[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Despite advancements in materials and techniques used for cranial reconstruction, complication rates following reconstructive cranioplasty remain significant. METHODS: In this study, the authors assessed the association of perioperative anticoagulation use and/or a hypercoagulable state with minor (i.e., not requiring surgical intervention) and major (i.e., surgical intervention required) complications after reconstructive cranioplasty for large skull defects. A retrospective cohort review of 108 consecutive cranioplasties performed between 2011 and 2014 was conducted. A multiple logistic regression analysis was performed to identify the adjusted association between the predictor variables and complications. RESULTS: Twenty-three primary (21.3 percent) and 85 secondary (78.7 percent) cranioplasties were performed on 94 patients with a median age of 50 years (interquartile range, 38 to 63 years). Median full-thickness calvarial defect size was 154 cm (interquartile range, 104 to 230 cm). Eleven minor (10.2 percent) and 18 major postoperative complications (16.7 percent) occurred in 26 cases (24.1 percent). Multiple logistic regression analysis revealed that coagulation status (i.e., perioperative use of anticoagulation therapy or hypercoagulable state) was statistically significant in predicting minor complications (OR, 7.8; 95 percent CI, 2.4 to 25.2; p = 0.001). Of note, the odds of a minor complication were an order of magnitude higher when both perioperative anticoagulation and a hypercoagulable state were present. CONCLUSION: To the authors' knowledge, this is the first study to document that the use of perioperative anticoagulant therapy for patients with thromboembolic conditions is a positive predictor of complications following cranioplasty reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
Full-text · Article · Feb 2016 · Plastic & Reconstructive Surgery
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Reinfections following implant-based cranioplasty, in the setting of previous bone flap osteomyelitis, are common and associated with significant morbidity. The timing of reconstruction following initial osteomyelitic bone flap removal remains controversial; most advocate for prolonged time intervals of approximately 6 to 12 months. Thus, the authors investigated their delayed cranioplasty outcomes following both early (between 90 and 179 days) and late (>/=180 days) time intervals with custom craniofacial implants to determine whether timing affected outcomes and rates of reinfection. METHODS: An institutional review board-approved retrospective cohort review of 25 consecutive cranioplasties, from 2012 to 2014, was conducted. A nonparametric bivariate analysis compared variables and complications between the two different time interval groups, defined as early cranioplasty (between 90 and 179 days) and cranioplasty (>/=180 days). RESULTS: No significant differences were found in primary and secondary outcomes in patients who underwent early versus late cranioplasty (p > 0.29). The overall reinfection rate was only 4 percent (one of 25), with the single reinfection occurring in the late group. Overall, the major complication rate was 8 percent (two of 25). Complete and subgroup analyses of specific complications yielded no significant differences between the early and late time intervals (p > 0.44). CONCLUSIONS: The results suggest that early cranioplasty is a viable treatment option for patients with previous bone flap osteomyelitis and subsequent removal. As such, a reduced time interval of 3 months-with equivalent outcomes and reinfection rates-represents a promising area for future study aiming to reduce the morbidity surrounding prolonged time intervals. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
Full-text · Article · Feb 2016 · Plastic & Reconstructive Surgery
[Show abstract][Hide abstract] ABSTRACT: Craniopharyngiomas are among the most complex tumors treated by neurosurgeons. Aggressive surgical management can lead to increased morbidity and mortality. Less invasive strategies which combine subtotal resection with local radiotherapy have proven effective, although endoscopic techniques could provide wider extent of resection with potentially decreased morbidity. Craniopharyngiomas are thought to arise from retained epithelial cell remnants after closure of the craniopharyngeal duct or from metaplasia of epithelial cells of the anterior lobe of the pituitary. Their most frequent location is in the sellar region, although there is extensive evidence that craniopharyngiomas can appear in ectopic locations. This can happen through direct anatomical seeding of cells during surgery for the removal of a sellar craniopharyngioma, secondary spread of the tumor after surgery to a distant location not related to the initial surgical approach, or the primary development of the tumor in a completely extrasellar location.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To estimate the incidence of surgical complications and associated in-hospital morbidity and mortality following surgery for malignant brain tumors.
Patients and methods:
The Nationwide Inpatient Sample (NIS) database was queried from 2002 to 2011. All adult patients who underwent elective brain surgery for a malignant brain tumor were included. Surgical complications included wrong side surgery, retention of a foreign object, iatrogenic stroke, meningitis, hemorrhage/hematoma complicating a procedure, and neurological complications. A regression model was conducted to estimate the odds ratios (OR) with their 95% confidence intervals (95% CI) of in-hospital mortality for each surgical complication.
A total of 16,530 admissions were analyzed, with 601 (36.2 events per 1000 cases) surgical complications occurring in 567 patients. Over the examined 10-year period, the overall incidence of surgical complications did not change (P=0.061) except for iatrogenic strokes, which increased in incidence from 14.1 to 19.8 events per 1000 between 2002 and 2011 (P=0.023). Patients who developed a surgical complication had significantly longer lengths of stay, total hospital costs, and higher rates of other complications. Patients who experienced an iatrogenic stroke had a significantly increased risk of mortality (OR 9.6; 95% 6.3-14.8) and so were patients with a hemorrhage/hematoma (OR 3.3; 95% CI 1.6-6.6).
In this study of an administrative database, patients undergoing surgery for a malignant brain tumor who suffered from a surgical complication had significantly longer lengths of stay, total hospital charges, and complication rates. Having a surgical complication was also an independent risk factor for in-hospital mortality. Nonetheless, it is unclear whether all surgical complications were clinically relevant, and further research is encouraged.
No preview · Article · Nov 2015 · Clinical neurology and neurosurgery
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Immune responses to antigens originating in the CNS are generally attenuated, since collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown.
The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGF-β secretion from microglia and in the serum and TGF-β signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. Additionally, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.
CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGF-β; however, blocking TGF-β signaling with a small molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios and decreased TGF-β secretion from microglia.
These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS. Anti-tumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in more contemporary melanoma models as well as human trials.
No preview · Article · Oct 2015 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.
Full-text · Article · Aug 2015 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) act as negative regulators of the immune system and can be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes can express multiple checkpoints (including TIM-3), and expression of 2 or more checkpoints corresponds to a more exhausted T-cell phenotype. Here, we hypothesized that the addition of a second checkpoint-blocking antibody could achieve additive or synergistic antitumor effects.
C57BL/6 mice were implanted with mouse glioma cell line GL261 transfected with luciferase and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1 + SRS, (6) anti-TIM-3 + SRS, (7) anti-PD-1 + anti-TIM-3, and (8) anti-PD-1 + anti-TIM-3 + SRS. Overall survival was measured. Brain, cervical lymph nodes, and peripheral blood were harvested on day 21 to assess immune activation.
Survival benefits were demonstrated with combined anti-TIM-3 antibody + SRS compared with anti-TIM-3 antibody alone with a median survival (MS) of 92 vs 25 days and overall survival (OS) of 50% vs 0%, respectively (P < .001 by log-rank Mantel-Cox). Dual blockade with anti-TIM-3 + anti-PD-1 antibody also improved survival compared with TIM-3 blockade alone (MS of 146 vs 25 days, OS 60% vs 0%, respectively, P < .05). Notably, the triple-modality treatment (anti-PD-1 + anti-TIM-3 + SRS) provided a significant improvement in survival compared with all other treatment arms with an OS of 100% by day 146 (P < .05). Flow cytometry of organs harvested on day 21 showed that, compared with dual-therapy groups, mice treated with the triple-modality treatment had increased tumor infiltration by interferon-gamma+ (IFN-γ) and tumor necrosis factor-alpha+ (TNF-α)-producing CD4 T cells, as well as IFN-γ+ CD8 lymphocytes.
Combining anti-TIM-3 with anti-PD-1 and radiation was synergistic and conferred a significant survival benefit.
[Show abstract][Hide abstract] ABSTRACT: Craniectomy defects following resection of calvarial lesions are most often reconstructed using on-table manufacturing. With the advent of computer-aided design/manufacturing and customized craniofacial implants (CCIs), there seems to be more suited alternatives. In this study, the authors report their institutional experience and outcome using immediate, single-stage, CCI-based reconstruction for benign and malignant skull neoplasm defects.
A retrospective review of a prospectively maintained database of all implant cranioplasties performed between 2011 and 2014, by a single craniofacial surgeon at a tertiary academic medical institution was performed. Preoperative and postoperative computed tomography scans with 3D reconstruction were performed for the purpose of assessing adequate resection and reconstructive outcomes. Primary endpoints included length of surgery, predicted defect versus postoperative implant surface area, contour irregularities, and complications.
Of the 108 patients with cranioplasty identified, 7 patients were found to undergo immediate CCI-based reconstruction for calvarial neoplasms; 4 patients (4/7, 57%) presented with malignant pathology. All defects were >5 cm. As compared with their original size, all implants were modified intraoperatively between 0.2% and 40.8%, with a mean of 13.8%. With follow-up ranging between 1 and 16 months, there were no implant-related complications identified. The immediate and long-term aesthetic results, as well as patient satisfaction, were ideal.
With this preliminary experience, the authors have successfully demonstrated that immediate customized implant reconstructive techniques, by way of intraoperative modification, are both safe and feasible for benign and malignant skull neoplasms. The authors believe that with wider acceptance of this multidisciplinary approach and increased surgeon familiarity, this technique will soon become the reconstructive standard of care.
No preview · Article · Jul 2015 · The Journal of craniofacial surgery