Temozolomide, a key drug in the treatment of malignant glioma, can cause profound lymphopenia and various opportunistic infectious diseases. A 79-year-old woman with anaplastic oligodendroglioma developed a fever and gross hematuria after 8 weeks of standard radiotherapy with concomitant temozolomide treatment. A cytomegalovirus (CMV) antigen test for pp65 antigenemia was positive (137 cells per 75,800 leukocytes), and the findings from a urine cytology test were consistent with CMV-induced hemorrhagic cystitis. She was treated with ganciclovir, and her condition improved. CMV monitoring is needed when patients develop symptoms related to opportunistic infections during temozolomide treatment for malignant glioma.

Unilateral lambdoid synostosis (ULS) is a rare suture anomaly and its diagnosis and treatment remain controversial. We investigated how to improve their function and morphology through the review of two cases of ULS with improved function and morphology by the same unreported operative procedure. Moreover, we discussed the diagnosis and treatment of ULS. Case 1 involved a 15-month-old female, brought for consultation because of suspected right ULS. She was diagnosed with right lambdoid and squamous synostoses and approximately 15 mm descent of the cerebellar tonsil. Thus, we performed foramen magnum decompression, first cervical vertebra laminectomy, and skull lengthening. Case 2 involved an 18-month-old female. She also consulted for suspected right ULS. Computed tomography revealed right ULS and squamous synostosis and magnetic resonance imaging showed approximately 9 mm descent of the cerebellar tonsil. We performed foramen magnum decompression and skull lengthening. Both procedures included decompression of the foramen magnum. We enforced osteotomy of the affected side of the lambdoid suture by crossing the superior sagittal sinus and added horizontal osteotomy from the superior right squamous suture to the coronal suture. Three extension devices were placed, two and one in the lambdoid and squamous sutures, respectively. After skull extension and descent of the cerebellar tonsil, exertion of the left frontal bone was improved. In cases of ULS, the squamous suture fusion and the drooping of the cerebellar tonsils can be complicated. Extending the lambdoid suture upward and downward and decompressing the posterior cranial fossa may improve the morphological and functional prognoses.

The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.