Kimberly A. Foster

Recurrence of synostosis following surgical repair of craniosynostosis.

Background: The incidence of resynostosis after surgical release of synostotic suture(s) is not well reported. The authors examined cases of nonsyndromic and syndromic craniosynostosis treated with surgical repair and established the rate of reoperation for synostosis. Methods: Charts were retrieved from 119 consecutive patients treated for craniosynostosis: 62 percent were boys, and 11 percent were treated for craniofacial dysostosis (Apert syndrome, n = 2; Crouzon syndrome, n = 4; Saethre-Chotzen syndrome, n = 5; and other, n = 2). Results: Eight patients (6.7 percent) underwent surgery for resynostosis [nonsyndromic, six of 106 (5.7 percent); syndromic, two of 13 (15.4 percent)]. Seventy-nine patients (66.4 percent) underwent primary surgery before 1 year of age. Analysis by age at primary operation yielded significantly lower resynostosis rates (p < 0.02) when patients younger than 1 year [two of 79 resynostosis cases (2.5 percent)] were compared with those older than 1 year [six of 40 resynostosis cases (15 percent)]. Further stratifications of age at initial operation did not yield significance for resynostosis. Four of eight patients who resynostosed had raised intracranial pressure, as indicated by lumbar puncture following the primary operation. A trend of increasing mean length of hospital stay, estimated blood loss, and operative time in the patients who eventually resynostosed was observed (data not significant). Conclusions: Resynostosis rates were higher in syndromic than in nonsyndromic children for whom a single suture was involved. Analysis of age at primary operation showed an increase in resynostosis when the primary operation occurred after age 1 year. Evidence of increased intracranial pressure following primary surgery may suggest recurrence.

Nasal ocular reflexes and eye symptoms in patients with allergic rhinitis

BACKGROUND Allergic patients often complain of eye symptoms during the allergy season. A possible mechanism for these eye symptoms is a nasal ocular reflex. OBJECTIVE To demonstrate eye symptoms after nasal allergen challenge. METHODS In a double-blind, placebo-controlled, crossover, clinical trial, 20 patients with seasonal allergic rhinitis were challenged in 1 nostril with antigen, and the response was monitored in both nostrils and in both eyes. Symptoms were recorded. Filter paper disks (intranasally) and Schirmer strips (intraocularly) were used for collecting secretions, which were subsequently eluted for the measurement of histamine and albumin levels. Patients were treated once topically at the site of challenge with azelastine or placebo. RESULTS After placebo treatment, ipsilateral nasal challenge caused nasal symptoms and an increase in secretion weights; both were blocked by treatment with azelastine. Histamine and albumin levels increased only at the site of nasal challenge. Azelastine pretreatment inhibited the increase in albumin but not histamine levels. Symptoms of itchy and watery eyes increased significantly compared with symptoms with sham challenge after nasal allergen and were blocked by azelastine use. Ocular secretion weights increased bilaterally after placebo use and were not inhibited by azelastine use. CONCLUSIONS Nasal allergen challenge releases histamine at the site of the challenge, which probably initiates a nasonasal and a nasal ocular reflex. This reflex is reduced by an H1-receptor antagonist applied at the site of the challenge. The eye symptoms associated with allergic rhinitis probably arise, in part, from a naso-ocular reflex.

Inhibition of Phosphatidylinositol 3-Kinase/AKT Signaling by NVP-BKM120 Promotes ABT- 737-induced toxicity in a caspase-dependent manner through mitochondrial dysfunction and DNA damage response in established and primary cultured glioblastoma cells

Identification of therapeutic strategies that might enhance the efficacy of B-cell lymphoma-2 (Bcl-2) inhibitor ABT-737 [N-{4-[4-(4-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-4-(3-dimethylamino-1-phenylsulfanylmethyl-propylamino)-3-nitro-benzenesulfonamide] is of great interest in many cancers, including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT-737 in glioma cell lines. Inhibitors of phosphatidylinositol 3-kinase (PI3K)/Akt are currently being assessed clinically in patients with glioma. Because PI3K/Akt inhibition would be expected to have many proapoptotic effects, we hypothesized that there may be unique synergy between PI3K inhibitors and Bcl-2 homology 3 mimetics. Toward this end, we assessed the combination of the PI3K/Akt inhibitor NVP-BKM120 [5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-amine] and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8 and -3, PARP, and cell death, irrespective of PTEN status. The enhanced lethality observed with this combination also appears dependent on the loss of mitochondrial membrane potential and release of cytochrome c, smac/DIABLO, and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, and activation of Bax and Bak caused by these inhibitors were the key factors for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony-forming ability, suggesting the potential use of NVP-BKM120 as a promising agent to improve the anticancer activities of ABT-737.

Convection-enhanced delivery for treatment of brain tumors

Recently, innovative therapies have been developed for the treatment of malignant gliomas. Unfortunately, adequate delivery of these therapies has been a major obstacle to clinical success. Intravenous administration is restricted by the presence of the blood–brain barrier while local delivery, such as with drug-impregnated wafers, results in limited parenchyma penetration. Convection-enhanced delivery is a promising method for the delivery of macromolecules to the CNS. Convection-enhanced delivery involves the infusion of therapeutic agents via surgically implanted catheters and uses a pressure gradient to achieve a greater volume of distribution compared with that seen with diffusion alone. This article will review the development of convection-enhanced delivery and its use in the treatment of malignant gliomas.

Survivin Inhibitor YM-155 Sensitizes Tumor Necrosis Factor– Related Apoptosis-Inducing Ligand-Resistant Glioma Cells to Apoptosis through Mcl-1 Downregulation and by Engaging the Mitochondrial Death Pathway

Induction of apoptosis by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor therapy. However, not all tumor cells are sensitive to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Inhibitor of apoptosis family member survivin is constitutively activated in various cancers and blocks apoptotic signaling. Recently, we demonstrated that YM-155 [3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(pyrazin-2-ylmethyl)-4,9-dihydro-3H-naphtho[2,3-d]imidazol-1-ium bromide], a small molecule inhibitor, downregulates not only survivin in gliomas but also myeloid cell leukemia sequence 1 (Mcl-1), and it upregulates proapoptotic Noxa levels. Because Mcl-1 and survivin are critical mediators of resistance to various anticancer therapies, we questioned whether YM-155 could sensitize resistant glioma cells to TRAIL. To address this hypothesis, we combined YM-155 with TRAIL and examined the effects on cell survival and apoptotic signaling. TRAIL or YM-155 individually induced minimal killing in highly resistant U373 and LNZ308 cell lines, but combining TRAIL with YM-155 triggered a synergistic proapoptotic response, mediated through mitochondrial dysfunction via activation of caspases-8, -9, -7, -3, poly-ADP-ribose polymerase, and Bid. Apoptosis induced by combination treatments was blocked by caspase-8 and pan-caspase inhibitors. In addition, knockdown of Mcl-1 by RNA interference overcame apoptotic resistance to TRAIL. Conversely, silencing Noxa by RNA interference reduced the combined effects of YM-155 and TRAIL on apoptosis. Mechanistically, these findings indicate that YM-155 plays a role in counteracting glioma cell resistance to TRAIL-induced apoptosis by downregulating Mcl-1 and survivin and amplifying mitochondrial signaling through intrinsic and extrinsic apoptotic pathways. The significantly enhanced antitumor activity of the combination of YM-155 and TRAIL may have applications for therapy of malignant glioma.

The development of Moyamoya syndrome after proton beam therapy.

The development of Moyamoya syndrome (MMS) after cranial irradiation for pediatric tumors has been well established. However, information on the development of MMS after proton beam radiotherapy is sparse. We present the case of a 2‐year‐old child who developed radiation‐induced MMS after treatment with proton beam therapy. Pediatr Blood Cancer 2014; 61:1490–1492.

Co-administration of ABT-737 and SAHA induces apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines

Abstract We previously observed that glioma cells are differentially sensitive to ABT-737 and, when used as a single-agent, this drug failed to induce apoptosis. Identification of therapeutic strategies to enhance the efficacy of the Bcl-2 inhibitor ABT-737 in human glioma is of interest. Histone deacetylation inhibitors (HDACI) are currently being assessed clinically in patients with glioma, as regulation of epigenetic abnormalities is expected to produce pro-apoptotic effects. We hypothesized that co-treatment of glioma with a BH3-mimetic and HDACI may induce cellular death. We assessed the combination of ABT-737 and HDACI SAHA in established and primary cultured glioma cells. We found combination treatment led to significant cellular death when compared to either drug as single agent and demonstrated activation of the caspase cascade. This enhanced apoptosis also appears dependent upon the loss of mitochondrial membrane potential and the release of cytochrome c and AIF into the cytosol. The upregulation of Noxa, truncation of Bid, and activation of Bax caused by this combination were important factors for cell death and the increased levels of Noxa functioned to sequester Mcl-1. This combination was less effective in PTEN-deficient glioma cells. Both genetic and pharmacologic inactivation of the PI3K/Akt signaling pathway sensitized PTEN-deleted glioma cells to the combination. This study demonstrates that antagonizing apoptosis-resistance pathways, such as targeting the Bcl-2 family in combination with epigenetic modifiers, may induce cell death. These findings extend our previous observations that targeting the PI3K/Akt pathway may be additionally necessary to promote apoptosis in cancers lacking PTEN functionality.

Chiari Drop Attacks: Surgical Decompression and the Role of Tilt Table Testing

Background: Chiari I malformation (CM1) is characterized by impaired CSF flow through the foramen magnum. Dysfunctional autonomic cardiovascular regulation may result in syncope. Syncope may be the primary presenting symptom of CM1: a syndrome termed Chiari drop attack. It has been postulated that Chiari drop attack is secondary to dysautonomia caused by hindbrain compression. There has been recent debate regarding the association between CM1, dysautonomia and Chiari drop attack. Methods: We selected patients with Chiari drop attacks who had negative workups for cardiac syncope, followed by tilt table testing and subsequent surgical decompression. We report test results and clinical outcomes following CM1 decompression. Results: Ten patients met the inclusion criteria: 5 patients had positive and 5 negative tilt table tests. Following decompression, 7 had symptomatic improvement or resolution and 3 failed to improve. The sensitivity and specificity of the tilt table test for detecting clinical improvement with surgical decompression was 43 and 33%, respectively. Tilt table testing had 40% accuracy in predicting clinical response to decompression. Conclusions: In this short series, surgical decompression of CM1 has a high success rate (70%) for patients with Chiari drop attacks. Tilt table testing has poor predictive value in judging the clinical response to surgical decompression and is not a useful test to guide surgical decision- making.

Calcium Phosphate Cement Cranioplasty Decreases the Rate of Cerebrospinal Fluid Leak and Wound Infection Compared with Titanium Mesh Cranioplasty: Retrospective Study of 672 Patients

OBJECTIVE A variety of biomaterials have been developed for cranial reconstruction after craniectomy, including polyethylene titanium mesh and calcium phosphate cement. This study sought to compare complication rates of calcium phosphate cement and titanium mesh cranioplasty in patients undergoing retromastoid craniectomy. METHODS The authors retrospectively reviewed clinical data from 672 consecutive patients who underwent retromastoid craniectomy at a single institution for microvascular decompression or tumor resection from July 2009 to July 2014. Of these, 336 patients received calcium phosphate cement cranioplasty and 336 underwent (polyethylene) mesh cranioplasty. Charts were abstracted for occurrence of cerebrospinal fluid (CSF) leak, wound infection and/or other wound complication, and the groups were compared. RESULTS In the mesh cranioplasty group, there were 38 complications related to the surgical site, including 18 infections (5.4%), 20 patients (6%) with CSF leak or pseudomeningocele, and no (0%) other wound complications. In the cement cranioplasty cohort, 2 patients (0.6%) experienced wound infection, no patients (0%) had CSF leak, and 2 patients (0.6%) had other wound complications (including one sterile wound dehiscence and one reoperation for removal of excess cement). There was a statistically significant decrease in the rate of wound infection and CSF leak in the patients who underwent cement cranioplasty (P <0.001 for both). CONCLUSIONS Calcium phosphate cement cranioplasty offers an alternative to titanium cranioplasty and may reduce the risk of surgical site complication. Randomized, prospective comparisons of cement cranioplasty to traditional techniques are warranted.

Bevacizumab for symptomatic radiation‐induced tumor enlargement in pediatric low grade gliomas

Radiation therapy (RT)‐induced effects in children treated for low grade glioma (LGG) can result in worsening of neurologic symptoms and clinical and radiographic deterioration. Treatment for radiation‐induced tumor enlargement is based on symptom control and usually involves steroids.