Carlstrom, Lucas P.

Abstract BACKGROUND Progress for gliomas is slowed in part by the paucity of mechanistic feedback during treatment with experimental therapies. Access to extracellular tumor pharmacodynamic biomarkers could provide an avenue to accelerate progress. We have initiated a program of intra-operative microdialysis to accelerate biomarker discovery and to identify candidate outcome measures for translational therapies. METHODS Intraoperative microdialysis was performed with M-dialysis 100kDA catheters and 107 variable rate pumps under an IDE. Four IDH-mutant and two IDH-WT lesions were studied intraoperatively with 3 divergently placed catheters. Microperfusate (artifical CSF+ 3% dextran) was perfused at 2uL/min and collected in 20 min increments. Paired CSF was also obtained when accessible. A parallel cohort of nude mice bearing human IDH-mutant, IDH-WT, or sham intracranial xenografts (n=6-12) underwent intratumoral microdialysis. A pilot murine study of intracranial drug delivery was performed via concurrent microdialysis during convection-enhanced delivery (CED) of saline or the IDH-inhibitor AG120. RESULTS Microdialysate from IDH-mutant intracranial xenografts revealed >100 differentially abundant metabolites compared to sham or IDH-WT tumors, including D2-HG (21x) and MTA(18x), p< 10^-5. The most significantly abundant metabolite was DMA (4x, p< 10^-10). 15-1000uM D2HG was recovered from intra-operative human IDH-mutant tumors and 1-2uM from normal brain adjacent to IDH-WT gliomas and < 1uM in all IDH-WT samples. Forty metabolites differentiated enhancing tumor from adjacent brain in 3/3 paired human samples including upregulated Aminoacyl-tRNA biosynthesis and downregulated purine metabolism. Serial aliquots of microdialysate during saline CED yielded steady D2-HG levels whereas CED with AG120 yielded undetectable D2-HG within 6 hours. CONCLUSION The extracellular metabolic landscape of glioma is diverse, dynamic and reflects tumor biology and response to therapy. Collectively, these studies suggest that intra-tumoral drug testing should be feasible with realistic expectation of gaining metabolic feedback within a short timeframe. Leveraging this paradigm can provide opportunities to accelerate therapeutic translation for gliomas.

OBJECTIVE The authors’ objective was to reevaluate the role of microsurgery for epidermoid tumors by examining the associations between extent of resection (EOR), tumor control, and clinical outcomes. METHODS This was a retrospective study of patients with microsurgically treated intracranial epidermoid tumors. The recurrence-free and intervention-free rates were calculated using the Kaplan-Meier method. EOR was graded as gross-total resection (GTR) (total resection without residual on MRI), near-total resection (NTR) (a cyst lining was left in place), subtotal resection (STR) (> 90% resection), and partial resection (PR) (any other suboptimal resection) and used to stratify outcomes. RESULTS Sixty-three patients with mean clinical and radiological follow-up periods of 87.3 and 81.8 months, respectively, were included. Sixteen patients underwent second resections, and 5 underwent third resections. The rates of GTR/NTR, STR, and PR were 43%, 35%, and 22%, respectively, for the initial resections; 44%, 13%, and 44% for the second resections; and 40%, 0%, and 60% for the third resections (p < 0.001). The 5- and 10-year cumulative recurrence-free rates after initial resection were 64% and 32%, respectively. When stratified according to EOR, the 10-year recurrence-free rate after GTR/NTR was marginally better than that after STR (61% vs 35%, p = 0.130) and significantly better than that after PR (61% vs 0%, p < 0.001). The recurrence-free rates after initial microsurgery were marginally better than those after second surgery (p = 0.102) and third surgery (p = 0.065). The 5- and 10-year cumulative intervention-free rates after initial resection were 91% and 58%, respectively. When stratified according to EOR, the 10-year intervention-free rate after GTR/NTR was significantly better than that after STR (100% vs 51%, p = 0.022) and PR (100% vs 27%, p < 0.001). The 5-year intervention-free rate after initial surgery was marginally better than that after second surgery (52%, p = 0.088) and significantly better than that after third surgery (0%, p = 0.004). After initial, second, and third resections, permanent neurological complications were observed in 6 (10%), 1 (6%), and 1 (20%) patients, respectively. At the last follow-up visit, 82%, 23%, and 7% of patients were free from radiological recurrence after GTR/NTR, STR, and PR as the initial surgical procedure, respectively. CONCLUSIONS GTR/NTR seems to contribute to better disease control without significantly impairing functional status. Initial resection offers the best chance to achieve better EOR, leading to better disease control.

Abstract BACKGROUND AND IMPORTANCE Progressive episodic spells of altered levels of consciousness, often advancing to include paroxysmal autonomic instability, may be indicative of a diencephalic dysfunction underlying spontaneous intracranial hypotension (SIH). A rare, and often indolent, etiology may be spinal cerebrospinal fluid (CSF) leak—an elusive diagnosis, especially in cases of CSF-venous fistula (CVF) that are often missed on routine computed tomography (CT) myelography and magnetic resonance imaging (MRI). CLINICAL PRESENTATION We report an unusual case of a 50-yr-old woman who presented with rapidly progressive cyclical, self-resolving episodes of altered mentation and decreased arousal later in the day. Scrutiny of serial brain MRIs led to a diagnosis of SIH, with severe downward diencephalic and brain stem displacement—resulting in cerebral aqueduct occlusion with obstructive hydrocephalus. Initial clinical improvement occurred with CSF diversion, but the patient quickly deteriorated—developing diencephalic spells, including extensor posturing and severely depressed levels of consciousness. Clinical improvement was seen with stopping CSF diversion and Trendelenburg-positioning. After intensive spinal imaging, dynamic CT myelography identified a left T10 nerve root diverticula and CSF-venous fistula. Surgical obliteration resulted in rapid, profound neurological improvement, and ultimately full neurological recovery by 1 yr. CONCLUSION In our patient, worsening episodes of confusion, postural headaches, and autonomic instability developed due to SIH, which induced profound downward displacement and compression of the diencephalon and brain stem, and accompanied by subsequent obstructive hydrocephalus. Diagnostic persistence identified the CVF, which had caused the complex multifold pathophysiology and clinical presentation. If suspicion remains high for CVF, persistent spinal imaging, particularly with dynamic myelography, may be crucial.

Abstract Objective Cerebrovascular complications (CVC) are rare consequences of vestibular schwannoma (VS) surgery. Our objective was to assess incidences of findings suggestive of postoperative CVC in a large single surgeon cohort, as well as potential risk factors, and implications. Study Design A cohort of 591 patients was retrospectively reviewed. Postoperative magnetic resonance images were screened for findings suggestive of stroke, T2 hyperintensity in the cerebellopontine angle structures or new encephalomalacia. Clinical records were queried for findings consistent with postoperative CVC. Results In total, 61 patients had radiographic findings consistent with possible postoperative CVC (10%); of them, eight had documented intraoperative vascular injury (1.4%), and four had postoperative clinical exam changes indicative of CVC (0.7%). Clinically manifest intraoperative vascular injuries occurred in four patients and involved the petrosal venous complex (n = 3, 5%) or anterior inferior cerebellar artery (n = 1, 2%); clinical deficits included hemiparesis (n = 1, 2%), facial anesthesia (n = 2, 4%), dysphagia (n = 2, 2%), and unfavorable facial nerve function in two (50%). Three out of four patients in this group required out-of-home placement (75%). Clinical CVCs (n = 4) were not significantly associated with tumor size, tumor cyst, gross total resection, or length of stay. Patients with clinical CVC were significantly more likely to require posthospitalization rehabilitation (19 vs. 75%, p = 0.02; 14 vs. 100%, p = 0.0002). Conclusion Although radiographic findings suggestive of CVC were unexpectedly common in this cohort, intraoperative vascular injury and postoperative clinical CVC were exceedingly rare. The association between unfavorable facial nerve outcome and clinical CVC is likely a marker for more difficult operations, predisposing to higher risk of complications.

A 25-year-old man presented with left-sided hearing loss, blurred vision and papilloedema. Imaging revealed a large, left-sided, contrast-enhancing cerebellopontine mass causing obstructive hydrocephalus, consistent with vestibular schwannoma (VS). Following an incomplete resection via retrosigmoid craniotomy at an outside facility, he was referred to our department, and cerebrospinal fluid diversion followed by repeat resection was recommended. A subtotal resection was achieved, and the patient was subsequently treated with adjuvant stereotactic radiosurgery (SRS). Progressive interval growth was observed on serial post-SRS MRI studies; correspondingly, at 31 months after treatment, the patient was initiated on antiprogrammed-death receptor 1 (PD-1) antibody treatment with pembrolizumab. Growth arrest was noted on subsequent serial imaging studies, which have been maintained for a total of 30 months since initiation of a 18-month anti-PD-1 course of therapy. Additional case accumulation and translational study is required to better characterise this therapeutic strategy; however, PD-1/programmed death-ligand 1 inhibition may offer a promising salvage therapy for refractory VS.

Abstract Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system, with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors presents opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from patient-derived xenografts (PDX) harboring mutant IDH-1 (R132H). Perfusates were collected from intra-cranial tumors in athymic nude mice sampled at baseline and 72h post treatment with temozolomide (TMZ), an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment. Perfusates were analyzed via untargeted metabolomic profiling using liquid chromatography-mass spectrometry. Tumor specific metabolites such as (D)-2 hydroxyglutarate, were detected in microdialysate from IDH-1 mutant tumor bearing mice compared to non-tumor bearing mice. We also found high levels of metabolites such as 5-methylthioadenosine, and dimethylarginine and wide range of amino acids in microdialysate from IDH-1 mutant tumor bearing mice. TMZ treatment induced changes to metabolites in creatine and histidine metabolism. Our results indicate that microdialysis is a feasible technology to identify metabolomics-based biomarkers in IDH1-mutant gliomas and their response to therapy. We suggest that in vivo intratumoral microdialysis over several days could yield metabolic pharmacodynamic biomarkers of value to therapeutic translation for IDH-mutant gliomas.