report: BRAF-inhibitor therapy in BRAF-mutated primary CNS tumours including one case of BRAF-mutated Rosai-Dorfman disease.

BRAF V600E oncogene mutations have been reported in multiple central nervous system (CNS) tumor types, and emerging evidence supports the use of targeted therapy in BRAF-mutated gliomas. BRAF oncogene mutations have been recently identified in Rosai-Dorfman disease (RDD)-a rare non-Langerhans cell histiocytosis. This series describes three patients from two neurosurgical centers in Ireland with BRAF V600E-mutated CNS tumors. The study participants include a 19-year-old male patient with ganglioglioma with anaplastic features, a 21-year-old male patient with CNS involvement of RDD, and a 28-year-old female patient with ganglioglioma with anaplastic features. Two patients received radiation with concurrent temozolomide before BRAF-targeted therapy. This case series describes clinical and radiological responses to BRAF-targeted therapy in BRAF V600E-mutated gliomas across multiple tumor grades and is only the second published report of response to targeted therapy in BRAF-mutated RDD. The durability of disease control with BRAF-targeted therapy was generally superior to that achieved with chemoradiation; one patient has experienced ongoing disease control for 5 years. The reported case of treatment response in BRAF-mutated RDD supports the strategy of genotyping and utilization of targeted therapy in this rare disease. The optimal sequencing of BRAF-targeted therapy in BRAF-mutated gliomas/glioneuronal tumors remains unclear, and further prospective studies are required to guide the use of genome-matched therapy in this patient population.

Multicystic Encephalomalacia: The Neuropathology of Systemic Neonatal Parechovirus Infection.

The Neuropathology of Human Parechovirus (HPeV) is not widely described due to the relatively recent discovery of the virus combined with a limited number of autopsy case reports. We report the case of an infant boy born at 38 weeks who, six days after birth, presented with fever and severe neurological dysfunction. Human Parechovirus Type 3 (HPeV3) RNA was detected in his cerebrospinal fluid (CSF) and blood. He died five days after his initial presentation. Neuropathologic examination demonstrated multicystic encephalomalacia (ME). This case report confirms that white matter pathology is dominant in HPeV3 infection. A unique feature, of HPeV encephalomalacia is absence of CSF pleocytosis and minimal inflammation in the meninges. The findings permit comment on the pathogenesis of brain injury by this virus.

A Surviving Case of Acanthamoeba Granulomatous Amebic Encephalitis in a Hematopoietic Stem Cell Transplant Recipient.

BACKGROUND Acanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant. CASE REPORT We report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation. CONCLUSIONS We report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.

Granulomatous interstitial nephritis secondary to adalimumab therapy.

Tumour necrosis factor α (TNF-α) inhibitors are frequently used for the treatment of immune-mediated diseases. Conversely, cytokine therapy has the potential to paradoxically induce autoimmunity. A number of case reports have emerged concerning sarcoid-like granulomatosis secondary to TNF-α therapy, an adverse effect that typically affects the pulmonary and cutaneous systems. Granulomatous interstitial nephritis (GIN) is a relatively unknown, relatively under-reported consequence of adalimumab therapy that can have important clinical implications. To our knowledge, this is the first case report of GIN secondary to anti-TNF-α therapy necessitating a prolonged period of dialysis and the first report demonstrating the successful use of secukinumab as an alternative immunomodulatory agent.

Lack of age-specific influence on leg blood flow during incremental calf plantar-flexion exercise in men and women.

PURPOSE: Age-related exercising leg blood flow (LBF) responses during dynamic knee-extension exercise and forearm blood flow responses during handgrip exercise are preserved in normally active men but attenuated in activity-matched women. We explored whether these age- and sex-specific effects are also apparent during isometric calf plantar-flexion incremental exercise. METHODS: Normally active young men (YM, n = 15, 24 ± 2 years), young women (YW, n = 8, 22 ± 1 years), older men (OM, n = 13, 70 ± 7 years) and older women (OW, n = 10, 64 ± 7 years) were tested. LBF was measured between contractions using venous occlusion plethysmography. RESULTS: Peak force obtained was higher (P < 0.05) in men compared with women and in young compared with older individuals. However, peak LBF (YM; 971 ± 328 ml min-1, OM; 985 ± 504 ml min-1, YW; 844 ± 366 ml min-1, OW; 960 ± 244 ml min-1) and peak leg vascular conductance [LVC = LBF/(MAP + hydrostatic pressure)] responses (YM; 6.0 ± 1.8 ml min-1 mmHg-1, OM; 5.5 ± 2.8 ml min-1 mmHg-1, YW; 5.3 ± 2.1 ml min-1 mmHg-1, OW; 5.5 ± 1.6 ml min-1 mmHg-1) were similar among the four groups. Furthermore, the hyperaemic (YM; 8.8 ± 3.7 ml min-1 %Fpeak-1 OM; 8.3 ± 5.4 ml min-1 %Fpeak-1, YW; 8.2 ± 3.5 ml min-1 %Fpeak-1, OW; 9.6 ± 2.2 ml min-1 %Fpeak-1) and vasodilatory responses (YM; 0.053 ± 0.020 ml min-1 mmHg-1 %Fpeak-1, OM; 0.048 ± 0.028 ml min-1 mmHg-1 %Fpeak-1, YW; 0.051 ± 0.019 ml min-1 mmHg-1 %Fpeak-1, OW; 0.055 ± 0.014 ml min-1 mmHg-1 %Fpeak-1) were not different among the four groups. These results were accompanied by similar resting LBF responses among groups and were not affected when data were normalised to estimated leg muscle mass. CONCLUSIONS: Our results demonstrate that exercising LBF responses during isometric incremental calf muscle exercise are preserved in older men and women, suggesting that the previously observed age-related attenuations in leg and forearm hyperaemia among women may be muscle-group specific.