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Darryl Lau, Caleb Rutledge, and Manish K. Aghi

OBJECT

Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD.

METHODS

A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase “(name of agent) and Cushing's” was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review.

RESULTS

A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%–100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth.

CONCLUSIONS

Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.

Free access

Darryl Lau, Stephen T. Magill, and Manish K. Aghi

Object

Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma.

Methods

A systematic search was performed with the phrase “(name of particular agent) and glioblastoma” as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies.

Results

A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10–15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%–20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%–20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied.

Conclusions

Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.

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Darryl Lau, Andrew K. Chan, Vedat Deverin, and Christopher P. Ames

OBJECTIVE

Adult spinal deformity (ASD) develops in the setting of asymmetrical arthritic degeneration, and can also be due to iatrogenic causes, such as prior surgery. Many patients who present with ASD have undergone prior spine surgery with instrumentation. Unfortunately, contemporary studies that evaluate the effect of prior surgery or instrumentation on perioperative outcomes, readmission rates, and need for reoperation are lacking.

METHODS

All ASD patients who underwent a 3-column osteotomy performed by the senior author at the authors’ institution for correction of thoracolumbar spinal deformity between 2006 and 2016 were identified. The authors compared surgical outcomes between primary (first-time) and revision cases. Further subgroup analysis was conducted to investigate the effect of the number of prior surgeries (0, 1, 2, 3, 4, and 5 or more) and the presence of spinal instrumentation on outcomes. Multivariate analysis was used to adjust for relevant and significant confounders.

RESULTS

A total of 300 patients were included; 38.3% of patients were male. The overall perioperative complication rate was 24.7%, and the mean length of hospitalization was 8.2 days. The 90-day readmission rate was 9.0%, and the overall follow-up reoperation rate was 26.7%. There were no significant differences in complication rates (26.6% vs 24.0%, p = 0.645), length of hospitalization (8.7 vs 7.9 days, p = 0.229), readmission rates (11.4% vs 8.1%, p = 0.387), or reoperation rates (26.6% vs 26.7%, p = 0.984) between primary and revision cases. There was no significant difference in wound complications (infections/dehiscence) requiring reoperation (5.1% vs 6.3%, p = 0.683). Subgroup analysis conducted to evaluate the effect of the number of prior spinal surgeries or the presence of spinal instrumentation did not reveal significant differences for the aforementioned surgical outcomes. In adjusted multivariate analysis, there were no significant associations between history of prior surgery (number of prior surgeries and prior instrumentation) and all of the surgical outcomes of interest.

CONCLUSIONS

The findings from this study suggest that patients who have undergone prior spine surgery with or without instrumentation are not at increased risk for perioperative complications, need for readmission, or reoperation following 3-column osteotomy of the thoracolumbar spine.

Free access

Darryl Lau, Adam Khan, Samuel W. Terman, Timothy Yee, Frank La Marca, and Paul Park

Object

Minimally invasive (MI) transforaminal lumbar interbody fusion (TLIF) has proven to be effective in the treatment of spondylolisthesis and degenerative disc disease (DDD). Compared with the traditional open TLIF, the MI procedure has been associated with less blood loss, less postoperative pain, and a shorter hospital stay. However, it is uncertain whether the advantages of an MI TLIF also apply specifically to obese patients. This study was dedicated to evaluating whether obese patients reap the perioperative benefits similar to those seen in patients with normal body mass index (BMI) when undergoing MI TLIF.

Methods

Obese patients—that is, those with a BMI of at least 30 kg/m2—who had undergone single-level TLIF were retrospectively identified and categorized according to BMI: Class I obesity, BMI 30.0–34.9 kg/m2; Class II obesity, BMI 35.0–39.9 kg/m2; or Class III obesity, BMI ≥ 40.0 kg/m2. In each obesity class, patients were stratified by TLIF approach, that is, open versus MI. Perioperative outcomes, including intraoperative estimated blood loss (EBL), complications (overall, intraoperative, and 30-day postoperative), and hospital length of stay (LOS), were compared. The chi-square test, Fisher exact test, or 2-tailed Student t-test were used when appropriate.

Results

One hundred twenty-seven patients were included in the final analysis; 49 underwent open TLIF and 78 underwent MI TLIF. Sixty-one patients had Class I obesity (23 open and 38 MI TLIF); 45 patients, Class II (19 open and 26 MI); and 21 patients, Class III (7 open and 14 MI). Overall, mean EBL was 397.2 ml and mean hospital LOS was 3.7 days. Minimally invasive TLIF was associated with significantly less EBL and a shorter hospital stay than open TLIF when all patients were evaluated as a single cohort and within individual obesity classes. Overall, the complication rate was 18.1%. Minimally invasive TLIF was associated with a significantly lower total complication rate (11.5% MI vs 28.6% open) and intraoperative complication rate (3.8% MI vs 16.3% open) as compared with open TLIF. When stratified by obesity class, MI TLIF was still associated with lower rates of total and intraoperative complications. This effect was most profound and statistically significant in patients with Class III obesity (42.9% open vs 7.1% MI).

Conclusions

Minimally invasive TLIF offers obese patients perioperative benefits similar to those seen in patients with normal BMI who undergo the same procedure. These benefits include less EBL, a shorter hospital stay, and potentially fewer complications compared with open TLIF. Additional large retrospective studies and randomized prospective studies are needed to verify these findings.

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Aaron J. Clark, John E. Ziewacz, Michael Safaee, Darryl Lau, Russ Lyon, Dean Chou, Philip R. Weinstein, Christopher P. Ames, John P. Clark III, and Praveen V. Mummaneni

Object

The use of intraoperative neurophysiological monitoring (IONM) in surgical decompression surgery for myelopathy may assist the surgeon in taking corrective measures to reduce or prevent permanent neurological deficits. We evaluated the efficacy of IONM in cervical and cervicothoracic spondylotic myelopathy (CSM) cases.

Methods

The authors retrospectively reviewed 140 cases involving patients who underwent surgery for CSM utilizing IONM during 2011 at the University of California, San Francisco. Data on preoperative clinical variables, intraoperative changes in transcranial motor evoked potentials (MEPs), and postoperative new neurological deficits were collected. Associations between categorical variables were analyzed with the Fisher exact test.

Results

Of the 140 patients, 16 (11%) had significant intraoperative decreases in MEPs. In 8 of these cases, the MEP signal did not return to baseline values by the end of the operation. There were 8 (6%) postoperative deficits, of which 6 were C-5 palsies and 2 were paraparesis. Six of the patients with postoperative deficits had demonstrated persistent MEP signal change on IONM. There was a significant association between persistent MEP changes and postoperative deficits (p < 0.001). The sensitivity of intraoperative MEP monitoring was 75%, the specificity 98%, the positive predictive value 75%, and the negative predictive value 98%. Due to higher rates of false negatives, the sensitivity decreased to 60% in the subgroup of patients with vascular disease comorbidity. The sensitivity increased to 100% in elderly patients and in patients with preoperative motor deficits. The sensitivity and positive predictive value of deltoid and biceps MEP changes in predicting C-5 palsy were 67% and 67%, respectively.

Conclusions

The authors found a correlation between decreased intraoperative MEPs and postoperative new neurological deficits in patients with CSM. Sensitivity varies based on patient comorbidities, age, and preoperative neurological function. Monitoring of MEPs is a useful adjunct for CSM cases, and the authors have developed a checklist to standardize their responses to intraoperative MEP changes.

Free access

Rajiv Saigal, Darryl Lau, Rishi Wadhwa, Hai Le, Morsi Khashan, Sigurd Berven, Dean Chou, and Praveen V. Mummaneni

Object

Long-segment spinal instrumentation ending at the sacrum places substantial biomechanical stress on sacral screws. Iliac (pelvic) screws relieve some of this stress by supplementing the caudal fixation. It remains an open question whether there is any clinically significant difference in sacropelvic fixation with bilateral versus unilateral iliac screws. The primary purpose of this study was to compare clinical and radiographic complications in the use of bilateral versus unilateral iliac screw fixation.

Methods

The authors retrospectively reviewed 102 consecutive spinal fixation cases that extended to the pelvis at a single institution (University of California, San Francisco) in the period from 2005 to 2012 performed by the senior authors. Charts were reviewed for the following complications: reoperation, L5–S1 pseudarthrosis, sacral insufficiency fracture, hardware prominence, iliac screw loosening, and infection. The t-test, Pearson chi-square test, and Fisher exact test were used to determine statistical significance.

Results

The mean follow-up was 31 months. Thirty cases were excluded: 12 for inadequate follow-up, 15 for lack of L5–S1 interbody fusion, and 3 for preoperative osteomyelitis. The mean age among the 72 remaining cases was 62 years (range 39–79 years). Forty-six patients underwent unilateral and 26 bilateral iliac screw fixation. Forty-one percent (n = 19) of the unilateral cases and 50% (n = 13) of the bilateral cases were treated with reoperation (p = 0.48). In addition, 13% (n = 6) of the unilateral and 19% (n = 5) of the bilateral cases developed L5–S1 pseudarthrosis (p = 0.51). There were no sacral insufficiency fractures. Thirteen percent (n = 6) of the unilateral and 7.7% (n = 2) of the bilateral cases developed postoperative infection (p = 0.70).

Conclusions

In a retrospective single-institution study, single versus dual pelvic screws led to comparable rates of reoperation, iliac screw removal, postoperative infection, pseudarthrosis, and sacral insufficiency fractures. For spinopelvic fixation, placing bilateral (vs unilateral) pelvic screws produced no added clinical benefit in most cases.

Free access

Ankush Chandra, Jonathan W. Rick, Cecilia Dalle Ore, Darryl Lau, Alan T. Nguyen, Diego Carrera, Alexander Bonte, Annette M. Molinaro, Philip V. Theodosopoulos, Michael W. McDermott, Mitchel S. Berger, and Manish K. Aghi

OBJECTIVE

Glioblastoma (GBM) is an aggressive brain malignancy with a short overall patient survival, yet there remains significant heterogeneity in outcomes. Although access to health care has previously been linked to impact on prognosis in several malignancies, this question remains incompletely answered in GBM.

METHODS

This study was a retrospective analysis of 354 newly diagnosed patients with GBM who underwent first resection at the authors’ institution (2007–2015).

RESULTS

Of the 354 patients (median age 61 years, and 37.6% were females), 32 (9.0%) had no insurance, whereas 322 (91.0%) had insurance, of whom 131 (40.7%) had Medicare, 45 (14%) had Medicaid, and 146 (45.3%) had private insurance. On average, insured patients survived almost 2-fold longer (p < 0.0001) than those who were uninsured, whereas differences between specific insurance types did not influence survival. The adjusted hazard ratio (HR) for death was higher in uninsured patients (HR 2.27 [95% CI 1.49–3.33], p = 0.0003). Age, mean household income, tumor size at diagnosis, and extent of resection did not differ between insured and uninsured patients, but there was a disparity in primary care physician (PCP) status—none of the uninsured patients had PCPs, whereas 72% of insured patients had PCPs. Postoperative adjuvant treatment rates with temozolomide (TMZ) and radiation therapy (XRT) were significantly less in uninsured (TMZ in 56.3%, XRT in 56.3%) than in insured (TMZ in 75.2%, XRT in 79.2%; p = 0.02 and p = 0.003) patients. Insured patients receiving both agents had better prognosis than uninsured patients receiving the same treatment (9.1 vs 16.34 months; p = 0.025), suggesting that the survival effect in insured patients could only partly be explained by higher treatment rates. Moreover, having a PCP increased survival among the insured cohort (10.7 vs 16.1 months, HR 1.65 [95% CI 1.27–2.15]; p = 0.0001), which could be explained by significant differences in tumor diameter at initial diagnosis between patients with and without PCPs (4.3 vs 4.8 cm, p = 0.003), and a higher rate of clinical trial enrollment, suggesting a critical role of PCPs for a timelier diagnosis of GBM and proactive cancer care management.

CONCLUSIONS

Access to health care is a strong determinant of prognosis in newly diagnosed patients with GBM. Any type of insurance coverage and having a PCP improved prognosis in this patient cohort. Higher rates of treatment with TMZ plus XRT, clinical trial enrollment, fewer comorbidities, and early diagnosis may explain survival disparities. Lack of health insurance or a PCP are major challenges within the health care system, which, if improved upon, could favorably impact the prognosis of patients with GBM.

Free access

Darryl Lau, Cecilia L. Dalle Ore, Phiroz E. Tarapore, Michael Huang, Geoffrey Manley, Vineeta Singh, Praveen V. Mummaneni, Michael Beattie, Jacqueline Bresnahan, Adam R. Ferguson, Jason F. Talbott, William Whetstone, and Sanjay S. Dhall

OBJECTIVE

The elderly are a growing subpopulation within traumatic spinal cord injury (SCI) patients. Studies have reported high morbidity and mortality rates in elderly patients who undergo surgery for SCI. In this study, the authors compare the perioperative outcomes of surgically managed elderly SCI patients with those of a younger cohort and those reported in the literature.

METHODS

Data on a consecutive series of adult traumatic SCI patients surgically managed at a single institution in the period from 2007 to 2017 were retrospectively reviewed. The cohort was divided into two groups based on age: younger than 70 years and 70 years or older. Assessed outcomes included complications, in-hospital mortality, intensive care unit (ICU) stay, hospital length of stay (LOS), disposition, and neurological status.

RESULTS

A total of 106 patients were included in the study: 83 young and 23 elderly. The two groups were similar in terms of imaging features (cord hemorrhage and fracture), operative technique, and American Spinal Injury Association Impairment Scale (AIS) grade. The elderly had a significantly higher proportion of cervical SCIs (95.7% vs 71.1%, p = 0.047). There were no significant differences between the young and the elderly in terms of the ICU stay (13.1 vs 13.3 days, respectively, p = 0.948) and hospital LOS (23.3 vs 21.7 days, p = 0.793). Elderly patients experienced significantly higher complication (73.9% vs 43.4%, p = 0.010) and mortality (13.0% vs 1.2%, p = 0.008) rates; in other words, the elderly patients had 1.7 times and 10.8 times the rate of complications and mortality, respectively, than the younger patients. No elderly patients were discharged home (0.0% vs 18.1%, p = 0.029). Discharge AIS grade and AIS grade change were similar between the groups.

CONCLUSIONS

Elderly patients had higher complication and mortality rates than those in younger patients and were less likely to be discharged home. However, it does seem that mortality rates have improved compared to those in prior historical reports.