Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial.

BACKGROUND: Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS: We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS: Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS: Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.

Increased Intracranial Pressure Damages Optic Nerve Structural Support.

Optic nerve sheath diameter (ONSD) is used clinically as a noninvasive measure for elevated intracranial pressure (ICP). This study had two purposes: to investigate the immediate effects optic nerve sheath (ONS) dilation post-ICP increase on trabecular fibers connecting the optic nerve to the ONS and to document any changes in these fibers 30 days post-increased ICP. In a swine model, ICP was increased by inflating a Foley catheter balloon in the epidural space. Three control pigs received the catheter insertion without inflation (no increase in ICP) and four experimental pigs received the catheter with inflation (increased ICP). The control and two randomly selected pigs with increased ICP were euthanized immediately after the procedure. The two other pigs were euthanized 30 days post-catheter inflation. For all pigs, the ONS was removed and imaged using a scanning electron microscope, calculating percent porosity values. Porosity values for the experimental groups (Immediately measured [IM] µ = 0.5749; Delayed measured [DM] µ = 0.5714) were larger than the control group (µ = 0.4336) and statistically significant (IM vs. Control, p = 0.0018; DM vs. Control, p = 0.0092). There was no significant difference (p = 0.9485) in porosity of the DM group when compared with the IM group. This study demonstrated that the trabecular fibers immediately post-increased ICP (ONS dilation) were more porous than the control and remained statistically different (more porous) after 30 days. These results suggest a structural change that occurs in the ONS with elevations in ICP.

Pediatric occipital condyle morphometric analysis using computed tomography with evaluation for occipital condyle screw placement.

OBJECTIVEOccipitocervical fusions in the pediatric population are rare but can be challenging because of the smaller anatomy. The procedure is even more exacting in patients with prior suboccipital craniectomy. A proposed method for occipitocervical fusion in such patients is the use of occipital condyle screws. There is very limited literature evaluating the pediatric occipital condyle for screw placement. The authors examined the occipital condyle in pediatric patients to determine if there was an age cutoff at which condylar screw placement is contraindicated.METHODSThe authors performed a retrospective morphometric analysis of the occipital condyle in 518 pediatric patients aged 1 week-9 years old. Patients in their first decade of life whose occipital condyle was demonstrated on CT imaging in the period from 2009 to 2013 at the Augusta University Medical Center and Children's Hospital of Georgia were eligible for inclusion in this study. Exclusion criteria were an age older than 10 years; traumatic, inflammatory, congenital, or neoplastic lesions of the occipital condyles; and any previous surgery of the occipitocervical junction. Descriptive statistical analysis was performed including calculation of the mean, standard deviation, and confidence intervals for all measurements. Probability values were calculated using the Student t-test with statistical significance determined by p < 0.05.RESULTSOverall, male patients had statistically significantly larger occipital condyles than the female patients, but this difference was not clinically significant. There was no significant difference in left versus right occipital condyles. There were statistically significant differences between age groups with a general trend toward older children having larger occipital condyles. Overall, 20.65% of all patients evaluated had at least one measurement that would prevent occipital condyle screw placement including at least one patient in every age group.CONCLUSIONSOccipital condyle screw fixation is feasible in pediatric patients younger than 10 years. More importantly, all pediatric patients should undergo critical evaluation of the occipital condyle in the axial, sagittal, and coronal planes preoperatively to determine individual suitability for occipital condyle screw placement.

Effect of History of Mild Traumatic Brain Injury on Optic Nerve Sheath Diameter Changes after Valsalva Maneuver.

Optic nerve sheath diameter (ONSD) measured by transocular ultrasound is a marker of real-time intracranial pressure (ICP). The objective of this study was to evaluate the association between optic nerve sheath (ONS) dilation after a Valsalva maneuver and a prior history of mild to moderate traumatic brain injury (mTBI) in a heterogeneous sample of participants. Participants were excluded if they had had a recent brain injury, were symptomatic from a prior brain injury, had a history consistent with severe TBI and/or had undergone intracranial surgery. Ninety-five participants with and without a history of mTBI were included in the study. Transocular ultrasound of the ONS was performed before and after a Valsalva maneuver. Differences in the ONSD before and after a Valsalva maneuver were analyzed and correlated to the participants' history of mTBI. Baseline ONSD measurements between groups were not statistically significant. Following Valsalva, participants with a history of mTBI had a statistically significant increase in the ONSD compared with participants with no history of mTBI. This significant difference persisted after controlling for age, race, and sex. This study demonstrated an association between a prior history of mTBI and dilation of the ONS after Valsalva maneuver in a sample of asymptomatic participants, which was not seen in participants without a history of mTBI.

Intracranial calcified pseudocyst reaction to a shunt catheter.

A 9-year-old boy with spina bifida, Chiari II malformation, and hydrocephalus presented with signs of increased intracranial pressure consistent with a shunt malfunction. Radiological investigations revealed an intracranial calcified lesion along the ventricular catheter. A shunt tap revealed a translucent milky white fluid. The patient underwent a ventriculostomy and, eventually, a shunt revision. Pathology findings were consistent with the formation of dystrophic calcification and a pseudocyst around the shunt catheter. Postoperatively, the patient returned to his neurological baseline. This is, to the best of the authors' knowledge, the first report of an intracranial calcified pseudocyst in a patient with normal renal function.

Venous air embolism from Tisseel use during endoscopic cranial vault remodeling for craniosynostosis repair: a case report.

Venous air embolism (VAE) is a potential complication during cranial vault remodeling requiring early detection and prompt therapeutic intervention. The incidence of VAE has been reported to be as high as 82.6% during open craniectomy for craniosynostosis repair. On the other hand, two separate studies reported a much lower incidence of VAE (8% and 2%) during endoscopic strip craniectomy. As surgical advancements progress, minimally invasive neurosurgical procedures are increasing in the pediatric population with reported benefits of decreased blood loss and need for transfusion, shorter hospital stay, decreased cost, lower morbidity, and mortality. In addition, there is a heightened emphasis on achieving hemostasis, which has led to the use of products such as antifibrinolytics and fibrin sealants. We present a case where a VAE causing significant hemodynamic instability (grade III) ensued immediately following aerosolized fibrin sealant application. Exploration of the potential source of VAE pointed to the high pressure and close proximity (between spray device and tissue) during application of the sealant, likely forcing air into the vascular system.

Endoscopic release of unicoronal craniosynostosis.

We demonstrate a novel method of endoscopic frontal-orbital advancement for the treatment of unicoronal craniosynostosis. The evolution of this cranioplasty modality burrows from an established precedent of safety and technical experience in strip craniectomies and endoscopic brow surgery. The procedure facilitates osteotomies similar to open frontal-orbital advancement and uses reabsorbable materials to achieve immediate intraoperative correction of unicoronal craniosynostosis through smaller incisions. The patients in the study underwent endoscopic frontal-orbital advancement and cranial vault remodeling. This was made possible with the use of a novel ultrasonic bone saw that permits osteotomies to be made with minimal disruption to the dura matter. After full frontal-orbital advancement, immediate reabsorbable fixation was used to stabilize the advancement as in the open technique. There were no major complications. All patients demonstrated improvement in plagiocephaly due to unilateral coronal synostosis. Patients and their families reported a 100% patient satisfaction and an improvement in cranial asymmetry from 10 to 2 mm (P < 0.5). This is a new endoscopic cranial vault remolding technique that achieves state-of-the-art correction of unicoronal craniosynostosis with less morbidity and mortality.