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Arman Jahangiri, Annette M. Molinaro, Phiroz E. Tarapore, Lewis Blevins Jr., Kurtis I. Auguste, Nalin Gupta, Sandeep Kunwar and Manish K. Aghi

Object

Rathke cleft cysts (RCC) are benign sellar lesions most often found in adults, and more infrequently in children. They are generally asymptomatic but sometimes require surgical treatment through a transsphenoidal corridor. The purpose of this study was to compare adult versus pediatric cases of RCC.

Methods

The authors retrospectively reviewed presenting symptoms, MR imaging findings, laboratory study results, and pathological findings in 147 adult and 14 pediatric patients who underwent surgery for treatment of RCCs at the University of Californial at San Francisco between 1996 and 2008.

Results

In both the adult and pediatric groups, most patients were female (78% of adults, 79% of pediatric patients, p = 0.9). Headache was the most common symptom in both groups (reported by 50% of pediatric patients and 33% of adults, p = 0.2). Preoperative hypopituitarism occurred in 41% of adults and 45% of pediatric patients (p = 0.8). Growth delay, a uniquely pediatric finding, was a presenting sign in 29% of pediatric patients. Visual complaints were a presenting symptom in 16% of adult and 7% of pediatric patients (p = 0.4). There was no difference between median cyst size in adults versus pediatric patients (1.2 cm in both, p = 0.7). Temporary or permanent postoperative diabetes insipidus occurred in 12% of adults and 21% of pediatric patients (p = 0.4). Kaplan-Meier analysis revealed an 8% RCC recurrence rate at 2 years for each group (p = 0.5).

Conclusions

The incidence of RCCs is much lower in the pediatric population; however, symptoms, imaging findings, and outcomes are similar, suggesting that pediatric RCCs arise from growth of remnants of the embryonic Rathke pouch earlier in life than adult RCCs but do not differ in any other way. It is important to consider RCCs in the differential diagnosis when pediatric patients present with visual impairment, unexplained headache, or hypopituitarism including growth delay. Although the average RCC size was similar in our pediatric and adult patient groups, the smaller size of the pituitary gland in pediatric patients suggests an increased relative RCC size.

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Aaron J. Clark, Nicholas A. Butowski, Susan M. Chang, Michael D. Prados, Jennifer Clarke, Mei-Yin C. Polley, Michael E. Sughrue, Michael W. McDermott, Andrew T. Parsa, Mitchel S. Berger and Manish K. Aghi

Object

The FDA approval of bevacizumab for recurrent glioblastoma has resulted in its increased use in this patient population. Phase II trials reported 4%–6% impaired wound healing for bevacizumab initiated postoperatively. The effect of preoperative bevacizumab on subsequent craniotomy healing has not been addressed.

Methods

The authors retrospectively reviewed the cases of patients who underwent craniotomy for recurrent glioblastoma between 2005 and 2009, evaluating bevacizumab therapy/duration and healing complications (dehiscence, pseudomeningocele, CSF leak, and wound/bone infection). The Wilcoxon rank-sum test and Kruskal-Wallis test were used to compare continuous variables between groups. The Fisher exact test was used to assess for an association between categorical variables, including the comparison of wound-healing complication rates. Logistic regression models were used to estimate odds ratios of wound-healing complications while adjusting for baseline variables.

Results

Two hundred nine patients underwent a second craniotomy (161 patients) or third craniotomy (48 patients) for recurrent glioblastoma. Twenty-six individuals (12%) developed wound-healing complications. One hundred sixty-eight patients received no bevacizumab, 23 received preoperative bevacizumab, and 18 received postoperative bevacizumab. Significantly more patients receiving preoperative bevacizumab developed healing complications (35%) than non–bevacizumab-treated patients (10.0%, p = 0.004). Postoperative bevacizumab was associated with 6% impaired healing, not significantly different from non–bevacizumab-treated controls (p = 1.0). Preoperative bevacizumab treatment duration (weeks) did not influence healing (OR 0.98, p = 0.55). More healing complications occurred in patients receiving preoperative bevacizumab than in non–bevacizumab-treated controls before the third craniotomy (44% vs 9%, p = 0.03).

Conclusions

Although subject to the limitations of a retrospective study, we demonstrate that preoperative bevacizumab treatment resulted in impaired healing after a second and third craniotomy, compared with minimal effect of postoperative bevacizumab. This effect is more striking for the third craniotomy and for a shorter delay between bevacizumab and surgery. These complications should be acknowledged as increased bevacizumab use results in more post–bevacizumab-treated patients in whom surgery for recurrent glioblastoma is considered. Based on these results, the authors recommend performing repeated craniotomy more than 28 days after last administered dose of bevacizumab whenever possible.

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David R. Raleigh, Zachary A. Seymour, Bryan Tomlin, Philip V. Theodosopoulos, Mitchel S. Berger, Manish K. Aghi, Sarah E. Geneser, Devan Krishnamurthy, Shannon E. Fogh, Penny K. Sneed and Michael W. McDermott

OBJECTIVE

Stereotactic radiosurgery (SRS) with or without whole-brain radiotherapy can be used to achieve local control (> 90%) for small brain metastases after resection. However, many brain metastases are unsuitable for SRS because of their size or previous treatment, and whole-brain radiotherapy is associated with significant neurocognitive morbidity. The purpose of this study was to investigate the efficacy and toxicity of surgery and iodine-125 (125I) brachytherapy for brain metastases.

METHODS

A total of 95 consecutive patients treated for 105 brain metastases at a single institution between September 1997 and July 2013 were identified for this analysis retrospectively. Each patient underwent MRI followed by craniotomy with resection of metastasis and placement of 125I sources as permanent implants. The patients were followed with serial surveillance MRIs. The relationships among local control, overall survival, and necrosis were estimated by using the Kaplan-Meier method and compared with results of log-rank tests and multivariate regression models.

RESULTS

The median age at surgery was 59 years (range 29.9–81.6 years), 53% of the lesions had been treated previously, and the median preoperative metastasis volume was 13.5 cm3 (range 0.21–76.2 cm3). Gross-total resection was achieved in 81% of the cases. The median number of 125I sources implanted per cavity was 28 (range 4–93), and the median activity was 0.73 mCi (range 0.34–1.3 mCi) per source. A total of 476 brain MRIs were analyzed (median MRIs per patient 3; range 0–22). Metastasis size was the strongest predictor of cavity volume and shrinkage (p < 0.0001). Multivariable regression modeling failed to predict the likelihood of local progression or necrosis according to metastasis volume, cavity volume, or the rate of cavity remodeling regardless of source activity or previous SRS. The median clinical follow-up time in living patients was 14.4 months (range 0.02–13.6 years), and crude local control was 90%. Median overall survival extended from 2.1 months in the shortest quartile to 62.3 months in the longest quartile (p < 0.0001). The overall risk of necrosis was 15% and increased significantly for lesions with a history of previous SRS (p < 0.05).

CONCLUSIONS

Therapeutic options for patients with large or recurrent brain metastases are limited. Data from this study suggest that resection with permanent 125I brachytherapy is an effective strategy for achieving local control of brain metastasis. Although metastasis volume significantly influences resection cavity size and remodeling, volumetric parameters do not seem to influence local control or necrosis. With careful patient selection, this treatment regimen is associated with minimal toxicity and can result in long-term survival for some patients.

▪ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective case series; evidence: Class IV.

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Arman Jahangiri, Jeffrey R. Wagner, Sung Won Han, Mai T. Tran, Liane M. Miller, Rebecca Chen, Maxwell W. Tom, Lauren R. Ostling, Sandeep Kunwar, Lewis Blevins and Manish K. Aghi

OBJECT

The impact of transsphenoidal surgery for nonfunctional pituitary adenomas (NFAs) on preoperative hypopituitarism relative to the incidence of new postoperative endocrine deficits remains unclear. The authors investigated rates of hypopituitarism resolution and development after transsphenoidal surgery.

METHODS

Over a 5-year period, 305 transsphenoidal surgeries for NFAs performed at The California Center for Pituitary Disorders were retrospectively reviewed.

RESULTS

Patients with preoperative endocrine deficits (n = 153, 50%) were significantly older (mean age 60 vs 54 years; p = 0.004), more frequently male (65% vs 44%; p = 0.0005), and had larger adenomas (2.4 cm vs 2.1 cm; p = 0.02) than patients without preoperative deficits (n = 152, 50%). Of patients with preoperative endocrine deficits, 53% exhibited symptoms. Preoperative deficit rates were 26% for the thyroid axis; 20% and 16% for the male and female reproductive axes, respectively; 13% for the adrenocorticotropic hormone (ACTH)/cortisol axis, and 19% for the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Laboratory normalization rates 6 weeks and 6 months after surgery without hormone replacement were 26% and 36% for male and 13% and 13% for female reproductive axes, respectively; 30% and 49% for the thyroid axis; 3% and 3% for the cortisol axis; and 9% and 22% for the IGF-1 axis (p < 0.05). New postoperative endocrine deficits occurred in 42 patients (13.7%). Rates of new deficits by axes were: male reproductive 3% (n = 9), female reproductive 1% (n = 4), thyroid axis 3% (n = 10), cortisol axis 6% (n = 19), and GH/IGF-1 axis 4% (n = 12). Patients who failed to exhibit any endocrine normalization had lower preoperative gland volumes than those who did not (0.24 cm3 vs 0.43 cm3, respectively; p < 0.05). Multivariate analyses revealed that no variables predicted new postoperative deficits or normalization of the female reproductive, cortisol, and IGF-1 axes. However, increased preoperative gland volume and younger age predicted the chances of a patient with any preoperative deficit experiencing normalization of at least 1 axis. Younger age and less severe preoperative hormonal deficit predicted normalization of the thyroid and male reproductive axes (p < 0.05).

CONCLUSIONS

After NFA resection, endocrine normalization rates in this study varied with the hormonal axis and were greater than the incidence of new endocrine deficits. Low preoperative gland volume precluded recovery. Patient age and the severity of the deficiency influenced the recovery of the thyroid and male reproductive axes, the most commonly impaired axes and most likely to normalize postoperatively. This information can be of use in counseling patients with hypopituitarism who undergo NFA surgery.

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Ankush Chandra, Jacob S. Young, Cecilia Dalle Ore, Fara Dayani, Darryl Lau, Harsh Wadhwa, Jonathan W. Rick, Alan T. Nguyen, Michael W. McDermott, Mitchel S. Berger and Manish K. Aghi

OBJECTIVE

Glioblastoma (GBM) carries a high economic burden for patients and caregivers, much of which is associated with initial surgery. The authors investigated the impact of insurance status on the inpatient hospital costs of surgery for patients with GBM.

METHODS

The authors conducted a retrospective review of patients with GBM (2010–2015) undergoing their first resection at the University of California, San Francisco, and corresponding inpatient hospital costs.

RESULTS

Of 227 patients with GBM (median age 62 years, 37.9% females), 31 (13.7%) had Medicaid, 94 (41.4%) had Medicare, and 102 (44.9%) had private insurance. Medicaid patients had 30% higher overall hospital costs for surgery compared to non-Medicaid patients ($50,285 vs $38,779, p = 0.01). Medicaid patients had higher intensive care unit (ICU; p < 0.01), operating room (p < 0.03), imaging (p < 0.001), room and board (p < 0001), and pharmacy (p < 0.02) costs versus non-Medicaid patients. Medicaid patients had significantly longer overall and ICU lengths of stay (6.9 and 2.6 days) versus Medicare (4.0 and 1.5 days) and privately insured patients (3.9 and 1.8 days, p < 0.01). Medicaid patients had similar comorbidity rates to Medicare patients (67.8% vs 68.1%), and both groups had higher comorbidity rates than privately insured patients (37.3%, p < 0.0001). Only 67.7% of Medicaid patients had primary care providers (PCPs) versus 91.5% of Medicare and 86.3% of privately insured patients (p = 0.009) at the time of presentation. Tumor diameter at diagnosis was largest for Medicaid (4.7 cm) versus Medicare (4.1 cm) and privately insured patients (4.2 cm, p = 0.03). Preoperative (70 vs 90, p = 0.02) and postoperative (80 vs 90, p = 0.03) Karnofsky Performance Scale (KPS) scores were lowest for Medicaid versus non-Medicaid patients, while in subgroup analysis, postoperative KPS score was lowest for Medicaid patients (80, vs 90 for Medicare and 90 for private insurance; p = 0.03). Medicaid patients had significantly shorter median overall survival (10.7 months vs 12.8 months for Medicare and 15.8 months for private insurance; p = 0.02). Quality-adjusted life year (QALY) scores were 0.66 and 1.05 for Medicaid and non-Medicaid patients, respectively (p = 0.036). The incremental cost per QALY was $29,963 lower for the non-Medicaid cohort.

CONCLUSIONS

Patients with GBMs and Medicaid have higher surgical costs, longer lengths of stay, poorer survival, and lower QALY scores. This study indicates that these patients lack PCPs, have more comorbidities, and present later in the disease course with larger tumors; these factors may drive the poorer postoperative function and greater consumption of hospital resources that were identified. Given limited resources and rising healthcare costs, factors such as access to PCPs, equitable adjuvant therapy, and early screening/diagnosis of disease need to be improved in order to improve prognosis and reduce hospital costs for patients with GBM.

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Stephen T. Magill, Cecilia L. Dalle Ore, Michael A. Diaz, Daara D. Jalili, David R. Raleigh, Manish K. Aghi, Philip V. Theodosopoulos and Michael W. McDermott

OBJECTIVE

Recurrent meningiomas are primarily managed with radiation therapy or repeat resection. Surgical morbidity after reoperation for recurrent meningiomas is poorly understood. Thus, the objective of this study was to report surgical outcomes after reoperation for recurrent non–skull base meningiomas.

METHODS

A retrospective review of patients was performed. Inclusion criteria were patients with recurrent meningioma who had prior resection and supratentorial non–skull base location. Univariate and multivariate logistic regression and recursive partitioning analysis were used to identify risk factors for surgical complications.

RESULTS

The authors identified 67 patients who underwent 111 reoperations for recurrent supratentorial non–skull base meningiomas. The median age was 53 years, 49% were female, and the median follow-up was 9.8 years. The most common presenting symptoms were headache, weakness, and seizure. The WHO grade after the last reoperation was grade I in 22% of cases, grade II in 51%, and grade III in 27%. The tumor grade increased at reoperation in 22% of cases. Tumors were located on the convexity (52%), parasagittal (33%), falx (31%), and multifocal (19%) locations. Tumors involved the middle third of the sagittal plane in 52% of cases. In the 111 reoperations, 48 complications occurred in 32 patients (48%). There were 26 (54%) complications requiring surgical intervention. There was no perioperative mortality. Complications included neurological deficits (14% total, 8% permanent), wound dehiscence/infection (14%), and CSF leak/pseudomeningocele/hydrocephalus (9%). Tumors that involved the middle third of the sagittal plane (OR 6.97, 95% CI 1.5–32.0, p = 0.006) and presentation with cognitive changes (OR 20.7, 95% CI 2.3–182.7, p = 0.001) were significantly associated with complication occurrence on multivariate analysis. The median survival after the first reoperation was 11.5 years, and the 2-, 5-, and 10-year Kaplan-Meier survival rates were 91.0%, 68.8%, and 50.0%, respectively.

CONCLUSIONS

Reoperation for recurrent supratentorial non–skull base meningioma is associated with a high rate of complications. Patients with cognitive changes and tumors that overlap the middle third of the sagittal plane are at increased risk of complications. Nevertheless, excellent long-term survival can be achieved without perioperative mortality.

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Stephen T. Magill, David S. Lee, Adam J. Yen, Calixto-Hope G. Lucas, David R. Raleigh, Manish K. Aghi, Philip V. Theodosopoulos and Michael W. McDermott

OBJECTIVE

Skull base meningiomas are surgically challenging tumors due to the intricate skull base anatomy and the proximity of cranial nerves and critical cerebral vasculature. Many studies have reported outcomes after primary resection of skull base meningiomas; however, little is known about outcomes after reoperation for recurrent skull base meningiomas. Since reoperation is one treatment option for patients with recurrent meningioma, the authors sought to define the risk profile for reoperation of skull base meningiomas.

METHODS

A retrospective review of 2120 patients who underwent resection of meningiomas between 1985 and 2016 was conducted. Clinical information was extracted from the medical records, radiology data, and pathology data. All records of patients with recurrent skull base meningiomas were reviewed. Demographic data, presenting symptoms, surgical management, outcomes, and complications data were collected. Kaplan-Meier analysis was used to evaluate survival after reoperation. Logistic regression was used to evaluate for risk factors associated with complications.

RESULTS

Seventy-eight patients underwent 100 reoperations for recurrent skull base meningiomas. Seventeen patients had 2 reoperations, 3 had 3 reoperations, and 2 had 4 or more reoperations. The median age at diagnosis was 52 years, and 64% of patients were female. The median follow-up was 8.5 years. Presenting symptoms included cranial neuropathy, headache, seizure, proptosis, and weakness. The median time from initial resection to first reoperation was 4.4 years and 4.1 years from first to second reoperation. Seventy-two percent of tumors were WHO grade I, 22% were WHO grade II, and 6% were WHO grade III. The sphenoid wing was the most common location (31%), followed by cerebellopontine angle (14%), cavernous sinus (13%), olfactory groove (12%), tuberculum sellae (12%), and middle fossa floor (5%). Forty-four (54%) tumors were ≥ 3 cm in maximum diameter at the time of the first reoperation. In 100 reoperations, 60 complications occurred in 30 cases. Twenty of the 60 complications required surgical intervention (33%). Complications included hydrocephalus (12), CSF leak/pseudomeningocele (11), wound infection (9), postoperative hematoma (4), venous infarction (1), and pneumocephalus (1). Postoperative neurological deficits included new or worsened cranial nerve deficits (10) and hemiparesis (3). There were no perioperative deaths in this series. On multivariate analysis, posterior fossa location was significantly associated with complications (OR 3.45, p = 0.0472). The 1-, 2-, 5-, and 10-year overall survival rates according to Kaplan-Meier analysis after the first reoperation were 94%, 92%, 88%, and 76%, respectively. The median survival after the first reoperation was 17 years.

CONCLUSIONS

Recurrent skull base meningiomas are surgically challenging tumors, and reoperation is associated with high morbidity and complication rates. Despite these cautionary data, repeat resection of recurrent skull base meningiomas in appropriately selected patients provides excellent long-term survival.

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William C. Chen, Stephen T. Magill, Ashley Wu, Harish N. Vasudevan, Olivier Morin, Manish K. Aghi, Philip V. Theodosopoulos, Arie Perry, Michael W. McDermott, Penny K. Sneed, Steve E. Braunstein and David R. Raleigh

OBJECTIVE

The goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and overall survival in patients undergoing primary resection of atypical meningioma, and to identify predictive factors to inform patient selection for adjuvant RT.

METHODS

One hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis.

RESULTS

The median patient age and imaging follow-up were 57 years (interquartile range [IQR] 45–67 years) and 4.4 years (IQR 1.8–7.5 years), respectively. Gross-total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1–0.9, p = 0.02) and MIB1 labeling index (LI) ≤ 7% (RR 0.4, 95% CI 0.1–0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1–0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1–0.4, p < 0.001), MIB1 LI ≤ 7% (RR 0.2, 95% CI 0.1–0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3–18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI ≤ 7% (RR 0.1, 95% CI 0.003–0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI ≤ 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04–0.7, p = 0.009) and ≤ 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03–0.4, p = 0.002) were predictive on MVA for local progression.

CONCLUSIONS

Adjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although independent validation is required, the authors’ results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma.

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Cecilia L. Dalle Ore, Stephen T. Magill, Adam J. Yen, Maryam N. Shahin, David S. Lee, Calixto-Hope G. Lucas, William C. Chen, Jennifer A. Viner, Manish K. Aghi, Philip V. Theodosopoulos, David R. Raleigh, Javier E. Villanueva-Meyer and Michael W. McDermott

OBJECTIVE

Extracranial meningioma metastases are uncommon, occurring in less than 1% of patients diagnosed with meningioma. Due to the rarity of meningioma metastases, patients are not routinely screened for distant disease. In this series, we report their experience with meningioma metastases and results of screening for metastases in select patients with recurrent meningiomas.

METHODS

All patients undergoing resection or stereotactic radiosurgery for primary or recurrent meningioma from 2009 to 2017 at a single center were retrospectively reviewed to identify patients who were diagnosed with or underwent imaging to evaluate for systemic metastases. Imaging to evaluate for metastases was performed with CT scanning of the chest, abdomen, and pelvis or whole-body PET/CT using either FDG or 68Ga-DOTA-octreotate (DOTATATE) tracers in 28 patients. Indications for imaging were symptomatic lesions concerning for metastasis or asymptomatic screening in patients with greater than 2 recurrences being evaluated for additional treatment.

RESULTS

Of 1193 patients treated for meningioma, 922 (77.3%) patients had confirmed or presumed WHO grade I tumors, 236 (19.8%) had grade II tumors, and 35 (2.9%) had grade III tumors. Mean follow-up was 4.3 years. A total of 207 patients experienced recurrences (17.4%), with a mean of 1.8 recurrences. Imaging for metastases was performed in 28 patients; 1 metastasis was grade I (3.6%), 16 were grade II (57.1%), and 11 were grade III (39.3%). Five patients (17.9%) underwent imaging because of symptomatic lesions. Of the 28 patients screened, 27 patients had prior recurrent meningioma (96.4%), with a median of 3 recurrences. On imaging, 10 patients had extracranial lesions suspicious for metastasis (35.7%). At biopsy, 8 were meningioma metastases, 1 was a nonmeningioma malignancy, and 1 patient was lost to follow-up prior to biopsy. Biopsy-confirmed metastases occurred in the liver (5), lung (3), mediastinum (1), and bone (1). The observed incidence of metastases was 0.67% (n = 8). Incidence increased to 2% of WHO grade II and 8.6% of grade III meningiomas. Using the proposed indications for screening, the number needed to screen to identify one patient with biopsy-confirmed malignancy was 3.83.

CONCLUSIONS

Systemic imaging of patients with multiply recurrent meningioma or symptoms concerning for metastasis may identify extracranial metastases in a significant proportion of patients and can inform decision making for additional treatments.