Sherry Krawitz

Outcomes of persons with blastomycosis involving the central nervous system

Blastomyces dermatitidis is a dimorphic fungus which is potentially life-threatening if central nervous system (CNS) dissemination occurs. Sixteen patients with proven or probable CNS blastomycosis are presented. Median duration of symptoms was 90 days; headache and focal neurologic deficit were the most common presenting symptoms. Magnetic resonance imaging (MRI) consistently demonstrated an abnormality, compared to 58% of computed tomography scans. Tissue culture yielded the pathogen in 71% of histology-confirmed cases. All patients who completed treatment of an amphotericin B formulation and extended azole-based therapy did not relapse. Initial nonspecific symptoms lead to delayed diagnosis of CNS blastomycosis. A high index of suspicion is necessary if there is history of contact with an area where B. dermatitidis is endemic. Diagnostic tests should include MRI followed by biopsy for tissue culture and pathology. Optimal treatment utilizes a lipid-based amphotericin B preparation with an extended course of voriconazole.

Chronic Traumatic Encephalopathy-Like Abnormalities in a Routine Neuropathology Service

Chronic traumatic encephalopathy (CTE) has been described mainly in professional athletes and military personnel and is characterized by deposition of hyperphosphorylated tau at the depths of cortical sulci and around blood vessels. To assess CTE-like changes in a routine neuropathology service, we prospectively examined 111 brains (age 18–60 years). The presence of tau-immunoreactive deposits was staged using guidelines described by others and was correlated with the medical history. 72/111 cases were negative for CTE-like changes; 34/111 were CTE stage <1; 3/111 were CTE stage 1; and 2/111 were CTE stage 2. The combined history of head injury and alcohol and/or drug abuse was a significant predictor of any CTE-like changes. Age was also a significant predictor; most with any CTE-like changes were >40 years old. CTE-like changes were not identified at sites of contusion. Among a separate group studied retrospectively, we identified 4 cases that met full criteria for CTE. We conclude that CTE-like findings are not confined to professional athletes; the risk factors of head injury and substance abuse are similar in the routine population. However, the significance of very small hyperphosphorylated tau deposits remains to be determined. In addition, the absence of typical CTE-like deposits near contusion sites keeps open the question of pathogenesis.

Platinum (IV) coiled coil nanotubes selectively kill human glioblastoma cells

UNLABELLED Malignant glioma are often fatal and pose a significant therapeutic challenge. Here we have employed α-helical right handed coiled coils (RHCC) which self-assemble into tetrameric nanotubes that stably associate with platinum (Pt) (IV) compound. This Pt(IV)-RHCC complex showed superior in vitro and in vivo toxicity in human malignant glioma cells at up to 5 fold lower platinum concentrations when compared to free Pt(IV). Pt(IV)-RHCC nanotubes activated multiple cell death pathways in GB cells without affecting astrocytes in vitro or causing damage to normal mouse brain. This Pt(IV)-RHCC nanotubes may serve as a promising new therapeutic tool for low dose Pt(IV) prodrug application for highly efficient and selective treatment of human brain tumors. FROM THE CLINICAL EDITOR The prognosis of malignant glioma remains poor despite medical advances. Platinum, one of the chemotherapeutic agents used, has significant systemic side effects. In this article, the authors employed α-helical right handed coiled coil (RHCC) protein nanotubes as a carrier for cisplatin. It was shown that the new compound achieved higher tumor kill rate but lower toxicity to normal cells and thus may hold promise to be a highly efficient treatment for the future.

Dovitinib enhances temozolomide efficacy in glioblastoma cells

The multikinase inhibitor and FDA‐approved drug dovitinib (Dov) crosses the blood–brain barrier and was recently used as single drug application in clinical trials for GB patients with recurrent disease. The Dov‐mediated molecular mechanisms in GB cells are unknown. We used GB patient cells and cell lines to show that Dov downregulated the stem cell protein Lin28 and its target high‐mobility group protein A2 (HMGA2). The Dov‐induced reduction in pSTAT3Tyr705 phosphorylation demonstrated that Dov negatively affects the STAT3/LIN28/Let‐7/HMGA2 regulatory axis in GB cells. Consistent with the known function of LIN28 and HMGA2 in GB self‐renewal, Dov reduced GB tumor sphere formation. Dov treatment also caused the downregulation of key base excision repair factors and O6‐methylguanine‐DNA‐methyltransferase (MGMT), which are known to have important roles in the repair of temozolomide (TMZ)‐induced alkylating DNA damage. Combined Dov/TMZ treatment enhanced TMZ‐induced DNA damage as quantified by nuclear γH2AX foci and comet assays, and increased GB cell apoptosis. Pretreatment of GB cells with Dov (‘Dov priming’) prior to TMZ treatment reduced GB cell viability independent of p53 status. Sequential treatment involving ‘Dov priming’ and alternating treatment cycles with TMZ and Dov substantially reduced long‐term GB cell survival in MGMT+ patient GB cells. Our results may have immediate clinical implications to improve TMZ response in patients with LIN28+/HMGA2+ GB, independent of their MGMT methylation status.

A de novo dominant mutation in ACTA1 causing congenital nemaline myopathy associated with a milder phenotype: Expanding the spectrum of dominant ACTA1 mutations

We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene (ACTA1) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype-phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations.

Intracranial atypical teratoid/rhabdoid tumor presenting as an axillary mass: a case report and review of literature.

Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon, high-grade pediatric malignancy of the central nervous system (CNS) that rarely metastasizes outside the CNS (Chang stage M4). We describe a child with the sole metastasis of an AT/RT to an axillary lymph node and no other site of extra-CNS disease at presentation. The tumor included areas of rhabdoid cells and failed to express the SMARCB1 gene product (INI1). The metastatic site in this patient is unusual for 3 reasons: (1) it is anatomically unexpected for a CNS tumor, (2) no other extra-CNS metastasis or primary tumor outside the CNS was found, and (3) no cardiac septal defect or vascular anomaly was identified. This site as the presenting lesion and sole metastasis of an intracranial AT/RT has not been previously reported. We attempt to explain this phenomenon.

Blastomyces species and orbital apex syndrome: Unsuspected co-infection

Blastomyces species are thermally dimorphic fungi existing as yeast in tissue. We report an initially immunocompetent patient with orbital apex syndrome (OAS) whose presentation suggested giant cell arteritis. Subsequently, metastatic carcinoma was entertained as a cause of OAS until bronchoscopy yielded Blastomyces species. The patient rapidly succumbed with multiorgan failure despite Amphotericin B administration. At post-mortem, Blastomyces co-infection with fungal hyphae in keeping with Aspergillus species was found in cavernous sinus and in infarcted optic nerve. To the best of our knowledge, co-infection with these two organisms in this clinical setting has not been reported.