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Alexander F. Haddad, Jacob S. Young, and Manish K. Aghi

The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Systemic immunotherapies also carry with them concerns surrounding systemic toxicities as well as penetration of the blood-brain barrier. These concerns may potentially limit their efficacy in GBM and preclude the use of combinatorial immunotherapy, which may be needed to overcome the severe multidimensional immune suppression seen in GBM patients. The use of viral vectors to deliver immunotherapies directly to tumor cells has the potential to improve immunotherapy delivery to the CNS, reduce systemic toxicities, and increase treatment efficacy. Indeed, preclinical studies investigating the delivery of immunomodulators to GBM using viral vectors have demonstrated significant promise. In this review, the authors discuss previous studies investigating the delivery of local immunotherapy using viral vectors. They also discuss the future of these treatments, including the reasoning behind immunomodulator and vector selection, patient safety, personalized therapies, and the need for combinatorial treatment.

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Darryl Lau, Alexander F. Haddad, Vedat Deviren, and Christopher P. Ames

OBJECTIVE

Rigid multiplanar thoracolumbar adult spinal deformity (ASD) cases are challenging and many require a 3-column osteotomy (3CO), specifically asymmetrical pedicle subtraction osteotomy (APSO). The outcomes and additional risks of performing APSO for the correction of concurrent sagittal-coronal deformity have yet to be adequately studied.

METHODS

The authors performed a retrospective review of all ASD patients who underwent 3CO during the period from 2006 to 2019. All cases involved either isolated sagittal deformity (patients underwent standard PSO) or concurrent sagittal-coronal deformity (coronal vertical axis [CVA] ≥ 4.0 cm; patients underwent APSO). Perioperative and 2-year follow-up outcomes were compared between patients with isolated sagittal imbalance who underwent PSO and those with concurrent sagittal-coronal imbalance who underwent APSO.

RESULTS

A total of 390 patients were included: 338 who underwent PSO and 52 who underwent APSO. The mean patient age was 64.6 years, and 65.1% of patients were female. APSO patients required significantly more fusions with upper instrumented vertebrae (UIV) in the upper thoracic spine (63.5% vs 43.3%, p = 0.007). Radiographically, APSO patients had greater deformity with more severe preoperative sagittal and coronal imbalance: sagittal vertical axis (SVA) 13.0 versus 10.7 cm (p = 0.042) and CVA 6.1 versus 1.2 cm (p < 0.001). In APSO cases, significant correction and normalization were achieved (SVA 13.0–3.1 cm, CVA 6.1–2.0 cm, lumbar lordosis [LL] 26.3°–49.4°, pelvic tilt [PT] 38.0°–20.4°, and scoliosis 25.0°–10.4°, p < 0.001). The overall perioperative complication rate was 34.9%. There were no significant differences between PSO and APSO patients in rates of complications (overall 33.7% vs 42.3%, p = 0.227; neurological 5.9% vs 3.9%, p = 0.547; medical 20.7% vs 25.0%, p = 0.482; and surgical 6.5% vs 11.5%, p = 0.191, respectively). However, the APSO group required significantly longer stays in the ICU (3.1 vs 2.3 days, p = 0.047) and hospital (10.8 vs 8.3 days, p = 0.002). At the 2-year follow-up, there were no significant differences in mechanical complications, including proximal junctional kyphosis (p = 0.352), pseudarthrosis (p = 0.980), rod fracture (p = 0.852), and reoperation (p = 0.600).

CONCLUSIONS

ASD patients with significant coronal imbalance often have severe concurrent sagittal deformity. APSO is a powerful and effective technique to achieve multiplanar correction without higher risk of morbidity and complications compared with PSO for sagittal imbalance. However, APSO is associated with slightly longer ICU and hospital stays.

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Darryl Lau, Alexander F. Haddad, Vedat Deviren, and Christopher P. Ames

OBJECTIVE

There is an increased recognition of disproportional lumbar lordosis (LL) and artificially high pelvic incidence (PI) as a cause for positive sagittal imbalance and spinal pelvic mismatch. For such cases, a sacral pedicle subtraction osteotomy (PSO) may be indicated, although its morbidity is not well described. In this study, the authors evaluate the specific complication risks associated with S1 PSO.

METHODS

A retrospective review of all adult spinal deformity patients who underwent a 3-column osteotomy (3CO) for thoracolumbar deformity from 2006 to 2019 was performed. Demographic, clinical baseline, and radiographic parameters were recorded. The primary outcome of interest was perioperative complications (surgical, neurological, and medical). Secondary outcomes of interest included case length, blood loss, and length of stay. Multivariate analysis was used to assess the risk of S1 PSO compared with 3CO at other levels.

RESULTS

A total of 405 patients underwent 3CO in the following locations: thoracic (n = 55), L1 (n = 25), L2 (n = 29), L3 (n = 141), L4 (n = 129), L5 (n = 17), and S1 (n = 9). After S1 PSO, there were significant improvements in the sagittal vertical axis (14.8 cm vs 6.7 cm, p = 0.004) and PI-LL mismatch (31.7° vs 9.6°, p = 0.025) due to decreased PI (80.3° vs 65.9°, p = 0.006). LL remained unchanged (48.7° vs 57.8°, p = 0.360). The overall complication rate was 27.4%; the surgical, neurological, and medical complication rates were 7.7%, 6.2%, and 20.0%, respectively. S1 PSO was associated with significantly higher rates of overall complications: thoracic (29.1%), L1 (32.0%), L2 (31.0%), L3 (19.9%), L4 (32.6%), L5 (11.8%), and S1 (66.7%) (p = 0.018). Similarly, an S1 PSO was associated with significantly higher rates of surgical (thoracic [9.1%], L1 [4.0%], L2 [6.9%], L3 [5.7%], L4 [10.9%], L5 [5.9%], and S1 [44.4%], p = 0.006) and neurological (thoracic [9.1%], L1 [0.0%], L2 [6.9%], L3 [2.8%], L4 [7.0%], L5 [5.9%], and S1 [44.4%], p < 0.001) complications. On multivariate analysis, S1 PSO was independently associated with higher odds of overall (OR 7.93, p = 0.013), surgical (OR 20.66, p = 0.010), and neurological (OR 14.75, p = 0.007) complications.

CONCLUSIONS

S1 PSO is a powerful technique for correction of rigid sagittal imbalance due to an artificially elevated PI in patients with rigid high-grade spondylolisthesis and chronic sacral fractures. However, the technique and intraoperative corrective maneuvers are challenging and associated with high surgical and neurological complications. Additional investigations into the learning curve associated with S1 PSO and complication prevention are needed.

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Rushikesh S. Joshi, Darryl Lau, Alexander F. Haddad, Vedat Deviren, and Christopher P. Ames

OBJECTIVE

Correction of rigid cervical deformities can be associated with high complication rates and result in prolonged intensive care unit (ICU) and hospital stays. In this study, the authors aimed to examine the risk factors contributing to length of stay (LOS) in both the hospital and ICU following adult cervical deformity (ACD) surgery and to identify severe adverse events that occurred in this setting.

METHODS

A retrospective review of ACD patients who underwent posterior-based osteotomies for deformity correction from 2010 to 2019 was performed. Inclusion criteria were cervical kyphosis > 20° and/or cervical sagittal vertical axis (cSVA) > 4 cm. Multivariate analysis was used to identify risk factors independently associated with ICU and hospital LOS.

RESULTS

A total of 107 patients were included. The mean age was 63.5 years, and 61.7% were female. Over half (52.3%) underwent 3-column osteotomies, while 47.7% underwent posterior column osteotomies. There was significant correction of all cervical parameters: cSVA (6.0 vs 3.6 cm, p < 0.001), cervical lordosis (8.2° vs −5.3°, p < 0.001), cervical scoliosis (6.5° vs 2.2°, p < 0.001), and T1-slope (40.2° vs 34.5°, p < 0.001). There were also reciprocal changes to the distal spine: thoracic kyphosis (54.4° vs 46.4°, p < 0.001), lumbar lordosis (49.9° vs 45.8°, p = 0.003), and thoracolumbar scoliosis (13.9° vs 11.1°, p = 0.009). Overall, 4 patients (3.7%) suffered aspiration-related complications, 3 patients (2.8%) experienced dysphagia requiring a feeding tube, and 4 patients (3.7%) had compromised airways, with 1 resulting in death. The mean ICU and hospital LOS were 2.8 days and 7.9 days, respectively. Multivariate analysis identified three factors independently associated with longer ICU LOS: female sex (3.0 vs 2.4 days, p = 0.004), ≥ 12 segments fused (3.5 vs 1.9 days, p = 0.002), and postoperative complication (4.0 vs 1.9 days, p = 0.017). These same factors were independently associated with longer hospital LOS as well: female sex (8.3 vs 7.3 days, p = 0.013), ≥ 12 segments fused (9.4 vs 6.2 days, p = 0.001), and complication (9.7 vs 6.7 days, p = 0.026).

CONCLUSIONS

Posterior-based osteotomies are very effective for the correction of ACD, but postoperative hospital stays are relatively longer than those following surgery for degenerative disease. Risk factors for prolonged ICU and hospital LOS consist of both nonmodifiable (female sex) and modifiable (≥ 12 segments fused and presence of complication) risk factors. Additional multicenter prospective studies will be needed to validate these findings.

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Matheus P. Pereira, Taemin Oh, Rushikesh S. Joshi, Alexander F. Haddad, Kaitlyn M. Pereira, Robert C. Osorio, Kevin C. Donohue, Zain Peeran, Sweta Sudhir, Saket Jain, Angad Beniwal, José Gurrola II, Ivan H. El-Sayed, Lewis S. Blevins Jr., Philip V. Theodosopoulos, Sandeep Kunwar, and Manish K. Aghi

OBJECTIVE

Life expectancy has increased over the past century, causing a shift in the demographic distribution toward older age groups. Elderly patients comprise up to 14% of all patients with pituitary tumors, with most lesions being nonfunctioning pituitary adenomas (NFPAs). Here, the authors evaluated demographics, outcomes, and postoperative complications between nonelderly adult and elderly NFPA patients.

METHODS

A retrospective review of 908 patients undergoing transsphenoidal surgery (TSS) for NFPA at a single institution from 2007 to 2019 was conducted. Clinical and surgical outcomes and postoperative complications were compared between nonelderly adult (age ≥ 18 and ≤ 65 years) and elderly patients (age > 65 years).

RESULTS

There were 614 and 294 patients in the nonelderly and elderly groups, respectively. Both groups were similar in sex (57.3% vs 60.5% males; p = 0.4), tumor size (2.56 vs 2.46 cm; p = 0.2), and cavernous sinus invasion (35.8% vs 33.7%; p = 0.6). Regarding postoperative outcomes, length of stay (1 vs 2 days; p = 0.5), extent of resection (59.8% vs 64.8% gross-total resection; p = 0.2), CSF leak requiring surgical revision (4.3% vs 1.4%; p = 0.06), 30-day readmission (8.1% vs 7.3%; p = 0.7), infection (3.1% vs 2.0%; p = 0.5), and new hypopituitarism (13.9% vs 12.0%; p = 0.3) were similar between both groups. Elderly patients were less likely to receive adjuvant radiation (8.7% vs 16.3%; p = 0.009), undergo future reoperation (3.8% vs 9.5%; p = 0.003), and experience postoperative diabetes insipidus (DI) (3.7% vs 9.4%; p = 0.002), and more likely to have postoperative hyponatremia (26.7% vs 16.4%; p < 0.001) and new cranial nerve deficit (1.9% vs 0.0%; p = 0.01). Subanalysis of elderly patients showed that patients with higher Charlson Comorbidity Index scores had comparable outcomes other than higher DI rates (8.1% vs 0.0%; p = 0.006). Elderly patients’ postoperative sodium peaked and troughed on postoperative day 3 (POD3) (mean 138.7 mEq/L) and POD9 (mean 130.8 mEq/L), respectively, compared with nonelderly patients (peak POD2: mean 139.9 mEq/L; trough POD8: mean 131.3 mEq/L).

CONCLUSIONS

The authors’ analysis revealed that TSS for NFPA in elderly patients is safe with low complication rates. In this cohort, more elderly patients experienced postoperative hyponatremia, while more nonelderly patients experienced postoperative DI. These findings, combined with the observation of higher DI in patients with more comorbidities and elderly patients experiencing later peaks and troughs in serum sodium, suggest age-related differences in sodium regulation after NFPA resection. The authors hope that their results will help guide discussions with elderly patients regarding risks and outcomes of TSS.

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Alexander F. Haddad, Jacob S. Young, Taemin Oh, Matheus P. Pereira, Rushikesh S. Joshi, Kaitlyn M. Pereira, Robert C. Osorio, Kevin C. Donohue, Zain Peeran, Sweta Sudhir, Saket Jain, Angad Beniwal, Ashley S. Chopra, Narpal S. Sandhu, Philip V. Theodosopoulos, Sandeep Kunwar, Ivan H. El-Sayed, José Gurrola II, Lewis S. Blevins Jr., and Manish K. Aghi

OBJECTIVE

Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs.

METHODS

The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected.

RESULTS

Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p < 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07–12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04–15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09–4.59; p = 0.030).

CONCLUSIONS

This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.

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Paul Park, Khoi D. Than, Praveen V. Mummaneni, Pierce D. Nunley, Robert K. Eastlack, Juan S. Uribe, Michael Y. Wang, Vivian Le, Richard G. Fessler, David O. Okonkwo, Adam S. Kanter, Neel Anand, Dean Chou, Kai-Ming G. Fu, Alexander F. Haddad, Christopher I. Shaffrey, Gregory M. Mundis Jr., and the International Spine Study Group

OBJECTIVE

Surgical decision-making and planning is a key factor in optimizing outcomes in adult spinal deformity (ASD). Minimally invasive spinal (MIS) strategies for ASD have been increasingly used as an option to decrease postoperative morbidity. This study analyzes factors involved in the selection of either a traditional open approach or a minimally invasive approach to treat ASD in a prospective, nonrandomized multicenter trial. All centers had at least 5 years of experience in minimally invasive techniques for ASD.

METHODS

The study enrolled 268 patients, of whom 120 underwent open surgery and 148 underwent MIS surgery. Inclusion criteria included age ≥ 18 years, and at least one of the following criteria: coronal curve (CC) ≥ 20°, sagittal vertical axis (SVA) > 5 cm, pelvic tilt (PT) > 25°, or thoracic kyphosis (TK) > 60°. Surgical approach selection was made at the discretion of the operating surgeon. Preoperative significant differences were included in a multivariate logistic regression analysis to determine odds ratios (ORs) for approach selection.

RESULTS

Significant preoperative differences (p < 0.05) between open and MIS groups were noted for age (61.9 vs 66.7 years), numerical rating scale (NRS) back pain score (7.8 vs 7), CC (36° vs 26.1°), PT (26.4° vs 23°), T1 pelvic angle (TPA; 25.8° vs 21.7°), and pelvic incidence–lumbar lordosis (PI-LL; 19.6° vs 14.9°). No significant differences in BMI (29 vs 28.5 kg/m2), NRS leg pain score (5.2 vs 5.7), Oswestry Disability Index (48.4 vs 47.2), Scoliosis Research Society 22-item questionnaire score (2.7 vs 2.8), PI (58.3° vs 57.1°), LL (38.9° vs 42.3°), or SVA (73.8 mm vs 60.3 mm) were found. Multivariate analysis found that age (OR 1.05, p = 0.002), VAS back pain score (OR 1.21, p = 0.016), CC (OR 1.03, p < 0.001), decompression (OR 4.35, p < 0.001), and TPA (OR 1.09, p = 0.023) were significant factors in approach selection.

CONCLUSIONS

Increasing age was the primary driver for selecting MIS surgery. Conversely, increasingly severe deformities and the need for open decompression were the main factors influencing the selection of traditional open surgery. As experience with MIS surgery continues to accumulate, future longitudinal evaluation will reveal if more experience, use of specialized treatment algorithms, refinement of techniques, and technology will expand surgeon adoption of MIS techniques for adult spinal deformity.